Hemodynamic Characterization of Pinacidil in Rats

Abstract

Pinacidil (N’’-cyano-N-4-pyridyl-N’-l,2,2-trimethylpropylguanidine monohydrate; P1134) is a new vasodilator drug with a direct relaxant effect on vascular smooth muscle. Its hemodynamic properties, in comparison with those of hydralazine, were studied in conscious normotensive and spontaneously hypertensive rats; anesthetized normotensive rats; pithed normotensive rats; pithed normotensive rats subjected to electrical stimulation of the spinal cord. Radioligand binding studies on rat cerebral membranes were carried out to study a possible affinity for pinacidil towards α₁ and α₂-adrenoceptors, respectively. The observations made in conscious and anesthetized rats suggest that both pinacidil and hydralazine are predominantly arterial vasodilators. In conscious animals reflex tachycardia was elicited by both drugs. Neither pinacidil nor hydralazine possessed substantial affinity for α₁or α₂adrenoceptors, as concluded from radioligand binding studies. Pinacidil interferes with the pressor response to postsynaptic α₂-adrenoceptor stimulation in pithed rats, possibly reflecting weak calcium antagonistic activity of the drug. Pinacidil did not interfere with the electrically induced release of noradrenaline from presynaptic sites. All results suggest that pinacidil is a direct-acting arteriolar dilator, which on a molar base is somewhat more potent than hydralazine.

Effect of Pinacidil on Sympathetic Neuroeffector Transmission in Rabbit Blood Vessels

“…Pinacidil most likely has a direct action on vascular smooth muscle (Olsen & Arrigoni-Martelli 1983;Thoolen et al 1983;Nielsen & Arrigoni-Martelli 1981;Mikkelsen & Pedersen 1982). This is supported by the present findings that pinacidil in high concentrations in a predominantly non-competitive manner reduced the contractions of rabbit aorta evoked by potassium and a number of agonists: noradrenaline, adrenaline, phenylephrine, serotonin and histamine.…”

Pinacidil

“…Both compounds display a more potent effect in hypertensive than in normotensive animals; on a weight basis, pinacidil appears to be more potent than hydralazine. The degree of reflex tachycardia proved similar for both compounds (1,20,32). In a multiple-dose study, pinacidil(O.5, 1.25,2.5 mgkg) and hydralazine (1.25, 2.5, 5.0 mgkg) were orally administered daily for 5 days to spontaneously hypertensive rats and blood pressure was measured by an indirect method (Gartner cuff) on the third and fifth day of treatment, 4 hr after dosing.…”

“…The influence of these compounds on the pressor responses to 8-lysine vasopressin may indicate a nonspecific type of interaction between the vasopressor compound and the vasodilators. The observation that neither pinacidil nor hydralazine influenced the tachycardia induced by electrical stimulation of the spinal cord in rats suggests that these drugs do not possess P,-adrenoceptor-blocking activity (32).…”

“…In normotensive rats anesthetized with pentobarbital, pinacidil and hydralazine administered intravenously also displayed dose-dependent and comparable hypotensive effects which were not accompanied by significant changes in heart rate (20,32). Cardiac output, determined by the thermodilution method, was significantly increased by both compounds (32), probably as a result of a rise in stroke volume, a hemodynamic pattern thought to be characteristic of vasodilators with a predominantly arterial site of action (29). This hypothesis is supported, albeit indirectly, by the finding that the venoconstriction induced by dihydroergotamine in pithed rats does not influence the hypotensive activity of pinacidil (20).…”

Variable metabolism of pinacidil: lack of correlation with the debrisoquine and trimethylamine C‐ and N‐oxidative polymorphisms.

“…Pinacidil, [NA"-cyano-N-4-pyridyl-N"-(1,2,2-trimethylpropyl] guanidine, is a new anti-hypertensive agent believed to produce its effect principally by arterial vasodilatation (Thoolen et al, 1983). Oral doses of the drug in man are rapidly absorbed with peak plasma concentrations at 0.5-1.2 h after dosing and the drug has a plasma elimination half-life of about 2 h (Eilertsen et al, 1982a).…”