Direct positive chronotropic effects of angiotensin II and angiotensin III in pithed rats and in rat isolated atria.

1. The direct positive chronotropic effects of angiotensin II (AII) and its degradation products angiotensin III (AIII) and angiotensin IV (AIV) were established in pithed rats and in rat spontaneously beating right atria. 2. In pithed rats, AII, AIII and AIV caused dose-dependent tachycardia with similar maximal responses (110 beats min-1). The beta-adrenoceptor antagonist propranolol (3.37 x 10(-6) mol kg-1) but not the alpha 1-adrenoceptor antagonist prazosin (2.38 x 10(-7) mol kg-1) significantly reduced these effects (P < 0.05; n = 7-8), but 20-25% of the responses could not be blocked by propranolol. 3. In isolated atria, AII, AIII and AIV caused concentration-dependent increases in beating rate with similar maximal responses to AII and AIII (34.3 +/- 0.4 and 34.7 +/- 0.4 beats min-1; n = 9-10), and a lower maximal response to AIV (26.8 +/- 0.6 beats min-1; P < 0.05; n = 8). AIII was about 9 times less potent than AII, whereas AIV proved approximately 3800 times less potent than AII. Neither propranolol (1 microM) nor prazosin (1 microM) could influence the effects of the angiotensin peptides. 4. In isolated atria, the selective AT1-receptor antagonist, losartan (10, 100 and 300 nM) caused parallel rightward shifts of the concentration-response curves for AII and AIII, whereas the selective AT2- receptor antagonist PD123177 (1 microM) did not influence the effects of AII and AIII. The aminopeptidase-A and -M inhibitor amastatin (10 microM), significantly steepened the slope of the AIII curves and increased the potency of AIII about 6 fold. Amastatin did not influence the responses to AII. 5. Our results indicate that both in vivo and in vitro, exogenous AII and AIII induced a direct dose-dependent chronotropic effect, which is independent of the adrenergic system. This chronotropic effect is mediated by AT1-subtype receptors.