D Davidesko

Selectivity of methoctramine for muscarinic receptors in porcine cerebral arteries

There was a clear difference in affinity (257-fold) for methoctramine between the muscarinic receptors involved in the methacholine-induced contraction of isolated pig coronary and basilar arteries, whereas atropine did not discriminate between the muscarinic receptors in these arterial smooth muscle preparations. Comparison of this finding with recent data on the selectivity of methoctramine suggests that the basilar artery contains M2 receptors whereas those in the coronary artery belong to the muscarinic receptor subtype which is present in exocrine glands (M3) and/or in ileal smooth muscle.

Binding of muscarine receptor antagonists to pig coronary smooth muscle

SummaryIn order to characterize the muscarinic binding site on coronary smooth muscle, we investigated the binding properties of (3H)quinuclidinyl benzilate (QNB) in membrane preparations of pig coronary arteries and atria. Scatchard analysis and Hill plot showed that (3H)QNB binds to a single population of sites in both tissues. The binding profiles of the muscarine receptor antagonists atropine, 11-((2-((dimethylamino)methyl)-1-piperidinyl)acetyl)-5,11-dihydro-6H-pyrido(2,3-b) (1,4)benzodiazepine-6-one (AF-DX 116), pirenzepine, and 4-diphenylacetoxy-Nmethylpiperidine methiobromide (4-DAMP) in both tissues were compared with binding data from other tissues, representative for different muscarinic binding site subtypes. It is concluded that the pig coronary smooth muscle muscarinic binding site is different from M1 and M2 binding sites investigated so far.

Role of ganglionic M-1 and M-2 receptors in the neuronal control of the cardiovascular system of the normotensive rat as determined with pilocarpine

The adrenoceptors involved in the increase in diastolic pressure and heart rate elicited by i.v. administration of pilocarpine to the pithed rat were assessed using as pharmacological tools the alpha 1-adrenoceptor antagonist prazosin, the alpha 2-adrenoceptor antagonist rauwolscine, the beta 1-adrenoceptor blocker atenolol and the beta 2-adrenoceptor blocker ICI 118,551. Pilocarpine indirectly activated vascular alpha 1- and cardiac beta 1-adrenoceptors. By using the M-1 antagonist pirenzepine and the mixed M-1/M-2 antagonist dexetimide, pilocarpine was shown to be a mixed M-1/M-2 agonist. Pilocarpine initiated antagonistic effects on intrasynaptic alpha 2-adrenoceptor-mediated pressor responses and not on those triggered by extrasynaptic alpha 2-adrenoceptors. During vasopressin infusion to counteract a possible vasodilator action of pilocarpine, it was demonstrated that pilocarpine indirectly activated alpha 1- and alpha 2-adrenoceptors. The results support the hypothesis that intra- and extrasynaptic alpha 2-adrenoceptors comprise different populations and that the neuronal control of alpha 2-adrenoceptors is mediated by ganglionic M-2 receptors.

Discrimination by N-ethylmaleimide between the chronotropic and inotropic response to muscarinic receptor stimulation in rat atrium

SummaryN-ethylmaleimide (NEM) rapidly blocked the negative chronotropic effect of carbachol on rat right atrium. In contrast, NEM did not reduce the negative inotropic response to muscarinic (M) receptor stimulation. Carbachol inhibited the specific binding of [3H]-N-methylscopolamine ([3H]-NMS) to membranes of rat atria as reflected by a shallow inhibition curve. Both guanosine triphosphate (GTP) and NEM shifted the [3H]-NMS inhibition curves of carbachol to the right. Pretreatment of the atrial membranes with NEM abolished the GTP-induced rightward shift. However, when instead of the membranes the intact atria were pre-incubated with NEM, no interaction between NEM and GTP in the membranal preparation was observed. The results indicate that NEM sharply discriminated between the inotropic and chronotropic effects to M-receptor stimulation in rat atria. The inhibitory effect of NEM on the M-receptor-mediated negative chronotropic effect in rat atrium cannot be explained by an interaction of the sulfhydryl reagent with GTP-binding proteins, like Ni or No.

Effect of pithing on the postjunctional sympatho-inhibitory action of captopril in cats

SummaryPithing of anaesthetized normotensive cats significantly lowered the arterial blood pressure and augmented plasma renin activity (PRA). Captopril dose-dependently diminished mean arterial blood pressure in both pithed and intact anaesthetized normotensive cats. The hypotensive effectiveness of captopril was most pronounced in pithed cats. Captopril inhibited the hypertensive response to intravenously administered noradrenaline in pithed cats, but did not attenuate the hypertensive response to noradrenaline in intact cats. The results do not exclude that the hypotensive activity of captopril in intact cats may be causally independent of the attenuating effect of converting enzyme inhibition on the postjunctional α-adrenoceptor mediated vasoconstriction as observed in pithed animals.