Comparison of the pharmacological properties of EDHF‐mediated vasorelaxation in guinea‐pig cerebral and mesenteric resistance vessels

Abstract

1 In the presence of L-NNA (100 mM), indomethacin (10 mM) and ODQ (10 mM), acetylcholine induced a concentration-dependent vasorelaxation of guinea-pig mesenteric and middle cerebral arteries precontracted with cirazoline or histamine, but not with high K + , indicating the contribution of an endothelium-derived hyperpolarizing factor (EDHF). 2 In cerebral arteries, charybdotoxin (ChTX; 0.1 mM) completely inhibited the indomethacin, L-NNA and ODQ-insensitive relaxation; iberiotoxin (IbTX, 0.1 mM), 4-aminopyridine (4-AP, 1 mM), or barium (30 mM) signi®cantly reduced the response; in the mesenteric artery, ChTX and IbTX also reduced this relaxation. Glibenclamide (10 mM) had no a ect in either the mesenteric or cerebral artery. 3 Neither clotrimazole (1 mM) nor 7-ethoxyresoru®n (3 mM) a ected EDHF-mediated relaxation in the mesenteric artery, but abolished or attenuated EDHF-mediated relaxations in the cerebral artery. AM404 (30 mM), a selective anandamide transport inhibitor, did not a ect the vasorelaxation response to acetylcholine in the cerebral artery, but in the mesenteric artery potentiated the vasorelaxation response to acetylcholine in an IbTX, and apamin-sensitive, but SR 141816A-insensitive manner. Ouabain (100 mM) almost abolished EDHF-mediated relaxation in the mesenteric artery, but enhanced the relaxation in the cerebral artery whereas the addition of K + (5 ± 20 mM) to precontracted guinea-pig cerebral or mesenteric artery induced further vasoconstriction. 4 These data suggest that in the guinea-pig mesenteric and cerebral arteries di erent EDHFs mediate acetylcholine-induced relaxation, however, EDHF is unlikely to be mediated by K + .

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

“…Various CYP450 inhibitors have been found to reduce EDHF-mediated relaxation of rat (34) and dog (31) pulmonary arteries. However, CYP450 inhibitors have not inhibited EDHFmediated vasodilation in other studies or have done so nonspecifically (14,18,23,24,33,36,42,58). In our study, 7-ethoxyresorufin and sulfaphenazole alone reduced, and the combination of inhibitors abolished, EDHF-mediated vasodilation in normotensive lungs.…”

“…For example, sulfaphenazole, an inhibitor of cytochrome 2C isozymes, inhibits EDHFmediated vasorelaxation in the porcine coronary artery (21) and 7-ethoxyresorufin, an inhibitor of CYP450 1A isozyme, inhibits the vasodilation in perfused rat mesenteric (1) and renal (2) vascular beds and the guinea pig cerebral artery (14). However, other studies in various arteries show that these and other CYP450 inhibitors fail to inhibit EDHF-mediated vasorelaxation, or do so nonspecifically, and do not support the involvement of CYP450 in the EDHF mechanism (18,23,24,32,36,42,58).…”

Mechanism Underlying Endothelium-Dependent Relaxation by 2-Methylthio-ADP in Monkey Cerebral Artery

“…In the present study, we found that ATK markedly suppressed the 2MeSADP-induced relaxation, indicating that PLA 2 activation is involved in the 'EDHFtype' relaxation in monkey cerebral artery. Activation of PLA 2 has been reported to be involved in 'EDHF-type' relaxation in monkey coronary and lingual arteries (15,17) as well as cerebral arteries from rat (28) and guinea pig (29). Treatment with ketoconazole inhibited the 'EDHF-type' relaxation induced by 2MeSADP in monkey cerebral artery.…”

Role of Cytoplasmic Phospholipase A2in Endothelium-Derived Hyperpolarizing Factor Dilations of Rat Middle Cerebral Arteries

“…This attenuation is consistent with reported IC 50 concentrations in the mol/L range (Bleasdale et al, 1990) and previously reported concentrations for inhibition of the EDHF response in the porcine coronary artery (20 mol/L abolished the EDHF response) (Weintraub et al, 1995) and rabbit mesenteric artery (0.5 mol/L produced greater than 50% inhibition) (Hutcheson et al, 1999). In guinea pig, 1 mol/L U73122 had no effect on the EDHF response in the mesenteric artery but produced a 39% inhibition in the MCA (Dong et al, 2000). Thus, while PLC, as determined by inhibitor studies with U73122, appears to be involved with the EDHF response in a number of arteries including the rat MCA, it may not be involved with the EDHF response in all vascular systems.…”

“…There are, however, three observations that support the idea that the EDHF mechanism is different in cerebral and peripheral vessels. First, the EDHF-mediated relaxations in guinea pig middle cerebral arteries (MCAs) and mesenteric resistance vessels were differently affected by a number of pharmacological inhibitors, including those that inhibit cytochrome P450 enzymes and potassium channels (Dong et al, 2000). Second, the presence of basal concentrations of NO attenuated the EDHF response by 50% to 100%, depending on the agonist and concentration in peripheral arteries (Bauersachs et al, 1996).…”