Impaired endothelium-mediated relaxation in isolated cerebral arteries from insulin-resistant rats.
Insulin resistance (IR) impairs vascular responses in peripheral arteries. However, the effects of IR on cerebrovascular control mechanisms are completely unexplored. We examined the vascular function of isolated middle cerebral arteries (MCAs) from fructose-fed IR and control rats. Endothelium-dependent vasodilation elicited by bradykinin (BK) was reduced in IR compared with control MCAs. Maximal dilation to BK (10(-6) M) was 38 +/- 3% (n = 13) in control and 19 +/- 3% (n = 10) in IR arteries (P < 0.01). N(omega)-nitro-L-arginine methyl ester (L-NAME; 10 microM) decreased responses to BK in control arteries by approximately 65% and inhibited the already reduced responses completely in IR MCAs. Indomethacin (10 microM) reduced relaxation to BK in control MCAs by approximately 40% but was largely ineffective in IR arteries. Combined L-NAME and indomethacin treatments eliminated the BK-induced dilation in both groups. Similarly to BK, endothelium-mediated and mainly cyclooxygenase (COX)-dependent dilation to calcium ionophore A23187 was reduced in IR arteries compared with controls. In contrast, vascular relaxation to sodium nitroprusside was similar between the IR and control groups. These findings demonstrate that endothelium-dependent dilation in cerebral arteries is impaired in IR primarily because of a defect of the COX-mediated pathways. In contrast, nitric oxide-mediated dilation remains intact in IR arteries.
Erdös
Benedek
B
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1083, USA.
Miller
Allison W
AW
Busija
David W
DW
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D020768:Middle Cerebral Artery / Q000502:physiology*; D009126:Muscle Relaxation; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction; D014664:Vasodilation / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D000001:Calcimycin; D019001:Nitric Oxide Synthase; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin