Evidence that the mechanism of the inhibitory action of pinacidil in rat and guinea‐pig smooth muscle differs from that of glyceryl trinitrate

Bray, Katharine; Newgreen, Donald; Small, R.C.; Southerton, J. S.; Taylor, Simon; Weir, Sheila W.; Weston, A.H.

doi:10.1111/j.1476-5381.1987.tb10297.x

Cited by 121 publications

(58 citation statements)

References 13 publications

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“…Pinacidil hyperpolarized smooth muscle cell membranes of the rabbit and guinea-pig mesenteric arteries, in a concentration-dependent manner, as observed in other vascular tissues (Bray et al, 1987;Cook et al, 1988;Hermsmeyer, 1988;Southerton et al, 1988;Videbaek et al, 1988 (Standen et al, 1989;Buckingham et al, 1989;Hiraoka & Fan, 1989;Kajioka et al, 1990). The resting membrane potential of smooth muscle cells in both tissues was almost the same.…”

Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

“…Pinacidil is a vasodilator currently under clinical investigation as a potential anti-hypertensive agent (Petersen et al, 1978;Arrigoni-Martelli et al, 1980;Carlsen et al, 1981;Bray et al, 1987;Cook et al, 1988). The main mechanism by which this drug relaxes vascular smooth muscle tissues is thought to be activation of a K channel which may be Ca-dependent (Bray et al, 1987;Cook et al, 1988;Hermsmeyer, 1988;Videbaek et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

“…The main mechanism by which this drug relaxes vascular smooth muscle tissues is thought to be activation of a K channel which may be Ca-dependent (Bray et al, 1987;Cook et al, 1988;Hermsmeyer, 1988;Videbaek et al, 1988). Thus, in vascular smooth muscle tissues, pinacidil consistently hyperpolarized the membrane (rat portal vein : Bray et al, 1987;rat aorta: Southerton et al, 1987; rat mesenteric artery: Videbaek et al, 1988). In addition, pinacidil also exhibits a bronchodilator action and the mechanism underlying this effect is thought to be the same as that observed in vascular tissues (Karlsson & Persson, 1981;Nielsen-Kudsk et al, 1988;Mellemkjaer et al 1989).…”

Section: Introductionmentioning

confidence: 99%

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Pinacidil inhibits neuromuscular transmission indirectly in the guinea‐pig and rabbit mesenteric arteries

Nakashima

Seki

et al. 1990

British J Pharmacology

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1 Effects of pinacidil were investigated on neuromuscular transmission in smooth muscle tissues of the rabbit and guinea-pig mesenteric arteries by both electrophysiological procedures and a bioassay of noradrenaline (NA) outflows. 2 Pinacidil (over 1 aM) hyperpolarized smooth muscle cell membranes in both tissues, in a concentration dependent manner. Pinacidil hyperpolarized and increased the ionic conductance of smooth muscle membrane more markedly in the rabbit mesenteric artery than in the guinea-pig. The hyperpolarization induced by pinacidil occurred in the presence or absence of endothelial cells and was blocked by glibenclamide. 3 Perivascular adrenergic nerve stimulation produced excitatory junction potentials (ej.ps) and repetitive stimulation produced a facilitation of ej.ps in both tissues. Pinacidil (over 1 piM) reduced the amplitude and the decay time of ej.ps to a consistently greater extent in the rabbit mesenteric artery than in the guinea-pig. However, the facilitation process of ej.ps was not modified following application of pinacidil (1 pM). The pinacidil-induced inhibition of ej.ps was prevented by pretreatment with glibenclamide.4 Pinacidil (30pM) marginally increased the overflows of NA and its metabolite, 3,4-dihydroxyphenylglycol (DOPEG) released following repetitive perivascular nerve stimulations. 5 Pinacidil (10pM) partly inhibited the voltage-dependent Ca channel, as estimated from the recovery process following removal of pinacidil, of action potentials evoked on ej.ps. 6 It is concluded that pinacidil increases ionic conductance and hyperpolarizes smooth muscle cell membranes of the guinea-pig and rabbit mesenteric arteries and as a consequence, inhibits the neuromuscular transmission process occurring on adrenergic nerve stimulation with no reduction in the amount of released transmitter.

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Section: Discussionmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pinacidil inhibits neuromuscular transmission indirectly in the guinea‐pig and rabbit mesenteric arteries

Nakashima

Seki

et al. 1990

British J Pharmacology

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“…Furthermore, the cells become less sensitive to depolarizing stimuli (Clapham & Wilson, 1987;Cook, 1988;1989). The vasodilator and cardiac effects of drugs like cromakalim Weir & Weston, 1988;Cook & Hof, 1988) and pinacidil (Bray et al, 1987) and also the cardiac effects of nicorandil (Weir & Weston, 1988) are mediated by opening of adenosine 5'-triphosphate (ATP)-dependent potassium channels. These potassium channels have been shown to be important in mediating the hypoxic dilatation of coronary arteries (Daut et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

Sassen

Duncker

Gho

et al. 1990

British J Pharmacology

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1 The systemic and regional haemodynamic effects of the potassium channel activator EMD 52692 or its solvent were investigated after intravenous and after intracoronary administration in anaesthetized pigs.2 Consecutive intravenous 10min infusions of EMD 52692 (0.15, 0.30, 0.60, 1.20pgkg Imin-'; n = 7) dose-dependently decreased mean arterial blood pressure by up to 50%. This was entirely due to peripheral vasodilatation, since cardiac output did not change. Heart rate increased by up to 50%, while left ventricular end diastolic pressure decreased dose-dependently from 6 + mmHg to 3 + mmHg (P <0.05), and stroke volume decreased from 30 + 2 ml to 21 + 2 ml (P < 0.05). Left ventricular dP/dt.. was not affected. 3 Although cardiac output did not change, EMD 52692 caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels. Blood flow to the adrenals, small intestine, stomach, bladder, spleen and brain increased, while renal blood flow decreased and blood flow to several muscle groups and skin were not altered. Vascular conductance was increased dose-dependently in all organs, except for the kidneys, where after the initial increase, vascular conductance returned to baseline with the highest dose. Particularly striking were the effects on the vasculature of the brain. With the highest dose of EMD 52692 blood flow more than doubled, while vascular conductance increased four fold. 4 Transmural myocardial blood flow increased slightly, which was entirely due to an increase in subepicardial blood flow. Myocardial O2-consumption and segment length shortening were not significantly affected. 5 After consecutive 10min intracoronary infusions (0.0095, 0.019, 0.0375 and 0.075Sugkg-'min-1; n = 7) into the left anterior descending coronary artery (LADCA), mean arterial blood pressure was maintained with the lowest two doses, but decreased by up to 15% with the higher doses, whereas heart rate increased by up to 24%. Blood flow to the LADCA-perfused myocardium doubled with the highest dose, the subepicardium benefitting the most. Coronary venous O2-saturation increased dose-dependently from 23 + 2% to 60 + 4%, while myocardial 02-consumption of the LADCA-perfused myocardium was not affected by the drug. 6 It is concluded that EMD 52692 is a potent vasodilator, with particularly pronounced effects on vasculature of the brain. Its selectivity for vascular smooth muscle cells exceeds that for the myocytes, since with doses that are much higher than those of potential clinical interest no negative inotropic effects were observed. The compound primarily dilates arteries but some venodilatation may also occur.

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Acute Hemodynamic Effects of Pinacidil in Hypertensive Patients with and without Propranolol Pretreatment

Stone

Wellington

Willick

et al. 1991

The Journal of Clinical Pharma

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To study the systemic and regional hemodynamic effects of the new antihypertensive agent pinacidil, the authors administered intravenously two doses of pinacidil (0.1 mg/kg) to patients with hypertension after 3 days of randomized, double-blind pretreatment with either propranolol or placebo. Pinacidil administration decreased systemic arterial pressure and total peripheral vascular resistance in both groups of patients. It also decreased pulmonary artery wedge pressure, and increased cardiac output, heart rate, and plasma norepinephrine levels; the changes in cardiac output and heart rate were attenuated by propranolol pretreatment. In addition, propranolol-pretreated patients responded to pinacidil with a decrease in forearm blood flow. In contrast, pinacidil administration exerted no significant effects on right atrial pressure, stroke volume, or mean pulmonary arterial pressure alone or in combination with propranolol. The results show that pinacidil is a potent arterial dilator but has little effect on the venomotor tone in patients with hypertension.

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Evidence that the mechanism of the inhibitory action of pinacidil in rat and guinea‐pig smooth muscle differs from that of glyceryl trinitrate

Cited by 121 publications

References 13 publications

Pinacidil inhibits neuromuscular transmission indirectly in the guinea‐pig and rabbit mesenteric arteries

Pinacidil inhibits neuromuscular transmission indirectly in the guinea‐pig and rabbit mesenteric arteries

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs

Acute Hemodynamic Effects of Pinacidil in Hypertensive Patients with and without Propranolol Pretreatment

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