Impaired vagal reflex activity in insulin-resistant rats.

ABSTRACT

Insulin resistance, without frank diabetes, is associated with sudden cardiac death. We postulated that a potential mechanism for this association is autonomic dysfunction. Male Sprague-Dawley rats were randomized into one of two groups (a) insulin resistant (IR; n = 15), or (b) control (n = 11). Animals were made insulin resistant with a fructose-rich diet, whereas control animals received standard rat chow. Four weeks after randomization, arterial pressure and baroreceptor reflex were assessed. Baroreflex sensitivity was defined as the heart-rate response to acute blood pressure changes caused by nitroprusside (0.5-18 micrograms) or phenylephrine (0.2-3 micrograms). To determine the role of vagal stimulation specifically, each animal was randomized to receive atropine sulfate (1 mg/kg) or vehicle (normal saline) before administration of phenylephrine. Mean arterial pressure and fasting insulin concentrations were increased in the insulin-resistant group, whereas there were no differences in body weight, fasting glucose concentrations, or resting heart rate. Phenylephrine increased arterial blood pressure to a maximum of 54 +/- 2 mm Hg for control and 45 +/- 6 mm Hg for IR, p = 0.7. The maximal heart-rate change response to the increased blood pressure was markedly blunted in IR as compared with control (-88 +/- 12 beats/min for IR vs. -238 +/- 18 beats/min for control; p < 0.001). Thus the baroreflex sensitivity (BRS) was threefold less in IR versus the control group (-1.8 +/- 0.2 vs. -4.6 +/- 0.7 beats/min/mm Hg; p = 0.001). Pretreatment with atropine sulfate decreased the BRS in both groups, eliminating the difference between groups (-0.96 +/- 0.5 beats/min/mm Hg for control and -0.56 +/- 0.3 beats/min/mm Hg for IR; p = 0.2). Thus atropine sulfate caused the phenylephrine-induced heart rate and arterial blood pressure response to be equal between groups. On the other hand, BRS to nitroprusside-induced blood pressure changes were similar between groups. Insulin resistance, without the confounding factors of obesity, diabetes, and significant hypertension, is associated with a large reduction in vagal activity, which occurs via attenuation in reflex activity. In contrast, the insulin-resistant syndrome does not affect baroreflex sensitivity via sympathetic reflex.