Abstract P075: Neuronal Nitric Oxide Synthase Contributes to the Beneficial Cardiac Effects of Exercise

Abstract

Exercise results in beneficial adaptations to the heart. These adaptations are observed at the level of the cardiomyocyte as increased Ca2+ cycling through the sarcoplasmic reticulum (SR) and greater fractional shortening. Interestingly, these adaptations are similar to the contractile effects of neuronal nitric oxide synthase (NOS1) signaling. Thus our objective is to determine if the exercise induced adaptations at the level of the cardiomyocyte are NOS1 mediated. After an 8 week high-intensity aerobic interval training program, exercise (Ex) mice had a higher VO2max, greater citrate synthase activity, decreased weight, increased heart-to-body ratio (P<0.05), but similar heart-to-tibia ratio compared to sedentary (Sed) mice. Isolated ventricular myocytes from the Ex mice exhibited larger Ca2+ transient and shortening amplitudes and faster Ca2+ transient decline rates (RT50) compared to Sed myocytes (P<0.05). There was also greater NOS1 expression levels in Ex ventricular myocytes (P<0.05 vs Sed). The greater NOS1 expression was observed functionally in myocyte contraction. That is, acute inhibition of NOS1 by S-methyl-L-thiocitrulline (SMLT) resulted in a greater reduction in Ca2+ transient amplitude, Ca2+ transient RT50, shortening amplitude, SR Ca2+ load, and SR Ca2+ fractional release in Ex versus Sed (P<0.05). Furthermore, acute NOS1 inhibition (SMLT) normalized the Ex induced increase in contraction (Ca2+ transients and shortening) and Ca2+ decline rates to Sed levels. These data demonstrate that the enhanced Ca2+ cycling through the SR observed after a training period is, in part, due to NOS1 signaling. Thus, NOS1 is a major contributor to the increased contractile amplitudes and relaxation observed with exercise. Hence, mimicking the beneficial effects of exercise to the heart may be obtainable by enhancing NOS1 signaling. This pathway may be a novel therapeutic for cardiac patients that are unable/unwilling to exercise.