Journal of Cardiovascular Pharmacology

Published by Lippincott, Williams & Wilkins
Print ISSN: 0160-2446
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Quality of life resides mainly in an individual's satisfaction with his role at work, at home, and in his community. Illness and treatment affect quality of life to the extent that they damage an individual's ability to perform these roles to his own satisfaction. Clinicians will increasingly have to take account of quality of life in assessing the effect of an illness and of their treatment for it. This is particularly so in chronic diseases for which there is no "cure" and in asymptomatic conditions, such as hypertension.
 
Both population (mass) strategies and targeted strategies for the management of high blood pressure are necessary. However, it has yet to be proven that reducing blood pressure by lifestyle changes in the population will confer the same cardiovascular benefit that results from lowering blood pressure by drugs. It is important to identify and correct those factors in hypertensive patients, such as obesity, smoking, elevated lipids, and diabetes, that confer high risk for an adverse cardiovascular event. It is now recognized that cardiovascular risk involves not only diet and lifestyle effects but that the structural and functional abnormalities resulting from high blood pressure are of great importance. There is a need to develop and validate new noninvasive methods for quantitating these structural and functional changes, together with assessment of endothelial dysfunction, hormonal profiling, and identification of susceptible genes so that high risk patients with hypertension can be selected for drug therapy. In the future, selection of an appropriate antihypertensive drug for an individual patient should also involve consideration of risk factors, structural changes, hormonal status, and genetic consideration. Central inhibition of peripheral sympathetic action by imidazoline receptor agonists, such as moxonidine, may lead to reversal of these structural and functional abnormalities without adverse effects on the central nervous system.
 
Current knowledge of atherogenesis is largely based on animal models of hypercholesterolemia, which rarely show changes similar to the lesions described in humans. We studied the influence of two low cholesterol-enriched diets on the development of anatomopathologic lesions and on the reactivity of the isolated aorta in rabbits. Compared with controls (rabbits fed a normal diet), a 0.1% cholesterol-enriched diet over a 6- or 9-month period produced increases of the 5-hydroxytryptamine (5-HT)-induced contractile responses, as well as a decreases in acetylcholine (ACh)-induced relaxing response (endothelium-dependent, through the production of NO). Noradrenaline (NA)-induced contractions and relaxations elicited by sodium nitroprusside (SNP; endothelium independent) were not significantly modified. Because at 6 months, significant anatomopathologic intimal early lesions were not found, functional endothelial changes can explain such findings. There was a defect in NO synthesis, release, or diffusion; 5 HT, but not NA, may be responsible for inducing NO production. In 0.2% cholesterol-fed rabbits at 4 and 12 weeks, increases of 5-HT- and NA-induced contractile responses were found. In both cases, there was a decrease of ACh-induced relaxing effect, whereas responses to SNP remained unchanged. Intimal early and advanced lesions were present at both the 4- and 12-week periods. These data suggest abnormalities of the NO system. The effects obtained with NA may be explained by a possible decrease of catechol-O-methyltransferase (COMT) or monoamine oxidase (MAO) activities or both or by decreased amine uptake. The extent to which NA may induce NO production is small, because changes in NA-induced contractions are verified only in the presence of significant alterations in the endothelium. The use of a 0.2% cholesterol diet for a short time may induce atherosclerotic lesions, whereas the 0.1% cholesterol diet for a 9-month period, besides being closer to the human diet, allows the detection of functional abnormalities before the evidence of structural lesions.
 
This double-blind, placebo-controlled, dose-ranging study recruited 170 patients with mild-to-moderate hypertension from nine centers. After a 4-week, single-blind, placebo run-in phase, patients were randomized in a double-blind fashion to four parallel groups that received either placebo or 0.5, 1, or 2 mg trandolapril for 4 weeks. Treatment was administered as a once-daily dose in the morning and blood pressure was measured 24 h after drug intake. The primary criterion of efficacy was a decrease in supine diastolic blood pressure. At the end of the study, the lowest dose of trandolapril that consistently produced a significant difference from placebo in reducing blood pressure was 1 mg (-6.6 mm Hg for supine diastolic blood pressure). It was effective from around 2 weeks onward; the 2-mg dose differed significantly from placebo from around 1 week onward. At the end of the study, the 1- and 2-mg doses were equally effective. The lowest dose tested, 0.5 mg, showed some evidence of an effect on systolic blood pressure and may well prove to be a useful dose in patients who are highly sensitive to the effect of ACE inhibition. Tolerance throughout the study was good for all doses tested.
 
The family of secretory phospholipase A2 (sPLA2) enzymes has been associated with inflammatory diseases and tissue injury including atherosclerosis. A-001 is a novel inhibitor of sPLA2 enzymes discovered by structure-based drug design, and A-002 is the orally bioavailable prodrug currently in clinical development. A-001 inhibited human and mouse sPLA2 group IIA, V, and X enzymes with IC50 values in the low nM range. A-002 (1 mg/kg) led to high serum levels of A-001 and inhibited PLA2 activity in transgenic mice overexpressing human sPLA2 group IIA in C57BL/6J background. In addition, the effects of A-002 on atherosclerosis in 2 ApoE mouse models were evaluated using en face analysis. (1) In a high-fat diet model, A-002 (30 and 90 mg/kg twice a day for 16 weeks) reduced aortic atherosclerosis by 50% (P < 0.05). Plasma total cholesterol was decreased (P < 0.05) by 1 month and remained lowered throughout the study. (2) In an accelerated atherosclerosis model, with angiotensin II-induced aortic lesions and aneurysms, A-002 (30 mg/kg twice a day) reduced aortic atherosclerosis by approximately 40% (P < 0.05) and attenuated aneurysm formation (P = 0.0096). Thus, A-002 was effective at significantly decreasing total cholesterol, atherogenesis, and aneurysm formation in these 2 ApoE mouse models.
 
The presence of endothelin (ET) receptors and the nature of the subtype and expression of ET were investigated in the human megakaryoblastic cell line MEG-01. By the RT-PCR procedure, we have shown that both ETA and ETB receptor subtype mRNAs are expressed in the cells. However, binding experiments have shown that the selective ETB receptor antagonist BQ788, but not the selective ETA receptor antagonist BQ123, competes with the specific binding of [125I]ET-1. Using immunocytochemistry, RIA, and RT-PCR Southern blot, we have shown that MEG-01 cells express ET-1. In addition, ET (1-21)-like immunoreactivity was released from the cells into the culture medium, and this release was modulated by thrombin. These data suggest that an ET-1-mediated autocrine loop could occur in the human megakaryoblastic MEG-01 cell line.
 
3-[[4-(2-Methoxyphenyl)piperazin-1-yl]methyl]-5-(methylthio)-2,3-dihydroimidazo[1,2-c]quinazoline (DL-017), a quinazoline derivative, exhibits alpha 1 -adrenoceptor antagonistic and type I antiarrhythmic effects on mammalian cardiac tissues. In the current study, the effects of DL-017 on the hemodynamic profile in anesthetized, spontaneously hypertensive rats were evaluated. Intravenous administration of DL-017 induced dose-dependent reductions of heart rate and blood pressure, which persisted over 2 h. DL-017 exerted a maximal antihypertensive effect at 0.1 mg/kg, which was similar to that of 0.1 mg/kg of prazosin. DL-017 was able to block the pressor response to phenylephrine but not to angiotensin II. Regional cerebral blood flow of the right parietal cortex decreased by 14 +/- 4% 10 min after bolus injection and then rapidly returned to control levels while the arterial pressure was still low. These results indicate that blockade of the alpha 1 -adrenoceptor by DL-017 contributes to reduction of arterial pressure. The antihypertensive effect without reflex tachycardia and loss of autoregulation of cerebral blood flow makes DL-017 suitable for chronic long-term treatment of hypertension.
 
The membrane potential of vascular smooth muscle cells of the porcine coronary artery was measured to examine whether serotonin evokes endothelium-dependent hyperpolarization, and if it does, whether the electrical responses are modulated by the chronic dietary intake of NC 020, a defined fish oil. Serotonin induced transient, concentration-dependent hyperpolarizations of coronary arterial smooth muscle cells. The hyperpolarization was observed in tissues with, but not in those without endothelium. In coronary arteries obtained from pigs fed chronically with NC 020, serotonin induced significantly larger hyperpolarizations than those observed in control arteries. These results suggest that endothelium-dependent hyperpolarization may contribute to the endothelium-dependent relaxation evoked by serotonin and to its potentiation by the dietary intake of fish oil (NC 020).
 
This study was designed to examine the preventive effect of a novel endothelin (ET)-receptor antagonist TA-0201 on the cerebral vasospasm in a canine double-hemorrhage model. TA-0201 (10(-9)-10(-7) M) inhibited ET-1-induced vasoconstriction in the isolated canine basilar artery without endothelium in a concentration-dependent manner. Its pA2 value was 9.2 (ET(A) antagonism). In a canine double-hemorrhage model, intravenous treatment with TA-0201 (3 mg/kg, twice a day for 7 days) ameliorated the basilar artery narrowing significantly on day 7 compared with that in nontreated dogs. The reductions of the basilar artery diameter were 26.1+/-3.9% and 40.5+/-4.1% with and without TA-0201 treatment, respectively (p<0.05). Histologic study on day 7 indicated that treatment with TA-0201 inhibited vessel-wall damage such as disintegration of endothelium architecture and degeneration of medial smooth-muscle cells. We conclude that intravenous treatment with TA-0201 prevents the development of cerebral vasospasm and accompanying pathologic changes of the vessel wall, probably through blockade of ET(A) receptors.
 
Endothelin (ET)-1 increases in plasma during congestive heart failure (CHF). Some ET antagonists improve hemodynamics, suggesting its potential benefits in the treatment of CHF. We examined the acute and chronic effects of a new ET receptor antagonist, T-0201 (Tanabe Seiyaku Co. Ltd., Japan), in CHF. To confirm the in vivo effects of T-0201, we observed the inhibitory effects of T-0201 (1-100 micrograms/kg) on the response of blood pressure to exogenously administered ET-1 (0.75 nmol/kg) in conscious normal dogs. Pretreatment with T-0201 significantly inhibited the ET-1-induced initial hypotension that is mediated by ETB receptors, and attenuated the subsequent hypertension, which is primarily mediated by ETA receptors. Thus, T-0201 at a dose of 100 micrograms/kg not only works as a potent ETA antagonist but also shows antagonist activity for ETB receptors in dogs. To evaluate the chronic therapeutic effects of T-0201, we administered T-0201 (0.3 mg/kg/day; n = 5) orally to dogs with CHF induced by rapid right ventricular pacing (22 days, 270 beats/min) for 15 days, beginning 8 days after pacing. T-0201 significantly prevented the deterioration of cardiorenal function during the development of CHF, expressed as a decrease in cardiac pressure and an increase in cardiac and urine output. These results suggest that chronic antagonism of both ET receptors prevents the progressive exacerbation of CHF.
 
The previous separation of the racemic cardiotonic thiadiazinone derivative EMD 53998 yielded two enantiomers with different pharmacologic properties: EMD 57,033, a potent Ca2+ sensitizer with some residual phosphodiesterase III (PDE III) inhibition, and EMD 57,439, a pure PDE III inhibitor. Although numerous in vitro studies demonstrated the ability of EMD 57,033 to increase the responsiveness of cardiac contractile proteins to Ca2+, in vivo evidence for such an action is lacking. Because there is no possibility of directly proving Ca2+ sensitization in vivo, we attempted to exclude PDE III inhibition as a major contributing component of the positive inotropic action of EMD 57,033. In anesthetized rats, EMD 57,033 increased left ventricular (LV) first derivative of change in systolic pressure over time (dP/dt max) without affecting blood pressure. In contrast, the PDE III-inhibitory enantiomer EMD 57,439 decreased blood pressure. The pattern of hemodynamic effects in anesthetized dogs revealed similar differences between EMD 57,033 and PDE inhibitors. Thus the increase in LV dP/dt max in response to EMD 57,033 was not accompanied by changes of heart rate and blood pressure. As expected for PDE inhibitors, pimobendan and milrinone increased cardiac contractile force in dogs, concomitant, however, with tachycardia, hypotension, and a decrease in total peripheral resistance. When regional contractility was measured separately in two different areas of the dog myocardium, the positive inotropic action of the PDE inhibitors pimobendan and milrinone was antagonized by local coronary infusion of acetylcholine. The cardiotonic effect of the Ca2+ sensitizer EMD 57,033 was entirely resistant to inhibition by acetylcholine. In conscious dogs, beta-blockade markedly attenuated the increase in LV dP/dt max produced by two different doses of the PDE III inhibitor EMD 57,439. In contrast, a dose of EMD 57,033 equieffective in positive inotropic action with the lower dose of EMD 57,439 remained unaffected by < b tau-blockade. We concluded (a) that EMD 57,033 increases cardiac contractile force in two species in vivo, (b) that this action is independent of the cardiac cyclic adenosine monophosphate (AMP) system, (c) that EMD 57,033 does not reduce blood pressure and increase heart rate, an action indicative of PDE inhibition, and (d) that, on the basis of numerous previous in vitro findings, the mechanism of action of EMD 57,033, also in vivo, is consistent with sensitization of the cardiac myofibrils to Ca2+. Of special importance is the finding that this Ca2+ sensitizer at appropriate doses may be able to improve systolic function without adverse effects on diastolic function, as indicated by a slight decrease in left ventricular end-diastolic pressure.
 
The purpose of this study was to investigate the effects of an endothelin-receptor antagonist TAK-044 on functional defects and metabolic derangement in myocardial ischemia/reperfusion injury. We sequentially measured high-energy phosphate metabolites and intracellular pH by phosphorus magnetic resonance spectroscopy during 35-min global ischemia followed by 60-min reperfusion in Langendorff-perfused rat hearts. TAK-044 (initial loading by 3 mg/kg followed by perfusion with 100 nM solution) was administered in two different ways: before ischemia or immediately after reperfusion. In addition, we investigated the effects of TAK-044 on functional defects and metabolic alterations induced by hydrogen peroxide (200 microM, 30 min). The recoveries of left ventricular developed pressure after reperfusion in TAK-044 groups (51 +/-12% in TAK-I, 61 +/- 12% in TAK-R) were better than in control (10 +/- 5% in control; p < 0.01). Increases in left ventricular end-diastolic pressure (LVEDP) in TAK-044 groups (22 +/- 5 mm Hg in TAK-I, 24 +/- 5 mm Hg in TAK-R) were less than in control (38 +/- 3 mm Hg; p < 0.01). Adenosine triphosphate (ATP) (33 +/- 5% in TAK-I, 28 +/- 4% in TAK-R) in TAK-044 groups were higher than in control (13 +/- 3%; p < 0.01). The creatine phosphokinase (CPK) release during reperfusion in TAK-044 groups (3.3 +/- 1.5 IU/g wet wt/60 min in TAK-I, 3.5 +/- 2.5 IU/g wet wt/60 min in TAK-R) were lower than in control (13.8 +/- 3.9 IU/g wet wt/60 min; p < 0.05). In contrast, TAK-044 did not attenuate the myocardial injury induced by hydrogen peroxide. TAK-044, even if administered simultaneous with coronary reperfusion, attenuated myocardial ischemia/ reperfusion injury. The energy-preservative effect of TAK-044 could be associated with the good functional recovery in ischemia/reperfused rat hearts.
 
The hemodynamic effects of endothelin (ET)-1 and TAK-044 (ET(A) and ET(B) receptor antagonist) were studied in a rat model of dilated cardiomyopathy after autoimmune myocarditis. Six weeks after immunization, survived Lewis rats (30/43 = 70%) were randomly allocated into five groups to be given 0, 0.3, 3, 30 and 60 mg/kg/day (groups F0, F0.3, F3, F30 and F60; each group, n = 4) of TAK-044 using an osmotic pump subcutaneously. Age-matched normal Lewis rats (n = 26) were also randomly divided into four groups to be given 0, 0.3, 3 and 30 mg/kg/day (groups N0, N0.3, N3 and N30; each group, n = 4). ET-1 concentrations in plasma and myocardium were measured, and immunohistochemical detection of ET-1 in the left ventricle from the remaining rats (groups F and N) was performed. After administration of TAK-044 for 7 days, 2, 4, 11, 21 and 42 ng/min ET-1 every 20 min was infused using a pump, and the change in mean arterial pressure of each group during the infusion was examined. The plasma and myocardial ET-1 concentrations were significantly higher in group F than group N (12.3 +/- 1.5 vs. 5.4 +/- 0.2 pg/ml and 426 +/- 31 vs. 98 +/- 6 pg/g tissue; both p < 0.01). Strong positive signals for ET-1 were found to be widely distributed in the left ventricular myocardium of both groups of rats. Although the ET-1-induced increase in the mean arterial pressure was abolished in group N30, the maximal dose of ET-1 produced a 34% increase in the mean arterial pressure in group F30. Even in group F60, ET-1-induced hypertension was blocked incompletely. These results indicate that the heart may be a major ET-1-producing organ, and a higher dose of ET-1 antagonist is needed to block the effect of ET-1 in rats with dilated cardiomyopathy.
 
We have demonstrated previously that endothelin-1 (ET-1) mRNA expression is increased in hypertensive rats. The aim of the study reported here was to elucidate the effects of the endothelin (ET) receptor antagonist on the hemodynamic and biochemical parameters in stroke-prone spontaneously hypertensive rats (SHRSPs/Izm). The endothelin-A- and -B- (ETA/ETB) receptor antagonist (TAK-044, Takeda Chemical Industries, Osaka, Japan) was administered subcutaneously at a dose of 10 mg/kg/day from the age of 8 weeks for 4 weeks. Blood samples and tissues of the kidney, heart and brain were obtained at the age of 12 weeks. Tissue expression of ET-1 mRNA was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) followed by Southern blot analysis. Treatment with TAK-044 resulted in a significant decrease in systolic blood pressure (SBP), blood urea nitrogen (BUN), serum creatinine concentration, plasma aldosterone level, heart weight, and kidney weight. In addition, ET-1 contents and mRNA expression level in the kidney, heart and brain were significantly decreased by the treatment with TAK-044. These results suggest that the ET receptor antagonist TAK-044 is able to attenuate ET-1 gene expression in addition to its specific antagonism of the biological actions of ET via the receptors.
 
To assess the role of endothelin-1 (ET-1) on cardiovascular remodeling, nonselective endothelin-receptor antagonist TAK-044 was administered for the long term to rabbits with or without arteriovenous (A-V) shunt formation. Six weeks after sham operation (n = 12) or carotid-jugular shunt formation (n = 21), TAK-044 (30 mg/day) or saline was infused subcutaneously using osmotic mini pumps for another 6 weeks. Twelve weeks after operation, left ventricular (LV) diameter was enlarged with the presence of an A-V shunt; however, the levels of LV diameter and arterial pressure or the postmortem weight of LVs of shunt rabbits were similar between saline and TAK-044 groups. A linear relation of the luminal diameter and the medial cross-sectional area of the left and right carotid arteries was similar between shunt + saline and shunt + TAK-044 groups. In saline groups, myocardial ET-1 levels were higher in shunt than in sham rabbits (217+/-22 vs. 136+/-19 pg/g tissue; p < 0.01 between rabbit groups) without changes in plasma ET-1 concentrations during saline infusion for 6 weeks. Differences in plasma ET-1 levels before and 6 weeks after the administration of TAK-044 were 0.32+/-0.78 and 0.16+/-0.28 pg/ml (NS between periods) in shunt and sham groups, respectively. In TAK-044 groups, myocardial ET-I levels 12 weeks after operation were similarly lower in both sham (105+/-7.4 pg/g tissue) and shunt rabbits (126+/-9.2 pg/g tissue) than in those with saline administration; however, the plasma ET-1 concentrations were increased significantly 6 weeks after TAK-044 administration by 5.0+/-0.6-fold and 3.5 +/-0.3-fold (p < 0.01) of the levels 6 weeks after operation in shunt and sham groups (NS between groups), respectively. Accordingly, myocardial but not plasma ET-1 levels were increased by a long-term burden of volume overload and were attenuated by a long-term administration of TAK-044 without altering drastically the hemodynamics or vascular remodeling. These results suggest that endogenous ET-1 does not play a major role in the compensatory stage of cardiovascular remodeling in the present volume-overload model.
 
The effects of TAK-044 on the extension of ischemia/reperfusion-induced myocardial infarction were studied in rats. Acute myocardial infarction was induced by occlusion of the left coronary artery for 1 h followed by reperfusion for 24 h. Infarct size and the area at risk were determined histochemically. Infarct size as a percentage of the area at risk (IS) was significantly reduced in a dose-dependent manner by TAK-044 administered 30 min before reperfusion (0.3-3.0 mg/kg, i.v.). Size-limiting effects similar to those in rats were also obtained in rabbits and dogs. In addition, TAK-044 administered 3 h after reperfusion also reduced the IS significantly. Preconditioning (5 min of LAD occlusion preceding 1 h of coronary occlusion) inhibited the extension of the IS. These effects of preconditioning and TAK-044 were inhibited by glibenclamide (0.1 mg/kg, i.v.; an inhibitor of the ATP-sensitive K channel) but not by DPCPX (1 mg/kg, i.v.; an adenosine A1 receptor antagonist). These results indicate that endogenous endothelin plays an important role in the extension of myocardial infarction and that the cardioprotective effects of TAK-044 can be partially explained by a mechanism similar to that of preconditioning in rats.
 
Platelet-activating factor (PAF), a likely mediator of endotoxin action, causes thromboxane A2 (TXA2) release and pulmonary hypertension in pigs. We examined the effect of selective TXA2 synthase inhibition with OKY-046 on cyclooxygenase metabolites during PAF-induced pulmonary hypertension. Six closed-chest pigs received PAF in escalating doses (0.1, 0.3, 1.0, and 3.0 nmol intravenously, i.v.) before and after (E)-3[4-(1-imidazolyl methyl) phenyl]-Z-propenoic acid hydrochloride monohydrate OKY-046, 10-mg/kg i.v. bolus plus 20-mg/kg/h infusion. Plasma samples at peak PAF effect had radioimmunoassay (RIA) for the stable metabolites of TXA2 (TXB2) and prostacyclin (6-keto-PGF1 alpha). Tachyphylaxis was not noted in 5 control pigs given sequential repeats of the PAF dosing series. Pulmonary vascular resistance (PVR) was 240 +/- 30 (SE) dyne s cm-5 at baseline and increased to 3,100 +/- 1,300 after 1.0 nmol PAF (p less than 0.05). When the same amount of PAF was given after OKY-046, PVR increased only to 820 +/- 280 dynes/s/cm-5. TXB2 was 34 +/- 7 pg/0.1 ml at baseline and increased to 70 +/- 4 pg/0.1 ml with PAF 1.0 nmol (p less than 0.001). TXB2 levels were unchanged from 34 +/- 4 pg/0.1 ml when PAF 1.0 nmol was administered after OKY-046 (NS vs. pre-OKY-046). In contrast, 6-keto-PGF1 alpha, 6 +/- 2 pg/0.1 ml at baseline, increased to 24 +/- 4 pg/0.1 ml after PAF 1.0 nmol and increased further to 50 +/- 8 pg/0.1 ml when PAF 1.0 nmol was given after OKY-046 (p less than 0.05 vs. pre-OKY-046).(ABSTRACT TRUNCATED AT 250 WORDS)
 
The efficacy, pharmacokinetics, safety, and tolerability of E 047/1, an amiodarone derivative, were evaluated in patients with acute supraventricular or ventricular arrhythmia. In an open, nonrandomized prospective multicenter trial, 20 patients were treated with three different i.v. dosage regimens of E 047/1. Arrhythmia termination indicated efficacy. Pharmacokinetics were determined by measurements of drug plasma levels. Safety was judged by changes of blood pressure, heart rate, ECG parameters, and appearance of adverse events. For local tolerability, effects at the site of infusion were assessed. In patients with atrial fibrillation and/or atrial flutter, drug plasma levels and prolongation of QT interval were correlated with efficacy. In 10 (50%) patients, therapeutic intervention with E 047/1 was successful. Drug plasma levels rapidly decreased within 1 h after administration. Blood pressure values and ECG parameters stayed constant during the observation period. Proarrhythmic effects were not observed. As adverse events, vertigo, vomiting, and nausea in three (15%) and hypotension in one (5%) patient, respectively, occurred in the high-dose bolus regimen only. At the site of infusion, no adverse effects were found. No dependency between drug plasma levels and arrhythmia termination was found. E 047/1 has proven to be efficient and safe in the treatment of arrhythmia. E 047/1 is characterized by rapid plasma elimination, absence of proarrhythmic or cardiodepressive effects, mild adverse events, and excellent local tolerability. For further investigation, we recommend a combined bolus- and weight-adapted infusion regimen.
 
Recently, the beta 1-adrenoceptor was shown to mediate direct coronary vasodilation independent of metabolic demand in canine arrested heart preparation. To investigate the beta 1-adrenoceptor-mediated direct vasodilation in a beating heart preparation, we compared coronary blood flow (CBF) and coronary sinus oxygen tension (PO2) in anesthetized open-chest dogs using a beta 1-selective agonist, T-0509. T-0509 (0.005-0.05 microgram/kg intravenously, i.v.) increased the maximal rate of increase in left ventricular pressure (LVdp/dtmax) and heart rate (HR) to an extent similar to that induced by isoproterenol (ISO) without decreasing diastolic blood pressure (DBP). A beta 1-adrenoceptor antagonist, (-)-bisoprolol (10 micrograms/kg), but not a beta 2-adrenoceptor antagonist, ICI 118,551 (30 micrograms/kg), inhibited the T-0509-induced increase in LVdp/dtmax and HR. Thus, T-0509 showed selective beta 1 stimulation at the doses used. T-0509 also caused beta 1-selective relaxation in isolated coronary arteries. ISO increased both CBF and PO2. The early phase of the increase in CBF and the concurrent increases in PO2 were inhibited by ICI 118,551, whereas the late phase of the increase in CBF was inhibited by (-)-bisoprolol. T-0509 increased CBF, and this increase was inhibited by (-)-bisoprolol. A slight but significant increase in PO2 induced by T-0509 was not altered by these doses of the antagonists. Our results indicate that the T-0509-induced increase in CBF is due mainly to an indirect effect on myocardial beta 1-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
 
In canine right ventricular muscle, the influence of ICI 147,798, a slowly dissociable beta 1-adrenoceptor antagonist, on the positive inotropic effect and cyclic AMP production of T-0509, a selective beta 1-agonist, and isoproterenol, a nonselective beta-agonist, were examined to elucidate the properties of the high- and low-affinity states or subtypes of beta 1-adrenoceptor. ICI 147,798 (1 x 10(-8) - 1 x 10(-5) M) produced biphasic concentration-response curves for the positive inotropic effect of T-0509 that were due to its insurmountable antagonism against the lower concentrations of T-0509. The maximum of the biphasic curves were almost the same as Camax. Analysis of hemiequilibrium antagonism by ICI 147,798 against T-0509 showed the dissociation constant (pKB) of ICI 147,798 to be approximately 8. On the other hand, ICI 147,798 produced a parallel rightward shift of the curves of isoproterenol. Schild analysis showed pA2 to be 7.98 +/- 0.04, suggesting competitive antagonism. The concentration-response curve for the increase in cyclic AMP elicited by T-0509 in the presence of 1 x 10(-6) M ICI 147,798 was also biphasic, but slightly depressed as compared with that of control, whereas that elicited by isoproterenol was shifted to the right. The positive inotropy and increase in cyclic AMP produced by T-0509 and isoproterenol in the presence of ICI 147,798 may be mediated by the low-affinity state of beta 1-adrenoceptor, which mechanism may be different from that producing the positive inotropy through the high-affinity state of beta 1-adrenoceptor.
 
Preliminary clinical studies of testosterone therapy in male patients with coronary artery disease raised promising results. However, there is no study on in vitro effects of testosterone in human isolated arteries. We investigated the effect of testosterone on contractile tone of human isolated internal mammary artery. The responses in human internal mammary artery (IMA) were recorded isometrically by a force-displacement transducer in isolated organ baths. Testosterone (10 nM to 100 microM) was added cumulatively to organ baths either at rest or after precontraction with KCl (68 mM) and PGF2alpha (10 microM). Testosterone-induced relaxations were tested in the presence of cyclooxygenase inhibitor indomethacin (10 microM), nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME, 1 microM), nonselective large-conductance Ca2+-activated and voltage-sensitive K+ channel inhibitor tetraethylammonium (TEA, 1 mM), ATP-sensitive K+ channel inhibitor glibenclamide (GLI, 100 microM), and voltage-sensitive K+ channel inhibitor 4-aminopyridine (4-AP, 1 mM). Testosterone produced relaxation in human IMA (Emax 33% and 41% of KCl- and PGF2alpha-induced contraction, respectively). Vehicle had no significant relaxant effect. Except for TEA, the relaxation at low concentrations is not affected by either K+ channel inhibitors (GLI and 4-AP) or L-NAME and indomethacin. We report for the first time that supraphysiological concentrations of testosterone induce relaxation in IMA. This response may occur in part via large-conductance Ca2+-activated K+ channel-opening action.
 
We studied the pharmacologic properties of LR-B/057, a novel nonpeptide angiotensin II (AII) receptor antagonist. The compound potently displaced [3H]AII from AT1 but not from AT2 receptors in rat adrenal cortex (Ki 3 nM), but did not modify the dissociation rate of the radioligand from the receptors. Both its affinity and the nature of its interaction with AT1 receptors (saturation studies) were markedly affected by the presence of bovine serum albumin (BSA) in the binding assay. In rabbit aorta, LR-B/057 caused nonparallel shifts to the right of the dose-response curve to AII and decreased the maximal response (pKB 9.6). Oral (p.o.) administration of LR-B/057 to conscious rats dose-dependently antagonized the pressor response to AII. LR-B/057 administered either intravenously (i.v.) or p.o. to conscious renal hypertensive rats produced a powerful dose-dependent antihypertensive effect. These results show that LR-B/057 is a potent and selective antagonist at AT1 receptors and has p.o. bioavailability.
 
We used a canine model of embolic pulmonary hypertension induced by intravenous (i.v.) injection of autologous thrombi to evaluate whether the novel recombinant plasminogen activator (r-PA) BM 06.022 reversed pulmonary hypertension. The effects of BM 06.022 after bolus injection were compared with those of vehicle, alteplase, urokinase, and anistreplase in 6 dogs per group. Thirty minutes after initiation of treatment, the decrease in pulmonary artery pressure (PAP) caused by a bolus of 200 kU/kg (0.35 mg/kg) BM 06.022 was greater (p < 0.05) than that caused by a 2-h infusion of 1.33 mg/kg alteplase or of 40,000 U/kg urokinase and that caused by a bolus of 0.4 U/kg anistreplase but not that caused by a 15-min infusion of 1 mg/kg alteplase. At 3 h, all thrombolytic agents had reduced PAP equally. The greatest measured plasma concentration of BM 06.022 was higher (p < 0.05) than that of 2-h infused alteplase (4,498 +/- 716 vs. 519 +/- 119 IU/ml). We conclude that because of its bolus-pharmacokinetics, BM 06.022 more rapidly reversed thromboembolic pulmonary hypertension than did 2-h infusion of alteplase or urokinase or a bolus of anistreplase.
 
We studied the thrombolytic dose-response relationship of a recombinant plasminogen activator (rPA) (BM 06.022) compared with alteplase in a canine model of coronary artery thrombosis. BM 06.022 consists of the kringle 2 and protease domains of human tissue PA (tPA) and lacks oligosaccharide side chains because of its expression in Escherichia coli. Thrombus formation in anesthetized, open-chest dogs was induced by electrical injury to the intimal surface of the left circumflex coronary artery in the presence of a critical stenosis. Intravenous bolus injection of BM 06.022 (50, 100, 140, and 200 kU/kg) or of alteplase (200, 800, 1,130, and 1,600 kU/kg) 30 min after coronary occlusion to six heparinized dogs per group achieved a dose-dependent increase in reperfusion rate and decrease in residual thrombus wet weight. Vehicle-treated dogs did not reperfuse. Semilogarithmic regression analysis showed that the effective dose that produced 50% reperfusion of BM 06.022 (83 kU/kg) was 11.6-fold lower than that of alteplase (951 kU/kg). Comparison with infusion experiments showed that intravenous bolus injection of 140 kU/kg of BM 06.022 was equieffective to a 90-min infusion of 800 kU/kg (= 1 mg/kg) of alteplase as a standard treatment regarding reperfusion rate (66%) and time to reperfusion (15 +/- 6 vs. 18 +/- 8 min). Pharmacokinetic analysis for functionally active BM 06.022 or alteplase in plasma revealed a total plasma clearance of 4.1-6.6 ml/min/kg for BM 06.022 and of 12.6-42.3 ml/min/kg for alteplase.(ABSTRACT TRUNCATED AT 250 WORDS)
 
The myocardial infarct size (IS)-limiting effect of CP-060S, a novel cardioprotective drug that prevents Na+-, Ca2+-overload and has Ca2+ channel-blocking activity, was compared with that of diltiazem, a pure Ca2+ antagonist, to determine whether the prevention of Na+-, Ca2+-overload contributes to this IS-limiting effect. Dogs were subjected to 90 min of left circumflex coronary artery (LCx) occlusion followed by 5 h of reperfusion. Either CP-060S (300 microg/kg) or diltiazem (600 microg/kg) was administered intravenously 20 min before the occlusion. CP-060S significantly limited IS compared with that of vehicle (percentage of the area at risk: vehicle, 50.64 +/- 6.08%; CP-060S, 21.13 +/- 3.75%; p < 0.01 vs. vehicle). Although diltiazem exerted a significant decrease in rate-pressure product (RPP; an index of myocardial oxygen consumption) during occlusion equal to that of CP-060S, diltiazem did not significantly reduce IS (33.90 +/- 4.30%). Regional myocardial blood flow (RBF) was not significantly different between any of the groups. Therefore the IS-limiting effect of CP-060S cannot be explained in terms of changes in RPP or RBF. Thus the IS limitation induced by CP-060S is probably the consequence of a direct cardioprotective effect on myocytes. The prevention of Na+-, Ca2+-overload may be the primary reason for this IS-limiting effect.
 
CP-060S is a novel compound that can inhibit the slow inward calcium current as well as the veratridine-induced, noninactivating sodium current. Antiischemic and cardiovascular effects of CP-060S were assessed by using halothane-anesthetized beagle dogs and compared with the effects of semotiadil, a benzothiazine calcium antagonist. The first or second diagonal branch was narrowed. ECG, unipolar electrograms from both ischemic and nonischemic regions, and systemic and left ventricular pressure were monitored. The left ventricle was electrically driven at 190-240 beats/min for 3 min to induce reversible myocardial ischemia. The severity of ischemia was judged by the magnitude of ST-segment depression. CP-060S (0.1 mg/kg, i.v.) significantly attenuated the pacing-induced ST-segment depression in the ischemic region >2 h, whereas during the sinus rhythm, it showed reversible negative chronotropic, inotropic, and dromotropic effects and induced transient depressor response, which would not necessarily be considered favorable (n = 8). A smaller dose of CP-060S (0.03 mg/kg, i.v.) showed a similar antiischemic and cardiovascular profile, but each effect was less potent than that of the higher dose (n = 7). Semotiadil (0.1 and 0.3 mg/kg, i.v.) also showed cardiovascular suppression similar to that of CP-060S; however, the antiischemic effect was not detected during the whole experimental period (n = 6). Thus the inhibition of the noninactivating sodium current may be the primary reason for the antiischemic effect of CP-060S and could become a new cytoprotective principle in the treatment of patients with ischemic heart disease.
 
The effects of TA-064 (TA) on "fast" and "slow" response action potentials and contractile tensions were studied in isolated guinea pig papillary muscles, and the findings were compared with those of isoproterenol (ISP) and ouabain. The results are as follows: (a) TA produced a dose-dependent (10(-7)-10(-5) M) increase in developed tension, with no significant changes in the resting membrane potential (RMP), action potential duration (APD), and maximum rate of rise of action potential (Vmax). (b) The concentration required to increase the developed tension by threefold ("equivalent concentration") were 10(-6) M with both TA and ouabain, while that of ISP was 5 x 10(-8) M. (c) TA increased the maximum rate of rise, dP/dtmax, and the maximum rate of fall, dR/dtmax, of the developed tension to the same extent, unlike those of ISP and ouabain. (d) Positive inotropic effects of TA (10(-7)-10(-5) M) were not completely abolished by atenolol (3.8 x 10(-5) M), a specific beta 1 blocker, whereas those of ISP were completely abolished. (e) The increasing effects of "equivalent concentration" of TA (10(-6) M) on the Vmax of the slow response were less than those of ISP (5 x 10(-8) M). These results suggest that the positive inotropic effects of TA are mainly due to stimulation of beta 1 adrenoceptors, but that the mode of action of the drug differs in several respects from that of ISP or ouabain.
 
We investigated the effects of a newly synthesized cardiotonic agent, TA-064, on helical strips of isolated canine cerebral, coronary, femoral, mesenteric, and renal arteries. TA-064 had no effect on isolated arterial strips under resting tension. When the arterial strips were partially contracted with prostaglandin F2 alpha, TA-064 caused markedly significant concentration-related relaxations in coronary arterial strips. However, the maximum relaxation induced by TA-064 in renal, mesenteric, and femoral arterial strips was only one-third or less of the coronary artery. On the other hand, cerebral arterial strips generated negligible responses to TA-064. Relaxation of renal, mesenteric, and femoral arteries was not potentiated by pretreatment with 10(-5) M phenoxybenzamine. The concentration-response curve for TA-064 in coronary artery was shifted to the right to a similar extent by exposure to 2 X 10(-7) M propranolol and 2 X 10(-7) M metoprolol. On the other hand, relaxation of renal arterial strips was only slightly attenuated by metoprolol but was inhibited by propranolol. Droperidol (3 X 10(-5) M) failed to significantly alter the concentration-response curve for TA-064 in coronary artery. These results indicate that TA-064 causes coronary arterial vasodilatation mediated by beta 1-adrenoceptors. It would further appear that the same mechanism may be responsible for the positive inotropic action of TA-064.
 
The hemodynamic effects of PY 108-068 (PY), a new benzoxadiazolyle dihydropyridine derivative with calcium antagonistic effects on vascular smooth muscle, were investigated in chloralose--urethane-anesthetized open-chest cats. Regional blood flow was measured with tracer microspheres. PY lowered blood pressure and increased cardiac output similarly to nifedipine (N). Unlike the latter drug, PY decreased heart rate without showing evidence of cardiodepression. Right atrial pressure increased slightly less than with N. All these effects were dose dependent in the dose range from 1 to 43 micrograms/kg i.v.. PY and N increased myocardial blood flow to the same extent initially, and redistributed it in favor of the outer layer of the left ventricle. The activity of sublingually administered PY was comparable to that of a similar intravenous dose. An approximately three times larger intraduodenal dose was needed for similar effects. Our results provide preliminary in vivo evidence that it is possible to separate the negative chronotropic from the negative inotropic effects of calcium antagonists.
 
The effects of a noradrenaline (NA, 1 microgram/kg min) or serotonin (5-HT, 10 micrograms/kg min) infusion on regional blood flow and conductance were assessed with tracer microspheres before and after administration of the calcium-antagonist PY 108-068 (PY; 30 micrograms/kg). Chloralose-urethane-anesthetized cats were pretreated with propranolol 1 mg/kg i.v. or chlorisondamine 1 mg/kg i.v. for the experiments with NA or 5-HT, respectively. PY attenuated the NA-induced increase of blood pressure and the decrease of total peripheral conductance. The NA-induced vasoconstriction, occurring mainly in the kidneys, adrenals, liver, spleen, and arteriovenous shunts, was significantly attenuated by PY. The vessels of heart, stomach, pancreas, and skeletal muscle were not constricted by NA. In contrast, 5-HT dilated or tended to dilate almost all vascular beds examined. Only arteriovenous shunts were constricted. PY did not antagonize this vasoconstrictor effect. Moreover, after but not before PY treatment, a coronary vasoconstrictor effect of 5-HT was seen. Antivasoconstrictor effects of PY were observed both in organs where dihydropyridines normally elicit vasodilatation and in organs where such compounds have no vasodilator effects in the absence of a vasoconstrictor infusion. The regional distribution of the antivasoconstrictor effects was different for each vasoconstrictor tested so far (angiotensin II, 5-HT, and NA). The sites of action of calcium antagonists in peripheral blood vessels appear to depend on the mechanism of activation operating at that site and at the time of the investigation.
 
The negative ino- and chronotropic effects of the new calcium antagonist, PY 108-068 (PY), were investigated and compared with several other calcium antagonists in paced left and spontaneously beating right atria of guinea pigs. The concentrations that decreased, by 25% (EC25), the contractile force and heart rate (HR), were determined. For PY, the concentration needed for the negative inotropic EC25 was 50 times higher than the concentration that diminished the HR by 25%. This ratio was also determined for the following calcium antagonists: nisoldipine, 27; verapamil, 2.8; gallopamil, 2.2; fendiline, 1.6; diltiazem, 3.4; and nifedipine, 0.35. The results obtained with PY and nifedipine were verified in rabbit right atria and papillary muscle. The separation between the two EC25 values was 23 for PY and 0.07 for nifedipine. Nitroglycerin had no effects on guinea pig and rabbit cardiac tissue in vitro. Conscious rabbits with chronically implanted catheters were used to determine if PY inhibits reflex tachycardia in vivo. The effects of nitroglycerin on blood pressure (BP) and HR served as a standard by which the effects of PY and nifedipine were compared. All three compounds lowered BP dose dependently and had similar initial effects on HR. While HR increased dose dependently with nitroglycerin and nifedipine, no such dose dependence was found with PY. PY thus inhibited reflex tachycardia in conscious rabbits. The wide separation between negative chronotropic and negative inotropic effects of PY implies that the calcium channels involved may be different. The selective action of PY could present a therapeutic advantage.
 
PY 108-068 (PY) is a new benzoxadiazolyle dihydropyridine derivative. It potently antagonizes calcium-induced contractions of rabbit aorta in depolarizing solution (PD'2:8.8). This antagonism is selective, since no relevant antagonistic effects against noradrenaline (NA)-, serotonin (5-HT)-, and angiotensin II (AII)-induced contractions are found at the highest concentration of PY (10(-5) M). Verapamil (V), examined for comparison, was less selective with respect to its antagonism: pA2 value against calcium-induced contractions in depolarizing solution: 7.6, pA2 against serotonin-induced contractions: 6.9. In calcium-free Krebs--Henseleit solution tachyphylaxis occurred after three to four administrations of NA, 5-HT, or AII. When calcium was added in the presence of one of these agonists, the slow phase of concentration, which depends on extracellular calcium, developed. This slow phase of contraction was not inhibited to a relevant extent by a 10(-5) M concentration of PY. Verapamil inhibited the tonic contraction induced by serotonin (pD'2: 5.5) but not to a relevant extent the contractions induced by the two other agonists. PY therefore, inhibits calcium-induced contractions of rabbit aorta in depolarizing solution very selectively, and shows hardly any effects on receptor-operated channels.
 
The objective of the present study was to determine the time-courses for depression and recovery of calcium-mediated action potentials in canine Purkinje fibers following exposure to dihydropyridine (DHP) calcium channel antagonists and to determine if the reported discrepancy (up to 1,000 X) between I50 values for inducing physiologic effects in isolated tissues and the dissociation constant (Kd) for [3H]nitrendipine binding to membrane sites could be reduced when physiologic measurements were made under experimentally determined steady-state conditions. Changes in dV/dtmax of slow calcium-mediated action potentials (20 mM KCl, 10(-6) M isoproterenol) were recorded at 10-min intervals during exposure (2-4 h) to nifedipine, nitrendipine, and PY 108-068 (10(-9) M-4 X 10(-8) M). Time to steady state was slow, with half-life t1/2 values of 40 min (nifedipine), 84 min (nitrendipine), and 81 min (PY 108-068). Steady state I50 values for depressing dV/dtmax were 12.08 (nifedipine), 5.74 (nitrendipine), and 4.88 nM (PY 108-068). In isolated cardiac sarcolemma preparations (37 degrees C), these compounds competed for [3H]nitrendipine binding sites with Ki values of 8.1, 1.3, and 4.9 nM, respectively. These results show that attainment of steady-state depression of calcium channel function can be slow, but that the discrepancy between the physiologic data and the binding data is reduced significantly (less than 5 X) when physiologic measurements are made at steady state and binding studies are performed at 37 degrees C.
 
We evaluated coronary vasodilator and cardiac effects of PY 108-068 on isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. PY 108-068 was administered intra-arterially (i.a.). PY 108-068 increased (coronary) blood flow in all preparations. In SA node preparations, the drug produced a decrease in sinus rate and, in large doses, atrial standstill. In AV node preparations, the drug produced an increase in AV conduction time. Large doses caused second- or third-degree AV block, but only when injected into the artery supplying the AV node. The doses producing a 15% (nearly half maximum) decrease in sinus rate or a 15% (nearly half maximum) increase in AV conduction time were two to three times the doses that doubled coronary blood flow. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. However, the dose required to reduce the force of contraction of the papillary muscle by 50% was about 30 times the dose that doubled coronary blood flow. The drug was entirely ineffective on rate of ventricular automaticity. We conclude that PY 108-068 is not likely to produce reflex tachycardia when administered systemically in coronary vasodilator doses.
 
The efficacy and safety of carvedilol, a [beta]-blocker with vasodilating properties, were compared at a dosage of 25 to 50 mg once daily with those of atenolol at a dosage of 50-100 mg once daily in a double-blind, randomized, parallel-group, multicenter study. After a single-blind placebo phase of 3 to 6 weeks, 47 patients (median age, 59 years) were randomized to receive carvedilol and 52 patients (median age, 57 years) were randomized to receive atenolol for an 8-week study period. Patients on carvedilol received 12.5 mg for the first 2 days and then 25 mg as a once-daily dosage. The initial dosage of atenolol was 50 mg once daily. The dosage of each treatment could be doubled (to 50 and 100 mg once daily, respectively) at week 4 if the response was inadequate. Sitting and standing blood pressures and heart rates were recorded 24 h after the dose at weeks 4 and 8. Data from 90 of 98 patients who completed the study were eligible for per-protocol analysis. Approximately one-third of the patients in each group required upward dose titration at week 4 because of inadequate response. At week 8, 84% patients receiving carvedilol and 91% receiving atenolol had sitting diastolic blood pressure <=90 mm Hg or decreased their blood pressure by >=10 mm Hg (95% confidence intervals for difference between carvedilol and atenolol, + 7% and - 21%). Safety profiles were similar between treatments. One patient withdrew; a skin rash developed during the fourth week of treatment with atenolol. There were no apparent clinically relevant trends in abnormal laboratory parameters. At the doses compared in this study, carvedilol and atenolol are similar in efficacy and tolerability. (C) Lippincott-Raven Publishers.
 
Effects of a new antiarrhythmic agent, E-0747, on action potentials of swine cardiac Purkinje fibers were studied using standard microelectrode techniques. E-0747 decreased the maximum rate of rise (Vmax) of action potentials at concentrations higher than 3 X 10(-7) M at a frequency of 1 Hz without change in resting membrane potential. E-0747 (3 X 10(-6) M) shifted the steady-state relationship between the Vmax and the resting membrane potential in a hyperpolarizing direction by 9.2 +/- 0.9 mV. E-0747 depressed the Vmax in a rate-dependent manner. At a concentration of 3 X 10(-6) M, the depression was approximately 50% at a stimulation of 3.3 Hz. E-0747 (3 X 10(-6) M) did not depress the Vmax of the first action potential after a rest period of approximately 30 min, but subsequently reduced the Vmax with successive stimulations reaching a new steady level after approximately 20 min. The time course of recovery from inactivation of the Vmax in the presence of E-0747 (10(-6) M) did not differ from that of the control. E-0747 shortened the action potential duration (APD), but did not affect the ratio of effective refractory period (ERP) to APD. These results suggest that E-0747 depresses the Vmax by closely associating with open and/or inactivated sodium channels. It may be classified as an antiarrhythmic agent of class 1C type of the Vaughan Williams' classification.
 
This study was conducted to characterize the multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-077825, a new direct renin inhibitor, in healthy male subjects. In this single-center, double-blind, placebo- and active- (20 mg enalapril) controlled, randomized multiple ascending dose study, ACT-077825 was administered q.d. for 7 days in the 50-1000 mg dose range to sodium- and potassium-restricted subjects. ACT-077825 pharmacokinetics on Days 1 and 7 were characterized by dose-proportional increases in Cmax and AUCτ. At steady state, accumulation was modest (1.5- to 1.7-fold). Enalapril caused an increase in plasma active renin (AR) concentration and plasma renin activity (PRA). ACT-077825 dose-dependently increased AR on day 1 and 7, and inhibited PRA dose-dependently only on day 1. On day 7, the maximal PRA inhibition was attained following 250 mg ACT-077825. In contrast to enalapril, ACT-077825 did not induce any consistent lowering effect on blood pressure when compared to placebo. Of the reported adverse events, diarrhea, headache, and postural dizziness were more frequent. The incidence of diarrhea was greater in the 1000 mg group and a dose of 500 mg ACT-077825 was identified as the maximum tolerated dose.Overall, pharmacokinetic, pharmacodynamic, and tolerability profiles warrant the further investigation of ACT-077825 in hypertensive patients.
 
The electromechanical properties of H 234/09 (Almokalant), a novel class III antiarrhythmic agent, was examined in isolated human ventricular muscle strips excised from patients undergoing mitral valve replacement. Using transmembrane microelectrode recording techniques, we demonstrated that H 234/09 markedly prolonged the action potential duration (APD) without affecting the maximal rate of depolarization or action potential amplitude. At 75 and 90% repolarization APD was prolonged to a similar extent, whereas the lengthening at 50% repolarization was somewhat less marked. In isometrically contracting muscle strips, H 234/09 increased peak developed force and its maximal rate of rise (dF/dt) and fall (-dF/dt) in a concentration-dependent manner, whereas time to peak developed force was unaltered. We conclude from these studies that H 234/09 is a class III agent in human ventricular muscle and that the class III effect is linked with a positive inotropic response.
 
The electrophysiologic and hemodynamic effects of H 234/09 (Almokalant), a novel class II antiarrhythmic agent, were studied in the anesthetized dog. H 234/09 (1.0 mumol/kg i.v.) significantly prolonged the atrial and ventricular effective refractory periods, the ventricular monophasic action potential duration, and the paced QT interval. At this dose, atrial, ventricular, and atrioventricular conduction was not affected, aortic blood pressure was not changed, and contractile force was transiently increased. The effects on cardiac repolarization and refractoriness induced by H 234/09 were both larger and more long lasting than the effects observed after quinidine (11.8 mumol/kg) and (+)-sotalol (9.7 mumol/kg). However, both quinidine and (+)-sotalol significantly reduced the aortic blood pressure and (+)-sotalol also decreased cardiac contractility. The effect of H 234/09 on atrial refractoriness was very little influenced by the paced heart rate and was twice as large as the corresponding effect in the ventricle. In conclusion, H 234/09 has electrophysiological properties suggestive of a class III antiarrhythmic. H 234/09 may have a favorable therapeutic profile compared to both quinidine and (+)-sotalol, especially for the treatment of atrial arrhythmias.
 
Studies were conducted in human isolated coronary arteries to explore the vascular effects of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant and to compare its coronary vasoconstrictive potential to that of zolmitriptan. KCl precontracted coronary vessels were shown to relax to human alphaCGRP, with the CGRP-mediated vasorelaxation completely blocked with 30 microM telcagepant. In coronary vessels at basal tone, zolmitriptan caused a concentration-dependent contraction (pEC50 = 6.9 +/- 0.1; slope 0.94), with the greatest contraction obtained between 1 and 10 microM in most tissues. In contrast, telcagepant at concentrations up to 30 microM evoked no change in contractile tone. These findings suggest the potential for CGRP receptor antagonists to exert antimigraine efficacy in the absence of adverse effects on coronary tone.
 
Recently, we demonstrated that the endothelium-dependent vasodilator effect of angiotensin(1-7) in the mouse aorta is abolished by genetic deletion of the G protein-coupled receptor encoded by the Mas protooncogene. To circumvent the limitations posed by the possible metabolism of Ang(1-7) in this vessel, in this work we studied the mechanism underlying the vasorelaxant effect of AVE 0991, a nonpeptide mimic of the effects of Ang(1-7), using wild-type and Mas-deficient mice. Ang(1-7) and AVE 0991 induced an equipotent concentration-dependent vasodilator effect in aortic rings from wild-type mice that was dependent on the presence of endothelium. The vasodilator effect of Ang(1-7) and AVE 0991 was completely blocked by 2 specific Ang(1-7) receptor antagonists, A-779 and D-Pro-Ang(1-7), and by inhibition of NO synthase with L-NAME. Moreover, in aortic rings from Mas-deficient mice, the vasodilator effect of both Ang(1-7) and AVE 0991 was abolished. In contrast, the vasodilator effect of acetylcholine and substance P were preserved in Mas-null mice. In addition, the vasoconstriction effect induced by Ang II was slightly increased, and the vasodilation induced by the AT2 agonist CGP 42112A was not altered in Mas-deficient mice. Our results show that Ang(1-7) and AVE 0991 produced an NO-dependent vasodilator effect in the mouse aorta that is mediated by the G protein-coupled receptor Mas.
 
The therapeutic utility of KATP channel opening agents (KCOs) in the treatment of overactive bladder may be limited by hypotension as a result of insufficient selectivity in vivo for bladder versus vasculature smooth muscle. Recently, we demonstrated that the putative uroselective KCOs, A-278637, ZD-6169, and WAY-133537 suppress unstable bladder contraction in an in vivo pre-clinical pig model of detrusor instability secondary to partial outlet obstruction. In the present study in the anesthetized dog we targeted plasma concentrations 3-, 10-, and 30-fold above a common index of in vivo efficacy (EC35) for suppression of unstable bladder contraction in pigs, to provide a comprehensive cardiovascular profile of these compounds. When compared at similar multiples of efficacy, dose-dependent reductions in SVR were greater in ZD-6169 and WAY-133537-treated animals versus A-278637. A-278637, unlike ZD-6169 or WAY-133537, produced no effect on MAP at concentrations 10-fold above the EC35. At concentrations 30-fold above the EC35, MAP in A-278637-treated animals was reduced -11% from baseline versus -24% and -42% for ZD-6169 and WAY-133537. Accordingly, at plasma concentrations approximately 30-fold above the EC35 reflex-mediated increases in HR were modest for A-278637-treated animals (15% above baseline) versus ZD-6169 (22%) or WAY-133537 (35%). Increases in both dP/dt and cardiac output occurred at lower therapeutic multiples and were greater in magnitude for animals treated with WAY-133537 (66% and 64% above baseline, respectively, 60 minutes into compound infusion) and ZD-6169 (10% and 13%) versus A-278637 (-2% and 6%). Thus, A-278637 exerted lesser effects on cardiovascular function at equivalent multiples of the EC35 than either ZD-6169 or WAY-133537. These data suggest that A-278637 possesses a greater functional selectivity for urinary bladder versus vascular smooth muscle in vivo and that A-278637 may exhibit a more favorable therapeutic index than either ZD-6169 or WAY-133537.
 
Electrical and mechanical effects of 3-[[4-(2-methoxyphenyl)piperazin-1-ly]methyl]-5-(methylthio)-2,3-+ ++dihydroimidazo[1,2-c]quinazoline (DL-017), a new synthesized antihypertensive agent, were studied in guinea-pig ventricular papillary muscles. In muscle fibers driven at 1 Hz, DL-017 decreased the twitch force in a concentration-dependent manner and significantly increased the action-potential duration and decreased intracellular Na+ activity (ai(Na)) and maximal rate of upstroke of action-potential (Vmax) when concentrations were greater than 1 microM. Phenylephrine in the presence of 1 microM propranolol produced a concentration-dependent positive inotropy. DL-017 (0.01 microM) antagonized the positive inotropic effect of phenylephrine and shifted the concentration-response curve to the right. In K+-depolarized muscle fibers, 0.1 microM DL-017 significantly decreased the contractile force without changing the slow action potential. In low-[K+]o and high-[Ca2+]o solutions, a train of stimuli triggered a spontaneous rhythm that could be abolished by 3 microM DL-017. Our results suggest that DL-017 not only exhibits an alpha1-antagonistic effect but also induces negative inotropy by a decrease in myofibrillar calcium sensitivity and inhibits Na+ channels at higher concentrations, contributing to the drug's negative inotropic and type-I antiarrhythmic effects.
 
N"-Cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine (P 1134) is a new vasodilating antihypertensive compound. In an open study, P 1134 was given in single oral doses of from 10 to 25 mg to 12 previously untreated patients with essential hypertension. All patients responded with decreases in mean arterial pressure (MAP) of at least 10 mm Hg and with almost equal blood pressure decreases in the supine and erect position. The increase of dose was significantly correlated with a progressive reduction of blood pressure. At a dose of 25 mg, the maximal decrease in supine MAP averaged 38 mm Hg, and the maximal increase in heart rate averaged 23 beats/min. Peak effect and serum concentration were seen about 1 h after tablet intake. The serum half-life from the peak concentration averaged 2.5 h. It is concluded that P 1134 is a fast-acting, effective antihypertensive agent.
 
ABBOTT-54741 was identified as a full alpha-adrenergic agonist; its interaction with the alpha-adrenergic receptor was compared to that of norepinephrine. ABBOTT-54741 lacks affinity for beta-adrenergic receptors. In radioligand binding studies, the affinity of ABBOTT-54741 for alpha 1-adrenoceptors (as measured against 3H-prazosin binding) was KI = 401 nM, and that for norepinephrine was 388 nM. The affinity of ABBOTT-54741 for alpha 2-adrenoceptors (as measured against 3H-rauwolscine binding) was greater than that of norepinephrine (KIA = 7 nM; KI NE = 37 nM). In vitro, ABBOTT-54741 exhibits high potency in vascular preparations (ED50NE/ED50A in rabbit aorta = 12.9; in phenoxybenzamine-treated dog saphenous vein = 188.5). In rabbit pulmonary artery, it shows greater potency for the presynaptic than postsynaptic receptors, corroborating the observations of selectivity obtained in binding studies. The observations in vivo reflect that in isolated tissues. In different species (dog, rat) and via different routes of administration (i.v., p.o., i.c.v., and nasal), ABBOTT-54741 exhibits cardiovascular effects reflecting the stimulation of both alpha 1- and alpha 2-adrenoceptors consistently with much greater potency than norepinephrine or any other alpha agonist known to the authors.
 
The possibility that D-myo-inositol-1,2,6-triphosphate (PP56), which has shown some specificity for antagonism of neuropeptide Y (NPY) in vitro, may antagonize responses to sympathetic nerve stimulation was investigated in canine blood-perfused gracilis muscle in situ after pretreatment with irreversible alpha-adrenoceptor blockade by phenoxybenzamine and beta-adrenoceptor blockade by propranolol. Sympathetic nerve stimulation (10 Hz, 2 min) increased muscle perfusion pressure and evoked overflow of norepinephrine (NE) from the tissue. PP56 at 50 and 500 microM (calculated local arterial plasma concentrations) did not influence NE overflow but attenuated the late phase of the vasoconstrictor response to nerve stimulation and reduced the increase in perfusion pressure evoked by exogenous NPY. PP56 also induced vasodilatation per se, but had no effect on the vascular response to exogenous angiotensin II (AII) or the remaining vasoconstrictor response to exogenous NE. PP56 antagonizes late components in the nonadrenergic sympathetic vasoconstriction and vasoconstriction evoked by exogenous NPY, without influencing transmitter release. Because previous results with this and other models propose a role for NPY in mediating nonadrenergic vasoconstriction, we suggest that PP56 may antagonize effects of neuronally released NPY at the postjunctional level.
 
A number of investigators have observed insufficient 25-hydroxyvitamin D status in patients with congestive heart failure, suggesting a role for vitamin D insufficiency in the pathogenesis of this disorder. We have observed cardiac hypertrophy and collagen accumulation in rats deficient in vitamin D and in the hearts of vitamin D-receptor knockout mice. Our studies indicate that absence of vitamin D-mediated signal transduction and genomic activation results in cardiomyocytes overstimulation including increased contractility. These events ultimately lead to cardiomyocyte hypertrophy. In this report, we used spontaneously hypertensive heart failure rats cp/+ (hemyzygous for the corpulent gene, a mutant isoform of the leptin receptor) fed a normal and a high-salt diet to assess the potential for activated vitamin D (1,25 dihydroxyvitamin D3) to prevent cardiac hypertrophy and increases in cardiac output. After 13 weeks, as compared with untreated rats, we observed that 1,25 dihydroxyvitamin D3 treatment in rats fed a high-salt diet resulted in lower heart weight, myocardial collagen levels, left ventricular diameter, and cardiac output despite higher serum leptin levels. These studies suggest that 1,25(OH)2D3 treatment may prevent the development of cardiac hypertrophy, an important contributing factor in the progression of congestive heart failure.
 
In pentobarbital-treated dogs and rats, AR-C239, a new and potent alpha-adrenoceptor blocking drug, competitively antagonized pressor responses to adrenaline and inhibited pressor responses to noradrenaline, phenylephrine, tyramine, and dimethylphenylpiperazinium. Injected intravenously into closed-chest dogs, AR-C239 (3-50 micrograms/kg) induced a progressive fall in blood pressure, heart rate, and sympathetic nerve activity. The drug appears to be devoid of direct vasodilator action, and the fall in blood pressure results from the peripheral alpha-blockade. AR-C239 did not change the tachycardia induced by stimulation of the cardiac nerve in dogs and, at least in this preparation, seems to be a specific alpha 1-adrenoceptor blocking drug. When administered into the cisterna magna of dogs, AR-C239 did not have any centrally mediated cardiovascular actions and heart rate. AR-C239 did not modify the functioning of the baroreflex arc. Due to its specificity for alpha 1-Adrenoceptors, AR-C239 may be useful for characterizing alpha-adrenoceptors.
 
The cardiovascular properties of a new noncatechol, nonglycoside cardiotonic agent, MDL 17,043, were investigated in anesthetized and conscious dogs and the dog heart-lung preparation. MDL 17,043 (0.1-1 mg/kg), administered to anesthetized dogs by intravenous injection, produced dose-related increases in cardiac contractile force lasting more than 1 h. It also produced relatively minor and shorter-lasting increases in heart rate, and brief decreases in blood pressure. These effects were not blocked by propranolol. Of these effects, the increase in cardiac contractile force was, by far, the most prominent. the cardiac effects were also observed in the dog heart-lung preparation. When administered to anesthetized dogs by constant intravenous infusion, MDL 17,043 (09.03 and 0.1 mg/kg/min) produced a marked and sustained increase in cardiac contractile force and a sustained decrease in blood pressure without altering heart rate, suggesting a wide separation between the inotropic instrumented dogs, MDL 17,043 (3-30 mg/kg) produced a sustained increase in dP/dt without altering heart rate or blood pressure. It reversed the depressant effect of pentobarbital on the ventricular function curve in the dog heart-lung. When the hemodynamic characteristics of compensated heart failure were produced by propranolol in anesthetized dogs, MDL 17,043 reversed these effects. These studies suggest that MDL 17,043 may have a beneficial effect in the treatment of heart failure.
 
The new bradycardic agent UL-FS 49 (1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-[[2-(3,4-dimethoxyphenyl]ethyl] methylimino]propyl]-2H-3-benzazepin-2-on-hydrochloride) was investigated in isolated guinea pig atria. In spontaneously beating preparations UL-FS 49, (0.03 and 0.1 microgram/ml) reduced the rate of contraction and decreased the maximal effect of isoprenaline added thereafter. The cumulative concentration-response curve of isoprenaline was antagonized, but not in a competitive manner, excluding an interaction at the beta-adrenoceptor. The rate of spontaneous electrical activity in sinoatrial node preparations was increased by superfusion with isoprenaline (0.1 microgram/ml). Addition of UL-FS 49 (0.1 microgram/ml) as well as propranolol (0.3 microgram/ml) reduced rate to control values. In electrically driven (1 Hz) left atria UL-FS 49 (1 microgram/ml) did not reduce contractile force and did not antagonize the positive inotropic effect of isoprenaline added cumulatively thereafter. When contractile force was first elevated by isoprenaline (0.1 microgram/ml), addition of UL-FS 49 (0.1 microgram/ml) did not affect contractility, whereas propranolol (0.3 microgram/ml) abolished the positive inotropic effect of isoprenaline. The experiments, therefore, demonstrate the specificity of UL-FS 49 to decrease heart rate but not contractility during beta-adrenoceptor stimulation. In contrast to propranolol (0.3 microgram/ml) UL-FS 49 (0.1 microgram/ml) also reduced sinoatrial rate elevated by histamine (1 microgram/ml) or theophylline (300 micrograms/ml), thus indicating a possible use as an antitachycardic drug at tachycardias of various origins. In sinus node preparations depolarized by high external K+ concentrations (10.8 mM), the bradycardic effect of UL-FS 49 (0.1 microgram/ml) was diminished.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Top-cited authors
Paul Vanhoutte
  • The University of Hong Kong
Hans R Brunner
  • University of Lausanne
Salvador mo Moncada
  • The University of Manchester
Garrett Gross
  • Medical College of Wisconsin
Thomas Unger
  • Maastricht University