Display of the characteristics of endothelium‐derived hyperpolarizing factor by a cytochrome P450‐derived arachidonic acid metabolite in the coronary microcirculation

1 We examined the vasodilatory e ect of hypercapnia in the rat isolated mesenteric vascular bed. The preparation was perfused constantly (5 ml min 71 with oxygenated Krebs-Ringer solution, and the perfusion pressure was measured. In order to keep the extracellular pH (pHe) constant (around 7.35) against a change in CO 2 , adequate amounts of NaHCO 3 were added to Krebs-Ringer solution. 2 In the endothelium intact preparations, an increase in CO 2 from 2.5% to 10% in increments of 2.5% decreased the 10 mM phenylephrine (PE)-produced increase in the perfusion pressure in a concentrationdependent manner. Denudation of the endothelium by CHAPS (3-[(3-cholamidopropyl)-dimethylammonio]-l-propanesulphonate) (5 mg l 71 , 90 s perfusion) abolished the vasodilatory e ect of hypercapnia. 3 An increase in CO 2 from 5% to 10% reduced the increases in the perfusion pressure produced by 10 mM PE and 400 nM U-46619 by 48% and 44%, respectively. N G -monomethyl-L-arginine (100 mM) and indomethacin (10 mM) did not a ect the vasodilatory e ect of hypercapnia, whereas the vasodilatory response of the preparation to hypercapnia disappeared when the preparation was contracted by 60 mM K + instead of PE or U-46619. 4 The vasodilatory e ect of hypercapnia observed in the PE-or U-46619-precontracted preparation was a ected by neither tetraethylammonium (1 mM), apamin (500 mM), glibenclamide (10 mM), nor 4-aminopyridine (1.5 mM). On the other hand, pretreatment with Ba 2+ at a concentration of 0.3 mM abolished the hypercapnia-produced vasodilation. 5 An increase in the concentration of K + in Krebs-Ringer solution from 4.5 mM to 12.5 mM in increments of 2 mM reduced the PE-produced increase in the perfusion pressure in a concentrationdependent manner. Pretreatment of the preparations with not only Ba 2+ (0.3 mM) but also CHAPS abolished the vasodilatory e ect of K + . 6 The results suggest that an increase in CO 2 produces vasodilation by an endothelium-dependent mechanism in the rat mesenteric vascular bed. The membrane hyperpolarization of the endothelial cell by an activation of the inward recti®er K + channel seems to be the mechanism underlying the hypercapnia-produced vasodilation. Neither nitric oxide nor prostaglandins are involved in this response.

Section: Discussionmentioning

confidence: 99%

Involvement of barium‐sensitive K⁺ channels in endothelium‐dependent vasodilation produced by hypercapnia in rat mesenteric vascular beds

Okazaki

Endou

Okumura

1998

“…The aim of the present study was to determine whether a crosstalk occurs between CB1 receptor activation or inactivation and endothelial autacoid production. To this end we studied the e ects of CB1 receptor agonists (HU 210, D 9 -THC and anandamide) and the selective antagonist/inverse agonist SR 141716A (Bouaboula et al, 1997) on the vascular tone of three di erent arteries all of which synthesize both nitric oxide (NO) and an EDHF which is characterized as a CYP-dependent metabolite of arachidonic acid (Bauersachs et al, 1994;Popp et al, 1996;.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the production of endothelium‐derived hyperpolarizing factor by cannabinoid receptor agonists

Fleming

Schermer

Popp

et al. 1999

1 The endogenous cannabinoid, anandamide, has been reported to induce an`endothelium-derived hyperpolarizing factor (EDHF)-like' relaxation in vitro. We therefore investigated the e ects of cannabinoid CB1 receptor agonists; HU 210, D 9 -tetrahydrocannabinol (D 9 -THC) and anandamide, and a CB1 antagonist/inverse agonist, SR 141716A, on nitric oxide (NO) and EDHF-mediated relaxation in precontracted rings of porcine coronary, rabbit carotid and mesenteric arteries. 2 In rings of mesenteric artery HU 210 and D 9 -THC induced endothelium-and cyclo-oxygenaseindependent relaxations which were sensitive to SR 141716A. Anandamide (0.03 ± 30 mM) induced a slowly developing, endothelium-independent relaxation which was abolished by diclofenac and was therefore mediated by cyclo-oxygenase product(s). None of the CB1 agonists tested a ected the tone of precontracted rings of rabbit carotid or porcine coronary artery. 3 In endothelium-intact segments, HU 210, D 9 -THC and anandamide did not a ect NO-mediated responses but under conditions of continuous NO synthase/cyclo-oxygenase blockade, signi®cantly inhibited acetylcholine and bradykinin-induced relaxations which are attributed to the production of EDHF. The e ects of HU 210 and D 9 -THC were not observed when experiments were performed in the presence of SR 141716A suggesting the involvement of the CB1 receptor. 4 In a patch clamp bioassay of EDHF production, HU 210 decreased the EDHF-mediated hyperpolarization of detector smooth muscle cells when applied to the donor segment but was without e ect on the membrane potential of detector cells. The inhibition of EDHF production was unrelated to alterations in Ca 2+ -signalling or cytochrome P450 activity. 5 These results suggest that the activation of endothelial CB1 receptors appears to be negatively coupled to the production of EDHF.

“…The relative contribution of these factors may vary under di erent experimental conditions as all three may cause hyperpolarization of vascular smooth muscle (Parkington et al, 1993), release of EDHF is attenuated by NO (Bauersachs et al, 1996), and NO may stimulate the synthesis of prostanoids (Salvemini et al, 1993). The chemical nature of EDHF is unknown, candidate mediators including the endocannabinoid, anandamide (Randall & Kendall, 1998), and epoxyeicosatrienoic acids (EETs) which are cytochrome P 450 mono-oxygenase derived metabolites of arachidonic acid (Bauersachs et al, 1994).…”

mentioning

confidence: 99%

Inhibition of the gap junctional component of endothelium‐dependent relaxations in rabbit iliac artery by 18‐α glycyrrhetinic acid

Taylor

Chaytor

Evans

et al. 1998

140

The gap junction inhibitor 18-a-glycyrrhetinic acid (a-GA, 100 mM) attenuated endothelium-dependent relaxations to acetylcholine and cyclopiazonic acid by *20% in rings of pre-constricted rabbit iliac artery. The nitric oxide synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME, 300 mM) inhibited relaxations to both agents by *65% and these were further attenuated by a-GA to 510% of control. In endothelium-denuded preparations, relaxations to sodium nitroprusside were not a ected by a-GA. Heterocellular gap junctional communication may therefore account for nitric oxide-independent relaxations evoked both by receptor-dependent and -independent mechanisms in rabbit iliac artery.