Augmented Ouabain-Induced Vascular Response Reduces Cardiac Efficiency in Mice with Migraine-Associated Mutation in the Na, K-ATPase α-Isoform.

Heterozygous mice (α mice) for the migraine-associated mutation (G301R) in the Na,K-ATPase α-isoform have decreased expression of cardiovascular α-isoform. The α mice exhibit a pro-contractile vascular phenotype associated with decreased left ventricular ejection fraction. However, the integrated functional cardiovascular consequences of this phenotype remain to be addressed in vivo. We hypothesized that the vascular response to α-isoform-specific inhibition of the Na,K-ATPase by ouabain is augmented in α mice leading to reduced cardiac efficiency. Thus, we aimed to assess the functional contribution of the α-isoform to in vivo cardiovascular function of wild-type (WT) and α mice. Blood pressure, stroke volume, heart rate, total peripheral resistance, arterial dP/dt, and systolic time intervals were assessed in anesthetized WT and α mice. To address rate-dependent cardiac changes, cardiovascular variables were compared before and after intraperitoneal injection of ouabain (1.5 mg/kg) or vehicle during atrial pacing. The α mice showed an enhanced ouabain-induced increase in total peripheral resistance associated with reduced efficiency of systolic development compared to WT. When the hearts were paced, ouabain reduced stroke volume in α mice. In conclusion, the ouabain-induced vascular response was augmented in α mice with consequent suppression of cardiac function.