In an experiment investigating vasoconstriction of the arterial wall, two samples of isolated porcine arterial vessels are studied. Vascular tone is measured in the control vessel during infusion of increasing doses of norepinephrine. The other vessel is pretreated with experimental drug A prior to infusion of norepinephrine. A graph of the study results is depicted below.
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Drug A is most similar to which of the following agents?
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Alpha-1 adrenergic receptors mediate arterial vasoconstriction whereas β2 receptors mediate vasodilation. Norepinephrine is an agonist at α1 and β1 receptors but has significantly less action at β2 receptors; it is therefore a potent vasoconstrictor. This experiment is testing the efficacy of drug A at blocking the α1-mediated vasoconstriction caused by norepinephrine administration.
The results show that pretreatment with drug A results in decreased maximal effect (Vmax) of norepinephrine without a significant change in the affinity (Km) of norepinephrine for α1 receptors. This suggests that drug A is acting as either a noncompetitive antagonist or an irreversible antagonist of α1 adrenergic receptors. Phenoxybenzamine is an irreversible α1 and α2 receptor antagonist that would produce results similar to those observed. It is primarily used in the treatment of pheochromocytoma, in which a tumor of the adrenal medulla overproduces norepinephrine, causing systemic arterial vasoconstriction.
(Choice A) Atropine is a competitive muscarinic acetylcholine receptor antagonist. Pretreatment with atropine would not alter norepinephrine's effects on vascular tone.
(Choices B and D) Labetalol is a reversible, competitive antagonist of α1 and β adrenergic receptors with partial β2 agonist activity that is used to treat hypertension. Phentolamine is a reversible, competitive α-adrenergic antagonist used in the management of catecholamine-induced hypertensive crises (eg, pheochromocytoma, monoamine oxidase inhibitor toxicity, cocaine intoxication). High doses of norepinephrine can overcome the α-adrenergic inhibition of these drugs.
(Choice E) Propranolol is a nonspecific β-adrenergic antagonist. Pretreatment with a β antagonist would potentiate the vasoconstrictive effects of norepinephrine due to unopposed α-adrenergic stimulation.
Educational objective:
Phenoxybenzamine is an irreversible α1 and α2 adrenergic antagonist that effectively reduces the arterial vasoconstriction induced by norepinephrine. Because phenoxybenzamine is an irreversible antagonist, even very high concentrations of norepinephrine, such as those seen in pheochromocytoma, cannot overcome its effects.