Effects of hypoxia on the vasodilator activity of nifedipine and evidence of secondary pharmacological properties

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The effects of hypoxia on the vasodilator response of endothelium-denuded rat aortic rings to the calcium channel blocker, nifedipine, were examined. Under normoxic conditions, nifedipine (10−8–3 × 10−6 M) attenuated the contractility of noradrenaline precontracted rings in a concentration-dependent manner, although the sensitivity was less than what occurs with K+ precontracted tissues. Under hypoxic conditions there was no relaxation by nifedipine. When a concentration–response curve to noradrenaline was constructed before and in the presence of a high concentration of nifedipine (10−5 M), the response to noradrenaline was unaffected in both normoxic and hypoxic conditions. When noradrenaline was replaced by phenylephrine (10−8–10−5 M), the maximum tension was reduced in the presence of nifedipine to 59 ± 6% of the pre-nifedipine value. Repetition of the experiment in the presence of cocaine (10−5 M) revealed the inhibitory effect of nifedipine on noradrenaline-induced contraction, the maximum contraction in the presence of nifedipine falling significantly (P < 0.005) to 67 ± 6% of the pre-nifedipine response. When propranolol (10−7 M) was present in the bath, the maximum contraction to noradrenaline was significantly (P < 0.05) reduced by nifedipine to 55 ± 4% of its previous value. The fact that nifedipine was able to inhibit phenylephrine-induced contractions and relax noradrenaline-precontracted aortic rings confirms its calcium channel blocking activity. The failure to inhibit noradrenaline when added prior to the noradrenaline-induced contractions suggests an opposing effect in addition to calcium channel blockade, which cancels out the attenuation of noradrenaline — but not phenylephrine-induced contractions. When neuronal uptake of noradrenaline was blocked with cocaine or β-adrenoceptors were blocked with propranolol, the inhibitory effect of nifedipine against noradrenaline-induced contractions was revealed. This suggests that the additional property was due to blockade of neuronal reuptake or antagonism at β-adrenoceptors. This study also showed that nifedipine is ineffective as a vasodilator in the rat aorta under hypoxic conditions.

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