(+)‐S‐12967 and (–)‐S‐12968: 1,4‐dihydropyridine stereoisomers with calcium channel agonistic and antagonistic properties in rat resistance arteries

Abstract

1 The actions of (+)-S-12967 and (-)-S-12968 two isomers of a new 1,4-dihydropyridine (DHP) derivative, were studied on 125 mm K + -, Ca2+-and noradrenaline-induced contractions in rat isolated mesenteric resistance arteries and compared to those of nifedipine. 2 The action of (+)-S-12967 and (-)-S-12968 was slow in onset in contrast to nifedipine. Both isomers had a dual contractile and relaxant action in arteries contracted with 125 mm K+; however, the (-)-isomer was about 300 times more potent than the (+)-isomer. The response to 125 mm K+, being depressed by 70%, recovered within 20 to 30 min for all DHP derivatives. All vessels were treated with 1 X 1O6 M phenoxybenzamine thus excluding the possibility that the contraction is mediated by activation of amine-receptors.

Role of Phosphatidylinositol 3-Kinase (PI3K), Mitogen-Activated Protein Kinase (MAPK), and Protein Kinase C (PKC) in Calcium Signaling Pathways Linked to the α1-Adrenoceptor in Resistance Arteries

“…However, Ca 2+ signaling mechanisms and the relative contribution of Ca 2+ sensitization and Ca 2+ mobilization mechanisms to arterial contraction are size-dependent. Thus, sensitivity of vasoconstriction and [Ca 2+ ] i changes induced by α 1 -adrenoceptor activation to pharmacological inhibitors of voltage-dependent L-type Ca 2+ entry is higher in resistance arteries compared to large conductance arteries (Prieto et al, 1991; Kitazawa and Kitazawa, 2012; Martinsen et al, 2012). Moreover, contractions of large arteries have been reported to involve kinases such as RhoK and PKC to varying degrees, while vasoconstriction of resistance arteries seem to be mediated exclusively by PKC (Budzyn et al, 2006; Kitazawa and Kitazawa, 2012).…”

Haemodynamic effects of a new dihydropyridine calcium entry blocker, S‐12968‐(−), in a rat model of cardiovascular calcium overload

“…Electrophysiological studies (Randle et al, 1990) do not confirm this hypothesis, however, so the mechanism of its pressor effect remains to be elucidated. Furthermore in vitro studies by Prieto et al (1991) show that in isolated mesenteric resistance arteries the two stereoisomers have both contractile and relaxant properties.…”

“…Although dihydropyridine calcium entry blockers (CEB) are widely used as first line therapeutic agents, many have a major disadvantage in the treatment of cardiovascular diseases in that they induce reflex tachycardia (Kiowski et al, 1986). Newer, longer acting dihydropyridines may have a certain advantage in this respect and in the present paper we present the cardiovascular effects in the rat of a new dihydropyridine, S-12968-(-), enantiomer of S-1568-([2-(7 amino 2,5-dioxaheptyl) 3-ethoxycarbonyl 4-)2,3-dichlorophenyl) 5methoxycarbonyl 6-methyl 1,4 dihydropyridine], see Figure 1 and Prieto et al, 1991). Its effects on blood pressure were compared to those produced by the stereoisomer S-12967-(+), nifedipine or sodium nitroprusside.…”