Gap Junction-Dependent Increases in Smooth Muscle cAMP Underpin the EDHF Phenomenon in Rabbit Arteries

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

“…Comparable to receptor-dependent agonists, the Ca 2ϩ -ATPase inhibitors cyclopiazonic acid and thapsigargin elicit endothelium-dependent vasodilation (35,52,53). After blockade of PGI 2 and NO synthesis, Ca 2ϩ -ATPase inhibitor-induced smooth muscle cell hyperpolarization and relaxation are attributed to EDHF.…”

“…Here again, however, the results are variable. Whereas most studies show inhibition of EDHF-mediated vasodilation by the blocker 18␣-glycyrrhetinic acid (10,16,23,27,29,36,52,53), some do not (3,32,50). Similarly, palmitoleic acid inhibited EDHF responses in rat mesentery (27) and skeletal muscle (56) arteries but not in pig coronary arteries (3).…”

“…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.…”

Enhanced inhibition of the EDHF phenomenon by a phenyl methoxyalaninyl phosphoramidate derivative of dideoxyadenosine

“…Electrotonic signalling may therefore underpin the NO-and prostanoid-independent relaxations that are often attributed to a freely transferable endothelium-derived hyperpolarizing factor or EDHF. ACh also stimulates prostanoidindependent synthesis of cAMP by the endothelium, thereby facilitating the spread of endothelial hyperpolarization through an action that involves phosphorylation of the connexin proteins that form gap junction channels and/or their rapid recruitment to the cell membrane (Paulson et al, 2000;Van Rijen et al, 2000;Taylor et al, 2001;Griffith et al, 2002). P-site inhibitors of adenylyl cyclase, such as the dideoxyadenosine nucleosides 2 0 ,3 0 -ddA and 2 0 ,5 0 -ddA, have thus been shown to attenuate EDHF-type smooth muscle hyperpolarizations and relaxations of rabbit arteries and veins when applied at concentrations in the range 30-200 mM (Griffith & Taylor, 1999;Taylor et al, 2001;Griffith et al, 2002;Chaytor et al, 2002;.…”

“…ACh also stimulates prostanoidindependent synthesis of cAMP by the endothelium, thereby facilitating the spread of endothelial hyperpolarization through an action that involves phosphorylation of the connexin proteins that form gap junction channels and/or their rapid recruitment to the cell membrane (Paulson et al, 2000;Van Rijen et al, 2000;Taylor et al, 2001;Griffith et al, 2002). P-site inhibitors of adenylyl cyclase, such as the dideoxyadenosine nucleosides 2 0 ,3 0 -ddA and 2 0 ,5 0 -ddA, have thus been shown to attenuate EDHF-type smooth muscle hyperpolarizations and relaxations of rabbit arteries and veins when applied at concentrations in the range 30-200 mM (Griffith & Taylor, 1999;Taylor et al, 2001;Griffith et al, 2002;Chaytor et al, 2002;. In cultured bovine endothelial cells, such P-site ligands also attenuate forskolin and isoproterenol-evoked increases in cAMP content with IC 50 values in the range 300-500 mM (Legrand et al, 1990), whereas in experiments with cell-free fractions or recombinant adenylyl cyclase IC 50 values are in the low micromolar range (Johnson et al, 1997;Desaubry & Johnson, 1998;Shoshani et al, 1999).…”