Cerebrovascular responses to insulin in rats.
Effects of insulin on cerebral arteries have never been examined. Therefore, we determined cerebrovascular actions of insulin in rats. Both PCR and immunoblot studies identified insulin receptor expression in cerebral arteries and in cultured cerebral microvascular endothelial cells (CMVECs). Diameter measurements (% change) of isolated rat cerebral arteries showed a biphasic dose response to insulin with an initial vasoconstriction at 0.1 ng/mL (-9.7%+/-1.6%), followed by vasodilation at 1 to 100 ng/mL (31.9%+/-1.4%). Insulin also increased cortical blood flow in vivo (30%+/-8% at 120 ng/mL) when applied topically. Removal of reactive oxygen species (ROS) abolished the vasoconstriction to insulin. Endothelial denudation, inhibition of K(+) channels, and nitric oxide (NO) synthase, all diminished insulin-induced vasodilation. Inhibition of cytochrome P450 enhanced vasodilation in endothelium-intact arteries, but promoted vasoconstriction after endothelial denudation. Inhibition of cyclooxygenase abolished vasoconstriction and enhanced vasodilation to insulin in all arteries. Inhibition of endothelin type A receptors enhanced vasodilation, whereas endothelin type B receptor blockade diminished vasodilation. Insulin treatment in vitro increased Akt phosphorylation in cerebral arteries and CMVECs. Fluorescence studies of CMVECs showed that insulin increased intracellular calcium and enhanced the generation of NO and ROS. Thus, cerebrovascular responses to insulin were mediated by complex mechanisms originating in both the endothelium and smooth muscle.
Katakam
Prasad Venkateswera Gurunath
PV
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston Salem, North Carolina 27157, USA. pkatakam@wfubmc.edu
Domoki
Ferenc
F
Lenti
Laura
L
Gáspár
Tamás
T
Institoris
Adam
A
Snipes
James Andy
JA
Busija
David William
DW
D000818:Animals; D001786:Blood Glucose; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000033:anatomy & histology / Q000502:physiology*; D002560:Cerebrovascular Circulation; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D015870:Gene Expression; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D014661:Vasoconstriction; D014664:Vasodilation
D001786:Blood Glucose; D007328:Insulin; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium