Adenylyl cyclase-dependent inhibition of myocardial norepinephrine release by presynaptic adenosine A1-receptors.
Adenosine A1-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 A1-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 A1-receptor activation. NE release was induced by electrical field stimulation and was assessed in the coronary effluent by high-performance liquid chromatography. Adenosine A1-receptor activation with 2-chloro-N6-cyclopentyladenosine (CCPA) decreased NE release by approximately 50% 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 approximately 20%. In the presence of forskolin, stimulation of adenosine A1-receptors with CCPA or inhibition of AC with SQ 22536 decreased NE release to baseline. These findings suggest a Gi-protein-independent but AC-dependent inhibition of NE release following adenosine A1-receptor activation.
Burgdorf
Christof
C
Medizinische Klinik II, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany. chbrg@compuserve.de
Schütte
Frank
F
Kurz
Thomas
T
Dendorfer
Andreas
A
Richardt
Gert
G
D058916:Adenosine A1 Receptor Antagonists; D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D005089:Exocytosis; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000502:physiology; D017661:Receptors, Presynaptic / Q000037:antagonists & inhibitors* / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology
D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D017661:Receptors, Presynaptic; D010738:Type C Phospholipases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases; D009638:Norepinephrine