Insulin-induced biphasic responses in rat mesenteric vascular bed: role of endothelin.
The vasodilatory capacity of insulin has been widely reported, yet some investigators have not noted this effect. Because insulin has been shown to enhance endothelin release, we speculated that endothelin could be attenuating insulin-evoked vasodilation. We examined the effect of ex vivo insulin perfusion on vascular resistance by using the Sprague-Dawley rat mesenteric vascular bed. In methoxamine-preconstricted preparations, insulin (3.0 pmol/L to 10 nmol/L) evoked a concentration-dependent decrease in perfusion pressure (PP) with a maximal response of 42.0+/-9.2%, whereas continuous exposure to 10 nmol/L insulin induced a 51.8+/-3.5% relaxation. Further exposure to 10 nmol/L insulin resulted in the generation of endothelin and a subsequent loss of the vasodilatory response. Indomethacin had no effect on vascular responses. The vasodilatory response was significantly inhibited by nitric oxide synthase inhibition (20.5+/-4.2%; P<0.01) and calcium-activated potassium channel blockade (28.5+/-3.7%; P<0.05). Endothelial denudation attenuated the vasodilatory component (20.3+/-7.1%; P<0.01) and altered the biphasic pattern of the response. The decline in insulin-evoked vasodilation was significantly prevented by an endothelin-A antagonist (BQ123), an endothelin-B antagonist (BQ788), and nonselective endothelin blockade with both BQ123 and BQ788. These results demonstrate that the endothelium is intimately involved in regulating the vascular response to insulin. Insulin promotes the release of nitric oxide and endothelium-derived hyperpolarizing factor. During sustained exposure to higher concentrations, this vasodilatory effect is countered by the pathological generation of endothelin. Endothelin receptor blockade facilitates the maintenance of vasodilation despite high insulin concentrations.
Misurski
D A
DA
Department of Pharmacology and the Cardiovascular Risk Factor Reduction Unit, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Wu
S Q
SQ
McNeill
J R
JR
Wilson
T W
TW
Gopalakrishnan
V
V
D000818:Animals; D016232:Endothelins / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*
D016232:Endothelins; D007004:Hypoglycemic Agents; D007328:Insulin