Pharmacological Inhibition of Mammalian Target of Rapamycin Attenuates Deoxycorticosterone Acetate Salt-Induced Hypertension and Related Pathophysiology: Regulation of Oxidative Stress, Inflammation, and Cardiovascular Hypertrophy in Male Rats.

ABSTRACT: The present study aimed to explore the contribution of mammalian target of rapamycin (mTOR) in deoxycorticosterone acetate (DOCA) salt-induced hypertension and related pathophysiological changes in cardiovascular and renal tissues. DOCA salt loading resulted in an increase in systolic blood pressure, diastolic blood pressure, and mean blood pressure along with the activity of ribosomal protein S6, the effector protein of mTOR. Treatment with rapamycin, the selective inhibitor of mTOR, initiated at the fourth week of DOCA- salt administration normalized the systolic blood pressure and attenuated ribosomal protein S6 activity in the heart, aorta, and kidney. Cardiac and vascular hypertrophy, oxidative stress, and infiltration of macrophages (CD68+), the marker of inflammation, were also reduced in rapamycin-treated, DOCA-salt, hypertensive rats. In addition, renal hypertrophy and dysfunction were also reduced with rapamycin-treated hypertensive rats. Moreover, these pathophysiological changes in DOCA-salt hypertensive rats were associated with increased NADPH oxidase (NOX) activity, gp91phox (formerly NOX2) expression, ERK1/2, and p38 MAPK activities in the heart, aorta, and kidney were minimized by rapamycin. These data indicate that mTOR plays an important role in regulating blood pressure and the development of cardiovascular and renal pathophysiological changes, most likely due to increased NOX expression/activity, ERK1/2, and p38 MAPK activity with macrophages infiltration in the heart, kidney, and aorta. Pharmacological inhibition of mTOR and related signaling pathways could serve as a novel target for the treatment of hypertension.

Effects of ethanol treatment on the neurogenic and endothelium-dependent relaxation of corpus cavernosum smooth muscle in the mouse.

The relaxation of cavernous smooth muscle is critical for inducing and maintaining a penile erection. The neurogenic- and endothelium-dependent relaxation of corpus cavernosum smooth muscle and the degenerative effect of subacute ethanol treatment on the endothelial cells of corpus cavernosum was investigated in mice. In the cavernous strips contracted with phenylephrine, electrical field stimulation (EFS), acetylcholine and exogenous nitric oxide (NO) induced relaxations in the control group. Ethanol treatment abolished the endothelium-dependent relaxations induced by acetylcholine but failed to alter the relaxation to EFS and NO. L-nitroarginine, a NO synthase inhibitor, reduced relaxations induced by EFS and acetylcholine, but not those induced by NO in control and ethanol-treated mice. L-arginine prevented the response inhibited by L-nitroarginine. ODQ, a guanylyl cyclase inhibitor, inhibited relaxations in response to EFS, NO and acetylcholine in control and ethanol-treated mice. Corpus cavernosum tissues were investigated using electron microscopy and endothelial damage was observed in ethanol-treated mice. These results suggest that ethanol impairs the endothelial function of corpus cavernosum in mouse, and it may lead to erectile dysfunction through a reduced NO release via endothelial impairment.