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.     

Simvastatin and atorvastatin enhance hypotensive effect of diltiazem in rats.

Effects of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin, on diltiazem-induced hypotension were examined in anaesthetized rats and compared to that of pravastatin. Vehicle, 2 mg/kg/day simvastatin, 2 mg/kg/day atorvastatin, or 4 mg/kg/day pravastatin was administered orally for 4 days. Diltiazem at 3 mg/kg was given orally 2 hours after the final administration of the inhibitors. Arterial blood pressure was measured via a cannula introduced into the left carotid artery, and heart rate was counted from the pulse pressure. In all groups, diltiazem significantly decreased the mean arterial blood pressure without any changes in heart rate. Pretreatment with simvastatin and atorvastatin significantly enhanced the hypotensive effect of diltiazem, while that with pravastatin did not. Heart rate was not modified by pretreatment with the inhibitors. The results indicate that concomitant use of diltiazem with simvastatin or atorvastatin enhances diltiazem-induced hypotension, probably by competitive inhibition of diltiazem metabolism with simvastatin and atorvastatin metabolisms.     

Effects of semotiadil (SD-3211), a benzothiazine calcium antagonist, on blood pressure and atrioventricular conductivity in anesthetized dogs.

We investigated the effects of semotiadil (SD-3211), a novel calcium antagonist, on blood pressure and the atrioventricular (AV) conduction time and functional refractory period (FRP) of the AV conduction system (AV conductivity) in anesthetized open-chest dogs. The heart was electrically stimulated at a constant rate. In dogs with an intact nerve supply to the heart, i.v.-injections of semotiadil (0.03 to 0.3 mg/kg) produced a fall of blood pressure in a dose-dependent manner. AV conduction time and FRP were prolonged by rather higher doses (0.3 mg/kg), and second-degree AV block occurred only with the highest dose (1 mg/kg). In dogs with the nerve supply to the heart interrupted, the vasodepressor effects and suppressant effects of semotiadil on AV conductivity were slightly enhanced. The suppressant effects on AV conductivity became marked as pacing rates were increased. These results suggest that semotiadil at appropriate doses produces a vasodepressor effect without affecting AV conductivity even in the heart deprived of nervous control, e.g., the heart with beta-adrenoceptors blocked. The frequency-dependent suppressant effect on FRP of semotiadil is also noteworthy in the treatment of reentrant supraventricular tachycardia that involves the AV node.     

Hypotensive effects of diltiazem hydrochloride in the normotensive, spontaneously hypertensive and renal hypertensive rats (author's transl)

In conscious and anesthetized normotensive rats, intravenous administration of diltiazem (0.1--3 mg/kg) produced a dose-related decrease in blood pressure. Administration of diltiazem (1--50 mg/kg) into the duodenum of anesthetized rats also reduced the blood pressure in a dose related manner. In parallel with the change in blood pressure, the heart rate increased in conscious rats and decreased in anesthetized animals. Such an increase in the heart rate was suppressed by pretreatment with propranolol. Similarly, in conscious spontaneously hypertensive rats (SHR), diltiazem dose-dependently decreased the blood pressure and increased the heart rate after intravenous administration (0.03--1 mg/kg). Oral administration of diltiazem (100 mg/kg) also reduced the blood pressure of SHR. In addition, the progressive increase in blood pressure in young SHR was significantly suppressed by chronic oral administration of diltiazem (30 mg/kg). The blood pressure in conscious renal hypertensive rats was also decreased with diltiazem (50 mg/kg p.o.). On the other hand, it was demonstrated that the pressor responses to norepinephrine and angiotensin II in the anesthetized normotensive rats were non-competitively inhibited by intravenous administration of diltiazem at a dose which had no effect on the blood pressure.     

Effects of bepridil, diltiazem and verapamil on atrial refractoriness and heart rate in the conscious dog: comparison with quinidine

1. Bepridil at cumulative doses between 1.25 and 8.75 mg/kg and quinidine between 2.5 and 17.5 mg/kg given in conscious dogs with chronic atrioventricular block and implanted atrial pacing electrodes, dose-relatedly lengthened atrial effective refractory period (AERP), as reflected by the decrease in maximal atrial frequency determined by pacing. 2. Diltiazem shortened AERP at 0.25 mg/kg and lengthened it at 1.75 mg/kg, but both effects were very slight. 3. Verapamil between 0.06 and 0.435 mg/kg did not alter AERP at all. 4. Except for diltiazem at 0.75 and 1.75 mg/kg and bepridil at 8.75 mg/kg, each dose of each drug increased atrial rate. Each drug produced an increase in ventricular rate and a short-lasting lowering in mean blood pressure. 5. Thus, these results indicate that bepridil exhibits more marked antiarrhythmic potentialities than quinidine and that the atrial and ventricular tachycardic effects observed are mainly baroreceptor reflex effects.     

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.     

The hemodynamic effects of lacidipine in anesthetized dogs: comparison with nitrendipine, amlodipine, verapamil, and diltiazem.

The hemodynamic effects of lacidipine in anesthetized, open-chest dogs were compared with those of nitrendipine, amlodipine, verapamil and diltiazem. Lacidipine administered intravenously induced dose-related, long-lasting reductions in systemic and coronary vascular resistance with corresponding increases in aortic flow and coronary blood flow. The hypotensive effect (ED25 for mean blood pressure reduction = 0.006 mg/kg) was still significant 120 min after administration with all doses tested. Nitrendipine was equipotent with lacidipine in reducing the mean blood pressure (ED25 = 0.005 mg/kg), but its effect was shorter acting (significant effect at 120 min only with the highest dose tested). Amlodipine caused a marked and long-lasting hypotension though at higher doses than lacidipine (ED25 = 0.50 mg/kg). Short-lasting hypotensive responses were also detected with verapamil (ED25 = 0.1 mg/kg) and diltiazem (ED25 = 0.12 mg/kg). A reflex increase in heart rate was observed with lacidipine, nitrendipine, and amlodipine, whereas verapamil and diltiazem showed a dose-related bradycardia. No effect on AV conduction was observed with lacidipine and nitrendipine, whereas amlodipine, verapamil, and diltiazem produced second- to third-degree AV block at the highest doses tested. Lacidipine and nitrendipine caused a reflex increase in contractile index at all doses, whereas amlodipine was more similar to verapamil since a marked decrease in contractile index was detected at the highest dose. Diltiazem was practically devoid of negative inotropic effect.     

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     

Vasodilator action of KB-944, a new calcium antagonist

Vasodilator action of diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944) was mainly examined in comparison with papaverine in isolated perfused heart and anesthetized or conscious dogs. In isolated perfused heart, KB-944 (1-30 micrograms/heart i.a.) and diltiazem (1-30 micrograms/heart i.a.) produced a dose-dependent increase in coronary flow, and dose-dependent decrease in the heart rate and the myocardial contractile force. On the other hand, papaverine (3-100 micrograms/heart i.a.) produced a dose-dependent increase in coronary flow and heart rate, and did not practically affect the myocardial contractile force. KB-944 was about 3 times as active as papaverine and diltiazem on the percent increase of coronary flow. In anesthetized dogs, KB-944 (0.03-0.3 mg/kg i.v. or 10 mg/kg i.d.), diltiazem (0.03-0.3 mg/kg i.v. or 10 mg/kg i.d.) and papaverine (0.1-1 mg/kg i.v.) significantly increased the coronary blood flow with hypotension. Simultaneously, KB-944 and diltiazem decreased the heart rate, whereas papaverine increased it. Furthermore, KB-944 and diltiazem selectively increased the coronary blood flow more than the carotid blood flow, though papaverine increased the carotid blood flow more than the coronary blood flow. In case of i.v. route, KB-944 and diltiazem were about 5 times as active as papaverine on the percent increase of coronary blood flow. In case of i.d. route, the effect on coronary blood flow and heart rate induced by KB-944 was quantitatively similar to that induced by diltiazem, although the decrease in blood pressure induced by diltiazem was lesser than that produced by KB-944. In conscious dogs, KB-944 (0.03-0.3 mg/kg i.v. or 10-100 mg/kg p.o.) produced a dose-dependent increase in coronary blood flow and heart rate. In case of i.v. route, this vasodilator activity of KB-944 was 10 times as potent as that of papaverine. Thus, KB-944 is a more potent coronary vasodilator. Furthermore, KB-944 is well absorbed from the intestinal tract, and produces a long-acting increase in the coronary blood flow.     

Pharmacokinetics and pharmacodynamic effects of aqueous diltiazem in healthy humans

Aqueous diltiazem was given to ten healthy male volunteers in a single oral dose of 2.5 mg/kg body weight. Serum diltiazem levels were measured at various intervals up to 24 hours after administration of the drug as were blood pressure, heart rate, and PR interval. The pharmacokinetics followed a one-compartment model in six and two-compartment model in four subjects. The mean distribution half-life in the latter four subjects was 15.8 +/- 3.7 minutes (range, 10.4-18.8 min). In the ten subjects, the peak serum diltiazem level was attained in 20 to 45 minutes (mean, 32.5 +/- 9.5 min) and ranged from 136 to 701 ng/mL (mean, 332 +/- 180 ng/mL). The elimination half-life ranged from 2.8 to 4.8 hours (mean, 3.8 +/- 0.6 hr). The area under the concentration-time curve varied from 508 to 2,245 ng-hr/mL, indicating differing bioavailability. Slight but significant blood pressure reduction was seen only at one to three hours. Changes in heart rate were not significant at any measurement. Transient facial flushing, beginning at ten to 20 minutes after administration, was noted in nine subjects, reflecting the vasodilatory effect of the drug. Significant prolongation (greater than 10%) of PR intervals began at ten minutes in three, at 20 minutes in six, and at 30 minutes in one participant, and progressed to second-degree Wenckebach atrioventricular (AV) block in six subjects 20 to 60 minutes after administration and third-degree AV block in one person 45 minutes after dosing. These AV blocks resolved by the third hour without treatment, and PR prolongation resolved by the fifth to seventh hours.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diltiazem and Propranolol,Alone and in Combination,on Exercise Performance and Left Ventricular Function in Patients with Stable Effort Angina: A Double-Blind,Randomized, and Placebo-Controlled Study

Abstract: Diltiazem and propranolol alone and in combination as antianginal agents were compared with placebo in 12 patients with stable exertional angina at Stanford University Medical Center. The patients performed symptom-limited, multi-stage upright bicycle ergometric exercise while undergoing radionuclide angiographic studies every two weeks while being treated with 90 mg of diltiazem four times daily, 60 mg of propranolol four times daily, a combination of 90 mg of diltiazem and 60 mg of propranolol four times daily, and placebo. Diltiazem, propranolol and a combination all significantly increased exercise duration compared to placebo (526 ± 149 , 525 ± 115 , and 549 ± 129 vs 430 ± 132 sec). Although rate pressure product and heart rate decreased with diltiazem therapy at submaximal workloads, these values were unchanged at peak exercise in contrast to propranolol or the combination of propranolol or diltiazem. Diltiazem decreased the sub-maximal and maximal degree of exercise-induced ST segment depression by over 50% compared to placebo (P < 0.01 vs placebo). Diltiazem resulted in a higher exercise left ventricular ejection fraction compared to placebo, propranolol or the combination of diltiazem or propranolol (all less than P < 0.05). Sinus bradycardia or orthostatic hypertension occurred in four patients on the high-dose combination therapy and required dose reduction. We concluded that high-dose diltiazem, appeared to be even more effective than moderate-dose propranolol or the combination of diltiazem and propranolol in improving exercise tolerance, electrocardiographic evidence of myocardial ischaemia and left ventricular function in patients with stable effort angina due to occlusive coronary artery disease.     

Tissue selectivity of the novel calcium antagonist sesamodil fumarate in isolated smooth muscles and cardiac muscles

The effects of the novel Ca2+ antagonist sesamodil fumarate (JAN), (+)-3,4-dihydro-2-[5-methoxy-2-[3-[N-methyl-N-[2-[(3,4- methylenedioxy)phenoxy]ethyl]amino]propoxy]phenyl]-4-methyl-3-oxo-2H- 1,4-benzothiazine hydrogen fumarate (SD-3211), on isolated smooth muscles and cardiac muscles were investigated and compared with those of diltiazem, verapamil, nifedipine and nicardipine. Ca2+ antagonistic activity of SD-3211 (pA2 = 8.42) was more potent than that of diltiazem and verapamil, but less potent than that of nifedipine and nicardipine in isolated pig coronary artery. The inhibition of Ca2(+)-induced contraction by SD-3211 was not reversed by drug washout, whereas that by diltiazem was easily reversed by drug washout. SD-3211 produced a concentration-dependent relaxation (EC50 = 5.7 x 10(-8) mol/l) of KCl-contracted pig coronary artery. The order of potency of the various compounds correlated with their respective Ca2+ antagonistic activities. SD-3211 antagonized KCl-induced contraction, but not that induced by A23187, in the rabbit aorta. On the other hand, negative inotropic and chronotropic effects of SD-3211 on the guinea pig right atria approximated those of diltiazem and verapamil. These results suggest that SD-3211 exerts a potent and long-lasting Ca2+ antagonistic effect on isolated arteries, possessing pharmacological properties diverse from those of known Ca2+ antagonists with respect to tissue selectivity, i.e., it is more vasoselective than diltiazem and verapamil, and more cardioselective than nifedipine and nicardipine.     

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.     

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. 2. The vasospasmolytic effect of SD-3211 was investigated using 3,4-diaminopyridine-induced rhythmic contraction, in comparison with its enantiomer (SD-3212), nicardipine and diltiazem. SD-3211 was shown to reduce the peak tension and increase the contraction frequency. The order of potency for the relaxation of the peak tension was as follows: nicardipine greater than SD-3211 greater than diltiazem greater than SD-3212 and being compatible with that for the relaxant effects of these compounds on KCl-induced contraction in the same specimen. 3. Furthermore, the effect of SD-3211 on myocardial damage due to global ischaemia for 60 min followed by 60 min of reperfusion was examined. SD-3211 at a concentration of 2 X 10(-8) mol/L was given for 40 min before and again for 60 min after the ischaemia. SD-3211 attenuated the increase in leakage of creatine phosphokinase from the hearts and the decrease in pH of perfusate during reperfusion, while concomitantly providing a significant improvement in the post-ischaemic recovery of developed tension. 4. These results suggest that SD-3211 has properties to reduce coronary vasospasm and to provide protection against ischaemic damage, both of which may have beneficial actions in the treatment of ischaemic heart disease.     

Direct effects of diltiazem, nifedipine and verapamil on peripheral sympathetic nerve function, cardiac impulse conduction and cardiovascular function in anesthetized dogs subjected to ganglionic blockade

The Ca2+ entry blockers diltiazem, nifedipine and verapamil produced dose-dependent increases in atrioventricular conduction time (A-H interval), while decreasing heart rate and mean arterial pressure in anesthetized dogs previously subjected to ganglionic blockade to prevent hypotension-induced reflex changes in sympathetic tone. Nifedipine and verapamil, but not diltiazem, also reduced (P less than 0.05) the tachycardia produced by electrical stimulation of the cardioaccelerator nerve at doses which did not alter the heart rate response to direct beta-adrenoceptor stimulation by isoproterenol (0.1 microgram/kg i.v.). The lowest doses of nifedipine (0.03 mg/kg) and verapamil (0.3 mg/kg) that produced decreases in mean arterial blood pressure were the same as or greater than those which selectivity reduced the tachycardiac effects of low frequency (1 Hz, 25-35 V, 5 ms), but not high frequency (10 Hz, 25-35 V, 5 ms) cardiac nerve stimulation. These data suggest that threshold vasodilator doses of some Ca2+ blockers may selectively reduce low level (or basal) sympathetic neurotransmission and this additional pharmacologic action may contribute to the antihypertensive mechanism. The failure to inhibit the high frequency nerve response may also help to explain the relatively low incidence of orthostatic hypotension associated with the clinical use of Ca2+ blockers as compared to other direct-acting vasodilators.     

Influence of indomethacin and clidanac on the blood pressure lowering effect of beta-blockers

In conscious rabbits, the intravenous administration of pindolol (1.25 mg/kg), propranolol (1 mg/kg) and alprenolol (2 mg/kg) induced a highly significant decrease of mean arterial blood pressure and significant bradycardia. In the same model, the intravenous administration of saline, indomethacin, and clidanac did not affect the mean arterial blood pressure and heart rate. Pretreatment with indomethacin and clidanac reduced the effect of these beta-blockers on the mean arterial blood pressure and had no effect on the heart rate. Treating of the guinea pig heart homogenate with 1 microM indomethacin or clidanac decreased the number of beta-adrenoceptors without changing their affinity. These results suggest that indomethacin and clidanac interfere with beta-adrenoceptor-mediated effects.     

MODIFICATION BY DILTIAZEM, A CALCIUM ANTAGONIST, OF THE PULMONARY VAGAL AND CARDIAC SYMPATHETIC CHEMOREFLEXES IN THE DOG

1. Experiments were performed on anaesthetized, open-chest dogs to determine the effects of diltiazem on: the pulmonary vagal chemoreflex evoked by intravenous (i.v.) injection of capsaicin; cardiac sympathetic chemoreflexes activated by epicardial application of bradykinin or capsaicin; and baroreflex-mediated changes in heart rate resulting from both pressor and depressor effects produced by i.v. injections of noradrenaline and bradykinin, respectively. 2. Diltiazem infused i.v. at a rate of 10-30 micrograms/kg per min (mean cumulative dose 0.53 +/- 0.05 mg/kg, n = 9), did not affect basal heart rate, despite significant (P less than 0.001) reduction of resting blood pressure. 3. Diltiazem treatment did not affect the pressor responses to i.v. noradrenaline (0.3 micrograms/kg) or the hypotensive effects of i.v. bradykinin (0.3 micrograms/kg), but reduced significantly both the baroreflex-mediated bradycardia (P less than 0.01) and tachycardia (P less than 0.05) occurring with noradrenaline and bradykinin, respectively. 4. In contrast, diltiazem greatly enhanced reflex bradycardia (P less than 0.001) and systemic hypotension (P less than 0.01) resulting from activation of the afferent vagal pulmonary receptors by i.v. capsaicin (3-5 micrograms/kg). 5. Reflex pressor responses evoked by activation of the afferent cardiac sympathetic neurons by epicardial application of bradykinin (1 microgram) or capsaicin (10-20 micrograms) were not affected by diltiazem, but the corresponding reflex increases in heart rate evoked by both substances were significantly (P less than 0.01) reduced. 6. The results indicate that diltiazem, while reducing the influence of sinoaortic baroreceptors on heart rate, facilitates the reflex vagal control of the cardiac pacemaker by the afferent cardiopulmonary vagal receptors. These nervous reflex mechanisms, which include attenuation of positive chronotrophic effects that may result from ischaemia-induced activation of the afferent cardiac sympathetic neurons, may play an important role in the protective action of diltiazem in ischaemic heart disease.     

The cardiovascular actions of thalicarpine

The iv administration of thalicarpine (2.5–20.0 mg/kg), a dimeric alkaloid, in the rhesus monkey caused an increase in pulse pressure and, except for the 2.5-mg/kg dose, varying degrees of hypotension. Carotid artery blood flow and heart rate increased after doses of 2.5–10.0 mg/kg. These latter effects were blocked by pretreatment with hexamethonium or dl-propranolol. Thalicarpine (5.0 or 10.0 mg/kg) increased cardiac output and decreased peripheral resistance. All doses of thalicarpine (2.5–20.0 mg) depressed force of contraction, heart rate and coronary perfusion pressure in the isolated, blood-perfused dog heart. The hypotension induced by thalicarpine appears to be due to a nonspecific vasodilation and myocardial depression.     

Effects of gallopamil, diltiazem and nifedipine on the loss of K from ischaemic pig hearts

K⁺ release into the extracellular space was investigated during repeated 6-min coronary occlusions before and after the intravenous administration of cardiovascular active doses of gallopamil (0.02; 0.05 mg/kg), diltiazem (1.0; 2.0 mg/kg) or nifedifine (0.01; 0.05 mg/kg) to anaesthetized pigs. [K⁺]_e was measured epicardially using silver valinomycin electrodes calibrated in vivo. During control occlusions [K⁺]_e rose steeply in all groups, from a pre-ischaemic baseline value of about 3.5 mmol/1 reaching a plateau value within the ischaemic period. This response was reproducible in an untreated control group. Gallopamil reduced the ischaemic K⁺ efflux dose dependently and significantly 10 min after injection; the higher dose also did 60 min after injection. Diltiazem had less effect on K⁺ efflux 10 min after administration and an effect was no longer detectable after 60 min. Nifedipine did not significantly inhibit the ischaemic K⁺ loss. Besides these differences in the direct protection of the ischaemic myocardium, the Ca²⁺ antagonists also had the following effects on the haemodynamic profile. Diltiazem and gallopamil significantly prolonged PQ intervals whereas nifedipine caused a shortening accompanied by a significant increase in heart rate. Blood pressure and LV dP/dt_max were significantly reduced by all compounds, but to a different degree. Diltiazem reduced blood pressure to a greater extent than did nifedipine and gallopamil. LV dP/dt_max was comparably reduced by gallopamil and diltiazem, while nifedipine had less effect. Thus, gallopamil exerted pronounced protective effects on the ischaemic pig heart.     

Pharmacodynamic and pharmacokinetic studies on prizidilol and nipradilol (K-351), antihypertensive drugs with combined vasodilator and beta-adrenoceptor blocking actions, in rabbits

Effects of prizidilol and nipradilol (K-351), beta-adrenoceptor antagonists with vasodilator action, on blood pressure and heart rate were studied in normotensive conscious rabbits after i.v. administration. In addition, we investigated relationships between plasma drug concentrations and beta-adrenoceptor blocking activity as estimated by the inhibition of isoproterenol-induced tachycardia and vasodilator activity as assessed by the inhibition of pressor response to angiotensin II (ANG II). Prizidilol (4 mg/kg) produced a significant and sustained fall in blood pressure and a slight increase in heart rate, while hydralazine (2 mg/kg) caused the same degree of hypotension and a marked tachycardia. Nipradilol (1 mg/kg) caused a significant reduction of resting heart rate, but had no significant effect on blood pressure. Propranolol (1 mg/kg) did not affect resting blood pressure and heart rate. Hypertensive response to ANG II was significantly attenuated only by hydralazine. Isoproterenol-induced tachycardia was significantly suppressed by prizidilol, nipradilol and propranolol. Good correlations were observed between beta-adrenoceptor blocking activity and plasma drug concentrations. These data suggest that prizidilol has an advantage over hydralazine to induce less tachycardia, but still may cause a certain degree of increase in heart rate. Nipradilol has a more potent beta-adrenoceptor blocking action than propranolol, while its vasodilator action is not obvious, at least in rabbits. Plasma concentrations of prizidilol and nipradilol are good indicators for beta-adrenoceptor blocking activity, but not for vasodilator activity.