Doxazosin modifies Bcl-2 and Bax protein expression in the left ventricle of spontaneously hypertensive rats

Background Increased apoptosis has recently been reported in the heart of s pontaneously hypertensive rats (SHRs), Objective To investigate the molecular basis of apoptosis in the left ventr icle of SHRs in terms of the expression of Bcl-2 protein (which protects fr om apoptosis) and Bar protein (which acts as an apoptotic promoter). In add ition, we analysed the involvement of alpha(1)-adrenergic receptors in the left ventricular apoptosis of SHRs, Methods The study was performed in untreated SHRs (n = 16) and SH Rs that w ere orally treated with doxazosin (10 mg/kg body weight per day, for 15 day s), a selective alpha(1)-receptor blocker (n = 16). A group of Wistar-Kyoto (WKY) rats (n = 16)was used as the control. Results The left ventricles of untreated SHRs showed a significant increase in Bcl-2 protein expression and a reduced presence of Pax protein, The rat io of Bcl-2:Bax in SHPs was higher than in WKY rats, suggesting an antiapop totic state. Paradoxically, both the number of apoptotic cardiac cells and the cleavage of an 85-kDa fragment of the poly (ADP-ribose) polymerase (PAR P), a marker of caspase-3 activity, were higher in the left ventricle of SH Rs than in WKY rats, suggesting an apoptotic situation. Bar promotes cell a poptosis when it is bound to Bcl-2, We then determined the abundance of Bax -Bcl-2 complexes in the left ventricle of the two groups of animals. Bax-Bc l-2 complexes were more abundant in SHRs than WKY rats. In a second set of experiments, we analysed the role of alpha(1)-adrenergic blockade by doxazo sin in the above-described mechanisms. Doxazosin treatment reduced the form ation of Bax-Bcl-2 complexes in the left ventricle of SHRs, and this was ac companied by a decrease in the levels of 85-kDa PARP and a reduction in apo ptotic left ventricular cells. Conclusions The present work suggests that the presence of Bax-Bcl-2 comple xes in the left ventricle could be a more reliable marker of the apoptotic state than the determination of the absolute expression of Bcl-2 and Bar pr oteins. Moreover, the inhibition of alpha(1)-adrenergic receptors by doxazo sin decreased the abundance of Bax-Bcl-2 complexes and promoted a reduction of apoptosis in the left ventricle of SHRs. J Hypertens 2000, 18:307-315 ( C) Lippincott Williams & Wilkins.