CALCIUM ENTRY BLOCKADE BY NITRENDIPINE AND ALPHA-ADRENERGIC RESPONSIVENESS INVIVO - COMPARISON WITH NONCALCIUM ENTRY BLOCKER VASODILATORS IN ABSENCE AND PRESENCE OF PHENOXYBENZAMINE PRETREATMENT

  • 1 January 1985
    • journal article
    • research article
    • Vol. 233  (3) , 636-642
Abstract
To investigate the in vivo interaction between Ca entry blockade by nitrendipine (a dihydropyridine Ca entry blocker) and .alpha.-adrenergic-mediated end-organ responsiveness, 4 series of experiments were carried out in normal Sprague-Dawley rats. In ganglion-blocked rats (hexamethonium, 10 mg/kg i.p. plus atropine, 1.0 mg/kg i.p.), nitrendipine (0.3 mg/kg) antagonized the pressor responses to angiotensin II and vasopressin as well as to norepinephrine, thus indicating the lack of specificity of its antagonism to .alpha.-adrenergic vasoconstriction. The results of the next 2 series of experiments showed first that, in pithed rats, nitrendipine (0.01-0.3 mg/kg) in presence of prazosin shifted the norepinephrine pressor dose-response curves to the right whereas it was ineffective in yohimbine/pretreated animals. These data, suggesting a preferential .alpha.-2 antagonism by nitrendipine, were confirmed further by its little effect on pressor responses to methoxamine as contrasted with its marked progressive depression of the maximum response to B-HT 920 (about 80% at the highest rate of infusion). However, qualitatively similar results were obtained by the noncalcium entry blocker vasodilators, both sodium nitroprusside and both of which led to minor shifts to the right of the methoxamine pressor dose-response curves, whereas dose-dependently depressing the maximum pressor response to B-HT 920 (about 70 and 40%, respectively). Thus, Ca entry blockade appeared to antagonize preferentially .alpha.-2-mediated vasoconstriction, but this effect was common to other vasodilators devoid of Ca entry blocking properties. The last series of experiments was designed to unmask the effect, if any, of these vasodilators, both the Ca entry and noncalcium entry blockers, on .alpha.-1 adrenoceptors. After partial .alpha.-adrenoceptor inactivation by phenoxybenzamine (0.3 mg/kg i.v.), all 3 vasodilators strongly depressed the dose-response curve to methoxamine. Under normal conditions, the presence of spare .alpha.-1 receptors concealed an underlying functional antagonism to .alpha.-1-mediated vasoconstriction. The nature of the adrenergic agonist utilized (full vs. partial) may explain in part the differential effect of vasodilators (including Ca entry blockers) on .alpha.-1 vs. .alpha.-2 vasoconstriction under normal conditions.

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