Kardiyak hipertrofide beta 3-AR'lerin NA+/K+-atpaz enzimi üzerindeki etkisi
Abstract
β3-ARs mediate negative inotropic effects, the physiological role of which is not clear in healthy heart. They are known to be upregulated in cardiac pathologies associated with sympathetic overactivation and their effects become more prominent. β3-ARs are shown to stimulate cardiac Na+/K+ pump via the reversal of an oxidative modification in the regulatory β1 subunit of the pump in healthy heart. However, their effects on the pump in the presence of a cardiac pathology are still not known. For this purpose, we aimed to investigate the effects of β3-ARs on Na+-K+ pump in hypertrophy related to sympathetic overstimulation. Firstly, we observed a decrease on Na+/K+ pump current and a slight increase on Na+ fluorescence on in vitro, short term (3 hours) noradrenaline incubated freshly isolated cardiomyocytes. When β3-AR agonist, BRL 37344 is added, pump current and Na+ fluorescence values returned to control values. To determine the in vivo effect, we treated rats with noradrenaline for 2 weeks and hypertrophy was induced. Cardiac function of these rats was investigated by the method of left ventricle pressure-volume analysis. Systolic function parameters ESP and dPmax, diastolic function parameter EDP were found to be increased and dPmin to be decrased in noradrenaline-treated rats with higher heart weight/body weight ratio. Heart rate was also increased in these rats. Moreover, load-independent contractility indexes PRSW, Ees and stiffness were increased in hypertrophic rats. On the other hand, BRL 37344 improved these parameters. However, end systolic, end diastolic ventricle volumes and stroke volume were not different among groups. Na+/K+ pump activity was also increased in hypertrophic rats. In addition to noradrenaline, when BRL 37344 was also added to the treatment, Na+/K+ pump activity returned to control values. Moreover, ANP which is an hypertrophy marker, was increased with hypertrophy and decreased with β3-AR stimulation. In hypertrophic rats, an increase was observed in β3-AR expression which was decreased by BRL treatment. On the other hand, NKA β1 subunit was not changed, however a slight increase in α1 subunit and a slight decrease in α2 subunit were determined. Our study which shows spesific in vivo β3-AR agonism has an antihypertrophic effect via the stimulation of Na+/K+ pump may be a promising therapeutic option for hypertrophy and provides better understanding of the pathophysiology of hypertrophy.