title: 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.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, Wright State University School of Medicine, Dayton, Ohio, USA.
authors.forename: G
authors.initials: G
authors.lastname: Han
authors.forename: J P
authors.initials: JP
authors.lastname: Kryman
authors.forename: P J
authors.initials: PJ
authors.lastname: McMillin
authors.forename: R E
authors.initials: RE
authors.lastname: White
authors.forename: G O
authors.initials: GO
authors.lastname: Carrier
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D000242:Cyclic AMP / Q000096:biosynthesis / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004298:Dopamine / Q000494:pharmacology* / Q000502:physiology; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D051036:Large-Conductance Calcium-Activated Potassium Channels; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D024681:Potassium Channels, Calcium-Activated; D017447:Receptors, Dopamine D1 / Q000502:physiology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D018491:Dopamine Agonists; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D017447:Receptors, Dopamine D1; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D002118:Calcium; D004298:Dopamine