Effect of pirenzepine and gallamine on cardiac and pulmonary muscarinic receptors in the rabbit

Abstract

1 The effect of muscarinic antagonists considered to be selective for M1 receptors (pirenzepine) and for M2 receptors (gallamine) were studied on bronchoconstriction and bradycardia elicited by stimulation of the vagal nerves and by i.v. acetylcholine (ACh) in anaesthetized rabbits. 2 Pirenzepine was equipotent as an antagonist of ACh-induced responses at postjunctional muscarinic receptors in the heart, lung and blood vessels, whereas gallamine was at least ten times less potent at pulmonary and vascular muscarinic receptors. Thus, gallamine never caused complete inhibition of bronchoconstrictor or hypotensive responses to i.v. ACh, whereas doses of pirenzepine in excess of 1 pmol kg1-abolished all muscarinic responses. 3 In the lung, both antagonists inhibited bronchoconstriction caused by vagal stimulation and ACh-induced bronchoconstriction to the same extent (pirenzepine, mean ED50 65 + 22 and 130 + 28nmolkg-1 respectively; gallamine, ED50> 10,OOOnmolkg-1 for both responses).Enhancement of vagally-induced bronchoconstriction was never observed. 4 In the heart, however, both pirenzepine and gallamine were ten times less potent as antagonists of vagally-induced bradycardia than of ACh-induced bradycardia. This differential blockade was unaltered by propranolol (1 mg kg-1) pretreatment. 5 It is concluded that there is no evidence for M1 or M2 muscarinic receptors in the pulmonary innervation of the rabbit and the potency of the antagonists in abolishing vagally-induced bronchoconstriction was consistent with blockade of M3 muscarinic receptors on airway smooth muscle. 6 The results suggest that M2 muscarinic receptors may exert an inhibitory effect on transmission in the parasympathetic nerves innervating the heart in the rabbit. Blockade of such neuronal receptors would increase transmitter output to the atrial cells and explain the low potency of both antagonists in abolishing vagally-induced bradycardia in the rabbit.

Dynamics of vagal chronotropic effects during blockade of different types of muscarinic cholinergic receptors

“…Higher doses of pirenzepine suppressed vagal regulation of myocardial activity probably due to atropine-like effects of cumulative doses. This explanation is in line with the finding that in a dose of 10 -6 mol/kg pirenzepine extends the spectrum of its blocking action with respect to differently located muscarinic receptors [11 ].…”

Identification of M1 muscarinic receptors in pulmonary sympathetic nerves in the guinea‐pig by use of pirenzepine

“…In each of these examples, the receptors exerted an inhibitory control on cholinergic neurotransmission to airway smooth muscle. This autoreceptor mechanism appears to be lacking in the rabbit (Maclagan & Faulkner, 1989) and in asthmatic patients (Minette et al, 1988). Figure 2 shows the mechanisms that underlie the results presented in this paper and in previous work from this laboratory showing that M1 muscarinic receptors with a facilitatory function exist in the sympathetic nervous pathway in the guinea-pig lung (this paper) and M2 receptors exist in the parasympathetic nerves in this species (Fryer & Maclagan, 1984).…”

Functional characterization of muscarinic receptors in murine airways

“…Knowledge about cholinoceptors and especially muscarinic receptor subtypes in airway smooth muscle is available in many animal species such as guinea-pig, ox, dog, rat, rabbit and man, but not in mice (Fryer & Mclagan, 1984;Blaber et al, 1985;Van Koppen et al, 1985;Faulkner et al, 1986;Eglen & Whiting, 1986;O'Rourke et al, 1987;Madison et al, 1987;Beck et al, 1987;Bloom et al, 1987;Roffel et al, 1988;Ito & Yoshitomi, 1988;Maclagan & Faulkner, 1989 Values are mean ± s.e. mean (n = 15 for each antagonist; n = 5 for each concentration).…”