The effects of the calcium entry blockers nifedipine, (-)-verapamil and the dihydropyridine derivative PY 108-068 were evaluated on the increase in diastolic pressure of pithed normotensive rats caused by the selective alpha 1-adrenoceptor agonists cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine, (-)-amidephrine and St 587 [(2-chloro-5-trifluoromethylphenylimino)-2-imidazolidine] as well as by the mixed alpha 1/alpha 2-adrenoceptor agonists clonidine and DPI [(3,4-dihydroxyphenylimino)-2-imidazolidine]. The calcium entry inhibitors (up to 3 mg/kg) caused 3- to 5-fold, parallel rightward shifts of the log dose-pressor effect curves to cirazoline, (-)-phenylephrine, (+/-)-erythro-methoxamine and (-)-amidephrine accompanied by only a slight depression of the maximal pressor response. In contrast, the calcium entry inhibitors produced a dose-dependent profound depression of both maximum and slope of the log dose-pressor response curves to St 587 and clonidine. For DPI about 10- and 100-fold parallel displacements to the right without reduction of the maximum were found following treatment with 1 and 3 mg/kg of nifedipine, respectively. Infusion of vasopressin to counteract the vasodilatory action produced by the calcium entry inhibitors did not significantly change the pattern of interference observed under the conditions of decreased baseline diastolic pressure. The results indicate that alpha 1-adrenoceptor-mediated vasoconstriction in the pithed normotensive rat, which is characterized by its sensitivity to blockade by prazosin and its relative insensitivity to antagonism by yohimbine or rauwolscine, can be subdivided into two distinct processes which are differentially influenced by blockade of calcium entry.(ABSTRACT TRUNCATED AT 250 WORDS)
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 α1 or 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.
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