Nebivolol

Abstract

Cardiomyocyte necrosis with attendant microscopic scarring is a pathological feature of human hypertensive heart disease (HHD). Understanding the pathophysiological origins of necrosis is integral to its prevention. In a rat model of HHD associated with aldosterone/salt treatment (ALDOST), myocyte necrosis is attributable to oxidative stress induced by cytosolic-free [Ca]i and mitochondrial [Ca]m overloading in which the rate of reactive oxygen species generation overwhelms their rate of detoxification by endogenous Zn-based antioxidant defenses. We hypothesized that nebivolol (Neb), unlike another β1 adrenergic receptor antagonist atenolol (Aten), would have a multifaceted antioxidant potential based on its dual property as a β3 receptor agonist, which activates endothelial nitric oxide synthase to stimulate nitric oxide (NO) generation. NO promotes the release of cytosolic Zn sequestered inactive by its binding protein, metallothionein. Given the reciprocal regulation between these cations, increased [Zn]i reduces Ca entry and attendant rise in [Ca]i and [Ca]m. Herein, we examined the antioxidant and cardioprotectant properties of Neb and Aten in rats receiving 4 weeks ALDOST. Compared with untreated age-/sex-matched controls, ALDOST alone or ALDOST with Aten, Neb cotreatment induced endothelial nitric oxide synthase activation, NO generation and a marked increase in [Zn]i with associated decline in [Ca]i and [Ca]m. Attendant antioxidant profile at subcellular and cellular levels included attenuation of mitochondrial H2O2 production and lipid peroxidation expressed as reduced 8-isoprostane concentrations in both mitochondria and cardiac tissue. Myocyte salvage was expressed as reduced microscopic scarring and tissue collagen volume fraction. Neb is a multifaceted antioxidant with unique properties as cardioprotectant in HHD.