ISSN:
1432-1912
Keywords:
Rat atrium
;
Descending staircase
;
Antimuscarinic action
;
Alinidine (St 567)
;
Muscarinic subreceptors
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Summary Contractile force of isolated atria from most mammalian species increases with the rate of electrical stimulation, resulting in an ascending staircase. In contrast, in the rat, contractile force decreases with increasing rate of stimulation (descending staircase). The bradycardic and antianginal drug alinidine (5.7–91.2 μmol/l) reversed the descending staircase to ascending by a positive inotropic effect at higher stimulation rates. Maximal positive inotropy was obtained with 45.6 μmol/l, a concentration which also caused maximal bradycardia in spontaneously beating atria. Concentrations of 1 μmol/l of the antimuscarinic compounds atropine as well as the quarternary salt ipratropium bromide also reversed the descending staircase of rat atria. Addition of alinidine did not cause any further increase in force of contraction under these conditions. Addition of 1 μmol/l physostigmine to isolated left atria from guinea pigs for blockade of acetylcholinesterase decreased contractility at all stimulation rates, but did not change the ascending character of the staircase. Alinidine antagonized the negative inotropic effect of physostigmine. The known antimuscarinic action of alinidine was quantified in electrically driven (0.25 Hz) left rat atria by antagonism of the negative inotropic effect of oxotremorine (0.01–10 μmol/l). Alinidine acted as a strictly competitive antagonist with a pA2 of 5.82. In isolated papillary muscle from guinea pigs, pretreated with reserpine for depletion of catecholamines, carbachol (0.1–3000 μmol/l) exerted positive inotropic effects. Alinidine antagonized also this effect in a competitive fashion with a pA2 value of 5.58. Investigations of the “specific” antimuscarinic compounds pirenzepine, methoctramine and AF-DX 116 in these models indicate that the negative inotropic effect in atria is mediated by M2a-receptors while the positive inotropic effect in papillary muscle is mediated by either the M2e-receptor or a yet unidentified muscarinic subreceptor. It is concluded that the descending staircase of electrically stimulated rat atria is due to the release of acetylcholine as well as to the short duration of its action potential which decreases further upon muscarinic stimulation, thus leading to a compromise of excitation-coupled calcium influx and negative inotropy, particularly at higher stimulation rates. Therefore, antimuscarinic drugs including alinidine reverse the descending staircase. Under physiological conditions of impulse generation and in the absence of vagal activity an ascending staircase is to be expected in rat atria as well.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00736061
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