Eringa EC, Stehouwer CD, Roos MH, Westerhof N, Sipkema P. Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats. Am J Physiol Endocrinol Metab 293: E1134-E1139, 2007. First published July 10, 2007; doi:10.1152/ajpendo.00516.2006.-Obesity is related to insulin resistance and hypertension, but the underlying mechanisms are unclear. Insulin exerts both vasodilator and vasoconstrictor effects on muscle resistance arteries, which may be differentially impaired in obesity. Objectives: To investigate whether vasodilator and vasoconstrictor effects of insulin are impaired in muscle resistance arteries of obese rats and the roles of Akt and endothelial NO synthase (eNOS). Methods/Results: Effects of insulin were studied in resistance arteries isolated from cremaster muscles of lean and obese Zucker rats. In arteries of lean rats, insulin increased activity of both NO and endothelin (ET-1), resulting in a neutral effect under basal conditions. In arteries of obese rats, insulin induced endothelin-mediated vasoconstriction (Ϫ15 Ϯ 5% at 1 nM, P Ͻ 0.05 vs. lean). Insulin induced vasodilatation during endothelin receptor blockade in arteries of lean rats (20 Ϯ 5% at 1 nM) but not in those of obese rats. Inhibition of NO synthesis increased vascular tone (by 12 Ϯ 2%) and shifted insulinmediated vasoreactivity to vasoconstriction (Ϫ25 Ϯ 1% at 1 nM) in lean rats but had no effect in arteries of obese rats, indicating reduced NO activity. Protein analysis of resistance arteries revealed that insulin-mediated activation of Akt was preserved in obese rats, whereas expression of eNOS was markedly decreased. Conclusions: Vasodilator but not vasoconstrictor effects of insulin are impaired in muscle resistance arteries of obese rats, and this selective impairment is associated with decreased protein levels of eNOS. These findings provide a new mechanism linking obesity to insulin resistance and hypertension. microcirculation; obesity; hypertension; nitric oxide OBESITY IS ASSOCIATED WITH impairment of insulin-mediated insulin resistance, i.e., glucose disposal (19) and hypertension (29), but the mechanisms behind these relationships have not been elucidated.We and others have hypothesized that impaired endotheliumdependent vasodilatation in resistance arteries plays an important role in both insulin resistance and hypertension (32). Impaired endothelium-dependent vasodilatation in these arteries increases vascular resistance, which, in muscle, may contribute to decreased insulin-mediated glucose disposal (7).A specific type of endothelium-dependent vasodilatation that may be relevant in this regard is insulin-mediated vasodilatation. Both vasodilator and vasoconstrictor effects of insulin have been described, the normal response to insulin being vasodilator or neutral (8, 36). We and others have previously shown that, in muscle resistance arteries, NO-dependent vasodilator effects of insulin are antagonized by endothelin-mediated vasoconstrictor effects. It was previously show...

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Contraction of vascular smooth muscle is determined not only by levels of intracellular free calcium but also by the sensitivity of its contractile apparatus. A potential modulator of the latter is rho-kinase. We addressed the question of a possible central role for rhokinase in the regulation of periglomerular microvascular tone. In the rat hydronephrotic kidney model, diameter changes of distal interlobular arteries, afferent and efferent arterioles were measured using three distinctly different stimuli: intravascular pressure changes, angiotensin II (AngII) and membrane depolarization, which is a physiological component of many signaling pathways, as evoked in two ways. Two selective, structurally different rho-kinase inhibitors, Y-27632 and HA-1077, were employed, as well as a selective protein kinase C alpha inhibitor. Preglomerular vasoconstriction induced by direct membrane depolarization, increases in pressure or AngII all depended for their effect on rho-kinase. A differing role for rho-kinase in efferent arteriolar constriction to AngII as compared to preglomerular microvessels was not found. In conclusion, our data indicate that in the kidney, rho-kinase is involved in a variety of signaling pathways leading to microvascular constriction. It plays a pivotal role not only in preglomerular but also in postglomerular tone.