Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat

Abstract

Romanko, Olga P., and David W. Stepp. Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat. Am J Physiol Heart Circ Physiol 289: H2097-H2102, 2005. First published June 10, 2005; doi:10.1152/ajpheart.00213.2005.-Obesity causes whole body insulin resistance and impaired vasodilation to nitric oxide (NO). Because NO is a major contributor to the regulation of mesenteric blood flow, the mesenteric circulation of obese animals is faced with reduced capacity to increase flow and increased demand for flow associated with elevated consumption of food. This study hypothesized that insulin resistance impairs NO-mediated dilation but that constrictor reactivity would be reduced to compensate in obese animals. We further hypothesized that elevated superoxide levels caused impaired responses to NO in insulin resistance. Vasodilator reactivity and vasoconstrictor reactivity of mesenteric resistance arteries from lean (LZR) and obese (OZR) Zucker rats were examined in vitro using videomicroscopy. Insulin resistance independent of obesity was induced via fructose feeding in LZR (FF-LZR). Endothelium-dependent NO-mediated dilation was reduced in OZR and FF-LZR compared with LZR. Impairments in NO-mediated dilation were reversed with 1 mM tempol, a SOD mimetic. Constrictor reactivity to norepinephrine was reduced in OZR but not in FF-LZR relative to LZR. Basal mesenteric vascular resistance was similar in LZR and OZR despite impaired NO-dependent dilation in OZR. Mesenteric vascular resistance was increased in FF-LZR relative to LZR. These data indicate that there is reduced constrictor reactivity in OZR that may offset the impaired NO-mediated dilation and preserve mesenteric blood flow in hyperphagic, obese animals. microcirculation; adrenergic; nitric oxide; superoxide OBESITY IS AN EMERGING EPIDEMIC in Western cultures, especially in the United States, where an estimated 180 million people are overweight. The causes of obesity vary but include metabolic impairment, a high-fat diet, and overeating (hyperphagia). Functional hyperemia of the gut is required for food absorption and thus weight gain, but the effects of obesity and chronic hyperphagia on mesenteric perfusion are incompletely understood.Obesity also induces whole body insulin resistance, resulting in impaired control of plasma glucose, hyperinsulinemia, and chronic triglyceride dyslipidemia. Insulin resistance is considered an emerging risk factor for vascular disease and has been documented to impair nitric oxide (NO)-dependent mesenteric vasodilation in animal models of insulin resistance (20,(22)(23)(24). Given that NO is a major contributor to absorptive functional hyperemia (1, 9, 12, 17) and flow-mediated regulation (2,12,19), it raises the question of how the mesenteric circulation compensates for the impaired dilator response caused by insulin resistance against the elevated metabolic demands associated with increased ingestion of food in obese or hyperphagic individuals. Potential mechanisms in...

Exaggerated Cardiovascular Stress Responses and Impaired β-Adrenergic–Mediated Pressor Recovery in Obese Zucker Rats

“…Previously, our laboratory has shown that whole animal adrenergic pressor reactivity during autonomic ganglion blockade is not enhanced in OZRs 13 and that, in isolated mesenteric resistance arteries from OZRs, constrictor responses to exogenous norepineph-rine are attenuated. 16 Thus, these data suggest that the elevated peripheral vascular resistance in the face of augmented sympathetic nerve activity may be because of suppressed ␤-adrenergic-mediated vasodilation.…”

“…Moreover, our laboratory has shown that systemic pressor responses to ␣-adrenergic stimulation are comparable in OZRs versus LZRs 13 and that constrictor responses are reduced in isolated mesenteric resistance arteries from OZRs. 16 Thus, any involvement of altered adrenergic responsiveness that would lead to an enhanced pressor response to stress or impaired MAP recovery after stress must invoke changes in ␤-adrenergic responses, that is, either through an increase in cardiac output or a decrease in ␤-adrenergic-mediated vasodilation. In the present study, ␤-adrenergic blockade did not affect the response to stress, whereas poststress recovery of MAP was significantly attenuated by propranolol in LZRs only; no effects with propranolol treatment were seen in OZRs.…”

Paradoxical Activation of Endothelial Nitric Oxide Synthase by NADPH Oxidase

“…Concentration-response curves were then constructed to phenylephrine (PE) and subsequently to ACh in vessels precontracted with a submaximal concentration of PE. 26 …”

Vibration Disrupts Vascular Function in a Model of Metabolic Syndrome

“…However, these studies were primarily looking at α-1 adrenoreceptor mediated constriction 11,13) . Other studies have demonstrated that mesenteric arteries of obese rats are less sensitive to adrenoreceptor-mediated vasoconstriction, and that this decrease in sensitivity may occur to compensate for the reductions in NO-mediated vasodilation, particularly in younger rats (i.e., rats less than 18 wk of age 23) ). In addition, we have recently demonstrated that vibration reduces vascular responsiveness to α1-adrenoreceptor-and 5-hydroxytryptamine-induced vasoconstriction in resistance arteries from rat paws, and that this reduced responsiveness appears to be the result of endothelial-generated reactive oxygen species interfering with the ability of vascular smooth muscle to respond to vasoconstricting factors 16) .…”