Cardiac and systemic hemodynamic actions of the slow channel calcium blocking agent, KB-944

The effects of KB-944 (10-400 micrograms/kg/min, i.v.), a new slow channel calcium blocking agent, on myocardial oxygen utilization, regional myocardial perfusion and hemodynamics were measured in anesthetized dogs. KB-944 produced significant dose-related increases in coronary blood flow and decreases in heart rate, left ventricular systolic pressure, aortic blood pressure and peripheral vascular resistance. At high doses, peak positive and negative dP/dt were both reduced and left ventricular end diastolic pressure increased. KB-944 reduced arterial-venous oxygen content difference across the heart while significantly increasing coronary blood flow. The pressure rate product, an index of myocardial oxygen consumption, was also reduced. KB-944 produced a uniform and dose-related increase in transmural tissue flow within the left ventricular free wall. These results indicate that KB-944, a new slow channel calcium blocking agent, is a potent peripheral and coronary vasodilator with negative inotropic and chronotropic properties and may be potentially useful in coronary artery disease or hypertension.     

Cardiovascular actions of buflomedil and possible mechanisms involved

Cardiovascular effects of buflomedil (Bufedil) were studied in dogs, rabbits and guinea pigs. 1. In pentobarbital-anesthetized dogs, buflomedil (0.32-5.12 mg/kg i.v.) induced a dose-dependent fall of blood pressure and a slight increase of heart rate at 0.32-1.28 mg/kg but a heart rate decrease at 2.56 and 5.12 mg/kg. 2. Buflomedil administered into the maxillary (10-320 micrograms/kg), internal carotid (40-320 micrograms/kg) and vertebral artery (20-640 micrograms/kg) increased respective blood flows dose-dependently. 3. Buflomedil (i.v.) also produced dose-dependent increases of the maxillary blood flow at 0.08-0.64 mg/kg, internal carotid flow at 1.28-5.12 mg/kg and vertebral flow at 0.32-5.12 mg/kg, respectively. These increasing effects were attenuated at larger doses because of marked hypotension. 4. Buflomedil (10 mg/kg i.v.) reduced pressor responses to norepinephrine (noradrenaline) and enhanced depressor responses to isoprenaline (isoproterenol), without affecting depressor responses to acetylcholine and positive chronotropic responses to norepinephrine and isoprenaline. 5. After buflomedil (i.v.), the femoral and coronary blood flow increased dose-dependently while renal blood flow decreased. These increasing effects were also reduced at larger doses because of hypotension. 6. Buflomedil (i.v.) induced a dose-dependent increase of cardiac output at 0.16-0.64 mg/kg, biphasic changes at 1.28 and 2.56 mg/kg and a marked decrease and subsequent slight increase at a large dose of 5.12 mg/kg. 7. 4-Desmethylbuflomedil (i.v.); elicited dose-dependent biphasic changes of blood pressure at 0.64-5.12 mg/kg, and a slight increase of heart rate at 0.32-2.56 mg/kg but decreases at 5.12 mg/kg. It also elevated, dose-dependently, the maxillary blood flow at 0.16-5.12 mg/kg and vertebral flow at 1.28-5.12 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiarrhythmic effect of KB-944, a new calcium antagonist. A comparison with verapamil and diltiazem

Effects of diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944), a new chemical class of Ca-antagonist, on three types of experimentally induced arrhythmias were evaluated and compared with those of verapamil and diltiazem. KB-944 at 0.02 to 0.1 mg/kg (i.v.) effectively reversed ventricular arrhythmias induced by a continuous infusion of ouabain into guinea-pigs, and its effect was 2 times more potent than that of diltiazem and 5 times less potent than that of verapamil. Epinephrine(adrenaline)-induced arrhythmias in guinea-pigs were prevented by an i.v. injection of KB-944 in doses of 0.025 to 0.2 mg/kg. KB-944 was approximately equipotent with diltiazem and 2 times less potent than verapamil. CaCl2-induced arrhythmias in rats were inhibited by KB-944 with rather high doses (ED50 2.6 mg/kg i.v.). The antiarrhythmic effect of KB-944 was 1.7 times less potent than that of diltiazem and 5 times less potent than that of verapamil. KB-944 was found to possess antiarrhythmic activities in animals qualitatively similar to those of verapamil and diltiazem.     

Cardiac action of KB-944, a new calcium antagonist

A comparative study was made between the cardiac action of diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944) and those of nifedipine, diltiazem and verapamil in anesthetized dogs and isolated right atria of guinea pigs. In anesthetized dogs, KB-944 caused a dose-dependent fall in mean blood pressure and dose-dependent increase in coronary sinus outflow. Coronary sinus outflow oxygen pressure was increased with increasing coronary sinus outflow; and consequently, the coronary arterio-venous oxygen difference was decreased. The cardiac output was slightly increased, while the myocardial oxygen consumption and myocardial work were reduced. In the isolated right atria of guinea pigs, KB-944 produced a decrease in spontaneous atria rate, and at the concentration of 10(-6) g/ml atrial standstill was seen in few preparations. The contractile force was decreased by KB-944. Especially, KB-944 exerted the weakest effect on contractile force among the tested drugs. These actions of KB-944 are very similar to those of nifedipine, diltiazem and verapamil.     

Cerebral vasodilating and spasmolytic actions of a new Ca-antagonist, clentiazem (TA-3090), in anesthetized animals.

The effect of a new 1,5-benzothiazepine calcium antagonist, clentiazem (TA-3090), on the cerebral circulation was studied in anesthetized animals. Intravenous infusion of clentiazem at doses of 2.5, 5, and 10 micrograms/kg/min increased vertebral blood flow without causing hypotension in anesthetized dogs. After i.v. injection to anesthetized dogs, clentiazem, diltiazem, and papaverine all dose-dependently increased the regional cerebral blood flow and raised the intracranial pressure (ICP). However, the effect of clentiazem on the ICP was weaker than that of diltiazem and papaverine. In anesthetized monkeys, clentiazem (3-100 micrograms/kg, i.v.) increased the internal carotid blood flow to the intracranial tissues. In anesthetized cats, topical or i.v. clentiazem inhibited basilar artery vasospasm induced by the topical application of serotonin, prostaglandin F2 alpha, and incubated blood. These findings suggest that clentiazem has favorable properties as a cerebral vasodilator.     

Cardiovascular effects of the new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate. 2nd communication: studies in dogs

The cardiovascular effects of 1,2-dihydro-6-methyl-2-oxo-5-(imidazo[1,2-a]pyridin-6-yl)-3-pyridine carbonitrile hydrochloride monohydrate (E-1020), a new nonglycoside, noncatechol cardiotonic agent, were investigated in dogs. In anesthetized dogs, E-1020 (10-100 micrograms/kg i.v.) dose-relatedly increased cardiac contractility (LV dP/dtmax), enhanced cardiac index and decreased systemic vascular resistance accompanying relatively small reduction in mean aortic pressure and a mild increase in heart rate. Coronary and femoral arterial blood flow were increased by either systemic intravenous or topical administration of E-1020. The degree of increase in myocardial oxygen consumption was only slight (10% at 30 micrograms/kg i.v.). The inotropic effect of E-1020 was not markedly affected by pretreatment with beta-adrenoceptor blockade, reserpine or other cardiotonic agents such as dobutamine or ouabain. In two experimental heart failure models induced by an excessive dose of propranolol or by coronary occlusion following volume-loading, E-1020 (30 micrograms/kg i.v.) rapidly reversed the cardiac depression. In chronically instrumented conscious dogs, E-1020 (30-100 micrograms/kg i.v. or 0.3-10 mg/kg p.o.) produced dose-dependent increases in LV dP/dtmax with minor increases in heart rate. E-1020 did not exacerbate arrhythmias of several experimental models in anesthetized dogs even at high dose of 100 micrograms/kg i.v. These results indicate that E-1020 is an intravenously and orally effective cardiotonic agent with vasodilating property, and that it may be beneficial in the treatment of acute and chronic congestive heart failure.     

Cardiovascular effects of a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent, YM-16151-4, in anesthetized and conscious dogs.

Cardiovascular effects of YM-16151-4, a combined calcium entry blocking and beta 1-adrenoceptor blocking agent, were evaluated in dogs. In anesthetized dogs, YM-16151-4 (0.01-1 mg/kg intravenously, i.v.) dose-dependently increased coronary blood flow (CBF) and decreased mean blood pressure (MBP), total peripheral resistance (TPR), dP/dtmax, double product, and left ventricular (LV) work without increasing heart rate (HR) and cardiac output (CO). YM-16151-4 increased vertebral blood flow as well as CBF, but had no effect on carotid, mesenteric, renal, and femoral blood flow. Coronary vasodilating activity of YM-16151-4 was also observed after intracoronary artery injection (i.a.). In anesthetized and vagotomized dogs, YM-16151-4 dose-dependently inhibited isoproterenol (0.2 micrograms/kg i.v.)-induced tachycardia and decrease in diastolic BP (DBP), with ED50 values of 0.039 and 0.52 mg/kg i.v., respectively. In conscious dogs, YM-16151-4 (0.1-1 mg/kg i.v.) produced a dose-dependent hypotensive effect with no effect on HR or PQ-interval. The hypotensive effect of YM-16151-4 (0.3 and 1 mg/kg i.v.) reached its maximum approximately 1-2 h after each dosing and lasted 6-8 h. These results suggest that YM-16151-4 actually behaves as a hybrid compound, combining calcium entry blocking and beta 1-adrenoceptor blocking activities, and that this compound could be a novel long-acting antianginal and antihypertensive agent.     

Effects of trapidil and nitroglycerin on coronary circulation in conscious dogs

Effects of trapidil and nitroglycerin (glyceryl trinitrate) on coronary blood flow or epicardial coronary diameter were studied in conscious dogs, instrumented with a Doppler flow probe or a pair of ultrasonic dimension crystals on the left circumflex coronary artery. Bolus intravenous injections of trapidil (0.5, 1.0 and 2.0 mg/kg i.v.) increased coronary blood flow, dose-dependently, such being comparable at the peak value seen with nitroglycerin (5, 10 and 20 micrograms/kg i.v.). Coronary blood flow following the intravenous administration of trapidil or nitroglycerin increased biphasically and returned to pre-drug levels in 1.4 +/- 0.2 min (trapidil 1 mg/kg i.v.) or 1.0 +/- 0.1 min (nitroglycerin 10 micrograms/kg i.v.), while the mean coronary diameter increased monophasically and approached the control level 5 min after drug administration. The first peak was observed before the maximal decrease in aortic pressure and the second peak was associated with concomitant increases in heart rate and myocardial contractility induced by a sudden hypotension. Propranolol, a beta-blocker, did not modify the initial peak but attenuated markedly the second peak (P less than 0.05) in case of trapidil (1.0 mg/kg i.v.) or nitroglycerin (10 micrograms/kg i.v.), which corresponded with reduced changes in reflex tachycardia and positive inotropism. Therefore, the direct effects of trapidil and nitroglycerin on coronary circulation of conscious dogs are an initial transient dilatation of the resistance vessels followed by a continuation of the dilatation of the conductance coronary vessels.     

Cardiac versus coronary vasodilator actions of KB-944, a new calcium antagonist, assessed in isolated, blood-perfused heart preparations of dogs

We compared the cardiac and coronary vasodilator actions of a new calcium-antagonistic vasodilator, KB-944, in isolated, blood-perfused heart preparations of dogs. In all preparations KB-944 injected intra-arterially produced an increase in blood flow. In sinoatrial (SA) node preparations KB-944 decreased sinus rate and in large doses produced atrial standstill. In atrioventricular (AV) node preparations KB-944 increased AV conduction time and in large doses produced second- or third-degree AV block only when injected into the artery supplying the AV node. In the same preparations KB-944 had virtually no effect on AV conduction when injected into the artery supplying the His-Purkinje-ventricular system. In papillary muscle preparations KB-944 in medium and large doses depressed force of contraction, the depressant action being greater at high rates of contraction. In the same kind of preparations KB-944 affected automaticity slightly and inconsistently. Depression by KB-944 of SA nodal automaticity and AV nodal conduction occurred pari passu with coronary vasodilation, whereas force of contraction was depressed to a lesser extent in coronary vasodilator doses. In these respects, KB-944 resembles verapamil and diltiazem rather than nifedipine and nicardipine.     

ASSESSMENT OF THE CORONARY VASODILATOR ACTION OF SK&F 24260 IN THE DOG

1. The effects of SK&F 24260 administered intravenously or intraduodenally on the coronary outflow, coronary arteriovenous oxygen difference (A-V O2), myocardial oxygen consumption (MVO2), systemic blood pressure, heart rate and atrioventricular (AV) conduction time were examined in open-chest dogs. 2. SK&F 24260 in doses of 0.3-10 microgram/kg, i.v., caused a dose-dependent increase in coronary sinus outflow, but the increase was smaller with 30 microgram/kg, i.v., than with 10 microgram/kg, i.v. 3. SK&F 24260 (0.3-30 microgram/kg, i.v.) decreased A-V O2 and MVO2 in a dose-dependent manner. 4. SK&F 24260 (0.3-30 microgram/kg, i.v.) decreased systemic blood pressure and heart rate, and increased AV conduction time. 5. Intraduodenal administration of SK&F 24260 (1 mg/kg) produced almost the same effects on coronary sinus outflow, A-V O2, MVO2, systemic blood pressure, heart rate and AV conduction time as did the intravenous administration of the compound (10 microgram/kg). 6. The property of SK&F 24260 to increase the coronary blood flow and to moderately decrease MVO2, systemic blood pressure and heart rate indicates that this agent is a potential antianginal drug.     

Cardiovascular pharmacology of cinepazide, a new cerebral vasodilator (author's transl)

Cardiovascular effects of cinepazide were compared with those of cinnarizine and papaverine. Cinepazide (3-30 mg/kg, i.v.) produced a dose-related and transient increase in vertebral, carotid, renal and femoral arterial flow as well as cardiac output and a decrease in total peripheral resistance in anesthetized dogs. The magnitude and duration of mesenteric vasodilatation induced by cinepazide was much greater as compared to other vascular effects, and these effects were associated with a prolonged hypotension. The drug exerted positive inotropic and chronotropic actions, the latter being followed by bradycardia with the highest dose. Cinnarizine (0.3-3 mg/kg, i.v.) produced a greater increase in vertebral blood flow with bradycardia and papaverine (0.1-1 mg/kg, i.v.) produced a remarkable carotid vasodilatation with cardiac stimulation. Both reference drugs decreased renal blood flow. Cinepazide (30 mg/kg, i.v.) potentiated the vertebral vasodilator response of dogs to intravertebral adenosine and cyclic AMP, while cinnarizine (3 mg/kg i.v.) reduced their vasodilator effects. Intravertebral cinepazide(1-10 mg), like cinnarizine (0.1-1 mg) and papaverine (0.1-1 mg), increased vertebral blood flow in a dose-related manner and the effect was partially inhibited by intravenous pretreatment with aminophylline but not by pretreatment with autonomic antagonists. These antagonists did not modify the cinnarizine effect. Cinepazide resembled cinnarizine and papaverine in that the drug antagonized rabbit aortic contraction induced by KCl, norepinephrine or CaCl2.     

Cardiovascular pharmacological studies on JTV-506, a new potassium channel opener. 1st communication: effects on myocardium and vasculature

The effects of JTV-506 ((-)-(3S,4R)-2,2-bis(methoxymethyl)-4-[(1,6-dihydro-1-methyl-6-oxo-3- pyridazinyl)amino]-3-hydroxychroman-6-carbonitrile hemihydrate, CAS 170148-29-5), a novel coronary vasodilator, on hemodynamics, cardiac function and cardiac oxygen consumption were evaluated in anesthetized dogs. In anesthetized, open-chest dogs, JTV-506 (0.3-10 micrograms/kg i.v.) induced a marked increase in coronary blood flow in a dose dependent manner, while at these doses it had smaller effects on vertebral and mesenteric blood flow and almost no effect on renal blood flow. JTV-506 (1-10 micrograms/kg i.v.) showed a tendency to decrease oxygen consumption of the heart and elevate myocardial oxygen pressure without cardiac suppression. Effects of JTV-506 on hemodynamics and the respiratory system following i.v. administration (0.3-300 micrograms/kg) were investigated in spontaneously breathing anesthetized dogs. The effective dose to induce hemodynamic changes was more than 3 micrograms/kg. JTV-506 did not have a crucial influence on electrocardiogram. JTV-506 caused marked increase in coronary blood flow and myocardial oxygen pressure with slight change in blood pressure. It is concluded that JTV-506 is a potent vasodilator, with particularly pronounced effect on vasculature of the heart. These results suggest that JTV-506 may be useful in the treatment of angina pectoris.     

Vasodilating effects of nicorandil and nitroglycerin in anaesthetized open-chest dogs

Vasodilating effects of intravenous administrations of nicorandil (SG-75) and nitroglycerin were analyzed in anaesthetized open-chest dogs by measuring simultaneously, and continuously, coronary (CBF), vertebral (VBF), renal (RBF) and aortic blood flow (AoF). Nicorandil 10-300 micrograms/kg i.v. and nitroglycerin 1-30 micrograms/kg i.v. decreased aortic blood pressure and increased CBF in a dose-dependent fashion. The doses of nicorandil and nitroglycerin which reduced coronary vascular resistance to about 60% of the predrug value were 100 micrograms/kg and 10 micrograms/kg, respectively. Nicorandil 100 micrograms/kg i.v. significantly increased AoF and heart rate, significantly decreased left ventricular end-diastolic pressure and did not significantly change VBF, RBF and left ventricular dP/dt. Nitroglycerin 10 micrograms/kg i.v. significantly increased VBF and heart rate, significantly decreased left ventricular end-diastolic pressure and produced an initial increase followed by a decrease in AoF and RBF. When compared with these doses of both drugs, the ratio of percent decrease in coronary vascular resistance to that in total peripheral resistance was over 1.0 in both drugs and the value of this ratio in nicorandil was significantly larger than that in nitroglycerin. The duration of increase in CBF produced by nicorandil 10-300 micrograms/kg i.v. was dose-dependent, but was not changed by nitroglycerin 1-30 micrograms/kg i.v. The results indicate that nicorandil and nitroglycerin dilate coronary vasculature more markedly than other vascular beds and that the potency of selective coronary vasodilatation and the duration of action are more significant in nicorandil than in nitroglycerin.     

Inhibitory effects of diltiazem, verapamil, nifedipine, and nicardipine on sympathetic tachycardia in decentralized hearts of anesthetized dogs.

Intravenous diltiazem (10-300 micrograms/kg), verapamil (10-300 micrograms/kg), nifedipine (1-100 micrograms/kg) and nicardipine (1-100 micrograms/kg) inhibited the tachycardia caused by cardiac sympathetic nerve stimulation (SNS, 0.5-4 Hz) in decentralized hearts of anesthetized dogs. The dose range of each drug required to inhibit the SNS-induced tachycardia was almost equivalent to that required to produce the increase in coronary blood flow and the decrease in blood pressure. Nifedipine and nicardipine were equi-active and about 10 times more potent than diltiazem and verapamil in inhibiting the SNS-induced tachycardia. They produced a slight but dose-dependent slowing of the resting heart rate. The negative chronotropic potency was approximately nicardipine, verapamil greater than nifedipine, diltiazem. Bay K 8644 (30 micrograms/kg) antagonized the inhibitory effects of diltiazem (100 micrograms/kg) and nifedipine (30 micrograms/kg) on the SNS-induced tachycardia. Tachycardia induced by intracoronary norepinephrine (0.03-0.3 micrograms) was suppressed by diltiazem (30-300 micrograms/kg) and nifedipine (10-100 micrograms/kg). The inhibitory effects of calcium entry blocking drugs on the sympathetic tachycardia appear to be explained by the interference of the beta-adrenoceptor-mediated increase in slow inward current in the sinoatrial (SA) node. It is also suggested that other mechanisms different from calcium entry blocking action contribute to the negative chronotropic response to these calcium entry blocking drugs.     

Acute effects of bunazosin on aortic, vertebral, coronary and renal blood flows of anesthetized dogs

Effects of 4-amino-2-(4-butyrylhexahydro-1H-1,4-diazepin-1-yl)-6,7-dime thoxy-quinazoline (bunazosin, E-643, Detantol) on aortic, vertebral, coronary and renal blood flows were investigated in anesthetized open-chest dogs. Bunazosin 1, 10 and 100 micrograms/kg i.v. dose-dependently decreased aortic blood pressure (AoP) and inhibited the increase in AoP by phenylephrine 5 micrograms/kg i.v. However, the increase in AoP by norepinephrine 0.5 microgram/kg i.v. remained even after bunazosin 100 micrograms/kg i.v. and was almost undetectable after additional administration of yohimbine 1000 micrograms/kg i.v. A hypotension by bunazosin persisted more than 15 min, but dose-dependent increases in heart rate (HR) induced by bunazosin 1, 10 and 100 micrograms/kg i.v. restored within 2 min. Bunazosin 100 micrograms/kg i.v. significantly but transiently increased aortic blood flow and decreased renal blood flow. Vertebral and coronary blood flows were not significantly changed. Left ventricular dP/dt was transiently increased. Calculated total peripheral vascular resistance and coronary vascular resistance were transiently but significantly decreased. No significant changes were observed in both vertebral vascular resistance and renal vascular resistance. The results indicate that bunazosin maintains the blood flows to brain, heart and kidney, and is continuously lowering AoP without significant changes in HR.     

Effects of nitrendipine on cardiovascular systems

Cardiovascular effects of nitrendipine were examined in anesthetized dogs, blood-perfused canine papillary muscles and isolated arteries. In anesthetized dogs, nitrendipine by intravenous (0.3-10 micrograms/kg) or intraduodenal (0.1 mg/kg) administration lowered blood pressure and increased coronary and vertebral blood flow. Nitrendipine also decreased the difference in oxygen concentrations between arterial and coronary sinus blood, which indicates that nitrendipine increased the oxygen supply to the heart. Myocardial oxygen consumption was slightly increased at a low dose (3 micrograms/kg, i.v.) accompanied with a small increase in max dP/dt, but was decreased at high doses (30-100 micrograms/kg, i.v.). A negative inotropic effect was observed in blood-perfused canine papillary muscles. However, nitrendipine is thought to be highly vasoselective because much higher doses were required to decrease the myocardial contraction than to increase the coronary blood flow. Furthermore, nitrendipine suppressed the contraction induced by KCl, acetylcholine, histamine, norepinephrine, 5-hydroxytryptamine and prostaglandin F2 alpha of porcine coronary arteries, and the rhythmic contraction induced by 3,4-diaminopyridine of canine coronary arteries. In isolated rabbit aortic preparations, nitrendipine strongly inhibited the KCl-induced contraction, but not the phenylephrine-induced contraction. These effects of nitrendipine were almost similar to those of nifedipine. It is suggested that nitrendipine decreases afterload (blood pressure), increases the blood flow and oxygen supply to the heart, and inhibits coronary spasm, which is due to the calcium antagonistic effect. Nitrendipine may be useful for the treatment of ischemic heart diseases.     

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.     

Cardiovascular actions of the dihydropyridine calcium antagonist nimodipine in the dog

When injected i.v. into anaesthetized, open-chest dogs, isopropyl (2-methoxyethyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3, 5-pyridinedicarboxylate (nimodipine, Bay e 9736) (0.3-10 micrograms/kg) produced an increase in coronary sinus outflow and decreases in mean arterial blood pressure, coronary resistance, arterio-venous oxygen difference and heart rate in a dose-dependent manner, but virtually no change in myocardial oxygen consumption. At 3 micrograms/kg i.v. of the drug coronary resistance fell nearly to half the pre-drug value, coronary sinus outflow nearly doubled and heart rate decreased by about 10 beats/min. Myocardial oxygen consumption was slightly reduced at 30 micrograms/kg i.v. and atrioventricular (AV) conduction time was slightly increased at 10 and 30 micrograms/kg i.v. of the drugs. When the coronary vascular and cardiac effects of nimodipine were assessed in isolated, blood-perfused dog heart preparations, i.e., sinoatrial node, AV node and papillary muscle preparations, by intra-arterial administration, the following was revealed. In nearly twice the dose doubling coronary arterial blood flow, nimodipine produced a 15% decrease in sinus rate and a 15% increase in AV conduction time. However, in reducing the force of contraction of the papillary muscle by half the pre-drug value was needed nearly 17 times the dose of nimodipine doubling coronary arterial blood flow. Suppression of AV conduction by large doses of nimodipine was evident only when it was injected into the artery supplying the AV node but not into the artery supplying the His-Purkinje-ventricular system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of oxybutynin on the cardiovascular system in dogs

The effects of oxybutynin, an anticholinergic and antispasmodic agent, on the cardiovascular system were studied in comparison with those of atropine in anesthetized dogs. Oxybutynin (0.1-10 mg/kg, i.v.) caused a transient hypotension, tachycardia, increases in femoral, stomach, mesenteric and common carotid arterial blood flows and a decrease in renal arterial blood flow. Atropine (0.1-10 mg/kg, i.v.) caused a stronger and more prolonged hypotension with bradycardia, accompanied by weaker blood flow changes than those by oxybutynin. In open-chest dogs, oxybutynin caused increases in cardiac output and coronary sinus outflow and decreases in heart rate and left ventricular pressure. The agent augmented dLVP/dt/P at doses up to 3 mg/kg, i.v., but reduced it at 10 mg/kg, i.v. Atropine caused stronger cardiosuppressive responses than those of oxybutynin. Coronary sinus outflow was decreased by atropine, unlike in the case of oxybutynin. The pressor responses of norepinephrine, epinephrine and tyramine were potentiated by pretreatment with oxybutynin (15 mg/kg, i.v.). However, pressor or depressor responses induced by histamine, isoproterenol, serotonin and DMPP were unaffected by oxybutynin. Intraarterial injections of oxybutynin, atropine and papaverine caused femoral and renal arterial vasodilations dose-dependently, in the following order of potency: papaverine greater than oxybutynin greater than atropine. In the isolated blood-perfused canine papillary muscle preparation, oxybutynin and atropine caused a negative inotropic action, whereas papaverine caused a positive inotropic action. From the above results, it is suggested that oxybutynin has milder cardiosuppressive and hypotensive effects than atropine in terms of potency and duration of action, and in addition, oxybutynin has a vasodilating action probably ascribable to its anticholinergic and antispasmodic actions.     

Pharmacological studies of a newly synthetized 1,4-dihydropyridine derivative, 2,6-dimethyl-3,5-dimethoxycarbonyl-4- (o-difluoromethoxyphenyl)-1,4-dihydropyridine (PP-1466)

Hemodynamic effects of a new 1,4-dihydropyridine derivative, 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl++ +)-1,4-dihydropyridine (PP-1466), were examined by measuring systemic blood pressure, various arterial blood flow such as femoral, vertebral, renal and superior mesenteric artery, heart rate and respiratory rate in anesthetized dogs. Cardiohemodynamic effects were examined by measuring cardiac output, coronary blood flow, maximal rate of rise of left ventricular pressure (dp/dt max.) and right atrial pressure. The changes in myocardial oxygen consumption associated with the parameters mentioned above were also examined by measuring coronary sinus outflow and oxygen content in blood samples. The results obtained are as follows: The intraarterial administration of PP-1466 to the femoral artery caused vasodilating response. The vasodilating effect of PP-1466 was approximately 200 times more potent than that of papaverine and comparable to that of nifedipine or nicardipine (YC-93). The effective dose to induce vasodilation on femoral, vertebral and superior mesenteric artery by the systemic use of PP-1466 was more than 0.3 microgram/kg i.v. and more than 0.03 mg/kg i.d. The vasodilation in vertebral artery was most prominent. After intravenous administration of PP-1466, renal blood flow decreased probably due to the fall in systemic blood pressure, whereas the flow progressively increased after intraduodenal administration. The effective dose to induce a fall in systemic blood pressure by PP-1466 was the range from 1 to 3 micrograms/kg i.v. and more than 0.1 mg/kg i.d., respectively. Diastolic hypotension was remarkable. Heart rate and respiratory rate were increased at the same time.(ABSTRACT TRUNCATED AT 250 WORDS)