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Central role of heterocellular gap junctional communication in endothelium-dependent relaxations of rabbit arteries

A. T. Chaytor, W. H. Evans * and T. M. Griffith

1. The contribution of gap junctions to endothelium-dependent relaxation was investigated in isolated rabbit conduit artery preparations pre-constricted by 10 µM phenylephrine (PhE).

2. Acetylcholine (ACh) relaxed the thoracic aorta by ~60 % and the superior mesenteric artery (SMA) by ~90 %. A peptide possessing sequence homology with extracellular loop 2 of connexin 43 (Gap 27, 300 µM) inhibited relaxation by ~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. N^G-nitro-L-arginine methyl ester (L-NAME, 300 µM), an inhibitor of NO synthase, attenuated ACh-induced relaxation by ~90 % in the aorta but only by ~40 % in SMA (P < 0·05). Residual L-NAME-insensitive relaxations were almost abolished by 300 µM Gap 27 in aorta and inhibited in a concentration-dependent fashion in SMA (~50 % at 100 µM and ~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.

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