title: Chronic treatment with Ang-(1-7) reverses abnormal reactivity in the corpus cavernosum and normalizes diabetes-induced changes in the protein levels of ACE, ACE2, ROCK1, ROCK2 and omega-hydroxylase in a rat model of type 1 diabetes.
abstract: Angiotensin-(1-7) [Ang-(1-7)] may have beneficial effects in diabetes mellitus-induced erectile dysfunction (DMIED) but its molecular actions in the diabetic corpus cavernosum (CC) are not known. We characterized the effects of diabetes and/or chronic in vivo administration of Ang-(1-7) on vascular reactivity in the rat corpus cavernosum (CC) and on protein expression levels of potential downstream effectors of the renin-angiotensin-aldosterone system (RAAS) such as angiotensin-converting enzyme (ACE), ACE2, Rho kinases 1 and 2 (ROCK1 and ROCK2), and omega-hydroxylase, the cytochrome-P450 enzyme that metabolizes arachidonic acid to form the vasoconstrictor, 20-hydroxyeicosatetraenoic acid. Streptozotocin-treated rats were chronicically administered Ang-(1-7) with or without A779, a Mas receptor antagonist, during weeks 4 to 6 of diabetes. Ang-(1-7) reversed diabetes-induced abnormal reactivity to vasoactive agents (endothelin-1, phenylepherine, and carbachol) in the CC without correcting hyperglycemia. Six weeks of diabetes led to elevated ACE, ROCK1, ROCK 2, and omega-hydroxylase and a concomitant decrease in ACE2 protein expression levels that were normalized by Ang-(1-7) treatment but not upon coadministration of A779. These data are supportive of the notion that the beneficial effects of Ang-(1-7) in DMIED involve counterregulation of diabetes-induced changes in ACE, ACE2, Rho kinases, and omega-hydroxylase proteins in the diabetic CC via a Mas receptor-dependent mechanism.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait.
authors.forename: Mariam H M
authors.initials: MH
authors.lastname: Yousif
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait.
authors.forename: Batoul
authors.initials: B
authors.lastname: Makki
authors.affiliation: Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait.
authors.forename: Ahmed Z
authors.initials: AZ
authors.lastname: El-Hashim
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait.
authors.forename: Saghir
authors.identifier: 0000-0003-3177-946X
authors.initials: S
authors.lastname: Akhtar
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110 Safat, Kuwait.
authors.forename: Ibrahim F
authors.initials: IF
authors.lastname: Benter
mesh_terms: D000803:Angiotensin I / Q000627:therapeutic use*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D042926:Cytochrome P-450 CYP4A / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D004195:Disease Models, Animal; D007172:Erectile Dysfunction / Q000188:drug therapy; D008297:Male; D010413:Penis / Q000187:drug effects*; D010446:Peptide Fragments / Q000627:therapeutic use*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013311:Streptozocin; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D013311:Streptozocin; D000803:Angiotensin I; D042926:Cytochrome P-450 CYP4A; C578418:ROCK1 protein, rat; C580818:ROCK2 protein, rat; D054460:rho-Associated Kinases; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)