IN-VIVO CHARACTERIZATION OF MUSCARINIC RECEPTOR SUBTYPES THAT MEDIATEVASODILATATION IN PATIENTS WITH ESSENTIAL-HYPERTENSION

Attenuated cholinergic Vasodilatation has been suggested as an endothe lium-related mechanism involved in essential hypertension. We investig ated the role of muscarinic (M) receptor subtypes in the forearm resis tance vasculature. In eight white men with essential hypertension and eight matched normotensive control subjects (age of both groups, 47+/- 4 years; mean+/-SEM), we infused the nonselective agonist methacholine in the presence of saline and the antagonists atropine (nonselective) , pirenzepine (M(1)-selective), and AF-DX 116 (M(2)-selective) into th e brachial artery and measured forearm blood flow and forearm vascular resistance using venous occlusion plethysmography. Affinity constants (pK(b) values) were determined from calculated plasma concentrations of the infused compounds and EC(50) values. Sodium nitroprusside was g iven as an endothelium-independent control, and minimal forearm vascul ar resistance after 10 minutes of ischemia was used as a marker of str uctural Vascular changes. Hypertensive patients showed higher minimal forearm vascular resistance, indicating structural vascular changes. H owever, sodium nitroprusside- and methacholine-induced vasodilatation was similar in both groups, with apparent EC(50) values (log moles per liter; mean+/-SEM) of -7.32+/-0.13 and -7.51+/-0.21 in hypertensive p atients and -7.37+/-0.13 and -7.45+/-0.02 in control subjects, respect ively, Atropine, pirenzepine, and AF-DX 116 caused a shift to the righ t of the concentration-response curve of methacholine, with apparent p K(b) values of 8.63+/-0.08, 6.81+/-0.13, and 5.51+/-0.29 in hypertensi ve individuals and 8.62+/-0.10, 6.95+/-0.08, and 5.49+/-0.09 in contro l subjects, respectively. Again, there were no statistically significa nt differences in these pharmacological parameters between hypertensiv e patients and normotensive subjects. The affinity constants and rank order for potency of the muscarinic antagonists, atropine>pirenzepine> AF-DX 116, indicate that cholinergic vasodilatation in the forearm vas cular bed is predominantly mediated by the M(3) receptor subtype. Desp ite indications for structural vascular changes in hypertensive subjec ts, the vasodilator responses to both sodium nitroprusside and methach oline were unchanged in these patients. Essential hypertension is not associated with changes in the pharmacological characteristics of musc arinic receptors in forearm resistance vasculature.