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

Abstract

The contribution of gap junctions to endothelium‐dependent relaxation was investigated in isolated rabbit conduit artery preparations pre‐constricted by 10 μM phenylephrine (PhE). 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. 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. 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. ACh‐induced relaxation of ‘sandwich’ mounts of aorta or SMA were unaffected by Gap 27 but completely abolished by L‐NAME. 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.

Endothelium‐dependent hyperpolarization and intercellular electrical coupling in guinea‐pig mesenteric arterioles

“…Rather, myoendothelial gap junctions seem to be crucial in this phenomenon. Although the significance of these gap junctions in large arteries was not assessed in the present experiments, recent studies show an important role of myoendothelial gap junctions in endothelium-dependent relaxation in rabbit thoracic aorta and superior mesenteric artery (Chaytor et al 1998). When ACh is applied for a long period (10 min), endothelium-derived NO is responsible for a small sustained component of the ACh-induced hyperpolarization in the rat aorta (Vanheel et al 1994).…”

Dominant role of an endothelium‐derived hyperpolarizing factor (EDHF)‐like vasodilator in the ciliary vascular bed of the bovine isolated perfused eye

“…Moreover, evidence has been reported suggesting that the process of relaxation involves hyperpolarization of endothelial cells (Edwards et al, 1998; and consequent gap junctional transmission between endothelium and smooth muscle, resulting in smooth muscle hyperpolarization and relaxation (Davies et al, 1988;Beny, 1990;Chaytor et al, 1998). Regardless of the con¯icting evidence for the proposed candidates, there is consensus that EDHF responses are mediated by an increase in K + conductance and thus are sensitive to depolarizing solutions of K + (Adeagbo & Triggle, 1993;Corriu et al, 1996a) and by inhibitors of certain types of K + channels.…”

EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs

“…The incidence of myoendothelial gap junctions is higher in resistance than in conduit arteries (46). Putative gap junction inhibitors, such as palmitoleic acid (13,27,56), 18␣-glycyrrhetinic acid (10,16,23,27,29,36,52,53), and Gap 27 (9,16,47,52), a synthetic peptide with sequence homology to a region of the second extracellular loop of Cx37 and Cx43, reduce EDHF-mediated hyperpolarization and relaxation in various arteries. These observations suggest that the EDHF signal represents electrotonic spread of hyperpolarization from the endo-thelium into the medial smooth muscle via myoendothelial and homocellular smooth muscle gap junctions.…”