Central role of heterocellular gap junctional communication in endothelium-dependent relaxations of rabbit arteries.
1. The contribution of gap junctions to endothelium-dependent relaxation was investigated in isolated rabbit conduit artery preparations pre-constricted by 10 microM phenylephrine (PhE). 2. Acetylcholine (ACh) relaxed the thoracic aorta by approximately 60 % and the superior mesenteric artery (SMA) by approximately 90 %. A peptide possessing sequence homology with extracellular loop 2 of connexin 43 (Gap 27, 300 microM) inhibited relaxation by approximately 40 % in both artery types. Gap 27 also attenuated the endothelium-dependent component of the relaxation induced by ATP in thoracic aorta but did not modify force development in response to PhE. 3. NG-nitro-L-arginine methyl ester (L-NAME, 300 microM), an inhibitor of NO synthase, attenuated ACh-induced relaxation by approximately 90 % in the aorta but only by approximately 40 % in SMA (P < 0.05). Residual L-NAME-insensitive relaxations were almost abolished by 300 microM Gap 27 in aorta and inhibited in a concentration-dependent fashion in SMA (approximately 50 % at 100 microM and approximately 80 % at 10 mM). Gap 27 similarly attenuated the endothelium-dependent component of L-NAME-insensitive relaxations to ATP in aorta. 4. Responses to cyclopiazonic acid, which stimulates endothelium-dependent relaxation through a receptor-independent mechanism, were also attenuated by Gap 27, whereas this peptide exerted no effect on the NO-mediated relaxation induced by sodium nitroprusside in preparations denuded of endothelium. 5. ACh-induced relaxation of 'sandwich' mounts of aorta or SMA were unaffected by Gap 27 but completely abolished by L-NAME. 6. We conclude that direct heterocellular communication between the endothelium and smooth muscle contributes to endothelium-dependent relaxations evoked by both receptor-dependent and -independent mechanisms. The inhibitory effects of Gap 27 peptide do not involve homocellular communication within the vessel wall or modulation of NO release or action.
Chaytor
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Department of Diagnostic Radiology, Cardiovascular Sciences Research Group, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK.
Evans
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Griffith
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D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D018031:Connexin 43 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D018031:Connexin 43; D004791:Enzyme Inhibitors; D007211:Indoles; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D000255:Adenosine Triphosphate; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; C000543:cyclopiazonic acid