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We investigated the ganglionic effects of angiotensin II (Ang II) and the signal transduction involved in the cardiac sympathetic ganglia by the direct administration of agents to the ganglia through the right subclavian artery and monitoring the heart rate as an indicator of the ganglionic function in pithed dogs. Ang II given i.a. caused increases in the heart rate, which was inhibited by the treatment with the AT1-receptor antagonist forasartan, but not by the AT2-receptor antagonist PD-123319. The stimulation by Ang II, but not by acetylcholine, was inhibited after treatment with an inhibitor of phospholipase C, U-73122; a cell-permeant modulator of the Ins(1,4,5)P3 receptors, 2-aminoethoxydiphenyl borate; an intracellular calcium and calcium-associated protein kinase inhibitor, HA-1077; calmodulin (CaM) inhibitor, W-7; Ca2+/CaM-dependent protein kinase II inhibitor, KN-93; a selective protein kinase C inhibitor, calphostin C; and Na+H+ exchange inhibitor, dimethylamiloride. These results suggest that Ang II stimulates the ganglionic transmission at postsynaptic sites via the activation of AT1 receptor coupled to either activation of phospholipase C, phosphoinositide hydrolysis and subsequent increase in intracellular Ca2+ and activation of protein kinase C and Ca2+/CaM kinase II, although this ganglionic stimulation seems to involve, at least in part, the protein kinases-dependent increase of amiloride-sensitive Na+ inflow.

The possible involvement of the local angiotensin system in ganglionic functions was investigated in the canine cardiac sympathetic ganglia. Positive chronotropic responses to preganglionic stellate stimulation at high frequencies, after intravenous administration of pentolinium plus atropine, were inhibited by the nonpeptide angiotensin AT(1) receptor antagonist forasartan or the angiotensin I-converting enzyme inhibitor captopril, whereas the rate increases elicited by the postganglionic stellate stimulation and norepinephrine given intravenously failed to be inhibited by these antagonists. The levels of endogenous immunoreactive angiotensin II, as determined by radioimmunoassay in the incubation medium of the stellate and inferior cervical ganglia, were increased after the high-frequency preganglionic stimulation of the isolated ganglia. The increment of the peptide was also antagonized by the pretreatment with captopril but not by a chymase inhibitor, chymostatin. The expression of angiotensinogen mRNA was observed in the stellate ganglion, adrenal, liver, and lung but not in the ovary and spleen. The expression of the mRNA in the stellate and inferior cervical ganglia increased after high-frequency preganglionic stimulation of the in vivo dogs for a period of 1 hour. These results indicate that an intrinsic angiotensin I-converting enzyme-dependent angiotensin system exists in the cardiac sympathetic ganglia, which is activated by high-frequency preganglionic stimulation.

We previously reported that endothelin (ET) 3 inhibited presynaptically the dog stellate ganglionic transmission. Here, we report the investigation of the possible involvement of nitric oxide pathway in the endothelin-induced inhibition of the ganglionic transmission. The amount of acetylcholine released by preganglionic stimulation for 10 min was concentration-dependently inhibited after exposure to ET-3 (10(-9)-10(-6) M) or IRL-1620, endothelin ET(B) receptor agonist (10(-8)-10(-5) M). The inhibition was antagonized by pretreatment with a nonselective endothelin receptors antagonist (bosentan) and an ET(B) receptor antagonist (BQ-788) or a neuronal nitric oxide synthase inhibitor, 3-bromo-7-nitroindazole, but was not inhibited by a selective ET(A) receptor antagonist, BQ-123. The reduction induced by ET-3 was also antagonized by treatment with a selective inhibitor of soluble guanylyl cyclase, 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one. In addition, similar reductions were also mimicked by exposure to cGMP analog, 8-bromoguanosine-3, 5-cyclic monophosphate and nitric oxide donor, S-nitroso-N-acetylpenicillamine. Exposure to ET-3 or IRL-1620 for a 30-min period increased the levels of total nitric oxide (NO), nitrite plus nitrate NO(x) concentration in the incubation medium, with the increase in NO(x) also being antagonized by BQ-788 at the same concentration. The ET-3-induced increase in NO(x) was antagonized by treatment with the same concentration of 3-bromo-7-nitroindazole or a selective inhibitor of receptor-mediated Ca(2+) entry, 1-[b-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl]-1H-imidazole (10(-5) M), and with a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. These results indicate that ET(B) receptor activation inhibits the sympathetic ganglionic transmission via reducing acetylcholine release from presynaptic nerve terminals, although this inhibition also seems to involve the ET(B) receptor-operated Ca(2+)-calmodulin-dependent activation of endogenous nitric oxide production.

We investigated the effects of endothelin-1 and endothelin-3 (ET-1, ET-3) on the ganglionic transmission of cardiac sympathetic ganglia in vivo by the direct administration of agents to the ganglia through the right subclavian artery while monitoring the heart rate (HR) as an indicator of the ganglionic function in spinal dogs. The positive chronotropic responses to dimethylphenylpiperazinium (DMPP) and McN-A-343 administered to the ganglia were similarly inhibited by ET-1 (0.05-0.2 microg) and ET-3 (0.5-2 microg), but ET-1 was approximately 10 times more potent than ET-3. The inhibition induced by ETs was antagonized by endothelin ETA receptor antagonist BQ-123 (20 microg). This inhibition was unaffected by pretreatment with indomethacin given intravenously (i.v.), ruling out the possible involvement of endogenous prostaglandins production. The voltage-sensitive Ca2+ channel antagonist nifedipine had no effect on inhibition. However, the inhibition was antagonized by pretreatment with the low conductance Ca2+-activated potassium channel antagonists, such as apamin (20 microg intraarterially, i.a.), scyllatoxin (10 mug i.a.) and D-tubocurarine (0.6 mg i.a.). On the other hand, the voltage-sensitive K+ channel antagonist 4-aminopyridine (4-AP), ATP-dependent K+ channel antagonist, glibenclamide, and high-conductance Ca2+-activated K+ channel antagonists iberiotoxin and charybdotoxin failed to affect the inhibition by ETs. The results suggest that ETs inhibit the nicotinic and muscarinic ganglionic transmission through the ETA receptor-operated low-conductance Ca2+-activated potassium channel at postganglionic sites.

Effects of nebracetam (4-aminomethyl-1-benzylpyrrolidine-2-one hemifumarate, WEB 1881 FU, CAS 118607-07-1), a new nootropic drug, on impulse transmission in the cardiac sympathetic ganglia were studied in spinal dogs by monitoring heart rate as an indicator of the ganglionic function. The ganglionic stimulants were given directly into the cardiac sympathetic ganglia through the right subclavian artery (i.a.). Nebracetam, 5 mg/kg, i.v. caused a slight and temporal increase in heart rate. After nebracetam, the frequency-response curves of heart rate for preganglionic stellate stimulation (0.25-4 Hz) were not altered in the untreated and atropine-pretreated animals, but the curves (2.5-40 Hz) were shifted to the left in the hexamethonium-pretreated animals. The enhancement of ganglionic muscarinic transmission was dose-dependent on nebracetam i.v. at doses ranging from 0.5 to 15 mg/kg, with a maximal effect at 5 mg/kg. This enhanced muscarinic transmission by nebracetam was almost abolished after subsequent administration of pirenzepine 0.5 mg/kg i.v. The enhancement in the muscarinic transmission by nebracetam was also eliminated after depletion of acetylcholine at preganglionic sites caused by treatment with hemicholinium-3 in combination with preganglionic stimulation. Furthermore, nebracetam failed to affect dose-dependent post-ganglionic stimulation by McN-A-343 (1-32 micrograms), 1,1-dimethyl-4-phenylpiperazinium (1-32 micrograms) and angiotensin II (0.1 and 0.2 micrograms) administered i.a. directly to the ganglia. These results suggest that nebracetam facilitates the ganglionic muscarinic transmission through acting on presynaptic sites.

The effects of endothelin-3 (ET-3) on ganglionic transmission of dog cardiac sympathetic ganglia and possible mechanisms involved were investigated in vivo and in vitro. Positive chronotropic responses to preganglionic stellate stimulation and those to dimethylphenylpiperazinium as well as McN-A-343 administered to the ganglia were inhibited by ET-3. The amount of acetylcholine released by preganglionic stimulation was reduced dose dependently after exposure to ET-3. The reduction elicited by ET-3 was antagonized by pretreatment with phospholipase A2 inhibitors (dexamethasone and methylprednisolone) and cyclooxygenase inhibitors (aspirin and indomethacin). In addition, the reduction of acetylcholine release was similarly induced by exposure to exogenously applied STA2, a stable thromboxane A2 analogue; U-46619, a TXA2/PGH2 receptor agonist; and prostaglandin E2. Furthermore, the reduction produced by ET-3 was antagonized by pretreatment with a thromboxane A2 synthetase inhibitor (OKY-046) and a specific thromboxane A2 receptor antagonist (S-145), but not by a specific prostaglandin E2 receptor antagonist (SC-19220). These results indicate that ET-3 inhibits the sympathetic ganglionic transmission via reducing acetylcholine release from the presynaptic nerve terminals of ganglia and that this inhibition involves the activation of endogenous thromboxane A2 production.

The antihypertensive effect of naftopidil (KT-611) following single oral administration was investigated in normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), DOCA-Salt hypertensive rats (DHR), 2-kidney 1-clip renal hypertensive rats (RHR) and Grollman type renal hypertensive dogs with 1-kidney (RHD); and it was compared with that of the selective alpha 1-adrenoceptor antagonist prazosin. The blood pressure and heart rate were measured under the unanesthetized, unrestrained state through an arterial catheter that was chronically implanted into the abdominal aorta. In SHR and WKY, both KT-611 (10 and 30 mg/kg, p.o.) and prazosin (1 and 3 mg/kg, p.o.) markedly inhibited the pressor response to the alpha 1-adrenoceptor agonist phenylephrine (3 micrograms/kg, i.v.). KT-611 (10 to 100 mg/kg, p.o.) showed a dose-dependent hypotensive effect in SHR, DHR and RHR but not in WKY. The hypotensive effect of KT-611 reached maximum at 0.5-1 hr, lasted for 4-6 hr and was more potent in DHR and RHR than in SHR. The potency of KT-611 was 1/10-1/30 weaker than that of prazosin. In RHD, single oral administration of KT-611 (1 to 10 mg/kg) caused a dose-dependent and long-lasting hypotensive effect. These results suggest that KT-611 has a long-lasting hypotensive effect in experimental hypertensive animal models.

The effects of catecholamines (CAs) on cardiac chronotropism were investigated in the spinal dog. The CAs were administered through the right subclavian artery (i.a.) to reach the cardiac sympathetic ganglia. Without preganglionic stimulation. CAs administered intra-arterially induced a slight negative chronotropic effect, which was reversed to a positive chronotropic effect after neostigmine (200 microgram, i.a.) in many cases. With preganglionic stimulation, intra-arterial injection of norepinephrine (0.5-25 microgram), epinephrine (0.1-10 microgram), or dopamine (0.1-500 microgram) caused dose-dependent bradycardia. The negative chronotropic effect of dopamine was significantly inhibited intra-arterial phentolamine (2 mg), dihydroergotamine (0.4 mg), apomorphine (0.5 mg), haloperidol (0.5 mg), or chlorpromazine (5 mg) but not by propranolol (0.1 mg) or bulbocapnine (1 mg), whereas the same effect of epinephrine was significantly reduced by alpha-blockade but not by propranolol or the dopamine antagonists. These results suggest that CAs exert a negative chronotropic action by inhibiting cardiac ganglionic transmission and that the receptors for dopamine are alpha-adrenergic and dopamine-specific and those for epinephrine are alpha-adrenergic specific.

The relative contribution of nicotinic and muscarinic receptors to the cholinergic transmission of the inferior mesenteric ganglion was studied in spinal dogs by recording changes in perfusion pressure of the inferior mesenteric artery as an indicator of ganglionic function. Preganglionic stimulation elicited a frequency (2.5--320 Hz)-dependent rise in the perfusion pressure, which was inhibited by i.v. hexamethonium (C6) (10 mg/kg) or atropine (0.1 mg/kg) administered after C6. Acetylcholine (ACh) (0.1--1000 microgram) administered into the inferior mesenteric artery to reach the mesenteric ganglion induced a dose-dependent rise in perfusion pressure and this dose-response curve was shifted to the right by C6 or atropine. Bethanechol (1--1000 microgram) i.a. produced a dose-dependent rise in the pressure, which was abolished after i.v. atropine. Tetramethylammonium (1--300 microgram) i.a. elicited an increase in the pressure thought the effects were decreased at larger doses, and these effects were strongly inhibited by i.v. C6. ACh (5--100 microgram) administered into the right subclavian artery to reach the cardiac sympathetic ganglia caused a dose-dependent positive chronotropic effect, which was inhibited by i.a. C6 or atropine. The results suggest that the inferior mesenteric ganglion seems to differ from the cardiac ganglia in relative contribution of nicotinic and muscarinic receptors to the cholinergic transmission.

The effects of angiotensin II and neuro-aminoacids administered through the right subclavian artery (i.a.) to the cardiac sympathetic ganglia were investigated in spinal dogs. Angiotensin II (1--8 micrograms) elicited a dose-dependent positive chronotropic effect which was reduced after i.a. injection of saralasin (100 micrograms). The effect of angiotensin II was not reduced after combined treatment with either hexamethonium (10 mg/kg) plus atropine (0.1 mg/kg) or hemicholinium-3 (5 mg/kg) plus preganglionic stimulation. The dose-dependent response to angiotensin II of heart rate was inhibited by GABA (50, 500 micrograms), GABOB (500 micrograms) and muscimol (50, 100 micrograms). The inhibition of the response to angiotensin II by a small dose of GABA (50 micrograms), but not by a high one (500 micrograms), was antagonized by i.a. injection of picrotoxin (2 mg). The positive chronotropism induced by bethanechol (25, 50 micrograms) and a small dose of acetylcholine (25 micrograms) were significantly inhibited by a high dose (500 micrograms) but not by a low dose (50 micrograms) of GABA. These results confirm that angiotensin II stimulates cardiac chronotropism by acting on the angiotensin II receptor located at the cardiac ganglia and show that this stimulant effect is antagonized by GABA.

Effects of brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f]-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin) on smooth muscle and other biological systems were examined. In isolated intestinal preparations, brotizolam in higher concentrations shifted the concentration-contractile response curve after addition of acetylcholine down to the right. However, brotizolam did not affect the intestinal transport. Therefore, even if brotizolam possesses a non-specific inhibitory action on smooth muscle, it would be quite weak. Brotizolam, nitrazepam and estazolam in high doses showed a miotic action. Brotizolam had no effect on the digestive system, that is, gastric secretion, bile secretion and intestinal propulsive activity were not influenced. A depression of salivary secretion, which may be due to an additive action of Eidelberg's mixture, was observed. Brotizolam, nitrazepam and estazolam enhanced the sleeping time induced by ethanol and increased locomotor activity induced by methamphetamine, but did not affect the chewing behavior. There was no indication that continuous administration of brotizolam affected significantly the levels of lipids and sugar in the blood serum.

Pharmacodynamic effects of ethyl 7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4- benzodiazepine-3-carboxylate (CM6912), a new benzodiazepine derivative, and its main metabolites (CM6913 = M1, CM7116 = M2) on the peripheral systems were investigated in several species of animals. In pentobarbital-anesthetized rabbits, CM6912 and M2 (1 or 5 mg/kg, i.v.) had little effect on blood pressure, heart rate and ECG, but it slightly reduced the respiration rate. M1 decreased the heart rate without affecting respiration, blood pressure and ECG. In conscious rabbits, CM6912 and M2 (1 mg/kg, i.v.) did not affect respiration, blood pressure, heart rate and ECG, but M1 (1 mg/kg, i.v.) increased the heart rate. CM6912 (5 or 30 mg/kg), when administered orally, also increased heart rate. In pentobarbital-anesthetized dogs, CM6912 and its metabolites (5 mg/kg, i.v.) decreased respiration and heart rate without affecting blood pressure and ECG. CM 6912 (5 mg/kg, i.v.) did not affect cardiovascular responses to the carotid occlusion, vagus stimulation, and pre- and post-ganglionic stimulation of cardiac ganglion in anesthetized dogs. CM6912 and its metabolites affected neither the spontaneous contraction nor the heart rate of isolated rabbit atria. These compounds also had no action on isolated aortic strips from rabbits. CM6912 and its metabolites did not affect the muscle tone of isolated guinea pig intestine, and it had no effects on the contractile responses to acetylcholine, histamine, serotonin and barium chloride. In isolated rabbit intestine, CM6912 and M2 slightly reduced the amplitude of contraction, while M1 had no effect. CM6912 and its metabolites did not affect the spontaneous motility of isolated non-pregnant and pregnant rat uteri as well as in situ non-pregnant rat uterus and isolated guinea pig vas deferens, including the contractile response to adrenaline. CM6912 and M2 relaxed isolated guinea pig trachea strips only at high concentrations. CM6912 and its metabolites did not affect the contractile responses of isolated rat diaphragm to electrical stimulation of the phrenic nerve. CM6912 (2 or 10 mg/kg, p.o.) did not affect the rat renal and hepatic functions. CM6912 influenced neither blood coagulation in rabbits nor blood hemolysis in rats. CM6912 and its metabolites did not affect the pupil size and its light reflex, and they did not produce a local anesthesia and edema. The present results suggest that CM6912 and its main metabolites exert only slight effects on the peripheral systems in animals.

The pharmacodynamic effects of 4-methyl-1-piperazinecarboxylic acid ester with (+/-)-6-(7-chloro-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-7-h ydr oxy-5H-p- dithiino[2,3-c]pyrrol-5-one (suriclone, RP-31264) and its principal metabolites M1 and M2 on respiration, cardiovascular system, autonomic nervous system, smooth muscle and other physiological parameters were investigated in various animal species. Suriclone, 1 mg/kg i.v., increased the amplitude of respiratory movement, decreased the respiratory rate and blood pressure and increased the heart rate in conscious rabbits. The respiratory and depressor effects were more evident in pentobarbital anesthetized rabbits. In anesthetized dogs, suriclone, 0.05 or 0.5 mg/kg i.v., produced essentially the same effects as seen in the anesthetized rabbits. The ECG pattern was not significantly changed in any animal. Such effects on respiration and on the cardiovascular system of metabolites M1 and M2 in the rabbits were weak. In the isolated guinea-pig atria, suriclone, 10(-6) g/ml, had no effect but increased contractility and decreased heart rate at a high concentration of 10(-5) g/ml. Both M1 and M2 had weak effects. Suriclone had no action on flow rate of the perfusate through the blood vessels of the isolated rabbit ear. In anesthetized dogs, suriclone 0.5 mg/kg i.v., did not affect the responses to vagal stimulation or to pre- and postganglionic stimulation of cardiac ganglion. Suriclone instilled onto the eye or i.v. had no appreciable effect on pupillary diameter or the miotic response in rabbits, but an abnormal oculogyration was evoked when the drug was given i.v. at 1 mg/kg. M1 or M2 had no such effect. Suriclone did not exert analgesic effects in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

1) In pentobarbital-anesthetized dogs, intravenous administration of CN-100 at 40 mg/kg exhibited a transient hypotension, accompanied with a slight respiratory excitation and a temporal increase of heart rate followed by slight and gradual decrease at 20 and 40 mg/kg. 2) In isolated guinea pig atria, CN-100 (10(-4), 10(-5) g/ml) decreased the heart rate, without influencing the myocardial contraction. 3) In anesthetized dogs, the vertebral and carotid blood flow slightly and gradually increased at 5-20 mg/kg and decreased at 40 mg/kg. The drug at 20 mg/kg similarly increased the femoral flow. 4) In anesthetized dogs, CN-100 (40 mg/kg) slightly potentiated hypertensive responses to noradrenaline and adrenaline, without affecting heart rate responses to these amines. 5) In anesthetized dogs, CN-100 (40 mg/kg) scarcely had effect on the blood pressure rise and bradycardia induced by respective proximal and distal end stimulation of the severed vagus nerve, but enhanced the hypertension due to the carotid sinus reflex. CN-100 augmented the tachycardia elicited by pre- and postganglionic stellate stimulation in spinal dogs. 6) In isolated guinea pig trachea muscle, CN-100 (3 x 10(-6) g/ml) reduced the resting tone and relaxation response to noradrenaline, but slightly enhanced contractile responses to field stimulation and acetylcholine. 7) These results suggest that CN-100 exerts weak cardiovascular and autonomic nervous actions.

Cardiovascular effects of NC-1100 (1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanol and possible modes of action were studied in dogs and guinea pigs. 1. In pentobarbital-anesthetized dogs, intravenous administration of NC-1100 (0.05-1.6 mg/kg) induced a dose-dependent fall of blood pressure, a bradycardia followed by temporal tachycardia, a slight and transient stimulation of respiration and a prolongation of the R-R interval with slight augmentations of P, R and T waves in ECG. 2. In pentobarbital-anesthetized dogs, NC-1100 (2.5-80 micrograms/kg) administered to the maxillary and vertebral artery dose-dependently increased the blood flow in the respective artery. 3. Intravenous administration of NC-1100 (0.05-1.6 mg/kg) also exhibited dose-dependent increases of the maxillary and vertebral blood flow, though the increase in maxillary flow was a little reduced at a high dose of 1.6 mg/kg. Intravenous administration of NC-1100 (0.1-1.6 mg/kg) caused a slight increase in the aortic and coronary blood flow, a decrease in renal flow and a slight and transient decrease followed by an increase in femoral flow. 4. In pentobarbital-anesthetized dogs, NC-1100 (1 mg/kg) administered i.v. did not affect responses of blood pressure and heart rate to norepinephrine and isoprenaline (isoproterenol) but slightly inhibited hypotensive responses to acetylcholine. NC-1100 had no effect on hypertension elicited by carotid sinus reflex and on bradycardia by vagus stimulation. NC-1100 slightly inhibited the tachycardia elicited by pre- as well as postganglionic stellate stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of brotizolam (2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno(3,2-fl-1,2,4-triazolo [4,3-a]-1,4-diazepine, We 941, Lendormin), a new thieno-triazolo-diazepine, on the heart, hemodynamic functions and the autonomic nervous system were investigated in rats, guinea pigs, rabbits, cats and dogs: In pentobarbital anesthetized dogs, 1 or 5 mg/kg brotizolam administered intravenously, decreased heart rate, with a frequency-dependent prolongation of the intervals and heightening of the T-waves in the electrocardiogram, depressed respiration, whereas the blood pressure was unaffected. In urethane anesthetized rabbits, 5 or 10 mg/kg brotizolam intravenously had almost no distinct effect on blood pressure and heart rate, though it slightly decreased respiratory rate at 10 mg/kg. In nonanesthetized rabbits, brotizolam exerted similar actions on respiration, blood pressure and heart rate. In isolated guinea pig atria, 1-10 mg/l brotizolam did not show noticeable effects on contractile force but decreased slightly the pulse rate. In pentobarbital anesthetized dogs, vertebral and carotid blood flow remained almost unchanged after 0.05 mg/kg brotizolam intravenously, but were increased following 0.5 mg/kg. Cardiac output and coronary flow were not changed by 0.5 mg/kg brotizolam but slightly decreased accompanied by a decrease in blood pressure and heart rate by 1 mg/kg. Femoral flow was not affected by 0.5 or 1 mg/kg. After 5 mg/kg brotizolam given intravenously in dogs, the pressor effect of epinephrine was significantly enhanced and the positive chronotropic effect increased to a certain degree. Both effects of norepinephrine also tended to be enhanced.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of brovincamine (BV) on peripheral nerves were studied in dogs and rats. 1) In pentobarbital-anesthetized dogs, BV (6.4 mg/kg) administered i.v. did not affect the changes of blood pressure and heart rate induced by noradrenaline and adrenaline, but slightly inhibited the hypotensive effect of acetylcholine. BV had no effect on the hypertension elicited by carotid sinus reflex, but diminished the bradycardia by vagus nerve stimulation. BV did not influence the tachycardia elicited by stimulation of the postganglionic nerve to stellate ganglion, but slightly inhibited that by the preganglionic stimulation. 2) In spinal dogs, BV (6.4 mg/kg) given i.v. slightly inhibited the increases of blood pressure and heart rate induced by i.v. dimethylphenylpiperazinium (DMPP). When i.v. administered in divided doses of 2 and 4 mg/kg, BV induced a slight but stepwise inhibition of the tachycardia elicited by direct administration of DMPP, bethanechol (BCH) and angiotension II (AT II) to the cardiac sympathetic ganglia via the subclavian artery. 3) In rat isolated diaphragm nerve preparations, BV at 10(-5) and 10(-4) g/ml dose-dependently reduced the twitch response to nerve stimulation. 4) In conclusion, BV does not affect the sympathetic activities but inhibits the cholinergic function in the autonomic nervous system.

The actions on the bronchial smooth muscle and cardiovascular system S-1540 (Bitolterol) (Shionogi Pharmaceuticals), a new bronchodilator which is chemically related to isoprenaline, and S-1541 which is the active metabolite of S-1540 were studied in comparison with the action of isoprenaline (isoproterenol) and orciprenaline (metaproterenol). 1) The relaxing effect on isolated guinea-pig tracheal muscle constricted previously with histamine BaCl2 or acetylcholine was highest with S-1541, followed by isoprenaline and orciprenaline, in that order, and lowest with S-1540. The relaxing effect of S-1541 on acetylcholine-induced tracheal constriction was reduced and that of S-1540 was completely abolished by a previous treatment with propranolol. The relaxing actions of those drugs on bronchial spasms induced by histamine in vivo were highest with S-1541, followed by isoprenaline, and lowest with S-1540. 2) All these drugs exhibited the depressor and positive chronotropic actions in guinea-pigs. The potencies of the actions were found to be in the following order; isoprenaline was most potent, followed by S-1541 with a little less intensity, orciprenaline much weaker, and S-1540 still weaker with a positive chronotropic action of about 1/1000 of S-1541 and depressor action about 1/500. In the open chest guinea-pig, positive inotropic and chronotropic actions of S-1541 were about the same or slightly more potent than those of isoprenaline; S-1540 had a very weak action, being only about 1/1000 as active as S-1541. These actions of S-1540 were completely eliminated by propranolol pretreatment. S-1540 induced to remarkable changes in the electrocardiogram wave forms even in high doses. 3) Those drugs elicited the depressor, positive chronotropic and inotropic actions in rabbits and dogs. In rabbits, isoprenaline was most potent; S-1541 was similar to or a little weaker than isoprenaline; and S-1540 was extremely weak. In the dog, isoprenaline showed the highest of the above effect, followed by S-1541, orciprenaline and S-1540 in that order, with S-1540 having an extremely low activity. 4) The actions of S-1541 and isoprenaline appeared very rapidly but were of short duration, the duration of orciprenaline was moderate, and the actions of S-1540 rapidly appeared and were of an extremely long duration. It is suggested that S-1540 itself has pharmacological activities in vivo and the active metabolites such as S-1541 also have the activities. S-1540 can be administered by the oral route, is of long duration, and is thus considered to be a bronchodilator with a relative high specificity.

Possible mode of vasodilative action of brovincamine was assessed in isolated cardiovascular preparations in comparison with verapamil and papaverine. Brovincamine (IC50: 1.2 x 10(-5) M), verapamil (IC50: 3.5 x 10(-7) M) or papaverine (IC50: 2.5 x 10(-5) M) caused a dose-dependent relaxation of potassium (30 mM)-contracture in the rabbit pulmonary arterial segment. This relaxation by verapamil or brovincamine, but not by papaverine, was antagonized by increasing external Ca2+ concentration to 12.4mM. Duration of slow action potentials of partially depolarized guinea-pig papillary muscle was reduced by 14 min exposure to brovincamine (5 x 10(-5) M) or verapamil (10(-5) M. These results suggest that brovincamine produces a vasodilation via a slow Ca2+-channel blockade.

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)

Pharmacodynamic effects of [6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin -5- yl]-4-methyl-1-piperazine-carboxylate (zopiclone, RP-27267), chemically unrelated to benzodiazepines and a potential new sleep inducer, on the peripheral system were investigated in several species of animals. The drug was dissolved in the vehicle of 0.01 mol/l HCl solution for intravenous administration or for addition to the bath medium and was suspended in 0.25% carboxymethylcellulose solution for oral administration. In unanesthetized rabbits, zopiclone, 0.5 mg/kg i.v., exerted no action and at 1 mg/kg slightly decreased respiration and heart rate without affecting blood pressure and ECG. Zopiclone at 10(-6) g/ml had no action in the isolated guinea-pig atria but at 10(-5) g/ml it produced a gradual and slight decrease in heart rate without affecting the contraction. In the isolated small intestine of rabbits and guinea-pigs, zopiclone at 10(-6) g/ml had no action but produced a slight inhibition in a dose of 10(-5) g/ml. Zopiclone, 10(-5) g/ml, did not affect the stimulatory effects of acetylcholine, serotonin, histamine and barium in the isolated guinea-pig intestine. Zopiclone, 1, 5 and 10 mg/kg i.v., exerted no action on rabbit intestinal movement in vivo. Zopiclone, 5, 10, 20 and 50 mg/kg p.o., had no effect on the propulsive motility of the mouse intestine. Zopiclone, 10(-5) g/ml, did not affect contractile movement of the uterus isolated from rabbits and did not influence the contractile response to epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)