Adenylyl cyclase-dependent inhibition of myocardial norepinephrine release by presynaptic adenosine A1-receptors

Adenosine A(1)-receptor-mediated inhibition of exocytotic norepinephrine (NE) release from sympathetic nerve endings has been implicated as an endogenous cardioprotective mechanism. So far, the intraneuronal signal transduction underlying the adenosine A(1)-receptor-elicited inhibition of NE release is not known. In the present study, we determined in isolated Langendorff-perfused rat hearts the role of inhibitory G-proteins and of adenylyl cyclase (AC) on NE release after pharmacologic adenosine A(1)-receptor activation. NE release was induced by electrical field stimulation and was assessed in the coronary effluent by high-performance liquid chromatography. Adenosine A(1)-receptor activation with 2-chloro-N-6-cyclopentyladenosine (CCPA) decreased NE release by similar to50% in hearts from both untreated and pertussis toxin-pretreated rats. In hearts from untreated rats, suppression of NE release in response to CCPA was completely abolished by the cell-permeable AC inhibitor 9(tetrahydro-2'-furyl)adenine (SQ 22536). Direct activation of AC with forskolin increased NE release by similar to20%. In the presence of forskolin. stimulation of adenosine A(1)-receptors with CCPA or inhibition of AC with SQ 22536 decreased NE release to baseline. These findings suggest a G(1)-protein-independent but AC-dependent inhibition of NE release following adenosine A(1)-receptor activation.