Kazushi Kushiku

Calcium antagonistic action involved in vasodilation by brovincamine.

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.

Upregulation of Immunoreactive Angiotensin II Release and Angiotensinogen mRNA Expression by High-Frequency Preganglionic Stimulation at the Canine Cardiac Sympathetic Ganglia

Abstract— 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 AT1 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.

CARDIOVASCULAR EFFECTS OF BROVINCAMINE AND POSSIBLE MECHANISMS INVOLVED

1. Cardiovascular effects of brovincamine (BV) and possible modes of action were studied in dogs, rabbits and guinea‐pigs.

Central effects of taurine: antagonistic effects on central actions of angiotensin.

Renin released from the juxtaglomerular apparatus of the kidney into the circulation produces angiotensin (AT) and this compound increases tubular absorption of sodium and water, resulting in an increase in circulating blood volume. In addition, AT evokes a net increase in sympathetic vasoconstrictor activity. The presynaptic effect of AT facilitates adrenergic transmitter release (16) and may also involve increased transmitter synthesis (3) and inhibition of adrenergic uptake (21). The postsynaptic effect appears to be due to an increase in sensitivity to norepinephrine (24). Furthermore, large doses of AT exert a constrictive action in the smooth muscle of blood vessels. Thus, the role of the peripheral renin-AT system in regulating the blood pressure is significant.

Antagonism by γ-aminobutyric acid of the stimulant effect of angiotensin II on cardiac sympathetic ganglia in spinal dogs

SummaryThe 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 μg) elicited a dose-dependent positive chronotropic effect which was reduced after i. a. injection of saralasin (100μg). 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 dosedependent response to angiotensin II of heart rate was inhibited by GABA (50, 500μg), GABOB (500μg) and muscimol (50, 100μg). The inhibition of the response to angiotensin II by a small dose of GABA (50μg), but not by a high one (500μg), was antagonized by i. a. injection of picrotoxin (2 mg). The positive chronotropism induced by bethanechol (25, 50μg) and a small dose of acetylcholine (25μg) were significantly inhibited by a high dose (500μg) but not by a low dose (50μg) 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.

Negative chronotropic effect of catecholamines on adrenergic receptors in cardiac ganglia in the spinal dog.

Summary 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 μg, i.a.) in many cases. With preganglionic stimulation, intra-arterial injection of norepinephrine (0.5–25 μg), epinephrine (0.1–10 μg), or dopamine (0.1–500 μg) 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 α-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 α-adrenergic and dopamine-specific and those for epinephrine are α-adrenergic specific.

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.

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.

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.

Effects of prostaglandins E1, E2 and F2α on the cardiac chronotropism by affecting the cardiac ganglionic transmission in spinal dogs☆

Abstract The effects of several prostaglandins (PGs) injected through the subclavian artery toward the cardiac sympathetic ganglia of spinal dogs were studied by utilizing changes of the heart rate as indicator of ganglionic function. PGF2α (10–270 μg) administered intra-arterially in the presence or absence of preganglionic stimulation produced weak positive chronotropic effects, which were increased by physostigmine. This positive chronotropic effect of F2α after physostigmine was inhibited by hexamethonium plus atropine, and depressed after hemicholinium-3 except for the response elicited by the first dose of F2α. PGE1 and E2 injected during preganglionic stimulation did not affect the heart rate. Intra-arterially administered epinephrine and dopamine depressed dose-dependently transmission in the cardiac ganglia, the effect being inhibited by E1 and E2 but not by F2α. These results suggest that F2α facilitates the release of acetylcholine from preganglionic nerve ending, whereas E1 and E2 antagonize the inhibitory actions of catecholamine in the cardiac ganglia.