Hideji Morishita

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.

Existence and pharmacological properties of dopamine D4 receptors in guinea pig vas deferens

This study was carried out to identify subtypes of dopamine D2-like receptors in guinea pig isolated vas deferens. Dopamine had no effect on the muscle tone in the presence of prazosin, an alpha1-adrenoceptor antagonist. However, contractile responses to adenosine triphosphate (ATP), noradrenaline and acetylcholine were potentiated in a concentration dependent manner by dopamine in the presence of prazosin. This potentiation was not inhibited by raclopride, an antagonist for dopamine D2 and D3 receptors. However, the potentiation of ATP- and noradrenaline-induced contraction was inhibited by clozapine and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3b][1,4]benzodiazepine (JL-18), dopamine D4 receptor antagonists. Further, the potentiation of noradrenaline- and acetylcholine-induced contraction was also inhibited by spiperone, an antagonist for dopamine D2, D3 and D4 receptors. These results suggest that the dopamine D4 receptor is located on the postsynaptic site of guinea pig vas deferens and that activation of the dopamine D4 receptor enhances contractile responses to agonists without affecting muscle tone.

Inhibition by sulfur-containing amino acids and GABA of sympathetic neurotransmission in guinea-pig vas deferens

Electrical stimulation produced a contraction in the isolated guinea-pig vas deferens. This response was blocked by tetrodotoxin, guanethidine and bretylium but not by atropine. The magnitude of the contractile response to electrical stimulation depended on the concentration of the external calcium. Sulfur-containing amino acids and GABA inhibited the electrically induced contraction but not that caused by noradrenaline and ATP. The order of potency for inhibition of the contraction at a concentration of 10(-4) M being GABA greater than or equal to cysteine greater than methionine greater than cysteic acid greater than taurine. The contractile response to electrical stimulation was also inhibited by EGTA, this inhibition being similar to that by cysteic acid and taurine but weaker than that by methionine, cysteine and GABA at a concentration of 10(-4) M. The inhibitory action of sulfur-containing amino acids and GABA was abolished by increasing the calcium concentration in the medium. The results suggest that sulfur-containing amino acids and GABA reduce transmitter release from the sympathetic nerve terminals by inhibiting calcium availability for the transmitter secretion process.

Existence of postsynaptic dopamine D2 receptor as an enhancer of contractile response in vas deferens

Effects of dopamine and (+/-)-2-(N-phenylethyl-N-propyl)amino-5-hydroxy-tetralin hydrochloride (N-0434), a dopamine D2 receptor agonist, in the presence of prazosin on the ATP- and acetylcholine-induced contraction were investigated in the guinea-pig vas deferens in order to test for the existence of postsynaptic dopamine receptors. The contraction induced by ATP was potentiated by dopamine and N-0434. This potentiation was antagonized by spiperone, a dopamine D2 receptor antagonist, but not by a dopamine D1 receptor antagonist and an alpha2-adrenoceptor antagonist. Similar results were also observed by acetylcholine as well as ATP. The contraction induced by transmural nerve stimulation in the presence of alpha-adrenoceptor antagonists was also potentiated by N-0434, and this potentiation was antagonized by spiperone. The results suggest that dopamine D2 receptors are located on the postsynaptic site of guinea-pig vas deferens and that the contractile responses to ATP and acetylcholine are potentiated via activation of dopamine D2 receptor.

Existence of dopamine D1 receptor on the sympathetic nerve endings in the guinea-pig vas deferens.

The effects of selective dopamine receptor agonists and antagonists on sympathetic neuromuscular transmission were investigated in the guinea-pig vas deferens in order to test for the presence of presynaptic dopamine receptors. A single-pulse field stimulus induced a rapid monophasic contraction which was strongly inhibited by alpha,beta-methylene ATP, a P2X purinoceptor desensitizing agent. The contraction was also inhibited by 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304), a selective alpha2-adrenoceptor agonist. This inhibition was antagonized by idazoxan, an alpha2-adrenoceptor antagonist, but not by R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride (SCH-23390), a dopamine D1 receptor antagonist. Furthermore, the contractions were inhibited in a dose-dependent manner by R(+)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) and (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-be nzazepine hydrobromide (SKF-82958), dopamine D1 receptor agonists, and the inhibition was antagonized by both SCH-23390 and idazoxan, but not by spiperone, a dopamine D2 receptor antagonist. The results suggest that dopamine D1 receptors are located on the sympathetic nerve endings of guinea-pig vas deferens.

Low calcium and calcium antagonist potentiate the contraction of guinea-pig vas deferen e induced by ATP: a permissive role for P2-purinoceptors

ATP, noradrenaline and KCl induced contractions of the isolated guinea-pig vas deferens. The ATP-induced contraction was potentiated by decreasing the external calcium concentration and was reduced by increasing the external calcium concentration. The maximum potentiation was obtained at a low calcium concentration (0.8 mM), the dose-response curve for ATP was shifted to the left in a parallel fashion at this concentration. Calcium antagonists, such as verapamil and diltiazem and MnCl2, induced a similar potentiation. On the other hand, the noradrenaline- and KCl-induced contractions were reduced by calcium antagonists and by decreasing the external calcium concentration. The ATP- and KCl-induced contractions were slightly potentiated by the removal of Mg ions from the medium, but the contractile response to ATP was not potentiated by pretreatment with difluorodinitrobenzene, an ecto-ATPase inhibitor. These results suggest that the affinity of P2-purinoceptors for ATP may be regulated by calcium sites to which calcium and calcium antagonists can bind.

Possible Involvement of Endogenous Substances in the Cardiovascular Actions of Dopamine

ABSTRACT The dose-dependent positive chronotropic effects of dopamine were potentiated by dopamine antagonists in pithed dogs. The effects of dopamine were also potentiated but those of norepinephrine were not affected after treatment with indomethacin. When the drugs were directly administered to the sinus node artery, the dose-dependent positive chronotropic effects of dopamine were reduced during infusion with PGE1 but this inhibition was completely antagonized by pretreatment with droperidol, whereas those of isoproterenol were not affected by either PGE1 or droperidol. In isolated atrial preparations of guinea pig, the dose-dependent positive chronotropic effects of PGE1 were inhibited by droperidol and chlorpromazine but not by bulbocapnine, while those of isoproterenol were not affected by these dopamine antagonists. The increases of renal blood flow elicited by dopamine and bradykinin were similarly potentiated after treatment with indomethacin in dogs. The increases elicited by dopamine were reduced but those by isoproterenol were not affected after cinnarizine. The results suggest that PGE-type are involved in the negative chronotropic action of dopamine and that the dopamine antagonists antagonize the cardiac action of PGE1. It is therefore probable that PGE-type released by dopamine may exert in part the dopamine specific receptor action in the heart.

Effect of drugs on femoral artery strips in the dog

イヌ股動脈条片について，その一般的性質を吟味し，さらに諸種薬物の作用を検討した．1)イヌ股動脈条片は固有緊張を保持し，自発性の律動的収縮を示さない．等張性に記録して，条片に49の負荷をかけると，条片は徐々に伸長して，指数函数的曲線を描き，その緊張は1.5～3時間でほぼ一定となる．収縮剤の作用はそれに伴って強く現われるようになり，反応性は1.5～3時間で最大となり，その後は7時間位まで一定である．2)Adrenaline，noradrenaline，dopamine，tyramine，ephedrineはこの順序の作用強度で，すぺて収縮を起こし，その収縮はphenoxybenzamineで完全に除かれる．isoprenalineは低濃度では弛緩，高濃度では収縮を起こし，弛緩はpropranolo1で，収縮はphenoxybenzamineで完全:に除去される．3)Acetylcholineはいかなる濃度でも弛緩を起こし，この作用はatropineと拮抗する．KClは強い収縮，histamineは弱い収縮を示す．以上のように，イヌ股動脈条片はウサギ大動脈条片に比べ，収縮作用のみでなく，弛緩作用も現われ，その反応性は生体における薬物の作用にきわめて類似している，したがって，薬物の血管に対する作用を検討するのに適した実験材料と考えられる．