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

• Published in: European journal of pharmacology Vol. 536; no. 3; pp. 279 - 286
• Main Authors: Broadley, Kenneth J., Penson, Peter E.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01-05-2006; Elsevier
• Subjects: Animals; Aorta; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiopathology; Biological and medical sciences; Calcium Channel Blockers - pharmacology; Cocaine - pharmacology; Dose-Response Relationship, Drug; Hypoxia; Hypoxia - physiopathology; In Vitro Techniques; Male; Medical sciences; Nifedipine; Nifedipine - pharmacology; Noradrenaline; Norepinephrine - pharmacology; Pharmacology. Drug treatments; Phenylephrine; Phenylephrine - pharmacology; Propranolol - pharmacology; Rats; Rats, Wistar; Vasoconstrictor Agents - pharmacology; Vasodilation - drug effects; Vasodilator Agents - pharmacology; Aorta; Hypoxia; Noradrenaline; Phenylephrine; Nifedipine; Agonist; Oxygen; Vasodilator agent; Antihypotensive agent; Calcium antagonist; α1-Adrenergic receptor; Catecholamine; Antiarrhythmic agent; Artery; Blood vessel; Vasoconstrictor agent; Dihydropyridine derivatives; α-Adrenergic receptor agonist; Norepinephrine; Circulatory system
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2006.02.039

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.