M₃muscarinic receptors mediate acetylcholine-induced pulmonary vasodilation in pulmonary hypertension.

Information about the muscarinic receptor subtype(s) mediating pulmonary circulatory vasodilator responses to acetylcholine (ACh) is limited. The aim of this study was to pharmacologically characterize the muscarinic receptors associated with ACh-induced pulmonary vasodilation in a pulmonary hypertension model. Vasodilation of rabbit isolated buffer-perfused lungs in which pulmonary hypertension was induced with the thromboxane A₂ analogue U-46619 was evoked by ACh at a just maximally effective concentration (2 x 10⁻⁷ M). The effects of cumulative concentrations of three specific muscarinic receptor subtype antagonists [pirenzepine (M₁), methoctramine (M₂), and 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, M₃] on ACh-induced pulmonary vasodilation were determined. Double vascular occlusion pressure was recorded to locate the muscarinic receptors within the pulmonary vasculature. Based on the 50% inhibitory concentrations (IC₅₀), the rank of order of antagonist potency was 4-DAMP >> pirenzepine > methoctramine. The vascular effects of all three inhibitors were localized to the precapillary segment. These findings suggest that the vasodilator action of ACh on rabbit isolated perfused U-46619 pretreated lungs is mediated by M₃ muscarinic receptors located in the pulmonary arterial bed.