angiotensin-i and Alcoholism

Angiotensin converting enzyme plays a key role in the regulation of blood pressure and inhibitors of the enzyme are effective antihypertensive agents. An association between hypertension and alcohol abuse has long been recognized and manipulations of the renin-angiotensin system in laboratory animals has been shown to alter their consumption of ethanol. Procedures that decrease the renin-angiotensin system increase ethanol consumption. Paradoxically, inhibitors of angiotensin converting enzyme also diminish drinking. Several possible explanations for this observation have been proposed. However, observations on the relationship between stress-induced drinking and the antidipsogenic action of a fragment of adrenocorticotropic hormone suggest another possibility: angiotensin converting enzyme may be involved in the metabolism of this peptide and thereby exert an influence on drinking behavior.

Topics: Alcohol Drinking; Alcoholism; Amino Acid Sequence; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Humans; Male; Molecular Sequence Data; Rats; Rats, Inbred Strains; Rats, Sprague-Dawley; Renin-Angiotensin System; Stress, Psychological

The brain renin-angiotensin system (RAS) has recently been implicated in the development of substance abuse and addiction. However, the integrative roles of the two counter-regulating RAS arms, including the ACE1/Ang II/AT1R axis and the ACE2/Ang(1-7)/MasR axis, in alcohol addiction remain unclear. Using the 20% ethanol intermittent-access two-bottle-choice (IA2BC) paradigm, we observed significant alcohol preference and addictive behaviors in rats. Additionally, we observed significant disruption in the RAS and redox homeostasis in the ventral tegmental area (VTA), as indicated by upregulation of ACE1 activities, Ang II levels, AT1R expression, and glutathione disulfide contents, as well as downregulation of ACE2 activities, Ang(1-7) levels, MasR expression and glutathione content. Moreover, dopamine accumulated in the VTA and nucleus accumbens of IA2BC rats. Intra-VTA infusion of the antioxidant tempol substantially attenuated RAS imbalance and addictive behaviors. Intra-VTA infusion of the ACE1 inhibitor captopril significantly reduced oxidative stress, alcohol preference, addictive behaviors, and dopamine accumulation, whereas intra-VTA infusion of the ACE2 inhibitor MLN4760 had the opposite effects. The anti-addictive effects of the ACE2/Ang(1-7)/MasR axis were further observed using intra-VTA infusion of Ang(1-7) and a MasR-specific antagonist A779. Therefore, our findings suggest that excessive alcohol intake causes RAS imbalance via oxidative stress, and that a dysregulated RAS in the VTA contributes to alcohol addiction by stimulating oxidative stress and dopaminergic neurotransmission. Breaking the vicious cycle of RAS imbalance and oxidative stress using brain-permeable antioxidants, ACE1 inhibitors, ACE2 activators, or Ang(1-7) mimetics thus represents a promising strategy for combating alcohol addiction.

Topics: Alcoholism; Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Antioxidants; Dopamine; Oxidative Stress; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Rats; Renin-Angiotensin System

We have altered the method for measuring plasma renin concentration (P.R.C.) originated by Haas, et al (7) by using radioimmunoassay of angiotensin I and avoiding the addition of extrinsic renin substrate. Thus modified, the method gives values for P.R.A. (plasma renin activity), P.R.C. (plasma renin concentration), and also P.R.R. (plasma renin reactivity), which is the rate of reaction of renin substrate in the plasma with added extrinsic renin. By applying this modified method to a wide variety of plasma samples and independently measuring plasma renin substrate concentration (P.R.S.) in the same samples, we found a good correlation between P.R.R. and P.R.S. Our results indicate that the rate of the renin - renin substrate reaction in human plasma is proportional to renin substrate concentration over a wide range of values up to 5000 ng angiotensin I/ml or higher. Thus, first order reaction kinetics with respect to substrate concentration is followed even at high substrate levels and the Km must be high. An additional finding was that pregnant women have elevated P.R.C. levels in contrast with women taking oral contraceptives who have P.R.C. levels lower than normal.

Topics: Alcoholism; Angiotensin I; Angiotensinogen; Contraceptives, Oral; Depression, Chemical; Diabetes Mellitus; Female; Humans; Liver Cirrhosis; Male; Pregnancy; Radioimmunoassay; Renin; Sex Factors