Biomedical subjects

R W Watkins

Publications and source records attributed to R W Watkins.

At least 19 recordsLinked to original sources

PubMed2001

SCH 57790, a selective muscarinic M(2) receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals.

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

Acetylcholine↗

PubMed2001

The synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in dogs.

Ezetimibe (SCH 58235) and SCH 48461 are potent cholesterol absorption inhibitors, which cause significant decreases in plasma cholesterol levels in cholesterol-fed animals and in humans with hypercholesterolemia. These compounds selectively block intestinal uptake and absorption of cholesterol. These cholesterol absorption inhibitors cause modest, inconsistent reductions in plasma cholesterol levels in animals fed cholesterol-free chow diets. Although, these compounds block cholesterol absorption and increase neutral sterol excretion, chow-fed animals compensate for the loss of biliary cholesterol by increasing hepatic cholesterol synthesis. Therefore, we determined the effect of SCH 48461 and ezetimibe in combination with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors in chow-fed dogs. A synergistic reduction in plasma cholesterol was observed in chow-fed dogs given SCH 48461 (0.1 mg/kg/d) and the HMG CoA reductase inhibitor, lovastatin (5 mg/kg/d). Neither SCH 48461 nor lovastatin alone affected plasma cholesterol levels. Their combination for 14 days caused a 36% reduction in plasma cholesterol levels from 129 mg/dL to 83 mg/dL (P <.05). Ezetimibe (0.007 mg/kg/d) also caused synergistic reductions in plasma cholesterol levels in chow-fed dogs when combined with HMG CoA reductase inhibitors for 2 weeks (5 mg/kg lovastatin -50%; 2.5 mg/kg pravastatin -41%; 5 mg/kg fluvastatin -60%, and -30% with low doses of simvastatin and atorvastatin 1 mg/kg). The combination of this class of cholesterol absorption inhibitors with an HMG CoA reductase inhibitor should be very effective clinically at reducing plasma cholesterol levels, even with reduced dietary intake of cholesterol.

Animals↗

PubMed1998

Disparate effects of thrombin receptor activating peptide on platelets and peripheral vasculature in rats.

The hemodynamic and platelet effects of the thrombin receptor activating peptide SFLLRN (TRAP) were evaluated in rats. TRAP failed to aggregate rat platelets in vitro (platelet rich plasma) or in vivo in the pulmonary microcirculation. In contrast, TRAP aggregated washed human platelets. Intravenous injection of TRAP (1 mg/kg) in inactin-anesthetized rats produced a biphasic response in blood pressure characterized by an initial depressor response (-25 +/- 3 mmHg for 15-30 s) followed by a pronounced pressor response (50 +/- 7 mmHg for 2-3 min). This increase in blood pressure can be attributed to increases in total peripheral resistance since cardiac output remained unchanged. Further, only the pressor responses were observed in pithed rats suggesting a direct effect of TRAP in causing smooth muscle contraction. Consequently, rat platelets differ from human platelets in that they are resistant to TRAP whereas rat vasculature is highly sensitive to TRAP. These observations suggest that while the thrombin receptors on rat vasculature may be similar to those on human platelets, the receptors and/or the coupling mechanisms in rat platelets appear different from human platelets.

Animals↗

PubMed1996

Antiplatelet and antiproliferative effects of SCH 51866, a novel type 1 and type 5 phosphodiesterase inhibitor.

SCH 51866 is a potent and selective PDE1 and PDE5 inhibitor. The antiplatelet, antiproliferative, and hemodynamic effects of SCH 51866 were compared with those of E4021, a highly selective PDE5 inhibitor. SCH 51866 inhibited PDE1 and PDE5 isozymes with a 50% inhibitory concentration (IC50) of 70 and 60 nM, respectively. SCH 51866 and E4021 inhibited washed human platelet aggregation induced by collagen with an IC50 of 10 and 4 microM, respectively, and attenuated (p < 0.05) the adhesion of 111indium-labeled platelets to the nylon filament-injured rat aorta. The doses of SCH 51866 and E4021 that inhibited platelet adhesion caused significant increases in platelet cyclic guanosine monophosphate (cGMP; p < 0.05). SCH 51866 (1-10 mg/kg, p.o. twice daily) but not E4021 (3-30 mg/kg, p.o twice daily) inhibited neointima formation in the carotid arteries of spontaneously hypertensive rats (SHRs) subjected to balloon angioplasty. Moreover, SCH 51866 (0.3-10 mg/kg, p.o.) elicited dose-dependent reduction in blood pressure in SHRs, whereas E4021 (3-30 mg/kg, p.o.) did not affect blood pressure in SHRs. In conclusion, the data suggest that inhibition of PDE1 and PDE5 isozymes by SCH 51866 exerts antiplatelet and vascular protective effects. In comparison, inhibition of PDE5 alone by E4021 exhibited antiplatelet effects without affecting neointima formation.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1994

Mercaptoacyl amino acid inhibitors of atriopeptidase. 1. Structure-activity relationship studies of methionine and S-alkylcysteine derivatives.

A broad series of N-(3-mercaptoacyl) amino acid derivatives was evaluated for their ability to inhibit atriopeptidase (neutral endopeptidase, EC 3.4.24.11) in vitro and in vivo. Structural parameters studied were (i) the substituent on the 2-position of the 3-mercaptopropionyl moiety, (ii) the amino acid component, (iii) the S-terminal derivative, and (iv) the C-terminal derivative. Optimum activity was observed for derivatives of methionine and S-alkylcysteines. N-[3-Mercapto-2(S)-[(2-methylphenyl)methyl]-1-oxopropyl]-L-methionine was identified as a highly effective inhibitor of atriopeptidase meriting evaluation as a potential cardiovascular therapeutic agent.

Amino Acid Sequence↗

PubMed1993

NG-nitro-L-arginine methyl ester does not affect balloon catheter-induced intimal hyperplasia in rats.

The L-arginine derived NO-cGMP pathway's role in the response of the arterial wall to balloon catheter injury was examined. Rats were given the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (10 mg/kg po twice daily) or vehicle for 6 days before and 2 weeks after balloon catheter injury. NG-nitro-L-arginine methyl ester treatment increased blood pressure and inhibited acetylcholine responses in aortic rings but did not alter the lesions produced by balloon injury. Our results suggest that the L-arginine derived NO-cGMP pathway does not play a significant role in the response of the artery wall to balloon injury in the rat.

Acetylcholine↗

PubMed1993

Inhibition of endothelial derived relaxing factor (EDRF) aggravates ischemic acute renal failure in anesthetized rats.

The relative importance of endothelial derived relaxing factor (EDRF)/nitric oxide (NO) in maintaining kidney function in normal condition and in acute renal failure (ARF) were evaluated in inactin anesthetized rats. ARF was induced by unilateral occlusion of the left renal artery (40 min) followed by reperfusion, with the contralateral kidney serving as normal control. This protocol resulted in marked reductions in renal plasma flow (RPF), glomerular filtration rate (GFR) and increases in fractional sodium excretion (FENa) and urinary protein excretion in the post-ischemic kidney in comparison to the contralateral normal kidney. Administration of the nitric oxide (NO) synthase inhibitor NG--monomethyl-L-arginine (0.25 mg/kg per min, L-NMMA) exacerbated the ischemia-induced changes in renal functions as reflected by further reductions in urine flow (V), GFR, marked sodium wasting and renal edema. Pretreatment of the animals with NO precursor L-arginine (2.5 mg/kg per min, L-Arg) abolished the detrimental effects of L-NMMA in ARF. In contrast, D-Arginine (2.5 mg/kg per min, D-Arg) failed to reverse the detrimental effects of L-NMMA. Infusion of L-Arg alone also resulted in improvements in RPF and GFR in the ischemic kidney. The results of the present study suggest that the function of the ischemic kidney is sustained by EDRF/NO and is thus more sensitive to NO synthase inhibition.

Acute Kidney Injury↗

PubMed1993

Disparate effects of phosphoramidon on blood pressure in SHR and DOCA-salt hypertensive rats.

Phosphoramidon inhibits both endothelin converting enzyme (ECE) and neutral metalloendopeptidase (NEP). The contribution of ECE and NEP inhibition to the antihypertensive effects of phosphoramidon was investigated in SHR and DOCA-salt hypertensive rats. SCH 32615, an active acid of the potent and selective NEP inhibitor prodrug SCH 34826 was used as a reference compound. Intravenous infusion of SCH 32615 (1.0 mg/kg/min x 2 hr) or phosphoramidon (0.3 and 1.0 mg/kg/min x 2 hr) did not reduce blood pressure (BP) in conscious SHR. The combination of SCH 32615 (100 mg/kg + 1.0 mg/kg/min) and phosphoramidon (0.3 mg/kg/min) also did not alter BP in SHR. In comparison, the BP of conscious DOCA-salt rats was significantly reduced by phosphoramidon (0.01, 0.1 and 1.0 mg/kg/min x 2 hr) (-28 +/- 6, -51 +/- 5 and -85 +/- 6 mmHg, respectively). SCH 32615 (100 mg/kg, i.v.) over 5 min followed by a sustained infusion of 1.0 mg/kg/min for 2 hr also reduced BP by 49 +/- 7 mmHg (P < .05) in DOCA-salt rats. However, phosphoramidon (0.1 mg/kg/min x 2 hr) failed to cause a further reduction in BP in DOCA-salt rats concurrently receiving SCH 32615. In contrast, a higher dose of phosphoramidon (0.3 mg/kg/min) in combination with SCH 32615 caused a greater reduction in BP in DOCA-salt rats than SCH 32615 alone. In anesthetized normotensive rats, phosphoramidon (0.01-1.0 mg/kg/min x 30 min) dose-dependently inhibited the BP responses to big endothelin-1 (BET-1) without blocking the pressor responses to ET-1. SCH 32615 failed to attenuate the pressor responses to either BET-1 or ET-1. The results indicate that SCH 32615 lacks in vivo ECE inhibitory activity. It is concluded that the antihypertensive action of SCH 32615 and low doses of phosphoramidon can be attributed to the inhibition of NEP which may presumably cause an accumulation of ANF. In comparison, at higher doses phosphoramidon causes a further reduction of BP in DOCA-salt hypertensive rats by inhibition of endothelin bioconversion.

Animals↗

PubMed1993

Atrial natriuretic factor potentiating and hemodynamic effects of SCH 42495, a new, neutral metalloendopeptidase inhibitor.

Neutral metalloendopeptidase (NEP) inhibitors delay atrial natriuretic factor (ANF) catabolism and potentiate biological responses to ANF. We describe biochemical and pharmacological profiles of a novel NEP inhibitor, SCH 42354 (N-[2(S)-(mercaptomethyl)-3-(2-methylphenyl)-4-oxopropyl]-L-methionine and its orally active ethylester prodrug, SCH 42495. SCH 42354 selectively inhibited hydrolysis of leu-enkephalin and ANF (IC50 of 8.3 and 10.0 nmol/L, respectively) in vitro. Plasma levels of exogenous ANF were augmented and ANF clearance from plasma was delayed by oral SCH 42495 (3 to 30 mg/kg) in normotensive rats. Plasma ANF levels in volume expanded rats were higher in SCH 42495-treated rats. Diuretic and natriuretic effects of ANF were increased in rats treated with SCH 42495. Oral doses of 1, 3, or 10 mg/kg of SCH 42495 produced significant reductions in blood pressure in DOCA-Na hypertensive rats of 22 +/- 6, 43 +/- 7, and 62 +/- 12 mm Hg, respectively, which were not associated with increases in heart rate. These doses did not alter urine flow, salt excretion, or plasma ANF. SCH 42495 produced significant elevation of urinary excretion of ANF and cGMP. In Dahl-S hypertensive rats, SCH 42495 (1 to 10 mg/kg orally) produced falls in blood pressure of a magnitude similar to that observed in DOCA-Na hypertensive rats. Significant hypotensive activity was observed 18 h after a single 10 mg/kg oral dose in Dahl-S hypertensive rats. In DOCA-Na hypertensive rats, a single dose of SCH 42495 significantly decreased cardiac output and did not lower systemic vascular resistance, a profile similar to that of ANF. The hypotensive response to SCH 42495 was not ascribable to ACE inhibition. Pithed rat preparations revealed no interaction of the drug with autonomic cardiovascular function. The antihypertensive effect of SCH 42495 likely results from potentiation of endogenous ANF via NEP inhibition.

Animals↗

PubMed1991

Neutral metalloendopeptidase inhibitors as ANF potentiators: sites and mechanisms of action.

Inhibition of the enzyme neutral metalloendopeptidase potentiates responses to atrial natriuretic factor and elicits reductions of blood pressure in desoxycorticosterone acetate sodium hypertensive rats. The present study evaluated the role of atrial natriuretic factor and bradykinin in the antihypertensive response to neutral metalloendopeptidase inhibition through the use of antibodies and antagonists, respectively. In addition, the pharmacokinetic mechanism by which neutral metalloendopeptidase inhibition interferes with atrial natriuretic factor metabolism was explored. The antihypertensive response to the neutral metalloendopeptidase inhibitor SCH 34826 was abruptly reversed by i.v. injection of a polyclonal antiserum to atrial natriuretic factor. In contrast, the antihypertensive response to SCH 34826 was unaffected by injection of the bradykinin antagonist Thi5,8-D-Phe7 bradykinin. The renal response to atrial natriuretic factor, SCH 34826, and phosphoramidon was inhibited by the bradykinin antagonist. The NEP inhibitor SCH 39370 significantly delayed the disappearance of TCA precipitable radioactivity from plasma following i.v. bolus dosing with 125I-labelled ANF 99-126. The effects were enhanced in the presence of the C receptor ligand. The results indicate that atrial natriuretic factor, but not bradykinin, plays an important role in the antihypertensive response to SCH 34826. Bradykinin plays a permissive role in the diuretic responses to atrial natriuretic factor and inhibitors of neutral metalloendopeptidase. Lastly, neutral metalloendopeptidase inhibition significantly alters the clearance and metabolism of tracer quantities of atrial natriuretic factor.

Animals↗

PubMed1990

Neutral metalloendopeptidase inhibition: a novel means of circulatory modulation.

Inhibition of the enzyme neutral metalloendopeptidase (NEP) potentiates responses to atrial natriuretic factor (ANF) and elicits reductions in blood pressure in deoxycorticosterone acetate sodium (DOCA Na) hypertensive rats. The present study evaluated the role of ANF and bradykinin in the antihypertensive response to NEP inhibition through the use of antibodies and antagonists, respectively. In addition, the pharmacokinetic mechanism by which NEP inhibition interferes with ANF metabolism was explored. The antihypertensive response to the NEP inhibitors SCH 34826 and 42495 was abruptly reversed by an intravenous injection of a polyclonal antiserum to ANF. In contrast, the antihypertensive response to SCH 34826 was unaffected by injection of the bradykinin antagonist [thi5,8-D-phe7] bradykinin, indicating that ANF, but not bradykinin, affects this response. The NEP inhibitor SCH 39370 significantly delayed the disappearance of trichloroacetic acid (TCA)-precipitable radioactivity and the appearance of TCA-soluble radioactivity in plasma following an intravenous bolus dose of 125I-ANF(99-126). The effects were enhanced in the presence of the C-receptor ligand des[gln18,ser19,gly20,leu21,gly22]r ANF(4-23)-NH2. These data suggest that the two clearance mechanisms interact to govern plasma levels of ANF.

Animals↗

PubMed1989

Preclinical pharmacologic properties of dilevalol, an antihypertensive agent possessing selective beta 2 agonist-mediated vasodilation and beta antagonism.

Dilevalol is a vasodilator with selective partial beta 2 agonism and nonselective beta-antagonist activity. In contrast to its potent beta 2-agonist activity, dilevalol is essentially devoid of beta 1-agonist action, and is therefore distinct from pindolol and celiprolol. Dilevalol inhibits beta 1- and beta 2-adrenergic receptors nonselectively in dogs, rats and in isolated tissues, including human myocardium, and its beta-antagonist potency is similar to that of propranolol. In contrast to its beta-antagonist activity, it exerts minimal if any alpha-adrenergic blockade. Dilevalol is 300- to 1,000-fold more potent at beta- than at alpha 1-adrenergic receptors, including those on human myocardium and mammary arteries. At antihypertensive and vasodilator doses in rats and dogs, dilevalol does not inhibit alpha 1-adrenergic receptors. Oral doses of 2.5 to 50 mg/kg of dilevalol reduce blood pressure in spontaneously hypertensive rats. Heart rate is not significantly affected. Tolerance does not develop to the antihypertensive response. In contrast, beta blockers such as propranolol do not reduce blood pressure in this model. Antihypertensive activity is also observed in dogs with renal hypertension. The hemodynamic profile of dilevalol is consistent with its vasodilator properties. In spontaneously hypertensive rats, antihypertensive doses of dilevalol reduce peripheral resistance without affecting cardiac output. Dilevalol also improves the compliance and distensibility of the large arteries. The vasodilator and antihypertensive responses to dilevalol are mediated by a partial agonist action at vascular beta 2 receptors, because they are inhibited by the nonselective beta blocker propranolol as well as the beta 2-selective antagonist ICI 118,551.

Adrenergic beta-Agonists↗

PubMed1989

SCH 39370, a neutral metalloendopeptidase inhibitor, potentiates biological responses to atrial natriuretic factor and lowers blood pressure in desoxycorticosterone acetate-sodium hypertensive rats.

SCH 39370 (N-[N-[1-(S)-carboxyl-3-phenylpropyl]-(S)-phenyl-alanyl]-(S)-isoserin e) is a potent and specific inhibitor of neutral metalloendopeptidase (NEP) from rabbit kidney (IC50 = 11.2 +/- 1.9 nM) and is devoid of angiotensin-converting enzyme inhibitory activity at 1 microM. We evaluated the effect of NEP inhibition with SCH 39370 on the inactivation of atrial natriuretic factor (ANF) and on cardiovascular function in rats. SCH 39370 effectively prevented in vitro degradation of ANF (99-126) by a purified rabbit kidney NEP. SCH 39370 (30 mg/kg s.c) significantly delayed the disappearance of immunoreactive (ir) ANF from plasma in rats after an i.v. infusion of ANF (1 microgram/kg/min for 30 min): the plasma ir ANF level at 15 min postinfusion was 1.5 +/- 0.3 ng/ml vs. 0.3 +/- 0.04 ng/ml in the control. SCH 39370 also delayed the disappearance of ir ANF after infusion of the peptide (0.1 microgram/kg/min for 30 min) which increased plasma levels to those observed during volume expansion. This effect was accentuated markedly in rats with bilateral nephrectomy. The hypotensive response to injection of ANF (30 micrograms/kg i.v.) in spontaneously hypertensive rats (-38 +/- 6 mm Hg vs. -13 +/- 2 mm Hg in the control) and the diuretic and natriuretic responses to ANF in normal rats were potentiated by SCH 39370 (30 mg/kg s.c.), respectively. The results suggest that NEP can play a role in ANF disposition in vivo and that potentiation of the biological activities of high doses of ANF by SCH 39370 may be consequent to its inhibitory effect on ANF degradation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Systemic effects resulting from topical ocular administration of SCH 33861, a novel ACE inhibitor ocular hypotensive agent.

SCH 33861 (7- N- 1(S)-(Carboxy)-3-phenylpropyl -(S)-alanyl 1,4-dithia-7-azaspiro 4.4 nonane-8(S)-carboxylic acid) is a novel, non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor with marked topical ocular hypotensive activity. The present study evaluated the degree of systemic ACE inhibition resulting from topical administration of 0.01 and 0.1% concentrations (10 and 100-fold greater than needed to lower IOP) of SCH 33861 in conscious rabbits. For reference purposes, captopril, a prototype ACE inhibitor, was examined at concentrations 5 and 20-fold greater than needed to lower IOP. Neither 0.01 nor 0.1% topical SCH 33861 led to inhibition of pressor responses to 0.3 micrograms/kg iv challenges with angiotensin I (AI) over a 4 hr period. Captopril, in contrast, caused significant attenuation of AI pressor responses. The magnitude and duration of systemic ACE inhibition following captopril administration was concentration related. Intravenous administration of the same dose administered topically did not cause any systemic ACE inhibition with 0.01% SCH 33861. Following iv 0.1% SCH 33861, 0.5 or 2.0% captopril, AI responses were inhibited 60-70% indicating the ability to inhibit ACE if any systemic absorption took place. Topical administration of 0.01% SCH 33861 twice daily for five days also did not produce systemic ACE inhibition. These findings indicate that topical amounts of SCH 33861 greatly in excess of those needed to effect reductions in IOP have an exceptionally low potential for producing systemic effects.

Administration, Topical↗

PubMed1988

Effects of the antihypertensive dilevalol on aortic compliance in anesthetized dogs.

The present study examined the actions of dilevalol, an antihypertensive beta-adrenoceptor blocker with arterial vasodilator actions, on aortic compliance (AC) in anesthetized dogs. AC was measured by sonomicrometric determination of the ratio of aortic systolic-diastolic diameters (mm) and arterial pulse pressure (mm Hg). One AC unit (ACU) equals 10(-3) mm/mm Hg. Dilevalol (0.032, 0.1, and 3.2 mg/kg intravenously, i.v.) significantly (p less than .05) increased AC by 1.4 +/- 0.3, 3.7 +/- 1.4, and 4.5 +/- 1.2 ACU from basal values of 4.7 +/- 0.4-5.6 +/- 0.4 ACU while reducing blood pressure by 20 +/- 2, 31 +/- 9, and 41 +/- 10 mm Hg, respectively (p less than 0.05). Increases in AC were not the passive result of altered blood pressure. Proximal mechanical aortic occlusion dropped systolic blood pressure as much as 70 mm Hg without altering AC. Hydralazine also (0.3 and 1.0 mg/kg i.v.) lowered blood pressure significantly (p less than 0.05) by 14 +/- 3 and 40 +/- 4 mm Hg but increased AC only at 1.0 mg/kg (+ 1.6 +/- 0.4 ACU, p less than 0.05). Phenylephrine (1-30 micrograms/kg i.v.) significantly raised blood pressure 25 +/- 3-95 +/- 8 mm Hg but decreased AC significantly by 1.2 +/- 0.3-2.4 +/- 0.3 ACU. Isoproterenol (ISO) (0.01-1.0 micrograms/kg) produced effects on AC similar to those of dilevalol. Propranolol pretreatment attenuated dilevalol and ISO-induced increases in AC. Propranolol (0.32 and 1.0 mg/kg) did not significantly change AC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1987

Nitroprusside, but not ANF inhibits venoconstriction in an in situ rat model.

Potential venodilator actions of nitroprusside (10 and 50 micrograms/min) and ANF (23 amino acid rat sequence, 10 and 30 micrograms/min) were assessed in rats subjected to cardiopulmonary bypass. Norepinephrine (NE, 10 micrograms) caused arterial pressor, i.e. increased perfusion pressure and venoconstrictor, i.e. increased venous flow, effects. ANF infusion failed to alter NE-induced pressor and venoconstrictor effects while nitroprusside significantly inhibited NE responses. Thus nitroprusside but not ANF, shows venodilator properties in this in situ rat model.

Animals↗

PubMed1987

Topical ocular hypotensive effects of the novel angiotensin converting enzyme inhibitor SCH 33861 in conscious rabbits.

SCH 33861 is a novel, non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor. Topical administration of the compound to the eye of conscious rabbits was employed to examine actions on intraocular pressure (IOP). Falls in IOP resulted from SCH 33861 (0.001-0.01%) administration. Ocular hypotensive responses were sustained for as long as 24 hrs following a single application of 0.001% SCH 33861. The RSS isomer of SCH 33861, which is 200-fold weaker an ACE inhibitor than SCH 33861, caused only transient falls in IOP at 0.1% concentration. The magnitude of the fall in IOP induced by 0.001% SCH 33861 (4.8 +/- 0.5 mmHg) was comparable to that produced by 0.5% timolol (4.5 +/- 0.3 mmHg). Other ACE inhibitors such as captopril (0.1%) and enalaprilic acid (0.01%) also reduced IOP by 4.0 +/- 0.4 and 4.7 +/- 0.4 mmHg, respectively. These findings indicate that SCH 33861 is 500-fold more potent on a weight basis than is timolol in lowering IOP. No loss of ocular hypotensive activity was observed when SCH 33861 was administered twice daily for 5 days suggesting little, if any, potential for tolerance development. SCH 33861, as well as the other ACE inhibitors, caused neither ocular irritation nor alteration of pupil diameter. These findings suggest that inhibition of ocular ACE may represent an effective means of reducing IOP.

Administration, Topical↗

PubMed1987

Pharmacologic, metabolic, and toxicologic profile of spirapril (SCH 33844), a new angiotensin converting inhibitor.

Spirapril (SCH 33844; 7-N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl-1,4-dithia- 7-azaspiro[4,4]-nonane-8(S)-carboxylic acid) is a new angiotensin-converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of hip-his-leu by rabbit lung ACE in a potent (Ki = 0.74 nM), selective, and noncompetitive fashion. SCH 33844 (0.03-1 mg/kg p.o.) produced dose-related inhibition of angiotensin I (AI) pressor responses in conscious rats with a duration of 24 h at the higher dose. SCH 33844 (0.3-30 mg/kg p.o.) reduced blood pressure in a dose-related manner in conscious SHR with a 24-h duration. Antihypertensive activity was enhanced in the presence of hydrochlorothiazide. The drug (1-10 mg/kg p.o.) also lowered blood pressure in conscious hydrochlorothiazide-treated normotensive dogs. In anesthetized dogs, SCH 33844 (1 mg/kg i.v.) reduced blood pressure and total peripheral vascular resistance and slightly increased cardiac output and stroke volume. These results suggest that peripheral vasodilation is the primary mechanism of the antihypertensive action. The metabolic profile of SCH 33844 was evaluated in dogs and rats. The compound was absorbed in a dose-proportional manner and excreted primarily as the diacid form. In contrast to captopril and enalapril, most of the drug (67%) was excreted into the feces following i.v. dosing. Chronic toxicological evaluation in dogs and rats demonstrated that the drug was relatively devoid of toxicity at oral doses as high as 400 and 450 mg/kg/day, respectively. Slight decreases in heart weight (rats) and increases in granularity of the juxtaglomerular apparatus were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗