The potassium channel opening action of pinacidil; studies using biochemical, ion flux and microelectrode techniques

Abstract

In rat aorta and rat portal vein, (-)- and (+)-pinacidil each produced a concentration-dependent inhibition of tension development. Although the (-) isomer was the more potent, concentration effect curves for each isomer were steep with similar slopes. In rat portal vein, tetraethylammonium and procaine antagonised the relaxant effect of (+/-)-pinacidil, whereas 3,4-diamino-pyridine was without effect. Intracellular microelectrode recording in rat portal vein showed that low concentrations of (+/-)-pinacidil reduced the duration of multispike electrical complexes. In both rat aorta and rat portal vein, higher concentrations of (+/-)-pinacidil hyperpolarised the membrane towards the potassium equilibrium potential. (+/-)-Pinacidil increased 86Rb efflux from rat aorta and rat portal vein in a concentration dependent manner. In a separate study, (+/-)-pinacidil increased 42K efflux from rat portal vein. (+/-)-Pinacidil had no effect on cyclic GMP or cyclic AMP levels in rat aorta. It is concluded that pinacidil opens 86Rb-permeable potassium channels in rat aorta and rat portal vein. This mechanism is independent of cyclic nucleotide changes and may be responsible for the antihypertensive effect of pinacidil.

Effects of several potassium channel openers and glibenclamide on the uterus of the rat

“…The potencies of cromakalim, RP 49356 and pinacidil in the isolated uterus against oxytocin-induced spasms were similar to those observed in vascular smooth muscle (Southerton et al, 1988;Cavero et al, 1989;Eltze, 1989 Glibenclamide is a blocker of ATP-dependent K+ channels in pancreatic fl-cells (Sturgess et al, 1988) and in smooth muscle (Standen et al, 1989). Glibenclamide has been used in smooth muscle as a pharmacological tool to demonstrate that cromakalim and related compounds act via ATP-dependent K+ channels (Quast & Cook, 1989b Eltze, 1989;Quast & Cook, 1989a;Wilson, 1989).…”

Ion channel modulation by NS 1619, the putative BKCa channel opener, in vascular smooth muscle

“…This is generated by the discharge of electrical multi-spike complexes which at their peak shift the membrane potential into the range -10 to 0 mV (Southerton et al, 1988). Since inhibitors of both IK(v) (phentolamine; Ibbotson et al, 1993b) and IBK(Ca) (charybdotoxin and penitrem A; present study) increase spontaneous activity in portal vein, both Kv and BKc.…”

Effects of pinacidil on contractile proteins in high K+‐treated intact, and in β‐escin‐treated skinned smooth muscle of the rabbit mesenteric artery

“…Pinacidil hyperpolarizes the smooth muscle membrane through activation of the K+ channel and then causes vascular relaxation (Southerton et al, 1988: Standen et al, 1989. Glibenclamide is a selective inhibitor of this channel in vascular smooth muscles (Standen et al, 1989).…”

“…Pinacidil ((±)-N-cyano-4-pyridyl-N-1,2,2-trimethyl-propylguanodine monohydrate) is a novel vascular relaxant which hyperpolarizes the membrane of vascular smooth muscle cells at concentrations between 0.1 yM and IOUMM in a concentration-dependent manner (Southerton et al, 1988;Videbaek et al, 1988;Quast & Cook, 1989;Standen et al, 1989;Nakashima et al, 1991). These authors suggested that the membrane hyperpolarization inhibits the vasospasmogenic agent-induced contraction by increasing the threshold for activation of the voltage-dependent Ca2+ channel.…”