Enalapril improves impairment of SERCA-derived relaxation and enhancement of tyrosine nitration in diabetic rat aorta

• Published in: European journal of pharmacology 2007-02, Vol.556 (1), p.121-128
• Main Authors: Taguchi, Kumiko, Kobayashi, Tsuneo, Hayashi, Yuko, Matsumoto, Takayuki, Kamata, Katsuo
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Angiotensin II; Angiotensin II - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Aorta, Thoracic - drug effects; Aorta, Thoracic - physiopathology; Biological and medical sciences; Blood Glucose; Blood Pressure; Diabetes; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Enalapril - administration & dosage; Enalapril - pharmacology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Male; Medical sciences; Muscle Relaxation - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiopathology; Nitric Oxide - metabolism; Peroxynitrite; Peroxynitrous Acid - metabolism; Pharmacology. Drug treatments; Rats; Rats, Wistar; Relaxation; Sarco/endoplasmic reticulum Ca 2+-ATPase (SERCA); Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors; Sarcoplasmic Reticulum Calcium-Transporting ATPases - physiology; Smooth muscle; Thapsigargin - pharmacology; Tyrosine - metabolism
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2006.11.026

We investigated the involvement of angiotensin II and vascular smooth muscle sarco/endoplasmic reticulum Ca 2+-ATPase (SERCA) function in the impaired NO-induced relaxation seen in established streptozotocin-induced diabetes. Plasma angiotensin II levels, which were elevated in untreated diabetic rats (vs age-matched controls), were improved by treatment with the angiotensin-converting enzyme inhibitor enalapril. Systolic blood pressure was significantly decreased in chronic enalapril-treated diabetics (vs the other two groups). Intact aortae from diabetic rats and chronic angiotensin II-infused control rats, but not those from diabetic rats treated with enalapril, showed impaired endothelium-dependent relaxations to acetylcholine (vs controls). The relaxation induced by Angeli's Salt (a NO donor) was significantly impaired in endothelium-denuded aortae from diabetic rats (vs controls) but it was normalised by enalapril treatment. After preincubation with the irreversible SERCA inhibitor, thapsigargin, the relaxation induced by Angeli's Salt was significantly impaired in endothelium-denuded aortae from the controls, but not from the diabetics, and there was no significant difference between the thapsigargin-treated groups. Nitrotyrosine, an indirect marker of peroxynitrite, was markedly increased in aortic smooth muscle from diabetic rats, while chronic enalapril administration reduced this increase. These results suggest that in streptozotocin-induced diabetic rats, excessive angiotensin II production may lead to the generation of peroxynitrite and that this may in turn trigger a dysfunction of vascular smooth muscle SERCA. Enalapril improved the diabetes-related impairments.