In Vivo Characterization of Muscarinic Receptor Subtypes That Mediate Vasodilatation in Patients With Essential Hypertension

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 1995-07, Vol.26 (1), p.70-77
• Main Authors: Bruning, Tobias A, Chang, Peter C, Hendriks, Maarten G.C, Vermeij, Pieter, Pfaffendorf, Martin, van Zwieten, Pieter A
• Format: Article
• Language: English
• Subjects: Arterial hypertension. Arterial hypotension; Atropine - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Forearm - blood supply; Humans; Hypertension - physiopathology; Male; Medical sciences; Methacholine Chloride - pharmacology; Middle Aged; Nitroprusside - pharmacology; Parasympatholytics - pharmacology; Pirenzepine - analogs & derivatives; Pirenzepine - pharmacology; Plethysmography; Receptors, Muscarinic - classification; Receptors, Muscarinic - physiology; Vasodilation - drug effects
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.26.1.70

Attenuated cholinergic vasodilatation has been suggested as an endothelium-related mechanism involved in essential hypertension. We investigated the role of muscarinic (M) receptor subtypes in the forearm resistance vasculature. In eight white men with essential hypertension and eight matched normotensive control subjects (age of both groups, 47 plus/minus 4 years; mean plus/minus SEM), we infused the nonselective agonist methacholine in the presence of saline and the antagonists atropine (nonselective), pirenzepine (M1 -selective), and AF-DX 116 (M2 -selective) into the brachial artery and measured forearm blood flow and forearm vascular resistance using venous occlusion plethysmography. Affinity constants (pKb values) were determined from calculated plasma concentrations of the infused compounds and EC50 values. Sodium nitroprusside was given as an endothelium-independent control, and minimal forearm vascular resistance after 10 minutes of ischemia was used as a marker of structural vascular changes. Hypertensive patients showed higher minimal forearm vascular resistance, indicating structural vascular changes. However, sodium nitroprusside- and methacholine-induced vasodilatation was similar in both groups, with apparent EC50 values (log moles per liter; mean plus/minus SEM) of -7.32 plus/minus 0.13 and -7.51 plus/minus 0.21 in hypertensive patients and -7.37 plus/minus 0.13 and -7.45 plus/minus 0.02 in control subjects, respectively. Atropine, pirenzepine, and AF-DX 116 caused a shift to the right of the concentration-response curve of methacholine, with apparent pKb values of 8.63 plus/minus 0.08, 6.81 plus/minus 0.13, and 5.51 plus/minus 0.29 in hypertensive individuals and 8.62 plus/minus 0.10, 6.98 plus/minus 0.08, and 5.49 plus/minus 0.09 in control subjects, respectively. Again, there were no statistically significant differences in these pharmacological parameters between hypertensive 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 vascular bed is predominantly mediated by the M3 receptor subtype. Despite indications for structural vascular changes in hypertensive subjects, the vasodilator responses to both sodium nitroprusside and methacholine were unchanged in these patients. Essential hypertension is not associated with changes in the pharmacological characteristics of muscarinic rece