Sodium nitrate supplementation prevents beneficial cardiac adaptations to running in female mice with few effects on male hearts.

While dietary nitrate supplements combined with aerobic activity are thought to enhance cardiac function, this has not been well investigated, and studies have used male animals only. We provided 7-9-month-old male and female mice with sodium nitrate (1 mM), running wheel access, both, or neither for 12 weeks and measured heart structure/function (echocardiography), contractions/calcium transients (ventricular myocytes), calcium handling genes and myofilament function (ventricles). In females, running increased heart mass and wall thickness. Nitrates alone had no impact, but nitrates plus running reduced global longitudinal strain, indicative of worse ventricular function. Running increased myocyte contraction and relaxation speed due to parallel changes in calcium transients in females. Interestingly, these benefits were abolished by nitrates but restored upon nitrate washout. Running also reduced Mg-ATPase activity in females at calcium > 1 µM, but not when given nitrates. In males, who ran less than females, nitrates (with or without running) had no effect on myocytes, but nitrates plus running prolonged isovolumic relaxation times. Mg-ATPase activity was unaffected at physiological calcium in males and there were few impacts on calcium handling in either sex. Thus, contrary to what is commonly thought, nitrate supplementation can have detrimental, if temporary, effects on cardiac contractility, especially in females.