Effects of hypoxia on the vasodilator activity of nifedipine and evidence of secondary pharmacological properties.
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)-3x10(-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 beta-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 beta-adrenoceptors. This study also showed that nifedipine is ineffective as a vasodilator in the rat aorta under hypoxic conditions.
Division of Pharmacology, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cathays Park, Cardiff, CF10 3XF, UK. BroadleyKJ@Cardiff.ac.uk
Kenneth J
KJ
Broadley
Peter E
PE
Penson
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009543:Nifedipine / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D002121:Calcium Channel Blockers; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D010656:Phenylephrine; D011433:Propranolol; D003042:Cocaine; D009543:Nifedipine; D009638:Norepinephrine