Mechanisms of Hypertension in Diabetes

Hypertension in insulin resistance states is generally attributed to hyperinsulinemia, with resulting increases in renal sodium retention and/or sympa-thetic nervous system activity. However, recent data from our laboratory suggest that cellular insulin re-sistance, rather than hyperinsulinemia per se, may lead to hypertension. The basic tenet proposed in this review is that the common mechanism involved in the development of hypertension in both type I and type II diabetes mellitus is a deficiency of in-sulin at the cellular level. Recent observations sug-gest that impaired cellular response to insulin pre-disposes to increased vascular smooth muscle (VSM) tone (the hallmark of hypertension in the diabetic state). For example, recently reported studies from our laboratory demonstrate that insulin in physio-logical doses attenuates the vascular contractile re-sponse to phenylephrine, serotonin, and potassium chloride. Thus, insulin appears to normally modulate (attenuate) VSM contractile responses to vasoactive factors, and insulin resistance should accordingly be associated with enhanced vascular reactivity. Abnormal VSM cell calcium [Ca2+li homeostasis may be the nexus between insulin resistance and increased VSM tone. The genetically obese, hyper- insulinemic, insulin-resistant Zucker rat demon-strates increased vascular reactivity, reduced mem-brane Ca2++-ATPase activity, increased cellular Ca2++ levels, and a marked impairment in vascular smooth muscle Ca2++ efflux compared to lean controls. Insulin stimulates membrane Ca-ATPase, blocks Ca2++ currents, and Ca2++-driven action potentials. Thus, an insulin-resistant state as exists in the Zucker rat may be associated with increased Ca2++ influx through voltage-dependent sarcolemmal Ca2++ channels and/or decreased production or activation of the VSM cell Ca-ATPase pump. The resulting sustained rise in VSM [Ca2++]i could then account, in part, for increased VSM tone characteristic of hypertension associated with non-insulin- dependent diabetes mellitus. Accordingly, we pro-pose that insulin resistance is associated with al-tered VSM membrane Ca2++ transport leading to a more sustained rise in VSM [Ca2++]i which, in turn, is associated with enhanced VSM contraction. Am J Hypertens 1991;4:177–182