In vivo administration of KCNQ channel modulators influences blood pressure and mesenteric vascular resistance in rats

Abstract

Recent work from our laboratory has shown that KCNQ channels are expressed in vascular smooth muscle cells where they contribute to vasopressin‐induced Ca2+ signaling. Suppression of KCNQ currents by vasopressin or pharmacological agents leads to membrane depolarization and activation of L‐type Ca2+ channels. To determine whether inhibition or activation of vascular KCNQ channels influences mesenteric vascular resistance (MVR) and mean arterial pressure (MAP) in vivo, adult Sprague‐Dawley rats were anesthetized with thiobutabarbital (125 mg/kg) and instrumented with femoral venous and arterial catheters for drug administration and arterial pressure determination. A perivascular blood flow probe was placed around the superior mesenteric artery. The KCNQ channel activator (flupirtine) or the inhibitor (linopirdine) was then administered in increasing concentrations (0.01 – 3.0 mg/kg i.v.). Flupirtine produced significant dose‐dependent decreases in MAP and MVR. Flupirtine (3.0 mg/kg) caused a 28.9 ± 1.2 mmHg decrease in MAP and a 33.5% decrease in MVR. In contrast, linopirdine produced dose‐dependent increases in MAP and MVR. A maximally effective concentration of linopirdine (1.0 mg/kg) produced a 9.9 ± 1.3 mmHg increase in MAP and a 19.2% increase in MVR. Flupirtine (3.0 mg/kg) also caused a modest, but significant decrease in HR of 26.3 ± 3.7 beat/min. Our results indicate that KCNQ channels contribute to tonic modulation of mesenteric vascular resistance and blood pressure. This work was supported by the NHLBI (R01 HL070670 to KLB) and the AHA (0715618Z to ARM).