Calcium antagonistic and binding properties of semotiadil (SD-3211), a benzothiazine derivative assessed in cerebral and coronary arteries.

The present experiments were undertaken to elucidate Ca2+ antagonistic and binding properties of semotiadil and its (S)-(-)-enantiomer (SD-3212) in plausible clinical target tissues such as cerebral and coronary arteries. Semotiadil was about six times more potent than D-cis-diltiazem for Ca2+ antagonistic action, with a long-lasting and wide spectrum of inhibitory effects on contraction of dog cerebral arteries elicited by various spasmogens and mechanical stretch. Semotiadil exhibited a weak, negative, and heterotropic allosteric effect on (+)-[3H]PN 200-110 binding to pig coronary artery membranes: Scatchard analysis of saturation isotherms indicated that semotiadil increased the equilibrium dissociation constant (Kd) of (+)-[3H]PN-200-110 binding without causing a significant change in the maximum binding density (Bmax). Furthermore, semotiadil significantly increased the dissociation rate (k-1) of (+)-[3H]PN 200-110 from the specific binding site. The enhanced binding of (+)-[3H]PN 200-110 to the coronary artery caused by D-cis-diltiazem was attenuated when semotiadil was present, whereas binding inhibited by verapamil was not affected in the presence of semotiadil. The results suggest that semotiadil exerts a potent Ca2+ antagonistic action by binding to a site in the Ca2+ channel distinct from the 1,4-dihydropyridine recognition site and interacts with the 1,4-dihydropyridine binding site in a negative, heterotropic, allosteric manner.     

Effects of semotiadil fumarate (SD-3211) on renal hemodynamics and function in dogs.

Studies were carried out to define the effect of semotiadil on renal hemodynamics, renal function and renin release in pentobarbital-anesthetized dogs. Intrarenal arterial infusion of semotiadil resulted in a significant increase in renal blood flow (RBF), glomerular filtration rate (GFR), urine flow, urinary excretion of electrolytes and renin release. Semotiadil did not affect the linear relationship between osmolar clearance and the free water reabsorption rate, and increased the urinary excretion of sodium and calcium to the same extent. These results suggest that the main tubular site of action of semotiadil is the proximal tubule. Intrarenal infusion of a potent non-peptide angiotensin II antagonist, DuP753 (15 micrograms/kg per min), resulted in an increase in RBF, GFR, urine flow and UNaV. In spite of the blockade of the intrarenal renin angiotensin system(RAS) with DuP753, semotiadil caused almost the same effects as it did in the absence of DuP753. These results suggest that the renal effects of semotiadil are independent of the intrarenal RAS.     

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 calcium antagonist, on blood pressure, heart rate, and atrioventricular conduction with those of diltiazem using conscious renal hypertensive dogs (one-kidney, one-clip type). We also examined the combined effects of these calcium antagonists with a beta-adrenoceptor antagonist, propranolol, on these variables. Oral administration of SD-3211 (1.25, 2.5, and 5 mg/kg) resulted in a dose-dependent 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 pressure 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 diltiazem was only 3 h. Diltiazem prolonged PR interval in a dose-dependent manner, causing second-degree atrioventricular block in some dogs. Combined administration 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 propranolol had little effect on the PR interval, whereas diltiazem plus propranolol 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 and, when administered alone or in combination with propranolol, may be useful in the treatment of hypertension.     

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 kaliuresis in SHR. In the chronic study using SHR, SD-3211 at 10 mg/kg/day showed an antihypertensive effect during an administration 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.     

Effects of KB-2796, a new diphenylpiperazine calcium antagonist, on renal hemodynamics and urine formation in anesthetized dogs.

The effects of KB-2796, a new calcium antagonist with a diphenylpiperazine moiety, on renal hemodynamics and urine formation were investigated in anesthetized dogs. Intravenous infusion of KB-2796 (10, 30, and 100 micrograms/kg/min) decreased mean blood pressure (MBP) and renal vascular resistance (RVR) in a dose-dependent manner, but did not change renal blood flow (RBF). At the highest dose, glomerular filtration rate (GFR) and urine flow (UF) tended to decrease. Nicardipine (0.1, 0.3, and 1 microgram/kg/min) also dose-dependently decreased MBP, RVR, GFR, and UF. When KB-2796 was infused into the renal artery at lower doses of 3 and 10 micrograms/kg/min, UF and urinary excretion of electrolytes increased without a significant change in RBF and GFR. Intrarenal infusion of KB-2796 at 30 micrograms/kg/min and nicardipine at 0.3 microgram/kg/min produced a significant increase in GFR, RBF, UF, urinary excretion of electrolytes, and renin secretion rate. These results suggest that KB-2796 administered intrarenally exerts a diuretic action via tubular effects and the alteration of renal hemodynamics. However, its diuretic action might be masked by diminished urine formation via a reflex activation of the sympathetic nerves and/or via a reduction of renal perfusion pressure when it is administered systemically.     

Cardiovascular effects of a new 1,5-benzothiazepine calcium antagonist in anesthetized dogs

Cardiovascular effects of TA-3090 ((+)(2S,3S)-3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2, 3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4-(5H)-one maleate), a new 1,5-benzothiazepine derivative, were studied in pentobarbital anesthetized dogs. TA-3090 administered intraarterially (i.a.) was 3 times more potent than diltiazem in increasing vertebral and coronary blood flows. In the autoperfused preparation, TA-3090 i.a. exhibited weak negative inotropic effect as compared with its coronary vasodilating effect; negative inotropy was less than 10% at a dose which increased coronary blood flow by 50%. The selectivity of TA-3090 for coronary artery was greater than that of verapamil. Intravenous administration of TA-3090 (0.025-0.2 mg/kg) produced increases in cardiac output and arterial, especially vertebral and coronary blood flow as well as in left ventricular dp/dtmax. The increasing effect in blood flow was most prominent in the vertebral artery. Upon intraduodenal administration of 2 and 5 mg/kg TA-3090, the increases in vertebral and coronary blood flow lasted for more than 2-5 h; the effect of TA-3090 on vertebral blood flow was approximately twice as potent as that of diltiazem. Thus, TA-3090 could be demonstrated to possess potent and long-lasting vasodilating activity with selectivity for vertebral and coronary arteries, exerting however, weak negative inotropic effect.     

Thyroid hypertrophic effect of semotiadil fumarate, a new calcium antagonist, in rats

We studied the effects of semotiadil fumarate (SF), a new calcium antagonist with a unique benzothiazine structure, on the thyroid gland and liver in rats and compared them with those of another calcium antagonist, nicardipine (NCD), a well-known thyroidal hypertrophic agent and microsomal enzyme inducer, phenobarbital (PB), and goitrogen propylthiouracil (PTU). In oral 2-week treatment, SF caused increases in hepatic microsomal protein levels, uridine diphosphate glucuronosyltransferase (UDPGT) activity and an increase in serum thyroid stimulating hormone (TSH) level together with decreases in serum thyroid hormone levels. These results suggest that SF accelerates peripheral disposition of thyroid hormones and subsequently stimulates secretion of TSH from the pituitary gland as a compensatory response. PB and NCD had similar effects on the thyroid gland and the liver. PTU showed obvious thyroid hyperplasia and an increase in relative liver weight. Drastic increase in TSH level was observed in the PTU-treated group together with significant decreases in serum thyroid hormone levels and an increase in hepatic UDPGT activity. Histopathologically, PTU depleted the colloids in follicles, suggesting the inhibition of thyroid hormone synthesis. SF, PB and NCD showed thyroidal hyperplasia, but the extent of the change was far more moderate than that induced by PTU. These results indicate that the effect of SF is similar to those of PB and thyroid hypertrophy seen in the oral 2-week treatment with SF, and may be caused by indirectly elevated TSH levels which resulted from the induction of hepatic UDPGT activity.     

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

The cardiac effects of SD-3211, a novel non-dihydropyridine 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 (Vmax). The Vmax of slow responses induced by high extracellular K+ and isoproterenol was inhibited by SD-3211 at concentrations of greater than 10(-6) M. Elevation of extracellular Ca2+ by 2 mM 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 (H-V 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 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.     

Pharmacological profile of semotiadil fumarate, a novel calcium antagonist, in rat experimental angina model.

1. The aim of the present study was to determine whether antianginal efficacy of semotiadil fumarate (SD-3211), a structurally novel calcium antagonist, is distinct from those of diltiazem, nifedipine and nisoldipine. 2. First, the duration of the inhibitory effects of semotiadil was compared with that of other Ca2+ antagonists in rat experimental angina evoked by vasopressin. Semotiadil (10 mg kg-1, p.o.) was effective for at least 9 h in the anginal model and those effects of semotiadil were longer-lasting than those of diltiazem (30 mg kg-1, p.o.), nifedipine (10 mg kg-1, p.o.), and nisoldipine (3 mg.kg-1, p.o.). 3. Second, the selectivity of actions of these Ca2+ antagonists for the coronary arteries and myocardium was evaluated in rat isolated perfused hearts. Diltiazem (10(-6) M) reduced cardiac contractility without inhibiting the elevation of perfusion pressure evoked by acetylcholine. Semotiadil (10(-7) M) significantly suppressed cardiac contractility and inhibited the coronary response to acetylcholine. In contrast, nifedipine (3 x 10(-9)-3 x 10(-8) M) and nisoldipine (3 x 10(-10)-10(-8) M) did not reduce cardiac contractility at concentrations which significantly inhibited the increase in perfusion pressure to acetylcholine. 4. The selectivity of semotiadil for coronary artery and myocardium is intermediate between diltiazem and dihydropyridines tested in the present study. 5. These findings suggest that semotiadil has an advantage of diltiazem, nifedipine, and nisoldipine in the treatment of angina with regard to long-lasting action and selectivity for coronary artery and myocardium.     

Effects of cadralazine on systemic blood pressure, renal function and plasma renin activity in anesthetized dogs

Renal effects of ethyl 6-[ethyl(2-hydroxypropyl)amino]-3-pyridazinecarbazate (cadralazine), a newly synthesized vasodilator with a pyridazine ring, were studied in anesthetized dogs. 30 min after intravenous (i.v.) injection of cadralazine in a dose of 1 mg/kg diastolic blood pressure (DBP) decreased from the control value of 115 +/- 4 mmHg to 108 +/- 3 mmHg. The decrease continued, being accompanied by an increase in heart rate, throughout the experimental period of 5 h. Renal vascular resistance was decreased significantly, while glomerular filtration rate and urine volume remained unchanged. Urinary excretions of sodium and potassium were increased about 1.5 to 2 times as compared to pre-injection control values. Hypotension and natriuresis were followed by increased plasma renin activity in the artery or renal vein. On the other hand, i.v. injection of hydralazine (0.3 mg/kg) promptly decreased DBP and urinary sodium excretion, 15 min after administration, with blood pressure tending to revert to the control value. These results indicate that cadralazine has hypotensive and renal vasodilating actions, characterized by a slow onset and long duration, when compared with hydralazine.     

Effects of NZ-105, a new calcium antagonist, on renal function in anesthetized spontaneously hypertensive rats.

The effects of a new dihydropyridine derivative, NZ-105, on renal function were investigated in anesthetized spontaneously hypertensive rats. Intravenous injection of NZ-105 (0.01 and 0.03 mg/kg of body weight) significantly increased the urine flow rate (UV) and renal absolute excretion of sodium and chloride. Potassium excretion also increased significantly, but it was relatively slight in comparison with sodium or chloride excretion. There was a decrease in mean blood pressure (-14.5 +/- 2.3 and -22.3 +/- 3.4 mm Hg, 20 min after the administration of 0.01 and 0.03 mg/kg of body weight, respectively). The glomerular filtration rate (GFR) was not changed; however, the renal plasma flow (RPF) was significantly increased. The tubular site of action of NZ-105 was investigated by the lithium clearance technique. Intravenous injection of NZ-105 inhibited sodium reabsorption beyond the proximal tubules about four to five times more effectively than at the proximal tubules. In conclusion, intravenous administration of NZ-105 in anesthetized spontaneously hypertensive rats caused diuretic and natriuretic action. The possible site of diuretic action may be mainly at the nephron segments beyond the proximal tubules.     

Antiarrhythmic effects of a benzothiazine derivative (SD-3211) and its stereoisomer (SA3212) in anaesthetized rats and isolated perfused rat hearts compared with bepridil

Summary The antiarrhythmic effects of a new calcium channel blocking agent (SD-3211) and its stereoisomer with additional sodium channel blocking activity (SA3212), were compared with those of a known antiarrhythmic drug (bepridil), using the left coronary artery ligation- and reperfusion-associated arrhythmia models both in isolated rat hearts and in anaesthetized rats.Isolated and perfused rat hearts were subjected to regional ischaemia for 15 min and subsequent reperfusion for 5 min. SD-3211 and SA3212 showed dose-dependently prolongations of the time interval between coronary ligation and first appearance of ventricular premature beats, reductions in the number of total ventricular premature beats during the ligation period and reductions in the incidence of reperfusion-induced ventricular fibrillation. The values of the negative logarithm of IC₅₀ (mol/l) of SD-3211, SA3212 and bepridil were 7.97, 7.41 and 6.64 for the reduction of ventricular premature beats during ligation and 6.43, 7.49 and 6.17 for the reduction of ventricular fibrillation during reperfusion, respectively. In a separate study on force of concentration and coronary flow in perfused heart paced at 340–360 beats/min SD-3211 caused a significant negative inotropic effect between 10^–7 and 10^–6 mol/l. SA3212 at the concentration of < 10^–6 mol/l did not result in any significant change in force of contraction. The coronary flow was increased dose-dependently by SA3212, while it was first increased and then reduced in the presence of higher concentration of SD-3211 (> 10^–7 mol/l). Hearts of aneasthetized rats were also subjected to regional ischaemia for 7 min and subsequent reperfusion. SD-3211, even at the lowest dose tested (25 mg/kg), had a marked protective effect against the ligation-associated arrhythmias. The highest dosage of SA3212 tested (100 mg/kg) also reduced them. SA3212, even at the lowest dosage (25 mg/kg), resulted in a significant reduction of the incidence of reperfusion-induced ventricular fibrillation, while only the highest dosage of SD-3211 (100 mg/kg) reduced it. As for the protective effect against ligation-associated ventricular premature beats SD-3211 is about seven times as potent as bepridil, and for the reduction in the incidence of reperfusion-induced ventricular fibrillation SA3212 is about fourteen times as potent as bepridil. Significant falls in systolic blood pressure and heart rate were observed at the higher doses of SD-3211 (50 and 100 mg/kg).Thus, SD-3211 affords substantial protection against ischaemia-induced ventricular antiarrhythmias partly through the negative inotropic and chronotropic effects, and reduction of afterload. The antiarrhythmic action of SA3212 against reperfusion-induced ventricular fibrillation may be partly explained by depression of automaticity together with a reduction of the inward sodium current.Send offprint requests to M. Fukuchi at the above address     

Reduction of myocardial ischemia-reperfusion injury by KT-362, a new intracellular calcium antagonist in anesthetized dogs

The effects of a new intracellular calcium antagonist, KT-362 (5-[3-[[2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]- 2,3,4,5,-tetrahydro-1,5-benzothiazepine fumarate) on myocardial infarct size following a 90-min occlusion and 3-h reperfusion of the left anterior descending coronary artery (LAD) were determined in anesthetized dogs. Regional myocardial blood flow was measured by radioactive microsphere technique, and infarct size was determined using triphenyltetrazolium chloride histochemical stain. Vehicle or KT-362 (300 micrograms/kg/min for 20 min followed by 150 micrograms/kg/min for 80 min) was administered intravenously (i.v.) 10 min prior to coronary occlusion and continued throughout the occlusion period in separate experimental groups. KT-362 produced a reduction in heart rate (HR) and the HR-systolic pressure product. Mean arterial pressure (MAP) was reduced during occlusion and early reperfusion in the KT-362-treated group, and segment function (% segment shortening) was improved during the first hour of reperfusion. There were no differences in collateral blood flow between the two groups. However, at 3 h postreperfusion, ischemic zone subendocardial blood flow in the KT-362-treated group was significantly greater than in the vehicle-treated group, resulting in an increase in endo/epi. There were no differences in ventricular mass, mass of the area at risk, or percentage of the left ventricle at risk. As compared with the control group, KT-362 produced a marked reduction in myocardial infarct size expressed as a percentage of the area at risk infarcted, percentage of the left ventricle infarcted, and absolute weight of infarcted tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intracoronary Bay k 8644, a calcium channel agonist, in anesthetized dogs

Bay k 8644, a new dihydropyridine calcium channel activator has been shown to have positive inotropic and vasoconstrictor properties following intravenous (i.v.) administration. In the present study, intracoronary administration of Bay k 8644 was used to isolate drug effects on regional myocardial blood flow and contractility independent of systemic hemodynamic actions in beta-adrenoceptor-blocked anesthetized dogs. Intracoronary infusion of Bay k 8644 (1.5, 3.7, 7.4, 14.8 micrograms/min) produced significant increases in contractility (percentage of segment shortening) in the drug-perfused region. Peak positive dP/dt, an index of global contractility, was increased in parallel with increases of regional contractility. No other changes in systemic hemodynamics occurred. Transmural tissue blood flow distribution as measured by radioactive microspheres was also unchanged by Bay k 8644. Intracoronary infusion of KB-944, a nondihydropyridine calcium channel blocking agent, increased coronary blood flow and decreased regional segment shortening and peak positive dP/dt. KB-944 inhibited increases in contractility produced by Bay k 8644. Thus, Bay k 8644 was shown to have a direct positive inotropic effect in vivo which was inhibited by calcium channel blockade.     

Antihypertensive effects of niguldipine-HCl (B 844-39), a new calcium antagonist in dogs

B 844-39 is a new dihydropyridine calcium antagonist with a long-lasting antihypertensive action. Preliminary tests in chronically instrumented normotensive dogs revealed that B 844-39 (0.3 mg/kg p.o.) caused a marked decrease in blood pressure which was accompanied by a counterregulatory increase in heart rate. Both effects outlasted the 6-h observation period. There was no sign of cardiac depression in left ventricular positive dP/dtmax or sonomicrometrically evaluated subendocardial systolic shortening. B 844-39 was also tested in renal hypertensive dogs over a period of 12 days to investigate its potential in the long-term treatment of hypertension. A dosage of 0.3 mg/kg given orally twice a day led to a marked and persistent decrease in blood pressure, which was accompanied by a positive chronotropic effect and increases in plasma renin activity and angiotensin II. This initial counterregulatory response was blunted within several days of chronic treatment. After completion of the 12-day treatment period, the blood pressure reduction persisted for greater than 14 days. B 844-39 induced a marked and persistent reduction in blood pressure in hypertensive dogs, even with prolongation of the dosing interval to 24 h. The hypotensive effect of this drug was more pronounced in hypertensive than in normotensive animals.     

Antiarrhythmic and electrophysiological effects of SD-3212, a novel Na+ and Ca++ channel blocker,in anaesthetized dogs with myocardial infarction in comparison with its stereoisomer (SD-3211) and bepridil

Summary Antiarrhythmic and electrophysiological effects of SD-3212, a novel antiarrhythmic agent, which has both Na⁺ channel and Ca⁺⁺ channel blocking activites, were compared with those of its (+)-stereoisomer, SD-3211, which has only a Ca⁺⁺ channel blocking activity, and bepridil, a known Ca⁺⁺ channel blocker with additional Na⁺ channel blocking activity, using the two-stage coronary ligation induced arrhythmia (24h after the ligation of the left anterior descending coronary artery) and 7 day-old myocardial infarcted hearts in anaesthetized dogs.SD-3212 showed a dose-dependent antiarrhythmic effect on the two-stage coronary ligation induced arrhythmia. SD-3212 at a dose of 3 mg/kg reduced the arrhythmic ratio, i.e. ectopic beats per min divided by the sum of ectopic beats and sinus beats per min, significantly from 1 up to 12 min after the administration. Neither bepridil (1–6 mg/kg) nor SD-3211 (1 mg/kg) had an antiarrhythmic effect. SD-3212 (0.3–3 mg/kg) prolonged both the conduction time in the normal myocardium and the delayed potential in the infarcted myocardium in the 7 day-old myocardial infarcted hearts in anaesthetized dogs in a dose-dependent manner. This effect of SD-3212 was shown at coupling intervals of 150–1000 ms increasing with decreasing interval. In this respect, SD-3212 is similar to drugs which show fast recovery of V_max from use-dependent block such as lidocaine. Bepidril (1–6 mg/kg) also prolonged these parameters in a dose-dependent manner, however, the prolongation induced by bedripil was limited to shorter coupling intervals as compared with that induced by SD-3212. SD-3212 (0.1–1 mg/kg) did not show this prolonging effect. SD-3212 increased the refractory period in the infarcted zone to a small extent (not significantly) at all strengths tested between 0.5–4 mA and also in the normal zone between 0.2–1 mA to an even lesser extent than in the infarcted zone. Bepridil produced a significant increase of refractory period in the infarcted zone. In the normal zone, bepridil produced a non-significant, but greater increase of the refractory period as compared with SD-3212. SD-3211 did not affect the refractory period in the infarcted zone or in the normal zone. None of the three drugs produced a significant change in the excitation threshold.Thus, SD-3212 showed electrophysiological properties of a drug with fast recovery kinetics without producing a significant increase of refractory period, and these properties are very similar to those of class Ib antiarrhythmic agents such as lidocaine. The present study suggests that there might be a possibility of SD-3212 to become a safe and unique antiarrhythmic agent with suppresses both Na⁺ and Ca⁺⁺ inward current.Send offprint requests to S. Nagashima at the above address     

Cardiovascular effects of the new calcium antagonist isradipine and of diltiazem in anesthetized open-chest dogs

Cardiovascular effects of the new calcium antagonist, isradipine (PN 200-110), were compared with those of diltiazem in anesthetized open-chest dogs. Isradipine 5 micrograms/kg i.v. produced significant decreases in systolic, diastolic and mean aortic blood pressure (AoP) concomitant with a decrease in mean renal blood flow (RBF) and increases in mean vertebral blood flow (VBF), mean coronary blood flow (CBF) and left ventricular dP/dt (LVdP/dt), but almost unchanged heart rate (HR) and left ventricular enddiastolic pressure (LVEDP). Diltiazem 300 micrograms/kg i.v. also produced decreases in AoP and RBF and increases in AoF, VBF and CBF. LVdP/dt and LVEDP were not significantly changed, but HR was decreased by this drug. Duration of increase in AoF, VBF and CBF was significantly longer in isradipine than in diltiazem. The decrease of coronary vascular resistance relative to total peripheral resistance was significantly greater than 1.0 for diltiazem, but not for isradipine. Results indicate that isradipine produces effects on AoP, AoF, VBF, CBF, RBF and LVEDP similar to diltiazem and the drug increases LVdP/dt without a decrease in HR in contrast to diltiazem, and that the effects of isradipine were long sustained when compared with those of diltiazem.     

Antiarrhythmic effects of a novel Na+ and Ca++ channel blocker,SD-3212: A comparison with its enantiomer (SD-3211)

The electrophysiological and antiarrhythmic effects of a structurally novel compound, SD-3212, were evaluated in comparison with its enantiomer (SD-3211). In isolated guinea pig ventricular muscles, SD-3212 reduced the maximum upstroke velocity and the plateau phase of action potential in a concentration-dependent manner, while SD-3211 significantly affected only action potential duration. SD-3212 had oral prophylactic effects against both ouabain-induced (in guinea pigs) and chloroform-induced (in rats) arrhythmas, whereas SD-3211 and verapamil were effective only on the former arrhythmia model and mexiletine was effective only on the latter. These results suggest that there is an enantiospecific interaction with cardiac Na⁺ and Ca⁺⁺ channels, and that the dual inhibitory action of SD-3212 on these channels may contribute to its antiarrhythmic properties.