The negative inotropic effects of amiodarone on isolated guinea pig heart: a possible role of Na(+)-Ca2+ exchange.

1. The negative inotropic effects of amiodarone (AM) were studied in isolated, isometrically contracting ventricular papillary muscles from guinea pigs. 2. AM, 4.4 x 10(-5) M, significantly decreased ouabain (10(-6) M)-induced increase in the developed tension. 3. Manganese (10(-2) M), a partial blocker of Na(+)-Ca2+ exchange, attenuated the AM's negative inotropy. 4. Theophylline (1.5 x 10(-2) M), an inhibitor of phosphodiesterase, produced a marked increase in the tension (about twice compared to the ouabain effect). 5. However, the magnitude of decrease by AM in the tension in the presence of theophylline was similar to that in the case of ouabain. 6. Tetrodotoxin (TTX) decreased the contraction by about a half, and then subsequent addition of AM in the presence of TTX led to a further decrease in the tension. 7. Eventually co-existence of TTX and AM led to a decrease in tension of same degree, compared to the decrease in tension by AM alone. 8. The results suggest that a large portion of negative inotropic action of AM may, at least, reflect interference with the Na(+)-Ca2+ exchange mechanism. 9. This interference with the Na(+)-Ca2+ exchange mechanism may exert a strong negative inotropic effect of the drug, in combination with a decrease in Ca2+ influx via Ca2+ channels and/or an impairment of Ca(2+)-sequestration.