Coronary effects of a combined beta adrenoceptor blocking and calcium antagonist therapy in running dogs.

The effects of YM-16151 (1 mg/kg, i.v.), a combined beta 1-adrenoceptor blocking and calcium antagonist drug, on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs at rest and during treadmill exercise. These effects were compared to those in the same animals of nicardipine (0.1 mg/kg, i.v.), atenolol (1 mg/kg, i.v.) and their combination (at the same doses). Circumflex artery diameter (CxAD) and coronary blood flow increased and coronary vascular resistance (CVR) decreased during control exercise under saline. YM-16151 and the nicardipine-atenolol combination similarly dilated large and small coronary arteries at rest, but dilation of large conductance vessels was abolished during exercise, while CVR decreased further. Both YM-16151 and the nicardipine-atenolol combination only slightly increased the rate-pressure product at rest, but strongly opposed its exercise-induced rise. Nicardipine maximally increased CxAD, decreased CVR, and enhanced the rate-pressure product at rest and during exercise. Conversely, atenolol decreased CxAD and the rate-pressure product and increased CVR at rest, but large coronary arteries remained constricted during exercise despite the concomitant dilation of small resistance vessels. Thus, in the coronary vascular bed of conscious dogs, YM-16151 really behaves as a hybrid drug, combining beta 1-adrenoceptor blocking and calcium antagonist properties, both at rest and during exercise. As a result, YM-16151 increases oxygen supply at rest and decreases oxygen demand during exercise. Finally, this study emphasizes the major role of beta 1-adrenoceptors in the mediation of exercise-induced dilation of large coronary arteries.     

Adrenoceptor blocking hemodynamic and coronary effects of YM-09538, a new combined alpha- and beta-adrenoceptor blocking drug, in anesthetized dogs

In anesthetized dogs. YM-09538, a new sulfonamide-substituted phenylethylamine, competitively antagonised the phenylephrine-induced vasopressor response with a DR10 of 0.50 mg/kg i.v. and the isoproterenol-induced positive chronotropic response with a DR10 of 0.66 mg/kg i.v., indicating that YM-09538 blocks both alpha 1- and beta 1-adrenoceptors and almost to the same extent. YM-09538 was 4 times more potent than phentolamine in blocking alpha 1-adrenoceptors and 3 times less potent than propranolol in blocking beta 1-adrenoceptors. YM-09538 non-selectively blocked cardiac beta 1- and vascular beta 2-receptors and was devoid of intrinsic beta-sympathomimetic and local anesthetic activities. In anesthetized closed-chest dogs, YM-09538 resembled propranolol in reducing heart rate, cardiac output, max. dLVP/dt and left ventricular cardiac work but differed from propranolol in decreasing total peripheral resistance, in increasing femoral blood flow, in causing larger falls in arterial blood pressure and in decreasing pulmonary arterial pressure. In anesthetized open-chest dogs, YM-09538 reduced heart rate, myocardial contractile force and arterial blood pressure. In non-ischemic myocardium, transmural flow and coronary vascular resistance were respectively strongly increased and decreased and the endo/epi flow ratio was slightly but not significantly reduced. In ischemic myocardium, YM-09538 also increased transmural flow and since endocardial and epicardial flows were augmented to the same extent, the endo/epi flow ratio remained unchanged. All these hemodynamic and coronary effects of YM-09538 can be accounted for the drug's combined alpha- and beta-adrenoceptors blocking properties.     

Adrenoceptor blocking and cardiovascular effects of the optical isomers of amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor blocking agent, and the corresponding desoxy derivative (YM-11133) in rats

The pharmacological activities of the enantiomers of amosulalol (YM-09538), a combined alpha- and beta-adrenoceptor antagonist, and the corresponding desoxy derivative (YM-11133) were investigated in the cardiovascular system of rats. The optical isomers of amosulalol and YM-11133 antagonized the vasopressor effect of phenylephrine and the positive chronotropic effect of isoproterenol in normotensive pithed rats. Based on DR2 values (micrograms/kg, i.v.) obtained from Schild plots, (+)-amosulalol and YM-11133 (DR2 = 30) were approximately 10 times more potent than (-)-amosulalol (DR2 = 324) in blocking alpha 1-adrenoceptors. For beta 1-adrenoceptors, in contrast, (-)-amosulalol (DR2 = 107) was approximately 60 times more potent than (+)-amosulalol (DR2 = 6460), which was almost equipotent with YM-11133 (DR2 = 3250). The results indicate that the optical isomers of amosulalol interact differently with alpha 1- and beta 1-adrenoceptors. The effects of these phenethylamines on blood pressure and heart rate were studied in urethane-anesthetized rats (i.v.). The rank order of hypotensive potency in anesthetized rats [+)- = desoxy greater than (-)-form) was consistent with the rank order of alpha 1-adrenoceptor antagonism in pithed rats. In contrast, (-)-amosulalol having a more potent beta 1-adrenoceptor antagonist activity than (+)-amosulalol and YM-11133 only produced dose-dependent bradycardia at the hypotensive doses. The results indicate that the vascular alpha 1- and cardiac beta 1-adrenoceptor blocking activities of the optical isomers of amosulalol contribute to their hypotensive and bradycardia, respectively. Thus, the racemate of amosulalol appears to exert an overall activity reflecting the activities of the individual isomers.     

Beta-adrenoceptor blocking activity of diprafenone in anesthetized dogs: comparison with propafenone and propranolol

The effects of diprafenone, a new class Ic antiarrhythmic agent, on canine hemodynamics and cardiac membrane beta-receptor antagonist binding activity, were compared with those of propafenone and propranolol. Mongrel dogs (4-5/group) were anesthetized intravenously (i.v.) with pentobarbital sodium (35 mg/kg) and instrumented for measurement of aortic and coronary blood flows (AF, CBF), blood pressure (BP), and heart rate (HR). Isoproterenol (ISO) was administered as bolus injections before (0.01, 0.03, and 0.1 micrograms/kg, i.v.) and after (0.01-3 micrograms/kg, i.v.) infusions of diprafenone or propafenone (0.3, 1, and 3 mg/kg) or propranolol (0.03, 0.1, and 0.3 mg/kg, i.v.). The ability of the antiarrhythmic agents to displace [3H]dihydroalprenolol (DHA) binding from isolated cardiac ventricular membranes in vitro was also evaluated. Each antiarrhythmic agent blocked the HR and BP responses to ISO in a competitive manner and decreased the specific binding of DHA to cardiac ventricular membranes. Propranolol was 2 to 7 times more potent as a beta-receptor blocking agent than diprafenone, which was 6 times more potent than propafenone. The equilibrium dissociation constants (Ki) for displacement of DHA by propranolol, diprafenone, and propafenone were 2.7, 14.3, and 252 nM, respectively, and have the same rank order of potency for in vivo inhibition of BP and HR responses to ISO. Diprafenone has significant beta-adrenoceptor blocking activity which may contribute to its efficacy as an antiarrhythmic agent and allow its use in treatment of arrhythmias refractory to therapy with class I and class II agents alone.     

Pharmacological studies of celiprolol: III. Effects of celiprolol on the cardiovascular system and renal function, and its antiarrhythmic effects

Effects of celiprolol on the cardiovascular system and renal function, and its antiarrhythmic effects were studied. 1. In anesthetized dogs, celiprolol (0.01-3 mg/kg, i.v.) dose-dependently depressed the maximum rate of rise of left ventricular pressure, cardiac output and cardiac work less severely than propranolol and atenolol. 2. Celiprolol (0.01 mg/kg, i.v.) decreased the myocardial oxygen consumption in anesthetized dogs as potently as propranolol. 3. Celiprolol (0.03-3 mg/kg, i.v.) tended to increase femoral blood flow. Celiprolol (1 mg/kg, i.v.) increased common carotid blood flow. 4. Celiprolol decreased urine volume and urinary excretion of Na+ and Cl- at doses of 1 and 10 mg/kg and increased the sodium reabsorption rate at a dose of 10 mg/kg in anesthetized dogs, whereas it produced no change in plasma renin activity. 5. Celiprolol inhibited both halothane-adrenaline arrhythmia in dogs and ouabain-induced arrhythmia in rabbits. Its antiarrhythmic effects were 1/10-1/3 as potent as those of propranolol. 6. Celiprolol suppressed the maximum rate of rise of action potential at a concentration of 3 x 10(-4) M, which was 30 times as high as that of propranolol. Celiprolol (3 x 10(-5)-3 x 10(-4) M) dose-dependently shortened the effective refractory period (ERP), but it produced no change in the ratio of ERP to action potential duration. 7. These results suggest that celiprolol may be a useful drug for the treatment of ischemic heart disease and some types of arrhythmia, and that it has only a little influence on renal function.     

Cardiovascular effects of E4080, a novel bradycardiac agent with coronary vasodilating properties, in anesthetized dogs.

The cardiohemodynamic effects of E4080, a novel bradycardiac agent with a coronary vasodilating feature, were studied in anesthetized open-chest dogs. E4080 (0.3 and 1 mg/kg i.v.) decreased heart rate (HR), mean aortic pressure (MAP) and total peripheral resistance, and increased coronary blood flow (CBF) without affecting cardiac output and the electrocardiogram. The maximum rate of rise in left ventricular pressure decreased at 1 mg/kg. In addition, E4080 (0.3 and 1 mg/kg i.v.) decreased myocardial oxygen consumption. On administration in sinus node artery, E4080 (10 and 30 micrograms) selectively decreased HR. Glibenclamide, an ATP-sensitive K+ channel blocker (5 mg/kg i.v.), inhibited both the increase in CBF and the decrease in MAP caused by E4080 (1 mg/kg i.v.) but did not inhibit the bradycardia. These results suggested that E4080 has both bradycardiac and coronary vasodilating effects, and that activation of ATP-sensitive K+ channel contributes to the vasodilating action of E4080 but not to the bradycardiac action.     

Pharmacological analysis of the mode of action of mandelamidine with sustained antihypertensive effect. (II). Mechanism of transient hypotensive action of mandelamidine]

The mode of a transient hypotensive action of dl-Mandelamidine (MA) was studied in both anesthetized and unanesthetized animals. In the blood pressure of unanesthetized rats, a transient hypotensive action of MA (1 approximately 30 mg/kg i.v.) like papaverine (1 approximately 10 mg/kg i.v.) was much less predominant than in rats anesthetized with urethane (1.5 g/kg s.c.). The transient hypotensive action of MA (10 mg/kg i.v.) in rats anesthetized with urethane (1.5 g/kg s.c.) was not reduced when MA was injected continuously. Moreover C6 (5 mg/kg i.v.), propranolol (1 mg/kg i.v.), diphenhydramine (10 mg/kg i.v.) and atropine (2 mg/kg i.v.) did not block this transient hypotensive action. MA blocked the pressor action of epinephrine (3 mug/kg i.v.) in three minutes, but then potentiated it. MA (10 mug/kg i.a. approximately 1 mg/kg i.a.) caused a temporary vasodilation on the perfused leg artery and vertebral artery in dogs anesthetized with sodium pentobarbital (30 mg/kg i.v.). In the perfused leg artery, atropine (2 mg/kg i.v.) and propranolol (1 mg/kg i.v.) did not block the vasodilation of MA, and MA showed no marked blocking effect of the vasoconstriction of norepinephrine (0.2 mug/kg i.a.). In the dog heart-lung preparation and the guinea-pig heart, MA showed inhibiting effects. On the contraction of the cat nictitating membrane elicited by the stimulation of the postganglionic cervical sympathetic nerve, the blocking action of MA (1 mug/kg i.a. approximately 1 mg/kg i.a.) was much less predominant than that of phentolamine (10 mug/kg i.a.). In the rabbit descending aorta, MA (3 X 10(-4) g/ml) antagonized non-competitively the contraction elicited by norepinephrine. These findings suggest that a transient hypotensive action of MA depends upon the inhibiting effects on the cardiovascular system, and the adrenergic alpha-blocking effect of MA may be very weak.     

Selective effects of lomerizine, a novel diphenylmethylpiperazine Ca2+ channel blocker, on cerebral blood flow in rats and dogs

1. In the present study we examined the effects of a new Ca2+ channel blocker (lomerizine), an antimigraine drug, on cerebral cortical blood flow (CBF) in anaesthetized rats (laser Doppler flowmetry) and on vertebral blood flow in anaesthetized beagle dogs (electromagnetic flowmeter). 2. Lomerizine (1.25-10 mg/kg, p.o.) dose-dependently increased CBF in rats without affecting blood pressure (BP) or heart rate (HR). 3. The plasma concentration of lomerizine (free base) in anaesthetized rats at 30 and 60 min after the initial administration of 5 mg/kg, p.o., time at which there was a significant increase in CBF, was similar to that reported in healthy subjects receiving lomerizine at 10 mg (2 x 5 mg)/day, p.o., a dose that significantly reduces the frequency and mean duration of headache attacks. 4. Flunarizine (10 mg/kg, p.o.) did not increase CBF significantly. Flunarizine (20 mg/kg, p.o.) did not increase CBF, but did decrease BP 30-120 min after its administration. 5. Lomerizine (2.5 and 5 mg/kg, intraduodenally) dose-dependently increased vertebral blood flow in dogs without significantly changing BP or HR. With 10 mg/kg intraduodenal lomerazine, vertebral blood flow remained elevated from 20 to 240 min after administration and BP was decreased from 20 to 120 min. 6. Thus, lomerizine had a greater effect on CBF than on BP and HR and, therefore, it may be clinically effective in conditions associated with circulatory disturbances in the brain, such as migraine, without producing systemic effects (e.g. hypotension) generally seen with other Ca2+ channel blockers.     

The central sympatho-inhibitory effect of 5,6-dihydroxy-2-dimethylaminotetralin (M7) is mediated by α2-adrenoceptors

M7 (5,6-dihydroxy-2-dimethylaminotetralin) produces in anesthetized rats a hypotensive response previously attributed to peripheral dopaminergic mechanisms. We re-examined the effects of this drug on arterial blood pressure, heart rate and sympathetic nerve activity in anesthetized rats and dogs. M7 (1–100 μg/kg i.v.) produced in the rats transient dose-dependent pressor effects, with bradycardia and sympatho-inhibition, followed by long-lasting dose-dependent hypotension, bradycardia and sympatho-inhibition. The sympatho-inhibitory and hypotensive effects were comparable in baroreceptor-denervated rats and were reversed by idazoxan (0.1 mg/kg i.v.). The sympatho-inhibitory response induced by M7 (1–100 μg/kg) was prevented by treatment with the specific α₂-adrenoceptor antagonist, 2-methoxy-idazoxan (0.03 mg/kg i.v.). This central effect of M7 was not altered by treatment with the α₁-adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.) and was reduced by treatment with the α₂-adrenoceptor antagonists, yohimbine (1 mg/kg i.v.) or idazoxan (0.3 mg/kg i.v.), and the dopaminergic antagonists, haloperidol (0.5 mg/kg i.v.) or sulpiride (3 mg/kg i.v.). Bilateral microinjections of M7 (0.3–3 nmol) into the rostroventral medulla in the rat produced dose-dependent hypotension, bradycardia and sympathetic nerve inhibition which were reversed and prevented by bilateral microinjection of 2-methoxy-idazoxan (1 nmol) into the same sites. Microinjections of 2-methoxy-idazoxan into the rostroventral medulla also inhibited the central effects of M7 at 0.03 mg/kg i.v. In anesthetized dogs, M7 administered into the cisterna magna (1–10 μg/kg) reduced arterial blood pressure, heart rate and sympathetic nerve activity; these effects were reversed by administration of 2-methoxy-idazoxan (0.03 mg/kg i.v.). In conclusion, M7, a rigid catecholamine, produces a potent central sympatho-inhibitory and hypotensive effect by activation of α₂-adrenoceptors.     

Effects of arotinolol on hemodynamics and adrenergically induced renin release and renal vasoconstriction

Effects of 5-[2-[(3-tert-butylamino-2-hydroxypropylthio)-4-thiazolyl]-2- thiophenecarboxamide hydrochloride (arotinolol, S-596) on hemodynamic and adrenergically induced renin release and renal vasoconstriction were investigated in pentobarbital anesthetized dogs. Arotinolol (1 mg/kg i.v.) decreased systemic blood pressure (SBP), heart rate (HR) and renin secretion rate without change in renal blood flow. Degree of hypotension induced by arotinolol and basal plasma renin activity prior to the injection of the drug showed significant correlation. Arotinolol (20 micrograms/min) produced significant suppression of renal nerve stimulation (RNS)-induced renin release and attenuated an increase in renal vascular resistance during RNS at 3 Hz. The same extent of inhibition in the renin secretion response to RNS was also obtained during the infusion of dl-propranolol (100 micrograms/min). The renal vasoconstriction induced by RNS and norepinephrine (NE) was inhibited dose-dependently during the infusion of arotinolol (10, 30 and 100 micrograms/min), phentolamine (3, 10 and 30 micrograms/min) or prazosin (1, 3 and 10 micrograms/min). Arotinolol and prazosin exerted a greater inhibitory effect on RNS- than NE-induced vasoconstriction, and the opposite was true of phentolamine. Arotinolol dose-dependently decreased SBP and HR in a dose range of 0.01 to 3.0 mg/kg. The greater reduction in HR was observed with arotinolol at a lower dose range (0.01 to 0.1 mg/kg) than with propranolol. Arotinolol produced larger reduction of SBP, and less increase in carotid, vertebral, renal and external iliac vascular resistances than propranolol. These results suggest that arotinolol posesses a- and beta-adrenoceptor blocking properties, which effectively contribute to the suppression of the adrenergically induced renin release and renal vasoconstriction, and to the hypotensive effect.     

Comparison of KRN2391 with nicorandil and nifedipine on canine coronary blood flow: antagonism by glibenclamide.

The mode of action of KRN2391 [N-cyano-N'-(2-nitroxyethyl)-3- pyridinecarboximidamide monomethanesulfonate] in coronary circulation was examined in anesthetized dogs in comparison with those of nicorandil and nifedipine. Administration of KRN2391 (10 micrograms/kg i.v.), nicorandil (300 micrograms/kg i.v.), and nifedipine (3 micrograms/kg i.v.) caused an increase in coronary blood flow (CBF) and decreases in mean blood pressure (MBP) and in coronary vascular resistance (CVR). Heart rate (HR) was slightly and simultaneously increased by the drugs. Glibenclamide (5 mg/kg i.v.) blocked the changes of these parameters caused by KRN2391 and nicorandil, but not those caused by nifedipine. The present study suggests that the mechanism of action through ATP-sensitive K channels which are blocked by glibenclamide may contribute, at least in part, to the effects of KRN2391 and nicorandil on CBF and blood pressure (BP).     

Investigations into the mechanism of the antihypertensive effect of SGB-1534, a novel alpha 1-adrenoceptor antagonist, in rats

Experiments in vitro and in vivo were undertaken to examine possible involvement of a central effect in the hypotensive mechanism of SGB-1534. SGB-1534 selectively antagonized the contraction of isolated rat aortae to phenylephrine with a pA2 value of 10.57, 3.9 times higher than prazosin, and markedly displaced the alpha 1-adrenoceptor ligand 3H-prazosin (pKi: 8.81) in rat brain. In anesthetized spontaneously hypertensive rats (SHRs), SGB-1534 (0.3-3 micrograms/kg) and prazosin (3-30 micrograms/kg) given intravenously (i.v.) and intracerebroventricularly (i.c.v.) produced a dose-dependent and long-lasting depressor response associated with no change in heart rate (HR). The two drugs (i.c.v.), however, significantly attenuated the pressor response to i.v. noradrenaline. Single i.v. injections of SGB-1534, prazosin and yohimbine dose-dependently inhibited the St 587 (a highly specific and centrally acting alpha 1-adrenoceptor agonist) enhanced flexor reflex and the pressor response to i.v. phenylephrine in pithed rats. However, the activities of SGB-1534 and prazosin in inhibiting the St 587-enhanced flexor reflex were 16,000 and 660 times, respectively, less than those in attenuating the pressor response to i.v. phenylephrine. It seems that the hypotensive action of SGB-1534 is due to the peripheral alpha 1-adrenoceptor antagonistic mechanism rather than the central one.     

Comparison of cardiovascular effects of SGB-1534 and prazosin, selective alpha 1-adrenoceptor antagonists, in anesthetized dogs

The cardiovascular effects of a novel antihypertensive agent, SGB-1534, and its alpha 1-adrenoceptor antagonism in the renal vasculature were investigated in anesthetized dogs and compared with those of prazosin. The doses of SGB-1534 (1-100 micrograms/kg) and prazosin (3-300 micrograms/kg) were increased by a factor of about 3 and given i.v. in a cumulative way. SGB-1534 produced dose-dependent decreases in systemic (systolic, mean and diastolic) blood pressure (SBP), left ventricular (LV) systolic and end-diastolic pressure, and femoral vascular resistance, accompanied by no changes in heart rate (HR), LVdP/dt max and pressure-rate product. Femoral blood flow tended to increase, but the change was not significant. Renal blood flow and the vascular resistance remained virtually unchanged. Similar results were obtained with prazosin for the cardiovascular parameters tested except diastolic SBP and femoral vascular resistance, in which no significant changes occurred. SGB-1534 and prazosin dose-dependently attenuated renal vasoconstrictor responses to a relatively selective alpha 1-adrenoceptor agonist, phenylephrine (3 or 10 micrograms) given into the renal artery. When the doses that attenuated the vasoconstrictor response to phenylephrine by 50% were compared on a weight basis, alpha 1-adrenoceptor antagonistic activity of SGB-1534 was approximately 25 times more potent than that of prazosin in the renal vasculature of dogs. Both alpha 1-adrenoceptor antagonists showed a significant positive correlation between the systemic hypotensive effects and the alpha 1-adrenoceptor antagonism in the renal vasculature. Thus, it seems that SGB-1534, like prazosin, has a balanced effect decreasing afterload as well as preload and that the hypotension is mainly due to the alpha 1-adrenoceptor antagonism in the peripheral vasculatures.     

Prazosin produces a sustained and reflex-mediated increase in renal sympathetic nerve activity in anesthetized dogs

Prazosin (1 mg/kg i.v.) produced a decrease in blood pressure associated with an increase in renal sympathetic nerve activity in anesthetized dogs. The sympathetic baroreflex curve was shifted to the left. Prazosin (10 micrograms/kg into the vertebral artery) did not change the blood pressure but increased renal sympathetic discharges. The baroreflex curve was not altered. Prazosin (100 micrograms/kg into the vertebral artery) induced a decrease in blood pressure and an increase in sympathetic discharges. Prazosin (1 mg/kg i.v. or 100 micrograms/kg i.c.) induced a fall in blood pressure without any change in sympathetic nerve activity in barodenervated dogs. Restoration of the resting blood pressure by angiotensin II infusion (10-20 ng/kg per min) restored the baroreflex curve in anesthetized dogs given prazosin (1 mg/kg i.v.) to close to the initial position. Prazosin, (1 mg/kg i.v.) did not change the sympathoinhibitory effect of clonidine (injected into the vertebral artery) and the reversal effect of piperoxan in barodenervated dogs. In conclusion, prazosin reduces blood pressure by blockade of peripheral alpha 1-adrenoceptors. The shift to the left of the sympathetic baroreflex curve is due to the hypotensive effect of prazosin. No evidence was found for a central sympathoinhibitory effect of prazosin.     

General pharmacological properties of an anti-ulcer drug, azuletil sodium (KT1-32)

Azuletil sodium (AZE, 100 mg/kg, p.o.) did not affect the general behaviors, spontaneous motor activity, pentobarbital-induced hypnosis and body temperature. Furthermore, it did not elicit anticonvulsant and muscle relaxant actions. However, AZE (300 mg/kg, p.o.) elicited a stiff gate and slightly inhibited the spontaneous motor activity and electroshock-induced convulsions. It had no influence on spontaneous EEG activities, even at 30 mg/kg, i.v. AZE inhibited acetic acid-induced writhing moderately at doses above 100 mg/kg. AZE at concentrations up to 10(-5) g/ml did not affect agonist-induced contractions of the isolated ileum, trachea, vas deference and uterus, but inhibited serotonin and oxytocin-induced contraction at concentrations above 3 x 10(-4) and 10(-5) g/ml, respectively; and it also depressed spontaneous movements of the ileum and uterus at concentrations above 3 x 10(-4) g/ml. AZE caused no changes in blood pressure (BP), heart rate (HR), left ventricular pressure, ECG, tracheal pressure (TP), femoral blood flow (FBF) and coronary blood flow (CBF) at doses up to 10 mg/kg, i.v. in anesthetized dogs, but it caused an increase or a decrease in BP, an increase in TP and an increase in CBF at 30 mg/kg, i.v. However, even at 300 mg/kg, p.o., it caused no changes in BP and HR in conscious rats. AZE moderately promoted the charcoal transport. AZE at doses up to 300 mg/kg, p.o. did not affect urine volume, urinary electrolyte excretion, blood glucose and prothrombin time. These results suggest that AZE at anti-ulcer doses of 10-100 mg/kg, p.o. does not have noticeable effects on general pharmacological properties, and there is no marked differences as compared with those of GAS.     

Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative.

The cardiovascular effects of NKH477 (6-(3-dimethylaminopropionyl)forskolin hydrochloride), a novel water-soluble forskolin derivative, were investigated in dogs. Intravenous (i.v.) injections of NKH477 (1-30 micrograms/kg) caused dose-related increases in left ventricular dP/dtmax (LVdP/dtmax), coronary and femoral artery blood flow (CBF, FBF), heart rate (HR), and myocardial oxygen consumption (MVO2) and a dose-related decrease in blood pressure (BP) in anesthetized dogs. The regression analysis between CBF and MVO2 showed that NKH477 did not influence substantially the balance of oxygen supply and demand. Infusions of NKH477 (0.15-0.6 microgram/kg/min i.v.) also increased LVdP/dtmax, cardiac output (CO), and HR and decreased BP, pulmonary arterial diastolic pressure, and total peripheral resistance (TPR) in a dose-dependent manner. In contrast to forskolin, NKH477 administered intraduodenally (0.05-0.2 mg/kg) and orally (0.15 and 0.3 mg/kg) clearly exhibited cardiovascular actions, as it did in i.v. administration, indicating that NKH477 is orally active. No arrhythmias were induced by NKH477 in any study. NKH477, like forskolin, showed adenylate cyclase stimulant activity in guinea pig ventricular membrane but did not inhibit Na+, K(+)-ATPase or phosphodiesterase (PDE) activity. Thus, NKH477 can be characterized as a potent, orally active, water-soluble forskolin derivative, which suggests that NKH477 is a useful inodilator for treatment of heart failure, especially in the severe stage with beta-adrenoceptor downregulation.     

Cardiohemodynamic and respiratory effects of eptazocine, a new analgesic agent, in anesthetized dogs

Cardiohemodynamic and respiratory effects of eptazocine, a new analgesic agent, were studied and compared with those of pentazocine and butorphanol in anesthetized dogs. Eptazocine (1 mg/kg, i.v.) increased the heart rate (HR), left ventricular dP/dt (LVdP/dt) and cardiac output (CO), and scarcely affected the blood pressure (BP), left ventricular end-diastolic pressure (LVEDP), right atrial pressure, pulmonary arterial pressure (PAP) and pulmonary capillary wedge pressure. On the other hand, eptazocine (3 mg/kg, i.v.) decreased BP, LVdP/dt, CO and LVEDP and did not influence the pulmonary circulation. Pentazocine (1 mg/kg and 3 mg/kg, i.v.) increased BP, LVdP/dt and CO, while HR was not altered. Pentazocine also increased PAP. Butorphanol (0.1 mg/kg and 0.3 mg/kg, i.v.) decreased BP, HR and LVdP/dt, while other hemodynamic parameters were not changed. In spontaneously breathing anesthetized dogs, eptazocine (1 mg/kg and 3 mg/kg, i.v.) caused a decrease of respiratory minute volume. The fall in PO2 and pH, and a rise in PCO2 were simultaneously observed in blood gas analysis. These respiratory depressant effects of eptazocine were short-lasting, and they were less potent than those of pentazocine. Butorphanol scarcely affected the respiration. These results suggest that eptazocine has different cardiohemodynamic effects than other analgesics and produces mild respiratory depression.     

Effects of (+/-)-4'-ethyl-2-methyl-3-(l-pyrrolidinyl) propiophenone hydrochloride (HY-770) on the bladder function

The effects of HY-770 on micturition reflexes in rats, dogs and cats and urethral pressure in dogs were compared with those of flavoxate.HC1 (flavoxate), terodiline.HCl (terodiline) and oxybutynin.HCl (oxybutynin). 1) HY-770, in intravenous (2 and 4 mg/kg) and intraduodenal (12.5 and 25 mg/kg) administrations, dose-dependently abolished the rhythmic bladder contractions in anesthetized rats. The activity of HY-770, in intravenous administration (i.v.), was almost equal to those of flavoxate, terodiline and oxybutynin; and the activity of HY-770, like terodiline, was more potent than that of flavoxate in intraduodenal administration (i.d.). 2) In the cystometrograms, HY-770 (3, 4 or 8 mg/kg, i.v.) dose-dependently increased the time to micturition (capacity of bladder) without decreasing the amplitude of micturition contraction in anesthetized rats, dogs and cats, and HY-770 (25 mg/kg, i.d.) also increased the capacity in anesthetized cats. 3) HY-770 (4 and 8 mg/kg, i.v.) dose-dependently increased the capacity of the bladder in the cystometrograms of pollakiuria induced by either transection of both the hypogastric nerves or chronic cannulation to the bladder in anesthetized or conscious rats, respectively. 4) HY-770 (25 mg/kg, i.d.) slightly decreased the urethral pressure in anesthetized dogs. These results suggest that HY-770 is a promising drug for the treatment of pollakiuria induced by a neurogenic bladder or unstable bladder, etc.     

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.     

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)