Possible involvement of calcium-calmodulin pathways in the positive chronotropic response to angiotensin II on the canine cardiac sympathetic ganglia.

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.

Upregulation of immunoreactive angiotensin II release and angiotensinogen mRNA expression by high-frequency preganglionic stimulation at the canine cardiac sympathetic ganglia.

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.

Contribution of nitric oxide to the presynaptic inhibition by endothelin ETB receptor of the canine stellate ganglionic transmission.

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.

The inhibition of ganglionic transmission via presynaptic dopamine DA1 and postsynaptic DA2 receptor activation in the canine cardiac sympathetic ganglia.

The involvement of dopaminergic mechanisms in modulating ganglionic transmission of the dog cardiac sympathetic ganglia were investigated in both in vivo and in vitro experiments. The positive chronotropic responses to preganglionic stellate stimulation were inhibited by R(+)SK&F38393 and talipexole administered directly to the ganglia through the artery, and the inhibitory effects were antagonized by pretreatment with R(+)SCH23390 and S(-)sulpiride, respectively. McN-A-343 and 1,1-dimethyl-4-phenylpiperazinium iodide given through the artery to reach the ganglia displayed dose-dependent positive chronotropic effects. The positive chronotropic effects were inhibited by (-)quinpirole and talipexole, but not by R(+)SK&F38393. The inhibitions were antagonized by S(-)sulpiride and tended to be antagonized by yohimbine. The acetylcholine output from the isolated stellate ganglia by preganglionic stimulation (5 Hz) was unaffected in the presence of (-)quinpirole and talipexole, but was concentration-dependently reduced in the presence of R(+)SK&F38393, and the reduction was antagonized by R(+)SCH23390. The results thus suggest that the dopamine receptor agonists inhibit the ganglionic transmission by reducting acetylcholine release via preganglionic DA1 receptor stimulation and by inhibiting postganglionic nicotinic and muscarinic activation via postganglionic DA2 receptor stimulation.

Ionotropic mechanisms involved in postsynaptic inhibition by the endothelins of ganglionic transmission in dog cardiac sympathetic ganglia.

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.

Activation of endogenous thromboxane A2 biosynthesis mediates presynaptic inhibition by endothelin-3 of dog stellate ganglionic transmission.

Effects of endothelin-3 on ganglionic transmission were investigated in dog cardiac sympathetic ganglia. Positive chronotropic responses to preganglionic stellate stimulation were inhibited by endothelin-3 (0.5-2 micrograms) given directly to the ganglia through the artery. To find possible inhibitory effects of the peptide at presynaptic sites, acetylcholine released from the isolated stellate ganglia was determined. The amount of acetylcholine released during preganglionic stimulation was reduced by exposure to endothelin-3 (10(-9) to 10(-6) M). A similar reduction of acetylcholine release was observed after application of a stable thromboxane A2, a thromboxane A2/prostaglandin H2 receptor agonist, U-46619, and prostaglandin E2 at concentrations from 10(-8) to 10(-4) M, but not by the same concentrations of prostaglandins F2 alpha and I2. The reduction elicited by endothelin-3 was unaffected by a phospholipase C inhibitor, neomycin, or a protein kinase C inhibitor, H-7, but was antagonized by pretreatment with phospholipase A2 inhibitors, dexamethasone or methylprednisolone, and by cyclooxygenase inhibitors, aspirin and indomethacin. In addition, the reduction also 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. Furthermore, endothelin-3 (10(-7) M) stimulated the OKY-046- and indomethacin-sensitive formation of thromboxane A2 in the ganglia. These results indicate that endothelin-3 inhibits the sympathetic ganglionic transmission by reducing acetylcholine release at preganglionic terminals and that this inhibition seems to involve activation of endogenous thromboxane A2 production.

Increase of acetylcholine release by nebracetam in dog cardiac sympathetic ganglion.

The effects of nebracetam (4-aminomethyl-1-benzylpyrrolidine-2-one hemifumarate, WEB 1881FU), a potential cognitive enhancer, on acetylcholine release from the preganglionic nerve terminals were investigated in the isolated dog stellate ganglia. Acetylcholine release from the isolated ganglia by preganglionic stimulation (5 Hz) was enhanced in the presence of nebracetam, 10(-7) to 10(-5) M. The release was decreased to a certain extent by bethanechol, 10(-5) M, and this decrease was completely antagonized by AFDX-116 (10(-5) M), a selective M2 muscarinic antagonist, but was unaffected by nebracetam (10(-6) M). Under the depleted condition of acetylcholine induced by pretreatment with hemicholinium-3 (10(-5) M) in combination with prolonged preganglionic stimulation, the release was increased to a degree by nebracetam or choline alone and was markedly increased in the presence of both nebracetam and choline. Nebracetam did not directly act on choline acetyltransferase activity, but acetylcholine formation was stimulated in the isolated ganglion incubated with the agent at 10(-6) M and in the ganglion isolated from the dog to which nebracetam, 5 mg/kg, was previously administered i.v. Uptake of choline in the isolated ganglia was not altered by nebracetam (10(-6) M) but was enhanced under the depleted conditions. These findings suggest that nebracetam enhances acetylcholine release from presynaptic sites of dog stellate ganglia not by blocking presynaptic M2 muscarinic autoreceptors but by accelerating acetylcholine formation, and by increasing choline uptake when acetylcholine is depleted.

Presynaptic facilitation by the new nootropic drug nebracetam, of ganglionic muscarinic transmission in the dog cardiac sympathetic ganglion.

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.

Endothelin-3 inhibits ganglionic transmission at preganglionic sites through activation of endogenous thromboxane A2 production in dog cardiac sympathetic ganglia.

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.

[Antihypertensive effect of naftopidil (KT-611), a novel alpha 1-adrenoceptor antagonist, in freely moving experimental hypertensive rats and dogs].

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.

[Effects of CN-100 (2-(10,11-dihydro-10-oxodibenzo [b,f] thiepin-2-yl) propionic acid) on cardiovascular and autonomic nervous function in the dog and guinea pig].

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 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)

Cardiovascular effects of 1-(3,4-dimethoxyphenyl)-2-(4-diphenylmethylpiperazinyl) ethanol and possible mechanisms involved.

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)

Increment of calmodulin in proportion to enhancement of non-nicotinic responses after preganglionic stimulation of the dog cardiac sympathetic ganglia.

The possible involvement of calmodulin in ganglionic function was investigated. Drugs were given directly into the cardiac sympathetic ganglia through the right subclavian artery (i.a.), unless otherwise stated. Positive chronotropic responses to angiotensin II (0.1 and 0.2 micrograms) were enhanced after repetitive high frequency preganglionic stimulation to the right stellate ganglion. After the stimulation, positive chronotropic responses to bethanechol (2.5, 5 and 10 micrograms), but not those to dimethylphenylpiperazinium (2.5, 5 and 10 micrograms), also were enhanced. The enhancement of response to angiotensin II was not affected by i.v. pretreatment with hexamethonium (40 mg/kg) plus atropine (1 mg/kg) or nifedipine (1 mg/kg). Responses to angiotensin II were not enhanced by A23187 (0.3 mg). The enhanced response to angiotensin II after the stimulation was reduced by the calmodulin antagonists, trifluoperazine (0.1, 0.2 and 0.4 mg) and by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (0.5, 1 and 2 mg), but not by promethazine (1 mg) and N-(6-aminohexyl)-1-naphthalenesulfonamide (0.5, 1 and 2 mg). The enhanced response to bethanechol after the stimulation also was inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. Pretreatment with N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide before the stimulation prevented development of the enhancement in responses to the peptide. The inhibition of endogenous protein synthesis by cycloheximide, 2.5 or 5 mg/kg i.v. 6 hr before surgical procedures, strongly inhibited development of the enhancement in responses to angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological effects of the antianxiety compound suriclone and its principal metabolites.

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)

Pharmacodynamic effects of the sleep inducer zopiclone.

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)

Effects of brotizolam on cardiovascular functions and autonomic nervous system.

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 brotizolam on smooth muscle and other organs.

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.

[Pharmacological effects of CM6912 and its main metabolites].

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.