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The effect of Ba2+ on the catecholamine biosynthetic activity was studied by measuring the formation of [14C]catecholamines from L-[14C]tyrosine in cultured adrenal chromaffin cells. In the absence of Ca2+, [14C]catecholamine formation was markedly stimulated by Ba2+, and this stimulation was observed in a manner dependent on its concentration. The stimulation of [14C]catecholamine formation by relatively low concentrations of Ba2+ was suppressed by polymyxin B, a typical inhibitor of Ca2+/phospholipid-dependent protein kinase (protein kinase C); and this inhibitory action of polymyxin B was attenuated by increasing the Ba2+ concentration. On the other hand, a tendency toward the enhancement of Ba2+-stimulated [14C]catecholamine formation was observed by a protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA). In contrast to the acute effect of TPA, [14C]catecholamine formation stimulated by Ba2+ was reduced by long-term exposure of chromaffin cells to a high concentration of TPA, which has already been reported to cause the reduction of protein kinase C activity as a result of the down-regulation of this enzyme. These findings suggest that Ba2+ stimulates catecholamine biosynthesis, probably through its direct action on protein kinase C in adrenal chromaffin cells.

Postsynaptic alpha-receptor blocking properties of E-643 were studied in vivo and in vitro and compared with these same properties of phentolamine and phenoxybenzamine. In anesthetized rats, E-643 (i.v.) attenuated pressor response to adrenaline dose-dependently and an adrenaline-reversal was seen with large doses. The in vivo alpha-adrenoreceptor blocking effect of E-643 was 3.4 times more potent than that of phentolamine. On the other hand, hypotensive action of E-643 was 9.4 times more potent than that of phentolamine. In the isolated rabbit aorta, E-643 blocked noradrenaline-induced contraction of the aorta with a parallel shift of the dose-response curve to the right. The pA2 values for E-643 and phentolamine were 8.60 and 7.65, respectively. The alpha-blocking effect of E-643 was reversible. E-643 protected alpha-receptors against irreversible inhibition by phenoxybenzamine. E-643 neither exhibited significant blocking effects on K+-, Ba2+- and angiotensin-induced contractions of the aorta nor caused relaxation of the aorta contracted by Ca2+. These data suggest that E-643 is a specific and competitive inhibitor of noradrenaline at the alpha-adrenoceptors.

Butylidenephthalide (BdPh), ligustilide and butylphthalide were isolated and purified from neutral oil of Ligusticum wallichii Franch. Among these three, BdPh proved to be the most active in inhibiting rat uterine contractions induced by prostaglandin F2 alpha, oxytocin and ACh. In studies done to compare the effects of BdPh and papaverine (Pap), guinea pig ileum, vas deferens and taenia coli were used. BdPh inhibited contractile responses of the ileum to agonists including ACh, K+ and Ba2+ in normal Tyrode solution and to exogenous Ca2+ in high K+ (80 mM), Ca2+-free Tyrode solution, and also responses of vas deferens responses to norepinephrine. Thus, BdPh is a non-specific antispasmodic but weaker in potency than Pap. However, as the inhibitory effects of BdPh on phasic contraction (PC) and tonic contraction (TC) of preparations, including depolarized and non-depolarized ileum and taenia coli, were much the same, it is suggested that the action mechanism of BdPh may differ from that of Pap which inhibited TC more selectively than PC. It may be concluded that BdPh possesses an non-specific antispasmodic action like Pap, the mechanism of action being different from that of Pap.