Effects of long-term pretreatment with isoproterenol on inotropic responsiveness to alpha-adrenoceptor stimulation: study in isolated perfused rat hearts

The effects of chronic pretreatment with isoproterenol (5 mg kg(-1)) daily for 10 days on cardiac alpha -adrenergic responsiveness in Langendorff hear t preparations were investigated. Isoproterenol pretreatment ca used cardia c hypertrophy (29 %) as shown by a significant increase in the ratio of ven tricular dry weight to body weight. In preparations from isoproterenol-pret reated rats, both maximum increases in left ventricular systolic pressure a nd heart rate elicited by isoproterenol (10(-12) to 10(-4) M) were signific antly reduced (the isoproterenol concentration producing 50 % of the maximu m positive inotropic and chronotropic responses was enhanced almost 32- and 4-fold, respectively), while the positive inotropic response to phenylephr ine (10(-12) to 10(-4) M) was significantly enhanced (the phenylephrine con centration producing 50% of the maximum positive inotropic effect was reduc ed almost 100-fold), compared with saline-pretreated rats. In preparations from both groups, phenylephrine infusion induced non-significant changes in heart rate and its positive inotropic response was reduced in the presence of propranolol (10(-7) M) in the perfusion medium. Even under beta -adreno ceptor blockade, the curve for the phenylephrine-induced positive inotropic effect remained shifted upward after isoproterenol pretreatment. Chronic i soproterenol pretreatment induces the expected cardiac beta -adrenoceptor d esensitization while simultaneously enhancing the positive inotropic respon siveness to phenylephrine in Langendorff heart preparations. These findings support the hypothesis that cardiac alpha (1)-adrenoceptor stimulation may contribute to the maintenance of myocardial function under conditions in w hich beta -adrenoceptor function is compromised.