Abstract 1139: BKCa Channel-Mediated Coronary Vasodilation is Significantly Impaired in Obese Ossabaw Swine with the Metabolic Syndrome
Our laboratory has demonstrated that obese animals with the metabolic syndrome display significant coronary vascular dysfunction. Although the mechanisms of this impairment have not been fully established, recent data suggest that obesity and insulin resistance diminish the function of large conductance Ca2+-activated K+ (BKCa) channels. Accordingly, the present study was designed to test the hypothesis that functional expression of coronary BKCa channels is decreased by the metabolic syndrome. Experiments were conducted in anesthetized, open-chest Ossabaw swine fed a normal maintenance diet (7% kcal from fat) or an atherogenic diet (45% kcal from fat and 2% cholesterol) for 9 weeks. This atherogenic diet induces many common features of the metabolic syndrome, including obesity, insulin resistance, impaired glucose tolerance, and dyslipidemia. In lean, control swine the BKCa channel opener NS1619 (3 – 100 μg) increased coronary blood flow dose-dependently from 0.61 ± 0.06 to 2.00 ± 0.32 ml/min/g (229 ± 38% increase). Coronary vasodilation to NS1619 was significantly attenuated in obese swine from 0.72 ± 0.16 to 1.08 ± 0.20 ml/min/g (53 ± 7% increase). Inhibition of BKCa channels with penitrem A (10 μg/kg, iv) attenuated vasodilation to NS1619 in lean pigs to a similar level as that observed in obese pigs (89 ± 30% increase). Whole cell patch clamp recordings demonstrated a significant reduction in outward current in vascular smooth muscle cells from obese vs. lean swine at potentials positive to +50 mV (e.g., 42% reduction at +100 mV), which is biophysically consistent with current mediated by BKCa channels. While BKCa channel function was diminished, Western blot analyses revealed a significant increase in BKCa channel protein expression (57% and 74% increases in α and β1-subunits, respectively) in coronary arteries from obese relative to lean swine. These data raise the possibility that the metabolic syndrome impairs BKCa channel trafficking or produces BKCa channels with less Ca2+/voltage-sensitivity. Further, these findings indicate that altered molecular and functional expression of BKCa channels could be an important mechanism of coronary microvascular dysfunction in the metabolic syndrome.