Effect of metoprolol on activity of β-adrenoceptor coupled to guanine nucleotide binding regulatory proteins in adriamycin-induced cardiotoxicity

Summary

Prevention of cardiotoxicity without interfering with the therapeutic efficacy of adriamycin is a very crucial question. We have investigated the activity of β-adrenoceptor coupled to guanine nucleotide binding regulatory proteins (G-proteins) and Ca²⁺-ATPase activity in experimental adriamycin-induced cardiotoxicity and the influence of metoprolol treatment on these variables. Adriamycin was administered to rats intravenously as a single dose of 6 mg/kg, and metoprolol was continuously given by means of implanted osmotic pumps. β-adrenoceptor characteristics were measured by radioligand-binding experiments and by basal and stimulated adenylyl cyclase activity. Northern blot and dot blot analysis was used to quantify G-protein mRNA. It was shown that adriamycin did not induce any change in the total β-adrenoceptor density, nor did the high affinity agonist binding to β-adrenoceptor change. Adriamycin did not induce any alteration in the amount of mRNA encoding for stimulatory (Gs) or inhibitory (Gi) G-proteins. Also, basal and stimulated adenylyl cyclase activities were identical in the different experimental groups. In contrast, the Ca²⁺-ATPase was shown to increase in adriamycin-treated rats compared to control rats (45 ± 3.8 versus 23 ± 1.2 μmol Pi/mg/h, P < .01). Metoprolol was shown to normalize this increase (29 ± 2.1 μmol Pi/mg/h). Thus, it may be concluded that in experimental adriamycin-induced cardiotoxicity, despite Ca²⁺-overloading, the β-adrenoceptor-G protein-adenylyl cyclase system remains intact. Metoprolol seems to prevent Ca²⁺-overloading independently of the β-adrenoceptors studied here.