Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity.

Abstract

Hypertension is often associated with insulin resistance, and several chemically diverse agents that increase insulin sensitivity attenuate the development of experimental hypertension. We undertook the present study to determine whether attenuation of hypertension by pioglitazone, a thiazolidinedione derivative that increases insulin sensitivity without increasing insulin secretion, is specifically related to its effect on insulin-mediated glucose uptake. Pioglitazone administered daily by oral gavage (20 mg/kg per day) for 3 weeks attenuated the development of hypertension in both the Dahl salt-sensitive (DS) rat (an insulin-resistant model of hypertension) and the one-kidney, one clip rat (a model of hypertension not associated with insulin resistance). Based on euglycemic I n humans, both epidemiologic and clinical evidence document an association between hypertension and resistance to insulin-stimulated glucose uptake. Although a number of putative mechanisms have been proposed, it is unclear whether insulin resistance, hyperinsulinemia, or both actually cause hypertension. 1To address this question, we and others have recently evaluated the effects of oral hypoglycemic agents on arterial pressure in several rat models of hypertension. Pioglitazone is a thiazolidinedione derivative that increases insulin sensitivity without stimulating endogenous insulin secretion. "10 This agent attenuates the development of hypertension in the DS rat 11 and also prevents increases in blood pressure in the rat caused by feeding high-carbohydrate or high-fat diets.1213 Ciglitazone and CS-045, other thiazolidinedione derivatives, also lower blood pressure in the insulin-resistant, obese Zucker rat. 17 Conversely, glyburide, a sulfonylurea antidiabetic agent, increases both plasma insulin concentrations and blood pressure in female (but not in male) stroke-prone SHR. 18The purpose of the present study was to define the relation between changes in insulin sensitivity and attenuation of hypertension. We have extended our studies in the DS rat to include the 1K1C Sprague-Dawley rat. In each model, we evaluated the effects of pioglitazone and metformin on both arterial pressure and insulin sensitivity, as assessed by the euglycemic insulin clamp technique. Methods Effects of Pioglitazone and Metformin on the Development of Hypertension and on Insulin Sensitivity in the DS RatWe have previously reported that pioglitazone attenuates the development of hypertension in the DS rat." Using an identical protocol in the present study we evaluated the effect of metformin on blood pressure in this animal model.Male DS rats (Brookhaven strain) were purchased from Harlan Sprague Dawley (Indianapolis, Ind) and arrived shortly after weaning. Initially, all animals were fed 0.45% NaCl (diet No. 88311, Teklad) for 1 week and subsequently a 3% NaCl diet (diet No. 89281, Teklad). The rats were housed in individual cages in a temperature-controlled (22°C) and light-controlled (12 hours on, 12 hours off) small-animal facility. All animals ...

Effect of an Insulin Sensitizer, Pioglitazone, on Hypertension in Fructose-Drinking Rats.

“…Therefore, it is suggested that pioglitazone exerts its antihypertensive effect by improving insulin sensitivity and also by another mechanism. In recent studies, pioglitazone showed a direct effect on vascular smooth muscle cells to inhibit calcium ion influx, resulting in the inhibition of blood vessel constriction and vascular cell growth and decreasing the blood pressure (27)(28)(29). In this study, however, the improvement of insulin resist ance rather than the direct effect of pioglitazone on arterial cells seems to contribute much to the blood pressure reduction.…”

PPARγ Agonist Rosiglitazone Improves Vascular Function and Lowers Blood Pressure in Hypertensive Transgenic Mice

“…[3][4][5][6]23,24 Similarly, others have demonstrated that the acute change in blood pressure and vascular function in rats caused by angiotensin II infusion (osmotic minipumps) or endothelin (deoxycorticosterone acetate [DOCA] salt) can be prevented by simultaneous treatment with TZDs. 25,26 This is the first study, to our knowledge, demonstrating that treatment with rosiglitazone can ameliorate lifelong renin-angiotensin-induced hypertension and extends the beneficial blood pressure effects of TZDs to a murine model of hypertension.…”

Troglitazone inhibits angiotensin II‐induced DNA synthesis and migration in vascular smooth muscle cells

“…This potent effect of troglitazone on All-induced signalling might contribute to the observed in vivo effects of troglitazone to prevent neointimal hyperplasia in the injured vessel and to lower blood pressure in some animal models of hypertension. Tro and related thiazolidinediones have been shown to attenuate hypertension an a variety of animal models [15,16]. As insulin sensitizers these agents could lower blood pressure indirectly by improving insulin resistance [17].…”