Enhanced responses to 17 beta-estradiol in rat hearts treated with isoproterenol: Involvement of a cyclic AMP-dependent pathway

We determined the effects of 17 beta-estradiol, the most effective estrogen , acutely administered, on the heart/ventricular myocyte with or without tr eatment with isoproterenol (Iso). At 0.1 to 1 nM, 17 beta-estradiol, which itself had no effect, reduced the heart rate and developed pressures in the isolated perfused heart treated with 10(-7) M Iso. One nanomolar 17 beta-e stradiol also inhibited the cyclic AMP (cAMP) production in Iso-treated ven tricular myocytes. At 10 nM to 1 mu M, 17 beta-estradiol itself reduced the heart rate and incidence of ischemia/reperfusion-induced arrhythmias, with the exception of diastolic pressure. The effects of 17 beta-estradiol on h eart rate, systolic and mean pressures, and arrhythmias were significantly enhanced in the heart/ventricular myocyte treated with Iso. Tamoxifen, an e strogen receptor antagonist, did not antagonize the effect of 17 beta-estra diol on the Ca2+ current in ventricular myocytes treated with Iso, nor did it alter the effect of the hormone on the cAMP production augmented by Iso and forskolin. The effects of 17 beta-estradiol on Ca2+ current in the pres ence or absence of tamoxifen and/or Iso were similar in male rats, which do not possess the estrogen receptor, and female rats, which have the estroge n receptor. In conclusion, we have shown for the first time that estrogen a t physiological concentrations modulates negatively the stimulatory actions of Iso on the heart rate and cardiac contractility. The effects may result from activation of an unknown membrane receptor and the adenylate cyclase/ cAMP pathway, which enhances Ca2+ influx across the L-type Ca2+ channel.