Chronic beta-blockade transregulates inhibitory A1 adenosine and muscarinic M2 receptors of the adenylyl cyclase system.

Chronic beta-blockade has evolved to an important therapeutic strategy in medicine. Not all its therapeutic effects may be explained by its direct action on the beta-adrenergic system. We therefore investigated if chronic beta-blockade in vivo or in isolated cell systems may modulate also inhibitory receptors of the adenylyl cyclase system. Chronic treatment with metoprolol for 6 days (10 mg/day) induced an increase of beta-adrenergic receptors in rat cardiac plasma membranes (53 +/- 8 vs 80 +/- 12 fmol/mg protein). Simultaneously the density of cardiac muscarinic M2 receptors decreased significantly from 150 +/- 17 to 110 +/- 12 fmol/mg protein without any change of the affinity of the receptors for their agonists or antagonists. By this mechanism chronic beta-blockade leads to an unexpected impairment of the muscarinic-mediated inhibition of the adenylyl cyclase. This transregulation of inhibitory receptors by chronic beta-blockade was not restricted to the heart but also reduced the muscarinic receptors of rat lung (35 +/- 4 vs 24 +/- 3 fmol/mg protein). Additionally, other inhibitory receptors of the adenylyl cyclase system such as the A1 adenosine receptors of rat brain were reduced by chronic beta-blockade (532 +/- 32 vs 444 +/- 26 fmol/mg protein). This transregulation of A1 adenosine receptors occurred only after chronic beta-blockade with the active stereoisomer (-)-metoprolol whereas the (+)-isomer was ineffective. The ability of the remaining A1 adenosine receptors to form the agonist-promoted high affinity state was unaltered. Their reduction, however, was sufficient to abolish the phenylisopropyl-mediated inhibition of the adenylyl cyclase. To evaluate if this regulation of various inhibitory receptors in different organs may represent a general cellular regulation mechanism, we investigated whether this transregulation also occurred in isolated cells. Isolated smooth muscle cells derived from the vas deferens (DDT1 MF-2) were cultivated in the presence of the beta-blocker atenolol (10(-5) M) for 3 days. Chronic beta-blockade in these isolated cells induced an increase of beta-adrenergic receptors and concomitantly a significant decrease of A1 adenosine receptors (460 +/- 42 vs 368 +/- 18 fmol/mg protein). The affinity of the A1 adenosine receptors for their agonists and antagonists and the ability of the remaining receptors to form the agonist-promoted high affinity state remained unaltered. In contrast, the reduction of receptor density greatly impaired the adenosine-mediated inhibition of the adenylyl cyclase. These data demonstrate that chronic beta-blockade leads to a functionally significant reduction of inhibitory receptors of the adenylyl cyclase system.(ABSTRACT TRUNCATED AT 400 WORDS)