Effect of n6-cyclopentyladenosine on ouabain-induced toxicity in isolated Guinea pig atria.

ABSTRACT The effect of N6-cyclopentyladenosine (CPA), an A(1)-selective adenosine agonist, was studied on ouabain-induced toxicity in spontaneously beating isolated guinea pig atria. CPA (2-16 nM) produced a dose-dependent decrease in the force of contractions (34%-51%) and in the rate of contractions (22%-48%). CPA significantly increased the time of onset of arrhythmia (toxicity) induced by ouabain (1.2 muM) when it was administered 10 min before ouabain was added in organ bath. Ouabain (1.2 muM) alone produced arrhythmia at 7 min and either asystole or standstill at 22 min. CPA (8 nM) increased the time required to produce arrhythmia to 27.5 min and prolonged beating atria to more than 63 min and prevented the occurrence of asystole. These findings indicated that CPA produces direct cardiac action, probably due the inhibition of cardiac Na(+) and Ca(2+) channels. Moreover, our results suggest that CPA may reduce the membrane conduction through inhibition of ionic channels, which decrease ouabain-induced toxicity.

Effect of amiloride on isolated guinea-pig atrium.

The effect of high concentrations (62.5-500 microgram/ml) of amiloride, a potassium sparing diuretic, was investigated in the isolated guinea-pig atrium. Amiloride decreased the frequency of contractions of the spontaneously beating right atrium in a time-dependent fashion. The inotropic effect of amiloride was frequency-dependent. It increased the peak developed tension of the electrically paced left atrium with 1 Hz stimulation. This was dose and time-dependent. Stimulation at 0.35 and 0.1 Hz resulted in no effect and a negative inotropic effect respectively. The effects of amiloride were not prevented by atropine, propranolol, phenoxybenzamine, metiamide, tetrodotoxin or by pretreatment of animals with reserpine. The positive inotropic effect (at 1 Hz) was inhibited by calcium antagonists verapamil or chlorpromazine. The negative inotropic effect (at 0.1 Hz) was prevented by doubling calcium concentration of the medium. Amiloride had no significant effect on sodium, potassium and calcium content of the tissue. It is concluded that high concentrations of amiloride decreases the frequency and changes the peak developed tension of the guinea-pig atrium possibly by decreasing sodium entry and altering the availability of calcium to the contractile elements.

Tachyphylaxis to ethacrynic acid in the isolated atrium of guinea-pig and its relation to noradrenaline stores.

1 The isolated electrically-paced atrium of the guinea-pig developed a dose-dependent increase in the force of contraction in response to ethacrynic acid (12-100 microgram/ml) which was blocked by pretreatment of the animals with reserpine but was unaffected by desipramine or colchicine added to the bathing medium. 2 There was a rapidly developing tachyphylaxis to repeated doses of ethacrynic acid which was not reversed by rest or incubation of the tissue with noradrenaline. 3 There was no cross tachyphylaxis between ethacrynic acid and tyramine, amphetamine or nicotine. 4 Ethacrynic acid (200 microgram/ml) decreased the noradrenaline content of the atria by 32%. 5 It is concluded that ethacrynic acid exerts its effects indirectly through the release of endogenous noradrenaline and that the mechanism of release seems to be different from that of other known indirect sympathomimetic drugs.

The effect of ethacrynic acid on the guinea-pig and rat isolated vas deferens.

1 The effect of ethacrynic acid (EA) was studied on guinea-pig and rat vas deferens in vitro.2 EA contracted the guinea-pig but not the rat vas deferens in a dose-dependent manner (50-800 mug/ml). Tyramine caused contraction in 10 out of 18 guinea-pig vas deferens; EA caused contraction in 17 of the preparations which did not respond to tyramine. Repeated doses of EA produced tachyphylaxis, but there was no cross tachyphylaxis to tyramine.3 The contractions produced by EA were prevented by phentolamine or reserpine pretreatment and potentiated by cocaine. A low concentration of desipramine (3 ng/ml) potentiated and higher concentrations (0.6 and 3.0 mug/ml) inhibited the response of vas deferens to EA.4 Hexamethonium (100 mug/ml) or atropine (0.1 mug/ml) did not inhibit the effect of EA, excluding the nicotinic and muscarinic receptors as the sites of action.5 The effect of noradrenaline (NA) on the guinea-pig and rat vas deferens was enhanced by EA pretreatment, which may be due to inhibition of NA uptake.6 It is concluded that EA releases NA from guinea-pig vas deferens. The mechanism of release seems to be different from that of tyramine.