Inducible Nitric Oxide Synthase Attenuates Adrenergic Signaling in Alcohol Fed Rats

Abstract

Chronic, excessive alcohol consumption is associated with myocardial dysfunction in humans. The molecular mechanisms and cellular signaling pathways contributing to this cardiac dysfunction remain largely unknown. This study examined the effects of chronic alcohol consumption on myocardial function and cardiac myocyte signaling pathways. Adult male rats were fed a commercially prepared diet containing either ethanol (13 g/kg/d) or isocaloric control diet for 1 month. In vivo hemodynamics were measured in awake rats after inserting a catheter tip in the left ventricle under general anesthesia. Ventricular dysfunction was evidenced in awake, alcohol-fed rats by increased left ventricular end diastolic pressure, decreased systolic developed left ventricular pressure, and decreases in both positive and negative dp/dt compared with controls. Cardiac myocytes isolated from alcohol-fed rats also demonstrated an attenuated response to the beta-adrenergic agonist, isoproterenol, compared to controls. This response was significantly reversed by the nitric oxide synthase (NOS) inhibitor, N-monomethyl-L-arginine (L-NMMA). Western analyses confirmed inducible nitric oxide synthase (iNOS) protein synthesis in cardiac myocytes isolated from alcohol fed rats. It is therefore concluded that chronic alcohol ingestion results in iNOS-mediated attenuation of adrenergic signaling and depression in both systolic and diastolic function in rats.

Chronic alcohol consumption enhances myeloid-derived suppressor cells in B16BL6 melanoma-bearing mice

“…Specifically, the metastatic B16BL6 melanoma cells used in this study express significantly higher levels of inducible nitric oxide synthase than the parent B16 cell line and the released nitric oxide is known to decrease the cytotoxicity of B16BL6-specific T cells [44]. Inducible nitric oxide synthase, which is upregulated by alcohol consumption [2, 15], also catalyzes the production of peroxinitrites through an arginine-dependent mechanism. Peroxinitrites inhibit the production of IFN-γ in T cells [21], and could be involved in the decreased IFN-γ that we observed as a function of late stage tumor growth (Fig.…”

Alcoholic Cardiomyopathy: Pathophysiologic Insights

“…Increased cardiac tissue iNOS levels can lead to the formation of superoxide and peroxynitrite (16). Ethanol-fed animals had reduced systolic contractility and responses to adrenergic stimuli (isoproterenol) compared to control animals (42). Pharmacological inhibition of iNOS with N G –monomethyl-L-arginine reversed this depression in systolic function and adrenergic signaling.…”

“…Khanna et al demonstrated that inducible nitric oxide synthase (iNOS) is increased in cardiomyocytes isolated from rats exposed to 1 month of ethanol (13 g/day, Lieber-DeCarli diet) (42). Increased cardiac tissue iNOS levels can lead to the formation of superoxide and peroxynitrite (16).…”

P38 MAP Kinase Inhibitor Prevents Diastolic Dysfunction in Rats Following HIV gp120 Injection In vivo

“…The measurement of hemodynamics in awake rats provides the opportunity to quantitatively assess the cardiac effects of HIV gp120 in the most physiologically relevant state [21,22]. There were no demonstrable differences in either systolic (?dp/dt) or diastolic (-dp/dt) function at 1, 24, 48 or 72 h following a single IV injection of HIV gp120 (50 lg/ kg) (Figs.…”

“…1 Bar graphs comparing systolic contractile function (?dp/dt) in freely ambulatory, awake rats at 1, 24, 48 and 72 h following a single intravenous injection of either recombinant HIV gp120 (50 lg/ kg) or vehicle (saline) (P = NS; n = 6-8) Hours after gp120 injection -dp/dt (mmHg/s) Control gp120 Fig. 2 Bar graphs comparing diastolic contractile function (-dp/dt) in freely ambulatory, awake rats at 1, 24, 48 and 72 h (P = NS; n = 6-8) following a single intravenous injection of either recombinant HIV gp120 (50 lg/kg) or vehicle (saline) systemic blood pressure and heart rate measurements were determined by using 3 French polyurethane catheters that were advanced into the left ventricle via the right carotid artery or a femoral artery catheter using a powerlab/4SP analog-to-digital converter (AD Instruments, Oxfordshire, UK), as we previously reported [21,22].…”