Hideyasu Yamauchi

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on tissue ACE activity in normotensive, spontaneously hypertensive, and renal hypertensive rats

Summary: Effects of an angiotensin-converting enzyme (ACE) inhibitor. SA446, on the renin–angiotensin system, particularly on tissue ACE activity, were studied in Wistar–Kyoto normotensive rats (WKY), spontaneously hypertensive rats (SHR), and two-kidney, one-clip renal hypertensive rats (RHR) by repeated oral administration for 7 days. SA446 (45 mg/kg/day p.o.) inhibited ACE activity in the lung, brain, kidney, heart, and whole blood throughout the administration period in WKY, but showed a slight hypotensive action and no inhibition of aorta ACE activity. On the other hand, SA446 had an apparent hypotensive action at the same dose in SHR and inhibited ACE activity significantly in the aorta as well as the kidney and whole blood during the administration period. Furthermore, enzyme activity in the aorta, kidney, heart, and whole blood was also inhibited at a hypotensive dose of SA446 (10 mg/kg/day p.o.) in RHR. The inhibition in whole blood and kidney was almost complete, and the inhibition in the aorta was greater on day 7 than on day 1. The maximum decrease of blood pressure was correlated with the maximum inhibition in aorta ACE activity, but not in brain, lung, or heart ACE activity. In addition, a good positive correlation was observed between the basal blood pressure and the basal aorta ACE activity in WKY, SHR, and RHR, although there was no correlation in the brain, lung, kidney, heart, or whole blood. These results suggest that the antihypertensive action of SA446 by repeated administration may be due to inhibition of arterial ACE activity in addition to inhibition of plasma and kidney ACE activity. It is also suggested that arterial ACE in SHR and RHR, being higher than in WKY, may be partially related to the maintenance of hypertension in these models.

Electrophysiological properties of SD-3211, a novel putative Ca2+ antagonist, in isolated guinea pig and rabbit hearts

Summary: The cardiac effects of SD-3211, a novel nondihydropyridine type of Ca2+ antagonist, were examined in isolated guinea pig and rabbit hearts using an electrophysiological technique. SD-3211 (10 -6-10-5 M) shortened the action potential duration of guinea pig papillary muscles in a concentration-dependent manner without affecting the resting potential or the maximum upstroke velocity (&OV0622; max). The &OV0622; max of slow responses induced by high extracellular K+ and isoproterenol was inhibited by SD-3211 at concentrations of >10-6 M. Elevation of extracellular Ca2+ by 2 m M reversed this inhibited response. The inhibitory effect of SD-3211 on the slow response was enhanced as the stimulation frequency was increased. In Langendorff-perfused rabbit hearts electrically driven at 2.0 Hz, SD-3211 (10 -8-10-6 M) produced a concentration-dependent prolongation of the atrium- His bundle conduction time (A-H interval) as well as a reduction in the developed tension of ventricular muscle, whereas SD-3211 did not affect the His bundle-ventricular conduction time (A-H interval) significantly. The potency of SD-3211 in A-H prolongation was greater than those of diltiazem and bepridil, but weaker than those of nicardipine, nifedipine, and verapamil. The effect of SD-3211 on the A-H interval was more pronounced at higher stimulation frequencies. SD-3211 was intermediate between nicardipine, nifedipine, and verapamil in its intensity of frequency- dependent effects on the A-H interval. These results suggest that SD-3211 has a preferential and frequency- dependent inhibitory action on cardiac slow Ca2 + channels

SD-3211, a novel benzothiazine calcium antagonist, alone and in combination with a beta-adrenoceptor antagonist, produces antihypertensive effects without affecting heart rate and atrioventricular conduction in conscious renal hypertensive dogs.

We compared the effects of SD-3211, a novel calcuim antagonist, on blood pressure, heart rate, and atrioventricular conduction with those of diltiazen usinng conscius renal hypertensice dogs (one-kidney, one-clip type). We also examined the combined effects of these calcium antagonists with a beta-adrenceptor antagonist. propranolo, on these variabes. Oral administration of SD-3211 (1.25. 2.5 and 5 mg/kg) resulted ion a dosedependent decrease in blood pressure without affecting heart rate. SD-3211 at all three doses significantly decreased systolic blood pressure. At 2.5 and 5 mg/kg the compound elicited significant decreases in mean blood presure and diastolic blood pressure. Hypotension obtained with the highest dose of SD-3211 lasted for at least 9 h. No significant alteration in PR interval was observed in electrocardiograms after administration of SD-3211. Diltiazem, given orally at doses of 2.5 and 5 mg/kg but not 1.25 mg/kg, produced significant hypotension with little change in heart rate. The duration of hypotension induced by the highest dose of dilitiazem was only 3 h. Diltiazem prolonged PR interval in a dose-dependent manner, causing second-degree atrioventricular block in some dogs. Combined adminstration of SD-3211 or diltiazem (2.5 mg/kg) with propranolol (30 mg/kg) resulted in enhanced hypotension with no alteration in heart rate. SD-3211 plus prolpranolol had little effect on the PR interval, whereas diltiazem plus propranlol caused a markedly enhanced prolongation. These results indicate that SD-3211 is an antihypertensive agent with long-lasting action and little effect on heart rate and atrioventricular conduction with propranolol. may be useful in the treatment of hypertension.

Cardiovascular characterization of SD-3211, a novel benzothiazine calcium channel blocker, in isolated rabbit hearts

The cardiovascular effects of SD-3211, a novel benzothiazine Ca++ channel blocker, were compared with those of diltiazem and nicardipine in Langendorff-perfused rabbit hearts. SD-3211 was more potent in increasing coronary artery flow than in depressing cardiac function (i.e., contractile force, heart rate and conduction time). The relative specificity of SD-3211 for coronary vasodilation to cardiodepression was clearly greater than that of diltiazem, but less than that of nicardipine. Thus, the present study demonstrates that SD-3211, despite a non-dihydropyridine type of Ca++ channel blocker, can be characterized as a potent coronary vasodilator with a little effect on cardiac function.

The role of prostaglandins in experimental ocular inflammations.

Intraocular inflammations (uveitis) were produced in rabbits by intravitreal injection of killed and driedMycobacterium butyricum orE. coli endotoxin, or paracentesis of the anterior chamber. The increase in permeability of the blood-aqueous barrier and the leucocyte migration into the aqueous humor were observed after these stimuli, although the leucocyte did not migrate after paracentesis. Topically applied indomethacin reduced these inflammatory parameters in the latter two models. However, the increased permeability afterM. butyricum injection was not affected by indomethacin, though the leucocyte migration was reduced. On the other hand, prostaglandin-like substances in the aqueous humor were significantly elevated in the latter models, whereas only traces of these substances were detected in the former model. These results indicate that, unlike the increase in the permeability of the blood-aqueous barrier after endotoxin injection and paracentesis, the response afterM. butyricum injection is not mediated by prostaglandins. The role of prostaglandins in the leucocyte migration in these ocular inflammations was also discussed.

Antihypertensive effect of a novel calcium antagonist, SD-3211, in experimental hypertensive rats.

The antihypertensive effect of SD-3211. a structurally novel type of nondihydropyridine calcium antagonist, was assessed using several types of experimental hypertensive rats. Oral administration of SD-3211 (10. 20, and 30 mg/kg) to conscious spontaneously hypertensive rats (SHR). deoxycorticosterone acetate-salt hypertensive rats (DHR) and 2-kidney, 1-clip renal hypertensive rats (RHR) resulted in a dose-dependent decrease in systolic blood pressure (SBP). The hypotensive effect of SD-3211 in these hypertensive rats was more pronounced than in normotensive rats (NR). The potencies of SD-3211 for the hypotensive effect in the hypertensive rats and NR were 5–7 times greater than that of diltiazem but 2–3 times less than that of nicardipine. Furthermore, SD-3211 showed longer-lasting hypotensive action than diltiazem and nicardipine, at the respective equihypotensive dose. During the course of hypotension. SD-3211 did not exert any influence on heart rate (HR) in any type of hypertensive rats or NR, in contrast to the appearance of tachycardia with nicardipine in SHR, DHR, and NR and of bradycardia with diltiazem in DHR. At doses of 10 and 30 mg/kg, the hypotensive doses; SD-3211 elicited a dose dependent natriuresis but no kaliuresisin SHR. In the chronic study using SHR. SD-3211 at 10 mg/kg/day showed an antihypertensive effect during anadministration period of 12 consecutive weeks. These results allow us to conclude that SD-3211 has a potent and long-lasting hypotensive action with little cardiac effect.

Passive Anaphylaxis in Rat Conjunctiva and Topical Effects of Antiallergic Agents. Hypersensitivity in Conjunctiva and Drug Efficacy

Homologous passive anaphylactic reaction mediated by a reaginic antibody was caused in rat conjunctiva and the effects of several drugs on this reaction were examined by estimating the leakage of dye

Potentiative effects of sulfhydryl compounds on carrageenin-induced oedema in rats and relationship to their potencies as inhibitors of angiostin-converting enzyme in vivo

Carrageenin-induced oedema in rats was potentiated by oral administration of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (SA291) and related sulfhydryl compounds, and the effect was closely correlated with their potencies as inhibitors of angiotensin-converting enzyme in vivo.

ANTI‐ISCHAEMIC AND VASOSPASMOLYTIC EFFECTS OF A NOVEL Ca2+ CHANNEL BLOCKER, SD‐3211, IN VITRO

1. The present study was undertaken to determine the vasospasmolytic activity of a novel non‐dihydropyridine type of Ca2+ channel blocker, SD‐3211, in isolated canine coronary arteries and its ability to reduce myocardial ischaemic damage in isolated perfused rabbit hearts.

Potentiative effects of a kininase II inhibitor (YS980) on carrageenan-induced oedema in rat hind paw and roles of plasma kininogen

Bradykinin is formed from high molecular weight kininogen in plasma through activation of a kininforming enzyme, kallikrein, and is inactivated by kinindegradating enzymes, kininase I and 11. The peptide is believed to be one of important chemical mediators in carrageenan-induced inflammation. The inflammation is suppressed by cellulose sulphate and bromelain which deplete plasma kininogen (Di Rosa et al 1971 ; Katori et al 1978). Recently, we reported carrageenan oedema to be potentiated by an orally active kininase I1 (EC 3.4.15. I ) inhibitor, (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid (YS980), and suggested that its potentiation of carrageenan oedema is due to its inhibitory action on kininase I1 in the inflamed site (Is0 et al 1978). We now report on the role of plasma kininogen in the development of potentiative effects of YS980 on carrageenan-induced oedema in rat hind paw.