Mechanism of Vascular Relaxation by Cholinomimetic Drugs with Special Reference to Pilocarpine and Arecoline

Abstract

The muscarinic receptor-mediated and non-muscarinic vascular effects of cholinomimetic drugs used in glaucoma were quantified. On the isolated rat aorta, the vascular tone induced by phenylephrine is functionally antagonized by cholinomimetic drugs. Based on EC₅₀, the relative order of potency for the endothelium-dependent vascular relaxation was acetylcholine (0.05 μM) 1 > ( ± )-methacholine (0.35 μM) 1/7 > carbachol (0.63 μM) 1/12 > ( ± )-aceclidine (1.26 μM) 1/25. The maximal effects of the four agonists varied between 82–87%. The muscarinic vascular relaxation of 0.03 μM to 100 μM pilocarpine was less than 15%. At high concentrations, pilocarpine had 1/20,000 the vascular activity of acetylcholine. Physostigmine failed to potentiate the vascular relaxation of exogenous acetylcholine, indicating the absence of acetylcholine esterase in the tissue. Arecoline, with an EC₅₀ of 7.76 μM, was partly sensitive to the removal of the endothelium. Atropine treatment did not block the vascular effect of high concentrations of pilocarpine. Atropine, as expected, blocked the vascular effects of carbachol with K_B = 3.2 nM. Pilocarpine produces vascular relaxation by its competition with spasmogens like phenylephrine, oxymetazoline, vasopressin or latanoprost. Arecoline also shares these properties with pilocarpine in the blood vessel. The molecular mechanism of the vascular effects as well as ocular clinical implications of cholinomimetic drugs is discussed.