Augmented Contractile Function and Abnormal Ca²⁺ Handling in the Aorta of Zucker Obese Rats With Insulin Resistance Free

To investigate the role of hyperinsulinemia/msulin resistance in vasomotor tone regulation, we studied the effects of vasoactive substances on tension and intracellular free calcium concentration ([Ca²⁺]_i) of aortic smooth muscle derived from rats that were made hyperinsulinemic by insulin infusion and from Zucker obese rats with insulin resistance. The tension and [Ca²⁺]_i of fura 2-loaded aortic strip preparations without endothelium were simultaneously measured by using a fluorimeter. Ten male Wistar rats received a continuous subcutaneous infusion of insulin (18 nmol · kg⁻¹ · day⁻¹) for 2 weeks with osmotic minipumps (INS group). A control group of 10 rats received vehicle. The plasma imnranoreactive insulin concentration in the INS group increased to 930 ± 54 Pmol/1. The increase in [Ca²⁺]_i and tension by KCI and phenylephrine (PE) were lower in the INS group without alteration of the [Ca²⁺]_itension relationship. The responses to serotonin (5-HT) in the INS group were similar to those in the control group. In contrast, responses to KCI, PE, and 5-HT were markedly enhanced in Zucker obese rats compared with those in Zucker lean rats. The pretreatment of aortic preparations from lean rats with Bay K 8644 significantly enhanced the responses to KCI to the level observed in the preparations from obese rats; however, Bay K 8644 failed to affect the responses to KCI in obese rats. These results suggest that enhanced vascular contractile responses to vasoactive substances, possibly due to altered function of the voltage-dependent Ca²⁺ channel in vascular smooth muscle, may play an important role in the pathogenesis of hypertension in the insulin resistance syndrome.