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Impaired relaxation of the hypertrophied myocardium is potentiated by angiotensin II
Abstract
Relaxation delay is an important feature of hypertensive heart disease which impairs diastolic coronary flow and ventricular filling and therefore contributes to heart failure. We investigated the hypothesis that impaired relaxation is a property of the myocardium, rather than the consequence of ischaemia or interstitial fibrosis. A new videomicroscope system was used to define the contraction-relaxation cycle of isolated cardiac myocytes from spontaneously hypertensive rats (SHR) and normotensive control (Wistar-Kyoto, WKY) rats. The SHR cells showed a marked relaxation delay. Angiotensin II (Ang II) increased the contraction maximum by about 35% in WKY rats and induced a relaxation delay. In SHR Ang II greatly potentiated this relaxation delay. Our results demonstrate that impairment of relaxation is a property of the single cardiomyocyte. Angiotensin II induces a relaxation delay that is independent of blood pressure. The combination of hypertrophy and high levels of Ang II potentiates relaxation impairment and may therefore contribute to hypertensive left ventricular failure.
... tissues and that augmented formation of ANG II, acting through the ANG II type 1 (AT 1 ) receptor on cardiomyocytes and fibroblasts, participates in the paracrine regulation of cardiac remodeling and ventricular function (36). Furthermore, prolonged elevation of ANG II has been associated with cardiac fibrosis (15,16), exacerbation of impaired contractility and relaxation in the hypertrophied failing heart (7,9,27,32), and arrhythmogenesis (9,19). These structural and functional consequences of hemodynamic overload have also been associated with changes in AT 1 receptor expression in the heart. ...
... ANG II has been shown to potentiate the impaired relaxation in isolated cardiomyocytes from rats with PO cardiac hypertrophy (27,32) and to exacerbate a negative inotropic effect on myocardium from rats with congestive heart failure (5,7). However, in this study, isolated cardiomyocyte function did not differ in PO and control dogs at rest or in response to isoproterenol despite a threefold increase in LV ANG II levels. ...
We studied the gradual onset of pressure overload (PO) induced by a mildly constricting aortic band in 8-wk-old puppies (n = 8) that increased to 98 +/- 11 mmHg at 9 mo. Left ventricular (LV) weight/body weight was increased in PO versus sham-operated littermate controls [8.11 +/- 0.60 (SE) vs. 4.46 +/- 0.38 g/kg, P < 0.001]. LV end-diastolic diameter, diastolic pressure, and fractional shortening did not differ in PO versus control dogs. There were no inducible arrhythmias in response to an aggressive electrophysiological stimulation protocol in PO dogs. Furthermore, isolated cardiomyocyte function did not differ between control and PO dogs. LV angiotensin II (ANG II) levels were increased (68 +/- 12 vs. 20 +/- 5 pg/g, P < 0.01) as steady-state ANG II type 1 (AT(1)) receptor mRNA was decreased 40% and endothelial nitric oxide synthase mRNA levels were increased 2.5-fold in PO versus control dogs (P < 0.05). Total ANG II receptor binding sites of freshly prepared cardiac membranes demonstrated no difference in the dissociation constant, but there was a 60% decrease in maximum binding (B(max)) in PO versus control dogs (P < 0.01). LV ANG II levels correlated negatively with AT(1) receptor mRNA levels (r = -0.75, P < 0.01) and total AT(1) receptor B(max) (r = -0.77, P < 0.02). These results suggest that LV ANG II negatively regulates AT(1) receptor expression and that this is an adaptive response to chronic PO before the onset of myocardial failure in the young dog.
... O menor comprometimento da função diastólica observado nos ratos tratados com lisinopril pode ser devido ao menor comprometimento da distensibilidade miocárdica decorrente da hipertrofia ventricular esquerda menos acentuada e/ou menor acúmulo de colágeno miocárdico 23,30,[41][42][43]48 . Alternativamente, a atenuação do comprometimento da função distólica do ventrículo esquerdo observada no grupo GL poderia ser devida aos efeitos do bloqueio ou redução da angiotensina II produzida localmente pelo SRAA tecidual miocárdico 11,16,49,50 . Trabalhos da literatura 49,50 apontam que na presença de hipertrofia ventricular esquerda a ativação da AII intracardíaca retarda e lentifica o relaxamento 49 e que a administração endovenosa de IECA em pacientes com EAo grave 50 melhoram a distensibilidade e o relaxamento miocárdico. ...
... Alternativamente, a atenuação do comprometimento da função distólica do ventrículo esquerdo observada no grupo GL poderia ser devida aos efeitos do bloqueio ou redução da angiotensina II produzida localmente pelo SRAA tecidual miocárdico 11,16,49,50 . Trabalhos da literatura 49,50 apontam que na presença de hipertrofia ventricular esquerda a ativação da AII intracardíaca retarda e lentifica o relaxamento 49 e que a administração endovenosa de IECA em pacientes com EAo grave 50 melhoram a distensibilidade e o relaxamento miocárdico. Assim, com base nos resultados observados é pertinente inferir que o SRAA é responsável, pelo menos em parte, pelo advento da hipertrofia cardíaca patológica, com conseqüente disfunção sistólica e diastólica do ventrículo esquerdo, descompensação cardíaca e morte prematura por mecanismos distintos daqueles relacionados com a elevação da pressão arterial e com o grau de hipertrofia ventricular esquerda. ...
To assess the effects of lisinopril (L) on mortality (M) rate and congestive heart failure (CHF), and the characteristics of geometrical myocardial remodeling and left ventricular function in rats with supravalvular aortic stenosis (SAS).
Some Wistar rats underwent SAS or the simulated surgery (CG, n=10). After 6 weeks, the animals were randomized to receive lisinopril (LG, n=30) or no treatment (SG, n=73) for 15 weeks. Cardiac remodeling was assessed in the sixth and 21st weeks after the surgical procedures through concomitant echocardiographic, hemodynamic, and morphological studies.
The M were 53.9% and 16.7% in SG and LG, respectively; the incidence of CHF was 44.8% and 20%, in SG and LG, respectively, (P<0.05). At the end of the experiment, the values of LV systolic pressure in SG and LG were equivalent and significantly greater than those in CG; (P<0.05) and did not differ from those observed 6 weeks after the surgical procedures. The values of LV diastolic pressure in SG were greater than those in LG; (P<0.05), and both were greater than those in CG; (P<0.05). The same behavior was observed with the following variables: E/A ratio; mass index; sectional area of the myocytes; and LV hydroxyproline content. Left ventricular shortening percentage was similar in CG and LG; (P>0.05), and both were greater than those in SG; (P<0.05). Similar results were obtained with the values of the positive and negative first derivate of LV pressure.
In rats with SAS, the treatment with L reduced M rate and ICC and had beneficial effects on geometrical myocardial remodeling and left ventricular function.
In hearts with myocardial damage secondary to myocardial infarction, chronic ischemia, inflammation, or pressure or volume overload, there is a complex sequence of compensatory events that ultimately result in an adversely remodeled myocardium and a dilated, thin-walled, spherical ventricle. For a period of time, a preclinical heart failure state may exist in which there is ventricular dysfunction caused by myocardial damage but no clinical evidence of cardiac insufficiency, circulatory congestion, or edema. However, in an attempt to maintain this state, there are ongoing myocardial adaptations resulting in a continual state of remodeling with progressive ventricular dilatation mediated by changes in myocyte morphology, intracellular calcium regulation, and extracellular matrix production. Although a number of growth-promoting factors have been implicated in cardiac hypertrophy and remodeling, angiotensin II (ANG II) is assumed to play a major role in this process because it is a potent growth factor for myocytes and fibroblasts in the heart [1,2]. It has been postulated that the cardiac renin-angiotensin system (RAS) is activated during compensated heart failure and that the continued presence of ANG II could have important local pathological functions in the transition to heart failure (Fig. 1). Alternatively, the heart is a target organ for ANG II, which produces a positive inotropic and chrono tropic effect on myocytes [4–6], stimulates the release of norepinephrine from cardiac sympathetic nerves [7,8], and acts as a growth factor for myocytes [1,2]. Thus, the failing heart may be dependent on local ANG II production to provide inotropic support and to promote myocyte hypertrophy to minimize wall stress. However, the identification of alternative ANG II-forming mechanisms in the heart and the role of angiotensin-converting enzyme (ACE) on bradykinin degradation have raised questions regarding the mechanism of ANG II production in the heart and the role of ANG II per se in cardiac hypertrophy and remodeling. This chapter reviews these issues and the results of animal models investigating the cardiac renin-angiotensin system in cardiac hypertrophy caused by pressure and volume overload.
Atrial natriuretic peptide (ANP) has, in vivo, negative or no effect on left ventricular (LV) systole and relaxation. The aim of this study was to test the effect of ANP on LV function and on the renin-angiotensin-aldosterone system (RAAS) in normal and moderately atherosclerotic male anesthetized New Zealand White (NZW) rabbits. Each group's individuals were divided into two subgroups of five animals each. Rabbits were rendered atherosclerotic by receiving for four weeks regular chow supplemented with 2% cholesterol and 6% com oil. Tthe LV and the left carotid artery were cannulated for left ventricular pressure (LVP) and blood pressure (BP) recordings, with concurrent ECG tracing. The left ventricular maximal pressure (LVPmax), the left ventricular end diastolic pressure (LVEDP), the maximal and the minimal change over time in LVP (LVmax dp/dt and LVmindp/dt), the Δd (time interval between LVmax dp/dt and LVmindp/dt = systole duration) and the left ventricular ejection time (LVET) were estimated and the Double Product (heart rate X systolic blood pressure- HR × SBP) was calculated. Central venous pressure (CVP) was also recorded from the right jugular vein and blood samples were taken forlipids, ANP, plasma renin activity (PRA) and aldosterone (Ado) levels measurement. Recordings and blood samples for hormones measurement (by RIA) were taken at 0 min) and 20, 40, 60 min following an intravenous 20-min administration of either 0.2 μg/kg/min hANP in 5ml normal saline (N/S) or only 5ml N/S. The results were analyzed by t-test and repeated measures ANOVA. Mild to moderate atherosclerosis was found in rings of ascending aorta. ANP infusion resulted in decrease (p<0.05) of BP in 20min time only, but decrease (p<0.05) of LVPmax from 20min, decrease (p<0.05) of LVEDP and LVmaxdp/dt from 40min, and less negative change (increase) (p<0.05) of LVmindp/dt from 40min. DP was increasd (p<0.05) from 20min only in atherosclerotic animals. PRA and aldo did not differ significantly at 0 min between atherosclerotic and normal; PRA in ANP receivers was smaller (p<0.01) whereas aldo tended to be smaller (p=0.06) than in N/S receivers. It is concluded that ANP administration, in doses to achieve levels approximately three fold the normal range, in normal and moderately atherosclerotic anesthetized NZW rabbits results in a negative effect on LV systolic function and relaxation and suppresses the RAAS activity independently of the atherosclerotic state.
Objective: A novel angiotensin receptor has been described and named AT4. Ligands for this receptor include the angiotensin II (Ang II) metabolite Ang II (3–8), known as angiotensin IV (Ang IV). There is 10-fold more AT4 receptor than AT1 receptor in rabbit myocardium. The AT4 receptor has a high affinity for Ang IV ( K i in rabbit myocardium 10−6). Although several functions have been attributed to the novel Ang IV peptide/AT4 receptor system, the effect of this system on left ventricular (LV) function has not been studied. We hypothesized (1) that Ang IV would affect LV function and (2) that any effects would be opposite to those of Ang II. Methods: Using the buffer-perfused (30°C) isolated rabbit heart, we studied the effect of the AT4 agonist Nle1-Ang IV on LV systolic function, quantified using both Frank–Starling and end-systolic pressure–volume relationships, and relaxation. We also studied the effect of the AT1/AT2 agonist, Sar1-Ang II on LV function. Finally, because the profile of effect of Nle1-Ang IV was similar to the reported effect of nitric oxide (NO), we also studied the effect of Nle1-Ang IV in the presence of the NO synthase inhibitor N G-monomethyl-l-arginine. Results: Nle1-Ang IV reduced LV pressure-generating capability at any volume but increased the sensitivity of pressure development to volume change. Nle1-Ang IV reduced LV ejection capability. Sar1-Ang II had the opposite effect – increasing both pressure generation and ejection capability. Finally, both Sar1-Ang II and Nle1-Ang IV speeded LV relaxation. Inhibition of NO synthase did not alter the effect of Nle1-Ang IV on LV systolic function or relaxation. Conclusions: AT4 receptor agonism has mixed effects on LV systolic function, depressing pressure-generation and ejection capabilities, but enhancing the sensitivity of pressure development to volume change. It also speeds relaxation. The effect of Ang IV on systolic function is generally opposite to the effect of Ang II, whereas the Ang IV influence on relaxation is similar to the effect of Ang II.
CGP 42 112 A and DuP 753 block [125I]-angiotensin II binding in rabbit ventricular myocardial membranes in a clearly biphasic manner, indicating the existence of high- and low-affinity sites for these highly selective agents. Assays using concentrations of either agent large enough to prevent high-affinity binding show that their respective high-affinity sites are distinct, and each corresponds to the low-affinity site of the other. The two receptor subsets, present in nearly equal proportions, are also distinguishable by their different sensitivities to dithiothreitol. These findings afford strong evidence for the existence of two distinct angiotensin II receptors in rabbit myocardium, corresponding to the A and B subtypes recently described in adrenals.
We sought to investigate the role of polymorphisms of the gene for angiotensin-converting enzyme in the development and progression of idiopathic dilated cardiomyopathy.
Cardiovascular renin-angiotensin systems may be involved in cardiac remodeling and fibrosis. The absence (deletion [D]) of a 287-base pair marker in the angiotensin-converting enzyme gene (introm 16) is associated with increased serum angiotensin-converting enzyme levels. The DD genotype may be a risk factor for the development of end-stage heart failure due to cardiomyopathy. We therefore examined the relation of the angiotensin-converting enzyme genotype to idiopathic dilated cardiomyopathy and to markers of disease severity.
We studied 364 control subjects and 99 consecutive patients with idiopathic dilated cardiomyopathy. When the incidence of the DD genotype in our control group was assumed to be similar to that previously reported (27%), this study had a power of 0.9 to detect a different incidence in the patient group, if the true incidence in patients was 42%. Deoxyribonucleic acid (DNA) was isolated from blood samples, and angiotensin-converting enzyme genotype was determined by specific polymerase chain reaction and separation of amplified fragments by agarose gel electrophoresis. We also compared genotype distribution with that in previously reported European control subjects. Functional status, clinical course over a mean +/- SD of 28 +/- 33 months and outcome were documented. Cardiac morphology and function and evidence of rhythm disturbance were noninvasively determined.
Angiotensin-converting enzyme genotype distribution and allele frequencies were similar in patients and control subjects to within 10% (with 95% confidence) and were also similar between patients and European control subjects. No markers of disease severity or progression other than duration of symptoms before diagnosis and the number of ventricular ectopic beats/h were significantly associated with the presence of the DD alleles.
We find no evidence to support an association between angiotensin-converting enzyme genotype and either the diagnosis of idiopathic dilated cardiomyopathy itself or progression of the disease.
Cardiac hypertrophy is associated with elevated intracardiac angiotensin-converting enzyme activity, which may contribute to diastolic dysfunction.
We infused enalaprilat (0.05 mg/min) for 15 minutes into the left coronary arteries of 20 adult patients with left ventricular (LV) hypertrophy due to aortic stenosis (mean aortic valve area, 0.7 +/- 0.2 cm2) and 10 patients with dilated cardiomyopathy (mean ejection fraction, 35 +/- 4%) and assessed (1) simultaneous changes in LV micromanometer pressure and dimensions, (2) LV regional wall motion analyzed by the area method, and (3) Doppler flow-velocity profiles. Systemic neurohormonal activation did not occur with the selective left coronary artery infusion; there were no changes in plasma renin activity, angiotensin-converting enzyme activity, or atrial natriuretic peptide. In patients with aortic stenosis, LV end-diastolic pressure declined from 25 +/- 2 to 20 +/- 2 mm Hg (P < .05). LV pressure-volume and LV pressure-dimension relations showed downward shifts by ventriculography and echocardiography, respectively, indicating improved diastolic distensibility. Regional area change during isovolumic relaxation increased in the anterior segments perfused with enalaprilat but decreased in the inferior segments, indicating acceleration of isovolumic relaxation in the anterior segments and reciprocal shortening in the inferior segments. Regional peak filling rate increased in the anterior segments but not in the inferior segments, and the regional area stiffness constant decreased in the anterior segments but not in the inferior segments. There were no changes in heart rate, cardiac output, or right atrial pressure, excluding alterations in right ventricular/pericardial constraint. In contrast, in the patients with dilated cardiomyopathy the decrease in LV end-diastolic pressure from 22 +/- 2 to 18 +/- 2 mm Hg (P < .05) was accompanied by a significant fall in right atrial pressure (9 +/- 1 to 6 +/- 1 mm Hg), implicating alterations in pericardial constraint. The patients with dilated cardiomyopathy showed no improvement in regional diastolic relaxation, filling, or distensibility.
Intracoronary enalaprilat at a dosage that did not cause systemic neurohormonal activation improved LV diastolic chamber distensibility and regional relaxation and filling in patients with LV hypertrophy due to aortic stenosis. In contrast, these effects of intracoronary enalaprilat on diastolic function were not observed in patients with dilated cardiomyopathy who did not have concentric hypertrophy. These observations support the hypothesis that the cardiac renin-angiotensin system is activated in patients with concentric pressure-overload hypertrophy and that this activation may contribute to impaired diastolic function.
We tested the hypotheses that long-term administration of the angiotensin-converting enzyme (ACE) inhibitor fosinopril will regress hypertrophy, modify the transition to heart failure, and prolong survival in rats with chronic left ventricular (LV) pressure overload due to ascending aortic stenosis.
Aortic stenosis was created in weanling male Wistar rats by a stainless steel clip placed on the ascending aorta. Age-matched control animals underwent a sham operation (Sham group, n = 57). Six weeks after surgery, rats with aortic stenosis were randomized to receive either oral fosinopril 50 mg.kg-1.d-1 (Fos/LVH group, n = 38) or no drug (LVH group, n = 36) for 15 weeks. Pilot studies confirmed that this dosage produced significant inhibition of LV tissue ACE in vivo. Animals were monitored daily, and survival during the 15-week treatment period was assessed by actuarial analysis. At 15 weeks, in vivo LV systolic and diastolic pressures and heart rate were measured. To assess contractile function, the force-calcium relation was evaluated by use of the isovolumic buffer-perfused, balloon-in-LV heart preparation at comparable coronary flow rates per gram LV weight. Quantitative morphometry was performed. Mortality during the 15-week trial was significantly less in the Fos/LVH group than in the LVH group (3% versus 31%, P < .005). No deaths occurred in the Sham group. In vivo LV systolic pressure was similar between Fos/LVH and LVH hearts (223 +/- 10 versus 232 +/- 9 mm Hg) and significantly higher than the Sham group (99 +/- 3 mm Hg, P < .05). In vivo LV diastolic pressure was significantly lower in Fos/LVH hearts than in LVH hearts (10 +/- 2 versus 15 +/- 2 mm Hg), and both were significantly higher than in the Sham group (5 +/- 1 mm Hg, P < .05). Heart rate was similar among all groups. Despite equivalent elevation of LV systolic pressure, fosinopril resulted in regression of myocyte hypertrophy in Fos/LVH versus LVH (myocyte cell width, 14.8 +/- 0.5 versus 20.8 +/- 2.2 microns, P < .05) to normal levels (Sham, 16.3 +/- 0.9 microns). Quantitative morphometry demonstrated that the regression of LV myocyte hypertrophy in the Fos/LVH group was associated with a relative increase in the fractional volume of fibrillar collagen and noncollagen interstitium. In the isolated heart experiments, LV systolic developed pressure relative to perfusate [Ca2+] was significantly higher in Fos/LVH hearts than in LVH hearts. The improvement in systolic function was not related to any difference in myocardial high-energy phosphate levels, since LV ATP and creatine phosphate levels were similar in Fos/LVH and LVH hearts.
In rats with ascending aortic stenosis, chronic ACE inhibition with fosinopril improved survival, decreased the extent of LV hypertrophy, and improved cardiac function despite persistent elevation of LV systolic pressure. The favorable effects of fosinopril may be related in part to inhibition of the effects of cardiac ACE on myocyte hypertrophy rather than to systemic hemodynamic mechanisms.
The intracardiac conversion rate of angiotensin (Ang) I to Ang II and the expression of angiotensin converting enzyme (ACE) mRNA are amplified in rat hearts with left ventricular hypertrophy (LVH). To examine whether the accelerated intracardiac Ang II generation in LVH is related to an induction of cardiac ACE, we studied localization and function of cardiac ACE in hypertrophied rat hearts using specific ACE inhibitors.
Cardiac ACE was localized and quantified in hearts from male Wistar rats with LVH due to chronic experimental aortic stenosis and from control rats. With the ACE inhibitor 125I-351A, a derivative of lisinopril, as a radioligand on coronal sections of LVH and control hearts, in vitro autoradiography demonstrated ACE binding in aorta, coronary arteries, atria, and ventricles of both groups. Quantitative analyses revealed that ACE density (counts per minute per cross-sectional area of tissue) was twofold higher within the myocardium of hypertrophied left ventricles compared with controls (p < 0.005). Quantitative morphometry demonstrated a modest increase in the fractional volume of myocytes as well as capillary volume without an increase in the fractional volume of endothelial cells in left ventricular tissue from aortic stenosis rats. These data suggest that an increase in endothelial cell volume per se cannot alone account for the observed doubling of ACE density and support an upregulation of ACE production in hypertrophied tissue. The role of cardiac ACE in intracardiac conversion of Ang I to Ang II and its specific inhibition was studied in isolated, isovolumic beating, buffer-perfused LVH and control hearts. Biochemical conversion rates as well as functional changes in response to 3 x 10(-7) M Ang I were examined in the absence or presence of the ACE inhibitor enalaprilat (4 x 10(-6) M). After a brief stabilization period, groups of LVH and control hearts were subjected to the following infusion protocols: 15 minutes of vehicle followed by 30 minutes of Ang I plus vehicle, 15 minutes of enalaprilat followed by 30 minutes of Ang I plus enalaprilat (enal/Ang I), or 45 minutes of vehicle only to allow comparison with a time control. Intracardiac Ang I-to-Ang II conversion rate was fourfold higher in LVH than in control hearts (p < 0.05). Infusion of enalaprilat reduced the intracardiac Ang I-to-Ang II conversion rate in LVH hearts by 70% (p < 0.05 versus Ang I). At similar levels of constant coronary flow per gram, Ang I increased coronary perfusion pressure by 23 +/- 5 mm Hg (p < 0.01 versus vehicle) in LVH hearts and by 36 +/- 10 mm Hg (p < 0.005 versus vehicle) in control hearts. When enalaprilat was infused with Ang I, the increase in perfusion pressure was limited to 5 +/- 5 mm Hg (NS versus vehicle) in LVH hearts and 12 +/- 3 mm Hg (p < 0.05 versus vehicle) in control hearts and was significantly lower than in hearts infused with Ang I only (p < 0.05 in LVH and p < 0.05 in control hearts, respectively). Systolic function was not affected by either infusion protocol. In contrast, Ang I infusion was associated with diastolic dysfunction. In LVH hearts, left ventricular end-diastolic pressure (LVEDP) increased from 10 +/- 1 mm Hg at baseline to 25 +/- 2 mm Hg at the end of the Ang I infusion (p < 0.001 versus vehicle), which was inhibited by infusion of enalaprilat. In control hearts, there was a lesser increase in LVEDP from 10 +/- 1 mm Hg to 15 +/- 1 mm Hg in response to Ang I (p < 0.05 versus LVH). Control hearts treated with enalaprilat with Ang I displayed no increase in LVEDP:
These observations indicate that ACE protein is increased within the myocardium of LVH hearts, extending recent findings of increased cardiac ACE activity and mRNA levels in this model of pressure-overload LVH in the rat. Blockade of the enzyme by an ACE inhibitor decreases intracardiac Ang I-to-Ang II conversion rate and prevents the functional changes of Ang I-to-Ang II activation
Alterations in the cardiac response to angiotensin II (Ang II) may contribute to the functional impairment in tachycardia-induced heart failure (congestive heart failure [CHF]). Accordingly, we studied the response to Ang II in eight conscious instrumented dogs before and after inducing CHF. Left ventricular (LV) performance was assessed by measuring LV pressure and LV volume. Isolated myocyte function was evaluated using computer-assessed videomicroscopy. In conscious animals before CHF, Ang II produced a load-dependent slowing of the time constant of LV relaxation (tau) and did not depress intact LV contractile function. After CHF, although Ang II produced a similar increase in LV systolic pressure, the increases in LV diastolic pressure and time constant tau were much greater, and contractile performance was depressed. These changes persisted when the elevation of end-systolic pressure was prevented by nitroprusside. Similar changes were also present after autonomic blockade. In isolated myocytes, before CHF, Ang II (10(-6) mol/L) produced a slight positive inotropic effect. In contrast, after CHF, Ang II produced a negative inotropic effect and slowed the rate of relengthening. The effects in the intact LV and myocytes were reversed by an Ang II AT1 receptor blocker (losartan). We conclude that pacing-induced CHF alters the LV and myocyte response to Ang II, so that Ang II produces direct depressions in intact LV contraction, relaxation, and filling and exacerbates myocyte contractile dysfunction. These effects are mediated through the activation of AT1 receptors.
Angiotensin II (AII) has been implicated as an important factor in the pathophysiology of heart diseases. Following the recent identification of two subtypes of the AII receptor in cardiac tissue of animals, we investigated the possible occurrence of these, or similar, subtypes in human atrial tissue. In right-atrial tissue from patients undergoing heart surgery, we determined the AII-receptor profile in receptor binding studies, using [125I]-angiotensin as radioligand and subtypes to identify and quantify AII-receptor subpopulations. In 35 patients (23 requiring coronary bypasses, 10 valvular surgery and two combined coronary and valvular surgery), the left-ventricular ejection fraction was determined in the preoperative phase, and right- and left-atrial pressure during surgery. In membranes of human right atria, AII receptors are present in high density (median: Bmax = 294 fmol.mg-1 protein, range: 111-2073) and two different subtypes can be distinguished. Type-1 receptors (AT1) accounted for 33 +/- 10% of the population whereas type-2 receptors (AT2) made up 67 +/- 10% of the population. There was no correlation between any of the measured cardiac functions and total AII-receptor density or receptor affinity. However, the percentage of AT1 receptors was higher in the atria of patients with normal right-atrial pressure; left-ventricular ejection fraction was positively and right-atrial pressure inversely correlated with the percentage of AT1 receptors (r = 0.740 and -0.901, respectively; P < 0.001, for both). Moreover, the percentage of AT2 receptors was directly correlated with the levels of left-atrial pressure (r = 0.853; P < 0.001). It is concluded that the ratio of AT1 to AT2 receptors correlates well with right-atrial pressure and left-ventricular function. This is a first indication of a possible involvement of AII-receptor subtypes in the pathophysiology of cardiac dysfunctions.
To evaluate the role of angiotensin II (AII) on diastolic function during post-myocardial infarction (MI) ventricular remodeling, coronary ligation or sham operation was performed in male Sprague-Dawley rats. Experimental animals were maintained on either irbesartan, a selective AT1-receptor antagonist, or no treatment. Measurement of cardiac hypertrophy, diastolic function, and sarcoendoplasmic reticulum adenosine triphosphatase (ATPase; SERCA) and phospholamban (PLB) gene expression was assessed at 6 weeks after MI. Myocardial infarction caused a significant increase in myocardial mass and left ventricular (LV) filling pressure, whereas LV systolic pressure and +dP/dt were reduced. The time constant of isovolumic relaxation (tau) was markedly prolonged after MI. Post-MI hypertrophy was associated with substantial increases in the messenger RNA (mRNA) expression of atrial natriuretic peptide (ANP), but no significant changes in SERCA or PLB levels. Although irbesartan treatment did not significantly alter post-MI LV systolic or filling pressures, it nevertheless effectively decreased ventricular hypertrophy, improved tau, and normalized ANP expression. These results demonstrate that AT1-receptor antagonism has important effects on myocardial hypertrophy and ANP gene expression, which are independent of ventricular loading conditions. In addition, the improvement in diastolic function was not related to changes in SERCA and PLB gene expression, suggesting that enhanced myocardial relaxation was related to the blockade of AII effects on myocyte function or through a reduction of ventricular hypertrophy itself or both.
A novel angiotensin receptor has been described and named AT4. Ligands for this receptor include the angiotensin II (Ang II) metabolite Ang II (3-8), known as angiotensin IV (Ang IV). There is 10-fold more AT4 receptor than AT1 receptor in rabbit myocardium. The AT4 receptor has a high affinity for Ang IV (Ki in rabbit myocardium < 2 x 10(-9)) and similar ligands, but very low affinity for Ang II (Ki in rabbit myocardium > 10(-6)). Although several functions have been attributed to the novel Ang IV peptide/AT4 receptor system, the effect of this system on left ventricular (LV) function has not been studied. We hypothesized (1) that Ang IV would affect LV function and (2) that any effects would be opposite to those of Ang II.
Using the buffer-perfused (30 degrees C) isolated rabbit heart, we studied the effect of the AT4 agonist Nle1-Ang IV on LV systolic function, quantified using both Frank-Starling and end-systolic pressure-volume relationships, and relaxation. We also studied the effect of the AT1/AT2 agonist, Sar1-Ang II on LV function. Finally, because the profile of effect of Nle1-Ang IV was similar to the reported effect of nitric oxide (NO), we also studied the effect of Nle1-Ang IV in the presence of the NO synthase inhibitor NG-monomethyl-L-arginine.
Nle1-Ang IV reduced LV pressure-generating capability at any volume but increased the sensitivity of pressure development to volume change. Nle1-Ang IV reduced LV ejection capability. Sar1-Ang II had the opposite effect-increasing both pressure generation and ejection capability. Finally, both Sar1-Ang II and Nle1-Ang IV speeded LV relaxation. Inhibition of NO synthase did not alter the effect of Nle1-Ang IV on LV systolic function or relaxation.
AT4 receptor agonism has mixed effects on LV systolic function, depressing pressure-generation and ejection capabilities, but enhancing the sensitivity of pressure development to volume change. It also speeds relaxation. The effect of Ang IV on systolic function is generally opposite to the effect of Ang II, whereas the Ang IV influence on relaxation is similar to the effect of Ang II.
The aim of this study was to evaluate the acute effects of E-3174, a human active metabolite of the AT1 receptor antagonist, losartan, on hemodynamic functions in dogs with severe heart failure (HF). In dogs, insignificant plasma levels of E-3174 are present following administration of losartan, and therefore, the effects of these two drugs can be studied independently in the dog. HF was established by rapid pacing of the right ventricle (250-270 beats/min) for 4 weeks. We examined changes in cardiovascular functions after acute intravenous administration of losartan (1 mg/kg) and E-3174 (0.3 and 1 mg/kg), as well as an ACE inhibitor, enalapril (0.3 and 1 mg/kg), under condition of HF. The HF before treatment was characterized by increases in pre- and after-load of the left ventricle (LV), consequent low cardiac output, and LV dilatation. E-3174 at 0.3 and 1 mg/kg reduced pulmonary artery pressure (-13+/-6% and -22+/-3% from baseline, respectively, p<0.05), pulmonary capillary wedge pressure (-18+/-4% and -36+/-10%, p<0.05) and mean arterial pressure (-24+/-2% and -36+/-7%, p<0.05), increased stroke volume (SV: +12+/-7% p>0.05; +36 +/-19%, p<0.05), and reduced peripheral resistance (-23+/-5% and -41+/-9%, p<0.05), but had no effect on the first derivative of left ventricular pressure (dP/dt/P) or the time constant for relaxation. Effects of losartan at 1 mg/kg were similar to those of 0.3 mg/kg of E-3174. Enalapril at 1 mg/kg caused changes comparable to those seen after E-3174 administration (1 mg/kg), except that the increase in SV (+16+/-8%, p<0.05) with enalapril was not as great as that with E-3174. Both losartan at 1 mg/kg and E-3174 at 0.3 and 1 mg/kg increased fractional shortening to a similar extent (FS: +52+/-12%, +47+/-8% and +56+/-8%), while enalapril at 0.3 and 1 mg/kg had no significant effects on FS. Reflex elevation of plasma renin activity induced by 1 mg/kg of E-3174 was similar to that caused by 1 mg/kg of enalapril, suggesting that the two drugs achieved similar inhibition of the endogenous renin angiotensin system. Our study demonstrated that acute blockade of the AT1 receptor with E-3174 reduced elevated pre- and after-load and consequently increased stroke volume in a canine HF model. With the exception of changes in stroke volume, these effects of E-3174 were comparable to those produced by enalapril, and were 3 times stronger than those by losartan.
Conventionally angiotensin-converting enzyme (ACE) inhibitors are contraindicated in patients with aortic stenosis. Abundant evidence is now available showing that angiotensin II has a central role in the development of left ventricular hypertrophy (LVH), myocardial contractile failure and diastolic dysfunction in response to pressure overload. In animal models, ACE inhibitors have been shown to attenuate these pathological responses. In humans there is no such evidence available, however uncontrolled studies have shown that these agents are not only tolerated but are associated with acute improvements in haemodynamics and diastolic function. Further studies are merited to assess the possible role of ACE inhibitors in aortic stenosis both before and after valve replacement. Potential benefits may include prevention of LVH, improved diastolic function, reduction of arrhythmias and preservation of left ventricular function.
The present study investigated if the inotropic effect of angiotensin II (AngII) is altered during post-ischaemic reperfusion in hearts subjected to mild and severe ischaemia. The possible involvement of protein kinase C (PKC) in the change in the inotropic effect was also investigated.
Isolated Langendorff-perfused rat hearts were perfused under constant flow with oxygenated Krebs-Henseleit buffer and paced at 360 beats min(-1). A saline-filled balloon catheter inserted into the left ventricle was used for measurement of contractile force. In the first series of experiments, hearts were subjected to continuous perfusion, 15- or 25-min global ischaemia followed by 45-min reperfusion. At the end of reperfusion, 0.1 micromol L(-1) AngII was infused for 5 min. In a second series of experiments, AngII was infused in hearts subjected to 25-min ischaemia followed by 45-min reperfusion in the absence or presence of the PKC inhibitor chelerythrine chloride (5 micromol L(-1)).
The current study demonstrates that AngII exerts a positive inotropic effect in normoxic hearts with an increase of left ventricular developed pressure (LVDP) by 11% (P<0.05 vs. prior to AngII infusion). In post-ischaemic hearts subjected to 15-min ischaemia no effect of AngII was observed. In hearts subjected to 25 min of ischaemia, however, AngII evoked a negative inotropic response with a decrease of LVDP by 18% (P<0.05 vs. prior to AngII infusion). The negative inotropic effect of AngII was inhibited by the PKC inhibitor chelerythrine chloride.
AngII exerts negative inotropic effect in severely injured post-ischaemic heart, possibly through the PKC pathway.
Pharmacological inhibition of components of the renin-angiotensin-system is one of the major therapeutically options to treat patients with heart failure. This study hypothesized that angiotensin II (Ang II) directly depresses contractile function (cell shortening) by activation of transforming growth factor-beta(1) (TGF-beta(1)). Moreover, we hypothesized that an inhibition of glycogen synthase kinase 3-betaGSK will compensate for this depressive effect by increasing SERCA2 expression. Isolated adult ventricular rat cardiomyocytes were used and cultured in the presence of Ang II (100 nM) for 24 h. Cell shortening and contractile dynamics were recorded at 2 Hz. Immunoblot techniques and gel mobility shift assays were used to demonstrate NFAT activation caused by inhibition of GSK and to demonstrate increases in the expression of SERCA2. Ang-II caused a nearly 20% decrease in cell shortening. This Ang II-dependent effect was mimicked by TGF-beta(1) (10 ng/ml), attenuated by addition of aprotinin, that was used to block the proteolytic activation of TGF-beta(1), or by application of a neutralizing antibody directed against TGF-beta(1). Inhibition of GSK activated NFAT, increased SERCA2 expression and improved cell function. In conclusion, the study identified a paracrine mechanism for the Ang II-dependent loss of cardiac function that occurs independently of hemodynamic changes. Furthermore, it characterized the differences between Ang II and alpha-adrenoceptor stimulation with respect to the maintenance of cellular function explaining cellular events contributing to the difference between adaptive (physiological) and mal-adaptive (patho-physiological) hypertrophy.
An experimental setup has been developed, which allows electrical stimulation of cardiac myocytes and simultaneous measurement of oxygen consumption, lactate production, extent of shortening and of substrate uptake. In resting cells and in cells stimulated with 120 to 480/min the oxygen consumption ranged from 25 to 100
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). When using 5 mM glucose plus 2 mM pyruvate or 10 mM lactate as substrates, isoproterenol (8 10–8 M) augmented contraction and VO2 at all rates of stimulation. Assuming Hook's law for passive elastic behavior for the contracting myocytes over the length change observed, a good correlation exists between the degree of cell shortening calculated from
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per beat and the degree of contraction measured. This correlation can be used as a measure of the economy of O2 utilization.