In view of the potentially important role of automaticity in the genesis of ventricular dysrhythmias, the effects of four widely used antidysrhythmic agents on ventricular automaticity were examined in anesthetized dogs at doses previously shown to antagonize experiments induced rhythm disturbances. Quinidine, and particularly procainamide, lidocaine and propranolol slowed ventricular rate in A-V blocked dogs. Quinidine and procainamide but particularly the last two agents also markedly prolonged overdrive suppression. Thus, all four substances depressed automaticity. However, propranolol was effective at doses substantially lower than those required to antagonize several experimental dysrhythmias.

Animals↗

PubMedDate not supplied

Hypotensive and postural effects of the gamma-aminobutyric acid agonist muscimol and of clonidine.

gamma-Aminobutyric acid (GABA) and GABA agonists, e.g., muscimol, have been shown to reduce blood pressure by a centrally mediated mechanism. The present series of experiments compared cardiovascular responses to muscimol with those of clonidine in anesthetized and conscious spontaneously hypertensive rats. Both agents given intraventricularly reduced blood pressure, heart rate, and spontaneous sympathetic outflow in anesthetized animals. Muscimol also produced marked hypotension in conscious rats. However, compensatory adjustments to upright tilt were inhibited only slightly at most by both agents, even at high doses. Therefore, muscimol, like other centrally acting hypotensive agents, appears to inhibit the sympathetic nervous system selectively.

Animals↗

PubMedDate not supplied

Studies on the mechanism of the acute antihypertensive and vasodilator actions of several beta-adrenoceptor antagonists.

Several new beta-adrenoceptor antagonists (sulfinalol, MK 761, and prizidilol) have been reported to possess direct vasodilator activity in addition to blocking beta-receptors. The mechanism of the hypotensive and vasodilator actions of these agents was examined and compared to that of pindolol and hydralazine. Intraarterial injection of each agent increased blood flow in the sympathetically denervated hindlimb of anesthetized dogs. Doses increasing flow by 50 ml/min (ED50) were 0.48, 0.24, 331, 0.3, and 51 micrograms for sulfinalol, MK 761, prizidilol, pindolol, and hydralazine, respectively, Intravenous injection of each agent reduced blood pressure of anesthetized, ganglion-blocked dogs. Vasodilation and hypotension to sulfinalol, MK 761, and pindolol, but not prizidilol or hydralazine were attenuated by propranolol pretreatment. Oral administration of sulfinalol (2.5 mg/kg), MK 761 (2.5 mg/kg), prizidilol (10 mg/kg), pindolol (0.1 mg/kg), and hydralazine (2.5 mg/kg) reduced pressure of conscious spontaneously hypertensive rats. Antihypertensive actions of sulfinalol and pindolol, but not MK 761, prizidilol, and hydralazine were inhibited by propranolol pretreatment (25 mg/kg, p.o.). With the exception of hydralazine, each agent demonstrated effective beta-adrenergic blockade at the antihypertensive dose tested as judged by inhibition of the chronotropic responses to sympathetic stimulation and isoproterenol in pithed rats. These data suggest that the acute vasodilator and blood pressure lowering effects of sulfinalol, MK 761, and pindolol, but not prizidilol and hydralazine, are mediated, at least in part, through activation of vascular beta-receptors.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Suppression of a somatosympathetic reflex by the gamma-aminobutyric acid agonist muscimol and by clonidine.

gamma-Aminobutyric acid (GABA) and GABA agonists, e.g., muscimol, reduce blood pressure and sympathetic outflow and inhibit the "carotid occlusion reflex." In contrast, muscimol exerted only marginal effects on postural reflexes in a prior study. The somatosympathetic reflex, i.e., potentials evoked in sympathetic nerves in response to sensory nerve stimulation, is a useful model for studying centrally acting drugs. Effects of muscimol on the reflex were examined in anesthetized normotensive rats. At doses which had previously been shown to reduce blood pressure but to produce only minimal attenuation of postural reflexes in conscious hypertensive rats, muscimol, administered intracerebroventricularly, reduced blood pressure and inhibited the somatosympathetic reflex in the present study. The time course of the evoked potential was not altered. Baroreceptor activation and intracerebroventricular clonidine also suppressed the reflex. The inhibitory effect of muscimol but not that of clonidine was prevented by pretreatment with the GABA antagonist bicuculline. Thus, the marked suppression of the somatosympathetic reflex by muscimol and by clonidine, in contrast to minimal effects on postural reflexes, point to the selectivity of their central inhibitory actions.

Animals↗

PubMedDate not supplied

Angiotensin-converting enzyme inhibitory activity of SCH 31846, a new non-sulfhydryl inhibitor.

SCH 31846, 1-(N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanyl)-cis, syn-octahydro-(H-indole-2-S)-carboxylic acid; CI-907; PD 109, 763-2, is a new non-sulfhydryl-containing, angiotensin-converting enzyme (ACE) inhibitor. The present investigation describes its ACE inhibitory properties and compares them to those of MK 421. The diacid of SCH 31846 inhibited rabbit pulmonary ACE with an IC50 of 2.2 nM (MK 421 diacid 2.5 nM). The drug behaved as a competitive and specific inhibitor in vitro. SCH 31846 and its diacid effectively inhibited pressor actions of intravenous injection of angiotensin I (AI) in anesthetized rats. ID50 values were 27 and 11 micrograms/kg for SCH 31846 and SCH 31846 diacid, respectively (MK 421 and MK 421 diacid 57 and 15 micrograms/kg, respectively). Oral administration of SCH 31846 (0.03-1 mg/kg) inhibited pressor actions of AI in conscious rats with a duration of over 16 h at 0.3 and 1 mg/kg. SCH 31846 was 2.2 times as potent as MK 421 in this regard. The diacid of SCH 31846 was considerably less potent than the ester, implying poor oral absorption of the former. Effective ACE inhibition, as judged by attenuation of pressor actions of AI, was noted in dogs after both intravenous and oral administrations of SCH 31846. Onset of action was more rapid than that of MK 421. Intravenous administration of SCH 31846 inhibited the renal vascular actions of intrarenal injection of AI, indicating effective blockade of the renal enzyme. Intracerebroventricular administration of SCH 31846 diacid blocked pressor responses to intracerebroventricular AI, whereas oral administration of SCH 31846 (10 mg/kg) did not, implying that SCH 31846 inhibits brain ACE but does not gain access to the cerebral enzyme when administered orally. These data indicate that SCH 31846 is a potent and specific non-sulfhydryl ACE inhibitor. As such, it should be useful in the treatment of hypertension and heart failure.

Administration, Oral↗

PubMedDate not supplied

Antihypertensive activity of SCH 31846, a non-sulfhydryl angiotensin-converting enzyme inhibitor.

The antihypertensive, hemodynamic, and autonomic actions of SCH 31846, a new, potent and long-acting non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, were evaluated in several experimental preparations. Oral administration of 0.3-3 mg/kg caused dose-related decreases in blood pressure in spontaneously hypertensive rats (SHRs). Pretreatment with a diuretic augmented the maximum hypotensive response attainable. Single doses (3 mg/kg) of SCH 31846 reduced pressure for over 24 h. Five-day treatment lowered pressure progressively. Single oral doses of 3.2 and 10 mg/kg reduced blood pressure of conscious normotensive dogs. Diuretic pretreatment also enhanced the response. The antihypertensive action of SCH 31846 in SHRs was eliminated by nephrectomy, but not attenuated by indomethacin, indicating its dependency on renal renin but not on prostaglandin synthesis. Other studies using SHRs pointed to an absence of a central effect. SCH 31846 (1 mg/kg i.v.) decreased blood pressure and peripheral resistance of anesthetized dogs but did not alter cardiac output. Autonomic interactions were examined in normal and diuretic-pretreated SHRs and anesthetized dogs. SCH 31846 affected the response to sympathetic nerve stimulation and cardiovascular reflexes only minimally. It is concluded that SCH 31846 is a potent and long-lasting antihypertensive agent, the action of which is mediated, in all probability, by ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗

PubMedDate not supplied

Hemodynamic actions of a synthetic atrial natriuretic factor.

The recently discovered atrial natriuretic factor (ANF), as well as synthetic ANF, has been demonstrated to produce diuresis and vasodilation. However, the vascular actions appear to be selective. In view of this apparent relative specificity, the hemodynamic actions of synthetic ANF (atriopeptin II, 23 amino acid rat sequence) were examined in intact animals and in vascular beds as well as in isolated cardiac preparations. Administration of 1-100 micrograms/kg of ANF i.v. into conscious spontaneously hypertensive rats (SHRs) resulted in a dose-related fall in blood pressure. Heart rate decreased at the lowest dose. Cardiac output was depressed. Infusion of 1 microgram/kg/min also reduced blood pressure and decreased cardiac output slightly (approximately 15%). Intraarterial (i.a.) administration or i.v. injection of ANF into the blood supply of a kidney of anesthetized SHRs augmented renal blood flow and reduced renal vascular resistance. In contrast, i.a. administration into the hindquarters failed to increase blood flow or decrease resistance of this bed significantly. The specific dopamine1 (DA1)-receptor agonist SKF 82526 was examined for comparative purposes and was found to augment both renal and hindquarter blood flow following i.a. administration. The renal vasodilator actions of SKF 82526 but not ANF were antagonized by the specific DA1-receptor blocker SCH 23390 (hindquarter effects were not evaluated). ANF did not affect the force of contraction or rate of beating of isolated guinea pig atria or isolated hearts and therefore does not appear to possess direct inotropic or chronotropic properties. In conclusion, ANF lowered blood pressure in conscious SHRs; the lowering of pressure was accompanied by a slight fall in cardiac output, but there was no reflex tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗