Negative lusitropic effect of DPI 201-106 and E4031. Possible role of prolonging action potential duration.

In open-chest anesthetized dogs, the time constant of isovolumic left ventricular pressure decay increased following the intravenous administration of either E4031, a class III antiarrhythmic agent which acts by K+ channel blockade, or DPI 201-106 (DPI), a cardiotonic agent which acts by delaying Na+ channel inactivation. In addition to prolonging cardiac refractoriness, both E4031 and DPI increased left ventricular +dP/dt but without significantly altering -dP/dt. Consequently, the value of the ratio (+dP/dt)/(-dP/dt) increased. There were no significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. Since both E4031 and DPI prolonged the action potential duration (APD) and the refractory period, and slowed relaxation in vivo, the possibility of a causal link between these effects was further investigated under in vitro conditions. In isometrically contracting rabbit papillary muscles, E4031 and DPI increased peak developed tension (DT) and its maximal rate of rise (+T). Since the maximal rate of fall of DT (-T) did not increase by the same factor that +T increased, the value of the ratio +T/-T increased. Time to half relaxation increased, whereas time to peak tension was not significantly changed by either E4031 or DPI. These negative lusitropic effects produced by E4031 or DPI were not observed when equivalent increases in contractility were produced by increasing the extracellular Ca2+ concentration. The effective refractory period measured in the papillary muscles increased following superfusion with either of the two drugs, consistent with their known ability to increase APD. A causal link between the prolongation of APD and the negative lusitropic effects of E4031 and DPI is postulated as the possible mechanism.

Influence of AQ-A39, a bradycardic agent, on cardiovascular responses to isoproterenol in the anesthetized dog.

The effects of AQ-A39, a selective bradycardic agent, on cardiovascular responses to beta-adrenergic stimulation with isoproterenol were investigated in open-chest, anesthetized dogs. Verapamil and timolol were also studied and compared with AQ-A39. All three compounds decreased basal heart rate and significantly decreased the chronotropic potency of isoproterenol. At 1.0 and 3.0 mg/kg, AQ-A39 reduced the relative potency of isoproterenol on heart rate to 0.730 and 0.312, respectively (control potency = 1.0). AQ-A39 enhanced the isoproterenol-mediated increases in cardiac output without affecting the potency of isoproterenol on mean arterial blood pressure or left ventricular dP/dtmax. Timolol reduced the potency of isoproterenol on all parameters studied. Verapamil decreased the left ventricular dP/dtmax response but did not change the mean arterial blood pressure or cardiac output responses to isoproterenol. Therefore, AQ-A39 demonstrated greater selectivity for inhibiting the chronotropic responses to beta-adrenergic stimulation in vivo than verapamil or timolol. Selective inhibition of positive chronotropic but not positive inotropic responses, as observed with AQ-A39, could be beneficial in the treatment of ischemic heart disease.

Cardiovascular responses to an isosterically modified prostaglandin analog in the anesthetized dog.

The cardiovascular responses to intravenous administration of an isosterically modified prostaglandin (PG) analog, (+)-4-(3-[3-[2-(1-hydroxycyclohexyl)-ethyl]-4-oxo-thiazolidinyl]-propyl) benzoic acid, were determined in open-chest, anesthetized dogs. These responses were compared to responses with the naturally occurring prostaglandings, PGD2 and PGI2, and vasodilators, hydralazine, sodium nitroprusside, nifedipine and verapamil. Following administration of 5, 20 and 100 micrograms/kg PG analog, total peripheral resistance was significantly decreased from 74 +/- 2 to 59 +/- 6, 37 +/- 5 and 24 +/- 1 mmHg/l per min, respectively. Cardiac output was increased by the highest dose of PG analog; however, heart rate, left ventricular contractility and left ventricular end diastolic pressure were not changed. This profile of cardiac and vascular responses was similar to responses with PGI2 and hydralazine suggesting that PG analog is a potent arterial vasodilator with no direct effect on cardiac function.

Comparison of cardiovascular responses to the bradycardic drugs, alinidine, AQ-A 39, and mixidine, in the anesthetized dog.

Cardiovascular responses to three bradycardic drugs, alinidine, AQ-A 39, and mixidine, were studied in open-chest, anesthetized dogs. All three drugs produced a dose-related decrease in heart rate at 0.3-10 mg/kg i.v. At 2.5 mg/kg i.v., spontaneous heart rates were decreased by 59 +/- 7, 52 +/- 6, and 39 +/- 6 beats/min with alinidine, AQ-A 39, and mixidine, respectively. The sinus node was an important site of action, because direct injection of alinidine, AQ-A 39, or mixidine to the sinus node via the sinus node artery (50 micrograms) elicited a negative chronotropic response. On systemic administration, total peripheral resistance was significantly increased with alinidine, significantly decreased with AQ-A 39, and not affected with mixidine. Increases in stroke volume accompanied bradycardic responses to AQ-A 39 and mixidine, and were prevented when heart rate was held constant by electrical pacing. Despite the production of similar effects on heart rate, AQ-A 39 differed from alinidine and mixidine in that it did not depress cardiac contractility in dogs with spontaneous heart rates. Therefore, all three drugs were effective and relatively selective in reducing heart rate; however, responses at the systemic vasculature and myocardium differed.

Effect of N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro and its ethyl ester (MK-421) on angiotensin converting enzyme in vitro and angiotensin I pressor responses in vivo.

The parent diacid (N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma angiotensin converting enzyme (ACE) by 50% (I50) at a concentration of 1.2 nM and was 17 times more potent than captopril. In vitro the I50 for MK-421, an ethyl ester, was 1200 nM because de-esterification did not occur. Similarly in the guinea-pig ileum, the diacid inhibitor and MK-421 potentiated the contractile effects of bradykinin at an AC50 of 77 pM and 18 nM, respectively. Inhibition of the pressor effects of angiotensin I by the diacid ACE inhibitor occurred at an ID50 of 8.2 micrograms/kg i.v. in rats and 6.4 micrograms/kg i.v. in dogs. Thus, the diacid was approximately 12 times more potent than captopril. The ID50 for MK-421 was 14 and 278 micrograms/kg i.v. in rats and dogs, respectively, because of differences in the rates of de-esterification. Oral ACE inhibitory activity was determined by blockade of the pressor effects of angiotensin I in conscious rats and dogs. In rats, but not in dogs, the diacid inhibitor was poorly absorbed, whereas MK-421 was well absorbed in both species. MK-421 inhibited the pressor effects of angiotensin I at 0.1 to 3.0 mg/kg p.o. for at least 6 hr in rats and dogs, and compared to captopril was 8.6 times more potent in rats and 4.6 times more potent in dogs. These data demonstrate that MK-421 and its parent diacid are potent, long-lasting orally active inhibitors of ACE. In addition, the low activity of MK-421 in vitro contrasts with its substantial in vivo activity, and supports the hypothesis that MK-421 is a prodrug that first must be de-esterified to permit full expression of its significant in vivo pharmacological activity.

Beta adrenoceptor blocking properties of MK-761.

MK-761 is a new class of compound which has beta adrenoceptor antagonist and vasodilating properties in a single molecule. The compound has in vitro beta adrenoceptor blocking activity in the isolated cat heart papillary muscle and isolated rat atria. Unlike propranolol, it did not depress contactile force. Intrinsic sympathomimetic activity was not observed in vitro, (isolated cat papillary muscle, isolated atria) but the compound has some intrinsic sympathomimetric activity because it slightly increased heart rate in reserpinized rats. MK-761 was found to be approximately as potent as timolol and pindolol in blocking cardiac and vascular beta adrenergic receptors in anesthetized dogs. The drug was not, however, cardioselective. Oral beta adrenoceptor blocking activity was observed in rats at doses similar to those which decreased blood pressure.

Central antihypertensive properties of muscimol and related gamma-aminobutyric acid agonists and the interaction of muscimol with baroreceptor reflexes.

The central antihypertensive properties of four gamma-aminobutyric acid (GABA) analogs were characterized in anesthetized cats with implanted intracerebroventricular cannulae. An intracerebroventricular infusion (icv) of muscimol, 0.1--0.5 microgram/min (total dose: 1--5 micrograms, icv), substantially reduced mean arterial pressure and slightly reduced heart rate. The compound was not hypotensive at 5 micrograms, iv (total dose) and only slightly hypotensive after an intracisternal injection (5 micrograms). Kojic amine (2-aminomethyl-5-hydroxy-4H-pyran-4-one) and baclofen were also hypotensive following an intracerebroventricular infusion, but they were less active than muscimol. GABA, at 15--150 micrograms/min, icv (total dose, 150--1500 micrograms, icv), was not hypotensive by itself and unlike muscimol its activity was not enhanced in cats pretreated with nipecotic acid, an uptake inhibitor of GABA. The ability of muscimol to interfere with baroreceptor reflexes was considered in experiments in which reflex vasoconstrictor (carotid occlusion) and reflex vasodilatation (acute elevation in mean arterial pressure with norepinephrine) was measured in the perfused hindlimb of cats previously prepared with intracerebroventricular cannulae. Muscimol significantly attenuated the response to bilateral carotid occlusion and completely abolished reflex vasodilatation. The results suggest that GABA agonists and analogs may regulate blood pressure centrally and, through an interaction with the central nervous system, may attenuate baroreceptor reflexes.

Some cardiovascular effects of ST-91 and clonidine.

St-91, 2(2,6-diethylphenylamino)-2-imidazoline, is a clonidine derivative which does not penetrate the blood-brain barrier. In spontaneously hypertensive (SH) rats is acutely increased arterial pressure and reduced heart rate while at 8 to 12 h after oral administration, it slightly lowered arterial pressure. In contrast, clonidine had acute antihypertensive activity at all doses used. By intracerebroventricular administration to SH rats, both drugs (St-91 and clonidine) reduced arterial pressure and heart rate; in this respect, clonidine was more potent then St-91. Cardiac acceleration induced by low frequency electrical stimulation of right cardiac sympathetic nerves in anesthetized and vagotomized dogs was reduced by St-91 at the same doses by clonidine. Phenoxybenzamine, phentolamine and desipramine antagonized the inhibitory effects of St-91 on electrically induced cardiac acceleration. It was concluded that St-91, like clonidine, stimulates inhibitory alpha-adrenergic receptors at the sympathetic nerve endings but, unlike clonidine, is substantially devoid of acute antihypertensive activity. This suggests that stimulation of peripheral presynaptic inhibitory alpha-adrenergic receptors is not likely to represent the sole mechanism of antihypertensive action of clonidine.

The antiarrhythmic and hemodynamic actions of alpha, alpha-dimethyl-4-(alpha, alpha, beta, beta-tetrafluorophenethyl) benzylamine (MK-251).

Alpha,alpha-Dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)benzylamine (MK-251) has been found to prevent certain types of experimentally induced ventricular arrhythmias and at maximally effective doses possesses substantial hemodynamic safety in contrast to standard antiarrhythmic agents. MK-251 prevented or modified ventricular arrhythmias produced by injection of tetrafluorohexachlorobutane into the coronary artery of dogs and baboons. In dogs, the dose estimated to prevent 80% of the arrhythmic impulses (ED80) was 0.5 mg/kg i.v. and 5.0 mg/kg p.o. The duration of action after oral administration of 5.0 mg/kg to the dog or baboon exceeded 5 to 6 hours. MK-251 delayed the onset of arrhythmias resulting from coronary artery ligation, reduced their severity and permitted a conversion back to normal sinus rhythm earlier than in control dogs. In cats, the doses of digoxin required to induce ventricular ectopic activity, ventricular tachycardia and ventricular fibrillation were elevated by MK-251. In anesthetized dogs, 4 times the i.v. ED80 produced no change in blood pressure, cardiac contractility or output, or in ventricular conduction. The only effect after 8 times the ED80 was a slight decrease in contractility. In contrast. lidocaine at its ED80 (0.21 mg/kg/min), decreased blood pressure and contractility; there was no change in ventricular conduction. Quinidine at the ED80 (8.8 mg/kg i.v.) and above produced hypotension, decreased contractility and prolonged conduction in a dose-related manner.