The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760

Abstract

Background Angiotensin converting enzyme 2 (ACE2) plays a crucial role in the infection cycle of SARS-CoV-2 responsible for formation of COVID-19 pandemic. In the cardiovascular system, the virus enters the cells by binding to the transmembrane form of ACE2 causing detrimental effects especially in individuals with developed hypertension or heart disease. Zofenopril, a H2S-releasing angiotensin-converting enzyme inhibitor (ACEI), has been shown to be effective in the treatment of patients with essential hypertension; however, in conditions of ACE2 inhibition its potential beneficial effect has not been investigated yet. Therefore, the aim of the study was to determine the effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats, an animal model of human essential hypertension and heart failure, under conditions of ACE2 inhibition induced by the administration of the specific inhibitor MLN-4760 (MLN). Results Zofenopril reduced MLN-increased visceral fat to body weight ratio although no changes in systolic blood pressure were recorded. Zofenopril administration resulted in a favorable increase in left ventricle ejection fraction and improvement of diastolic function regardless of ACE2 inhibition, which was associated with increased H2S levels in plasma and heart tissue. Similarly, the acute hypotensive responses induced by acetylcholine, L-NAME (NOsynthase inhibitor) and captopril (ACEI) were comparable after zofenopril administration independently from ACE2 inhibition. Although simultaneous treatment with zofenopril and MLN led to increased thoracic aorta vasorelaxation, zofenopril increased the NO component equally regardless of MLN treatment, which was associated with increased NO-synthase activity in aorta and left ventricle. Moreover, unlike in control rats, the endogenous H2S participated in maintaining of aortic endothelial function in MLN-treated rats and the treatment with zofenopril had no impact on this effect. Conclusions Zofenopril treatment reduced MLN-induced adiposity and improved cardiac function regardless of ACE2 inhibition. Although the concomitant MLN and zofenopril treatment increased thoracic aorta vasorelaxation capacity, zofenopril increased the participation of H2S and NO in the maintenance of endothelial function independently from ACE2 inhibition. Our results confirmed that the beneficial effects of zofenopril were not affected by ACE2 inhibition, moreover, we assume that ACE2 inhibition itself can lead to the activation of cardiovascular compensatory mechanisms associated with Mas receptor, nitrous and sulfide signaling.

The hepatoprotective effect of 4-phenyltetrahydroquinolines on carbon tetrachloride induced hepatotoxicity in rats through autophagy inhibition

“…The sample size for this study was determined using G*power 3.1 software [ 40 ], taking into consideration the different mean values obtained from previous studies in the literature [ 24 , 41 , 42 ]. A power analysis was conducted to determine the minimum sample size required to detect a statistically significant effect with effect size 0.55, α-error 0.05, and power 0.85 [ 43 ].…”

Ca2+-Dependent Cl− Channels in Vascular Tone Regulation during Aging

“…Since the [Cl − ]i of endothelial cells is slightly lower than that of VSMC, and the equilibrium potential for Cl − of endothelial cells is unknown, the activation of CaCCs leaves open two possibilities, i.e., that CaCCs may promote depolarization and nitric oxide (NO) release from intact endothelium, or that CaCCs may cause hyperpolarization (Figure 1). NO is produced by NOS from L-arginine, and various mechanisms deploy their beneficial effects through the activation of endothelial NOS [44][45][46][47] or the inhibition of inducible NOS [48]. TMEM16A on endothelial cells are localized not only at the plasma membrane but also at the mitochondrial membrane; thus, it is important to distinguish which channels are influenced while carrying out a study with CaCCs.…”