Gap junction-dependent increases in smooth muscle cAMP underpin the EDHF phenomenon in rabbit arteries.
We have investigated the role of cAMP in nitric oxide (NO)- and prostanoid-independent vascular relaxations evoked by acetylcholine (ACh) in isolated arteries and perfused ear preparations from the rabbit. These EDHF-type responses are shown to be associated with elevated cAMP levels specifically in smooth muscle and are attenuated by blocking adenylyl cyclase or protein kinase A (PKA). Relaxations are amplified by 3-isobutyl-1-methylxanthine, which prevents cAMP hydrolysis, while remaining susceptible to inhibition by the combination of two K(Ca) channel blockers, apamin and charybdotoxin. Analogous endothelium- and cAMP-dependent relaxations were evoked by cyclopiazonic acid (CPA) which stimulates Ca(2+) influx via channels linked to the depletion of Ca(2+) stores. Responses to ACh and CPA were both inhibited by interrupting cell-to-cell coupling via gap junctions with 18alpha-glycyrrhetinic acid and a connexin-specific Gap 27 peptide. The findings suggest that EDHF-type responses are initiated by capacitative Ca(2+) influx into the endothelium and propagated by direct intercellular communication to effect relaxation via cAMP/PKA-dependent phosphorylation events in smooth muscle.
Taylor
H J
HJ
Department of Diagnostic Radiology, University of Wales College of Medicine, Cardiff, CF14 4XN, United Kingdom.
Chaytor
A T
AT
Edwards
D H
DH
Griffith
T M
TM
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001685:Biological Factors / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D017629:Gap Junctions / Q000502:physiology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001685:Biological Factors; D007211:Indoles; C067410:endothelium-dependent hyperpolarization factor; D010656:Phenylephrine; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D000242:Cyclic AMP; D015126:8,11,14-Eicosatrienoic Acid; D000109:Acetylcholine; D015056:1-Methyl-3-isobutylxanthine; C000543:cyclopiazonic acid