title: Reactivity of mesenteric arteries from fructose hypertensive rats to endothelin-1.
abstract: We previously demonstrated that mesenteric arteries from hyperinsulinemic, insulin resistant fructose hypertensive (FH) rats contain a higher absolute amount of ET-1 and exhibit defective endothelium-dependent vasodilation. Furthermore, chronic ET receptor blockade with bosentan completely prevented the rise in blood pressure in these rats. The present study was undertaken to examine 1) whether the reactivity of mesenteric arteries to ET-1 is altered in FH rats, and 2) whether chronic bosentan treatment has any effect on ET-1 responsiveness and endothelium-dependent vasodilation. Male Sprague Dawley rats were divided into four groups: control (C), control bosentan-treated (CB), fructose (F) and fructose bosentan-treated (FB). Chronic oral bosentan treatment (100 mg/kg/day) was initiated in the CB and FB groups 1 week prior to initiating the fructose diet. At week 16, the F group was hyperinsulinemic and hypertensive when compared to the C group (plasma insulin: 5.8 +/- 0.3 v C 3.2 +/- 0.5 ng/mL, P < .001; systolic BP: 157 +/- 5 v C 130 +/- 4 mm Hg, P < .001). Treatment of the F group with bosentan prevented the rise in BP (FB: 133 +/- 3 mm Hg; P < .001 v F). Analysis of the pressurized mesenteric resistance arterioles demonstrated that the wall thickness as expressed as percentage of internal diameter did not differ between arteries from C and F rats, when measured over a range of transmural pressures. Constrictor responses of resistance arterioles to NE were similar for C and F rats when studied at transmural pressures of either 120 mm Hg or 160 mm Hg, respectively. The maximum contractile response and the sensitivity of superior mesenteric arteries to NE did not differ between the groups, either with or without the endothelium. However, the maximum contractile response to ET-1 was depressed in the F group both with (+) and without (-) the endothelium [(+): 1.50 +/- 0.11 v C 1.88 +/- 0.1 g/mm3, P < .05, (-): 1.68 +/- 0.11 v C 2.05 +/- 0.1 g/mm3, P < .05.]. Furthermore, the endothelium intact F arteries exhibited a decreased sensitivity to ET-1 (pD2 values F 8.36 +/- 0.11 v C 8.83 +/- 0.07). Chronic bosentan treatment of the F group restored the maximum tension responses of arteries to ET-1 [(+) in the FB group: 1.88 +/- 0.12 g/mm3 v C, P > .05, (-): 1.95 +/- 0.05 g/mm3 v C, P > .05] but had no effect on the responses of the CB group. In arteries with intact endothelium, bosentan treatment restored the sensitivity of the F arteries to ET-1 (pD2 values FB 8.82 +/- 0.05 v C, P < .05). Endothelium-dependent relaxation responses were diminished in the F group, which were unaffected by bosentan treatment. These data suggest that mesenteric arteries from FH demonstrate a specific alteration towards the reactivity to ET-1, which is restored by long-term bosentan treatment.
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, Vancouver, British Columbia, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Verma
authors.forename: P
authors.initials: P
authors.lastname: Skarsgard
authors.forename: S
authors.initials: S
authors.lastname: Bhanot
authors.forename: L
authors.initials: L
authors.lastname: Yao
authors.forename: I
authors.initials: I
authors.lastname: Laher
authors.forename: J H
authors.initials: JH
authors.lastname: McNeill
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D019332:Endothelin-1 / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005632:Fructose; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000503:physiopathology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014655:Vascular Resistance; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D019332:Endothelin-1; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D005632:Fructose; D000077300:Bosentan; D009638:Norepinephrine