Comparative effects of SCH 19927 and timolol on intraocular pressure of conscious rabbits and relative systemic beta-blockade resulting from topical administration.

SCH 19927, the RR isomer of labetalol, has been shown to possess beta-blocking and vasodilator properties. It was compared to timolol for ability to lower intraocular pressure (IOP) in conscious rabbits. Its potential for systemic beta-blockade after topical administration was also assessed. Dose-related reductions in IOP followed topically applied SCH 19927 (0.1-1.0%). Timolol in concentrations less than 0.5% was not effective in lowering IOP. Timolol (0.1 and 0.5%) strongly inhibited tachycardia induced by iv isoproterenol. A 1.0% concentration of SCH 19927 was less effective than 0.5% timolol in inhibiting the isoproterenol-induced tachycardia; 0.1% SCH 19927 caused only minor inhibitory actions. Thus, not only is SCH 19927 at least as potent in lowering IOP in conscious rabbits, its topical administration results in less systemic beta-blockade than does timolol.

Analysis of the vasoconstrictor responses to potassium depolarization and norepinephrine and their antagonism by differing classes of vasodilators in the perfused rat hindquarters.

Although the role of calcium in activation of vascular smooth muscle has received considerable attention, few studies have analyzed responses of resistance vessels. We therefore evaluated the role of calcium in vasoconstriction induced by norepinephrine (NE) and by high potassium depolarization in the resistance vessels of the Krebs'-perfused rat hindquarters. In addition, responses to vasodilators of differing classes were assessed. Injection of NE (0.3-100 micrograms) into the hindquarters increased perfusion pressure in a dose-related manner. Perfusion of the hindquarters with a depolarizing salt solution (80 mM K+) produced a sustained vasoconstriction (perfusion pressure = 143 +/- 4 mm Hg). Vasoconstriction to NE and high K+ was abolished during perfusion with a Ca-free salt solution containing 2 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid. In addition, the potassium-induced vasoconstriction was slightly reduced (perfusion pressure = 119 +/- 4 mm Hg) in animals pretreated with reserpine (5 mg/kg i.p.) indicating a slight neurogenic contribution to the response. The calcium channel blockers nifedipine (0.03-10 micrograms), diltiazem (0.3-30 micrograms) and verapamil (0.1-10 micrograms) produced dose-related vasodilation of hindquarters constricted with either NE (7.1 microM) or high potassium. These drugs were 4 to 10-fold more potent against potassium-induced vasoconstriction. Reserpine pretreatment enhanced the vasodilator response to nifedipine in potassium-depolarized preparations. Nitroprusside and nitroglycerin relaxed both NE and potassium-constricted hindquarters. The calmodulin blockers trifluoperazine and W-7 likewise produced vasodilation; trifluoperazine being 12.5 times more potent against NE-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

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 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.

Antihypertensive and orthostatic responses to drugs in conscious dogs.

In view of the frequent occurrence of orthostatic hypotension in antihypertensive therapy, the orthostatic potential of various classes of drugs was evaluated in conscious normotensive dogs in order to assess the utility of this model. Antihypertensive effectiveness was ascertained initially in hypertensive dogs. Inhibitors of peripheral sympathetic vasoconstrictor mechanism (phentolamine, prazosin, guanethidine) produced marked orthostatic hypotension at antihypertensive doses. In contrast, clonidine did not. The vasodilator hydralazine and, to some extent, minoxidil also caused postural effects. It is concluded that conscious dogs are useful in assessing the orthostatic potential of antihypertensive drugs but that their predictability to humans is not universal.

Captopril, alone and in combination with hydrochlorothiazide, on responses to upright tilt in conscious dogs.

Orthostatic hypotension occurs relatively frequently in antihypertensive therapy. Although vasodilators are usually not associated with this response, hydralazine and to some extent minoxidil produced marked orthostasis in conscious dogs in a prior series of experiments. Captopril also reduces blood pressure by a peripheral mechanism. Therefore, its influence on responses to upright tilt were evaluated. Oral administration of captopril reduced blood pressure of conscious normotensive dogs. Even greater falls occurred after pretreatment with hydrochlorothiazide. However, the increases in blood pressure and heart rate observed during upright tilting were not altered by captopril.