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Insulin Resistance vs. Hyperinsulinemia in Hypertension: Insulin Regulation of Ca²⁺ Transport and Ca²⁺-Regulation of Insulin Sensitivity¹

Department of Nutrition The University of Tennessee Knoxville, TN 37996-1900

Hypertension in obesity and insulin resistance has been attributed to insulin stimulation of sympathetic neural output and renal sodium retention. However, recent data demonstrates a significant vasodilatory effect of insulin and suggests that vascular smooth muscle resistance to this action may instead be the cause of hypertension in insulin resistance. This concept is supported by the observation that pharmacological amplification of peripheral insulin sensitivity results in reduced arterial pressure. Insulin attenuates vasoconstrictor responses to pressor agonists and accelerates vascular smooth muscle relaxation, while these effects are blunted in obesity and insulin resistance. Insulin regulation of vasoconstriction and vascular relaxation appears to be secondary to regulation of intracellular Ca²⁺([Ca²⁺]i), as insulin attenuates both voltage- and receptor-mediated Ca²⁺ influx and stimulates both the transcription and activity of Ca²⁺-ATPase in vascular smooth muscle cells. Further, these effects are also blunted in insulin resistance. Although [Ca²⁺]i plays a poorly understood role in insulin signalling, increases beyond an optimal range results in impaired insulin sensitivity, possibly by Ca²⁺-inhibition of insulin-induced dephosphorylation of insulin-sensitive substrates. Consistent with this concept, ectopic over-expression of the agouti gene in the viable yellow (A^vy) mouse results in increased skeletal myocyte [Ca²⁺]i. Accordingly, increased [Ca²⁺]i in primary insulin target tissues appears to result in peripheral insulin resistance which then results in aberrant regulation of vascular smooth muscle [Ca²⁺]i and increases in arterial pressure.

KEY WORDS: • agouti • calcium • Ca-ATPase • insulin • insulin resistance • intracellular calcium • obesity

¹ Presented as part of the symposium "Insulin Resistance, Obesity and Hypertension" given at the Experimental Biology '94 meeting, Anaheim, CA, on April 27, 1994. This symposium was sponsored by the American Institute of Nutrition. Guest editor for this symposium was Michael B. Zemel, The University of Tennessee, Knoxville, TN.