A novel transduction mechanism mediating dopamine-induced vascular relaxation: opening of BKCa channels by cyclic AMP-induced stimulation of the cyclic GMP-dependent protein kinase

• Published in: Journal of cardiovascular pharmacology Vol. 34; no. 5; p. 619
• Main Authors: Han, G, Kryman, J P, McMillin, P J, White, R E, Carrier, G O
• Format: Journal Article
• Language: English
• Published: United States 01.11.1999
• Subjects: Animals; Calcium - physiology; Cyclic AMP - biosynthesis; Cyclic AMP - physiology; Cyclic GMP-Dependent Protein Kinases - metabolism; Dopamine - pharmacology; Dopamine - physiology; Dopamine Agonists - pharmacology; Dose-Response Relationship, Drug; In Vitro Techniques; Ion Channel Gating - drug effects; Ion Channel Gating - physiology; Large-Conductance Calcium-Activated Potassium Channels; Muscle Relaxation - drug effects; Muscle Relaxation - physiology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Muscle, Smooth, Vascular - physiology; Potassium Channels - metabolism; Potassium Channels - physiology; Potassium Channels, Calcium-Activated; Receptors, Dopamine D1 - physiology; Swine; Vasodilation - drug effects; Vasodilation - physiology
• ISSN: 0160-2446
• DOI: 10.1097/00005344-199911000-00001

Dopamine dilates the coronary, renal and other vascular beds; however, the signaling pathway underlying this effect is unclear. In this study the signal-transduction process mediating dopamine-induced relaxation of porcine coronary arteries was investigated in isolated vessels and single arterial myocytes. Dopamine-induced relaxation of arteries was mediated through the DA- receptor and involved K+ efflux, and subsequent patch-clamp studies demonstrated that either dopamine or fenoldopam, a selective DA-1 agonist, increased the opening probability of the large-conductance, calcium- and voltage-activated K+ (BKCa) channel in coronary myocytes. Moreover, blockade of this channel by iberiotoxin prevented dopamine-induced coronary relaxation. Dopamine stimulation of BKCa channels was completely prevented by a DA-1-receptor antagonist, but was unaffected by propranolol. Furthermore, inhibiting adenylyl cyclase activity prevented stimulation of BKCa channel activity, whereas chlorophenylthio (CPT)-cyclic adenosine monophosphate (AMP), a membrane-permeable analog of cyclic AMP, mimicked the effects of dopamine. Interestingly, inhibiting the cyclic AMP-dependent protein kinase (PKA) did not affect the response to dopamine, whereas dopamine-induced channel activity was completely blocked by inhibiting the activity of the cyclic guanosine monophosphate (GMP)-dependent protein kinase (PKG). These findings demonstrate that activation of DA-1 receptors causes stimulation of BKCa channel activity by a mechanism involving cyclic AMP-dependent stimulation of PKG, but not PKA, and further suggest that this cross-reactivity mediates dopamine-induced coronary vasodilation.