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ABSTRACT: Guinea-pig isolated left atria, paced at 2 Hz were incubated with 86rubidium (86Rb) for 120 min. They were then washed every 2 min for 2 hr, each sample being retained for scintillation counting. Left atrial isometric tension was recorded simultaneously. A concentration-response curve for the muscarinic agonist carbachol or the P1-receptor agonists adenosine and L-N6-phenyl-isopropyladenosine (L-PIA) was obtained. Antagonists were present from 20 min before agonist exposure. The rate constant (k) for 86Rb efflux was calculated for each 2 min sample and the mean increase for each concentration of agonist determined. In the absence of drugs there was no significant alteration in the rate constant during the 2 hr experimental period. Adenosine, L-PIA and carbachol produced concentration-related increases in rate constant for 86Rb efflux. The adenosine and L-PIA concentration-response curves were virtually superimposed upon the curves for the negative inotropic responses. The 86Rb efflux induced by adenosine was antagonized in an apparently parallel manner by 8-phenyltheophylline (8-PT) indicating involvement of P1-receptors. Alone, the putative potassium channel blockers, 4-aminopyridine (4-AP) and bromobenzoylmethyladamantylamine (BMA) caused, respectively, no change and a reduction in resting 86Rb efflux immediately prior to the agonist exposure. 4-AP reduced the L-PIA- and adenosine-induced increases in 86Rb efflux and, to a lesser extent, the negative inotropic response to adenosine. BMA caused "flattening" of the dose-response curves for 86Rb efflux induced by L-PIA, adenosine and carbachol with a significant reduction in response at the highest concentrations of adenosine and carbachol. The negative inotropic response to adenosine was also reduced. These results suggest that 4-AP and BMA block the P1-receptor-linked potassium channels and that BMA interacts with common K+ channels linked to P1- and muscarinic receptors. The negative inotropic responses of the guinea-pig left atrium to P1- and muscarinic agonists can be attributed, at least in part, to the opening of outward K+ channels.
Biochemical Pharmacology 08/1991; 42(3):655-62. · 4.70 Impact Factor
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ABSTRACT: The purpose of this study was to explore the relationship between the thyroid status and both ventricular and atrial electrophysiology in the rat. The study was extended to consider the effects of altering the extracellular calcium concentration. The work was performed in two sections. First, hypothyroid animals were compared with euthyroid (untreated animals); second, hypothyroid animals were compared with hyperthyroid animals. Rats were rendered hypothyroid by pretreatment with the goitrogen methimazole and hyperthyroid by additional treatment with triiodothyronine. Action potential recordings were obtained using standard microelectrode techniques. Action potential measurements were made initially in a Krebs solution to which had been added 2.55 mM calcium (higher Ca Krebs solution) and at the end of each experiment after stabilization with Krebs solution to which had been added 1.28 mM calcium (lower Ca Krebs solution). Assessment of the change in action potential duration on transition from higher to lower Ca Krebs solution revealed that the euthyroid preparations demonstrated less prolongation of action potential duration than the hypothyroid group, and the hyperthyroid group showed hardly any response to reduction in calcium concentration.
Canadian Journal of Physiology and Pharmacology 03/1988; 66(2):90-4. · 1.95 Impact Factor
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ABSTRACT: Increases in cardiac activity induce autoregulatory coronary vasodilation. The intermediate steps which trigger this process are thought to be myocardial hypoxia which induces the release of vasodilator mediator(s). The present study examines the relationships between mechanical activity, oxygen tension, and release of vasodilator material in isolated perfused hearts. Guinea-pig isolated hearts were perfused in series, the effluent from donor hearts being regassed prior to entry to recipient hearts. Histamine (1 microgram) and isoproterenol (10 ng) increased the rate and tension of donor hearts and produced predominant coronary vasodilator responses which were followed by the appearance of vasodilator material in the recipient (falls in perfusion pressure, 9.8 +/- 1.1 and 9.1 +/- 2.5 mmHg) (1 mmHg = 133.322 Pa). Exposure of donor hearts to hypoxia also caused vasodilatation and release of vasodilator material (fall in pressure, 11.4 +/- 1.6 mmHg). Pacing-induced tachycardia (6 Hz) of donor hearts promoted the release of vasodilator material, the fall in recipient heart pressure being 11.5 +/- 1.8 mmHg. This was abolished by beta-adrenoceptor blockade and when donor hearts were from reserpine-pretreated guinea pigs. In was concluded that pacing released endogenous catecholamines which in turn released the vasodilator material. Pacing per se did not cause vasodilatation or release of the vasodilator. The Po2 of perfusates from donor hearts was reduced by pacing at 5 Hz (25.7 +/- 5.2 mmHg) and by isoproterenol (10 ng, 32.0 +/- 3.7 mmHg), indicative of an elevated oxygen extraction. The isoproterenol-induced falls in Po2 were abolished by beta-adrenoceptor blockade. However, the pacing-induced falls in Po2 persisted, the values occurring before (25.7 +/- 5.2 mmHg) and after propranolol (45.7 +/- 4.5 mmHg) and before (32.1 +/- 1.1 mmHg) and after practolol (27.3 +/- 4.1 mmHg) not differing significantly (p greater than 0.05). These falls in perfusate Po2 were not accompanied by coronary vasodilatation or release of vasoactive material. Perfusate Po2 changes could therefore be dissociated from the coronary vasodilatation and vasoactive material release, suggesting that hypoxia may not be a prerequisite for the metabolic autoregulatory vasodilatation in response to myocardial hyperactivity induced by cardiac stimulants.
Canadian Journal of Physiology and Pharmacology 05/1986; 64(4):388-97. · 1.95 Impact Factor
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ABSTRACT: Donor and recipient guinea-pig hearts were perfused in series, the recipient being perfused with regassed donor effluent. Coronary perfusion pressure and force and rate of contraction were measured. Exposure of donor hearts to hypoxia (1.5 min) and to isoprenaline (5 ng) caused the appearance of vasodilator material in recipient hearts, the direct beta-adrenoceptor effects of isoprenaline carried over in the effluent being antagonized in the recipient by propranolol. Cyclo-oxygenase was inhibited by infusion of meclofenamate (60 micrograms X min-1) which consistently abolished the vasodilator responses to arachidonic acid added to the donor. The vasodilator responses of the donor to hypoxia and isoprenaline were unaffected by meclofenamate. The falls in perfusion pressure of the recipient in response to material released by these procedures were also not significantly different before (hypoxia, 11.5 +/- 2.6mm Hg; isoprenaline, 10.3 +/- 1.3mm Hg) and during the infusion (hypoxia, 10.2 +/- 4.1; isoprenaline, 11.0 +/- 1.3mm Hg). The coronary vasodilator responses to hypoxia and isoprenaline and the vasodilator material released by these procedures do not therefore appear to be due to products of arachidonic acid via cyclo-oxygenase pathways. Furthermore, since there was also no potentiation of the responses, there does not appear to be a concomitant release of a prostanoid to inhibit the major vasodilator material. Adenosine, as the likely candidate for this predominant vasodilator mediator, is discussed.
Prostaglandins 03/1986; 31(2):295-306.
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ABSTRACT: In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%. When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg-1), prenylamine (0.5 mg kg-1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg-1) and cinnarizine (0.25, 0.5 and 1.0 mg kg-1) protected against these arrhythmias. Higher doses of verapamil (0.1 and 0.5 mg kg-1), prenylamine (5 mg kg-1) and flunarizine (2.5 mg kg-1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine-treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation. Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine. These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia-induced arrhythmias, this protective effect may be limited to a narrow concentration range.
British Journal of Pharmacology 10/1984; 83(1):299-304. · 4.41 Impact Factor
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ABSTRACT: The release of coronary vasodilator mediator(s) from guinea pig isolated hearts was demonstrated by a technique employing donor and recipient hearts perfused in series. Vasodilator mediator release followed the positive inotropic, chronotropic, and coronary vasodilator responses of donor hearts to isoprenaline and their exposure to hypoxia. Isoprenaline-induced coronary vasodilatation of donor hearts was accompanied by a fall in perfusate pO2, indicative of a raised myocardial oxygen consumption. Measurement of perfusate pO2 levels showed that the regassing procedure was adequate and the fall in pO2 level no longer occurred after isoprenaline. However, at high resolution, small changes in pO2 could still be detected by these were not sufficient to induce vasodilatation of the recipient. The technique was adapted to enable simultaneous measurement of perfusate pO2 and release of vasodilator mediator following administration of isoprenaline. The value of this in examining the relationship between myocardial oxygen consumption and vasodilator mediator release is discussed.
Journal of Pharmacological Methods 04/1982; 7(2):91-103.
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ABSTRACT: The coronary vasodilatation that accompanies cardiac stimulation by catecholamines and histamine or exposure to hypoxia is thought to be due to the release of a coronary vasodilator metabolite. Adenosine has been proposed as a likely candidate and this study examines its possible involvement by use of hexobendine, an agent that enhances the effects of adenosine. The force and rate of contraction and coronary perfusion pressure of isolated guinea-pig hearts were recorded. Adenosine exerted dose-dependent negative chronotropic effects and coronary vasodilatation. Both responses were potentiated during perfusion with hexobendine. However, hexobendine did not potentiate the coronary vasodilator responses to isoprenaline, suggesting that adenosine was not involved. Isolated hearts were then perfused in series, the donor heart supplying perfusate to the recipient. Stimulation of donor hearts by isoprenaline or histamine resulted in coronary vasodilator activity appearing in the recipient, which had received the appropriate antagonists of beta-adrenoceptors of histamine H1- and H2-receptors. Exposure of donor hearts to hypoxia also caused vasodilator metabolite release. Infusion of hexobendine into the recipient heats potentiated the vasodilator metabolite release. Infusion of hexobendine into the recipient hearts potentiated the vasodilator responses to exogenous adenosine, however, the responses to vasodilator metabolite released by the three procedures was not affected. Furthermore, there were no negative chronotropic responses accompanying the vasodilator metabolite release as there were with adenosine in a dose that produced equivalent vasodilatation. These results provide evidence that the vasoactive metabolite released by catecholamines, histamine and hypoxia is not adenosine.
Cardiovascular Research 11/1981; 15(10):599-610. · 6.06 Impact Factor
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ABSTRACT: Guinea-pig isolated hearts were perfused in series, the donor heart perfusate supplying the recipient heart. Isoprenaline increased the rate and force of contraction and oxygen consumption of donor hearts and produced a coronary vasodilatation. This was accompanied by the release of vasodilator metabolite as demonstrated by vasodilatation of the recipient heart, the beta-adrenoceptors of which were antagonized by propranolol. During arrest of donor hearts by either carbachol or application of a fibrillating current, isoprenaline still released vasodilator metabolite and increased oxygen consumption but without changes in rate or tension. This release was prevented by beta-adrenoceptor blockade. It is concluded that the sympathomimetic-induced coronary vasodilatation is mediated via the release of a vasoactive metabolite, the trigger for which is not the concomitant mechanical hyperactivity.
Pflügers Archiv - European Journal of Physiology 09/1981; 391(2):147-53. · 4.46 Impact Factor
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ABSTRACT: We assessed the antiarrhythmic activity of ICS 205-930 [(3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester], a selective antagonist at neuronal 5-hydroxytryptamine M-receptors, against the arrhythmias that occur following occlusion of the left main coronary artery in anaesthetised rats and subsequent release (reperfusion). The incidence of reperfusion-induced ventricular fibrillation and ventricular tachycardia was significantly reduced by pretreatment with ICS 205-930 (0.3 and 1.0 mg kg-1 i.v. and 10 and 30 mg kg-1 p.o.). The arrhythmias that occurred during 30 min of coronary artery occlusion were also less severe in animals given ICS 205-930 (1.0 and 5.0 mg kg-1 i.v.). Arterial blood pressure was not altered by the drug, and heart rate was only slightly reduced by the highest intravenous dose. In vitro, ICS 205-930 reduced the maximum rate of rise of phase 0 of normal sheep Purkinje fibre action potentials in concentrations from 0.5 to 5.0 mg L-1. Action potentials depressed by superfusion with a physiological salt solution modified to mimic the conditions occurring during mild ischaemia were similarly affected by ICS 205-930. The highest drug concentration studied under these conditions was 1.5 mg L-1 since, in combination with the modified physiological salt solution, this rendered some of the Purkinje fibres inexcitable. These results indicate that ICS 205-930 possesses marked antiarrhythmic activity against ischaemia-induced arrhythmias in anaesthetised rats and that a direct electrophysiological effect of the drug may, at least in part, underlie its protective action.
Journal of Cardiovascular Pharmacology 7(3):550-5. · 2.29 Impact Factor
