Possible role of exogenous cAMP to improve vascular endothelial dysfunction in hypertensive rats.
The study has been designed to investigate the effect of 8-Br-cAMP, an activator of protein kinase A, in hypertension-induced vascular endothelial dysfunction. Rats were uninephroctomized and desoxycortisone acetate (DOCA) (40 mg/kg, s.c.) was administered to rats to produce hypertension (mean arterial blood pressure > 140 mmHg). Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. The expression of mRNA for p22phox and eNOS was assessed by using reverse transcriptase-polymerase chain reaction. Serum thiobarbituric acid reactive substances concentration and aortic superoxide anion concentration were estimated to assess oxidative stress. 8-Br-cAMP (5 mg/kg, i.p.) or atorvastatin (30 mg/kg, p.o.) prevented hypertension-induced attenuation of acetylcholine-induced endothelium-dependent relaxation, impairment of vascular endothelial lining, decrease in expression of mRNA for endothelial nitric oxide synthase (eNOS), serum nitrite/nitrate concentration and increase in expression of mRNA for p22phox, superoxide anion and serum TBARS. The ameliorative effect of 8-Br-cAMP was prevented by N-nitro-L-arginine methyl ester (25 mg/kg, i.p.) and glibenclamide (30 mg/kg, i.p.). It may be concluded that 8-Br-cAMP may stimulate expression and activity of eNOS and suppress expression of p22phox subunit of NADPH oxidase to reduce oxidative stress and subsequently improve vascular endothelial dysfunction.
Shah
Dhvanit I
DI
Department of Pharmaceutical Sciences & Drug Research, Faculty of Medicine, Punjabi University, Patiala 147002, Punjab, India. dhvanitshah@gmail.com
Singh
Manjeet
M
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000097:blood; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects*; D006538:Heptanoic Acids / Q000008:administration & dosage; D006973:Hypertension / Q000150:complications / Q000188:drug therapy*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009566:Nitrates / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D011758:Pyrroles / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014664:Vasodilation / Q000187:drug effects
D006538:Heptanoic Acids; D009566:Nitrates; D009573:Nitrites; D011758:Pyrroles; D017392:Thiobarbituric Acid Reactive Substances; D013481:Superoxides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000069059:Atorvastatin; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C515768:Cyba protein, rat