Synergistic actions of enalapril and tempol during chronic angiotensin II-induced hypertension.
Experiments were designed to test the hypothesis that antioxidant treatment would increase the anti-hypertensive actions of endogenous kinins during angiotensin converting enzyme (ACE) inhibition. Four groups of rats, all given angiotensin II (Ang II) for 2 weeks, were studied: 1) control, 2) enalapril, 3) tempol or 4) both tempol and enalapril. Ang II significantly increased systolic blood pressure (BP) when compared with the baseline (170+/-8 vs. 128+/-4 mm Hg, P<0.05). Neither enalapril nor tempol alone was able to attenuate the elevation in BP (165+/-7 and 164+/-6 mm Hg, respectively). In contrast, combined administration of tempol and enalapril prevented the increase in BP (137+/-5 mm Hg). Plasma 8-isoprostane increased in Ang II-infused rats when compared with control untreated rats (69+/-14 vs. 23+/-0.5 pg/ml, P<0.05). Tempol alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane (29+/-6 and 34+/-7 pg/ml, respectively). In additional experiments, we used the bradykinin B(2) antagonist, icatibant to determine if increased B(2) receptor contributes to the anti-hypertensive effect of combined tempol and enalapril in Ang II-infused rats. Icatibant decreased the ability of this combination to lower arterial pressure. Additionally, a significant increase in B(1) receptor protein expression in renal cortex of Ang II-infused rats was observed compared to control suggesting that bradykinin receptor activation could account for the effect of enalapril to enhance the actions of tempol. These data support the hypothesis that combined reduction of superoxide along with enhanced endogenous kinins may facilitate blood pressure lowering in Ang II hypertension.
Elmarakby
Ahmed A
AA
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912, USA.
Williams
Jan M
JM
Imig
John D
JD
Pollock
Jennifer S
JS
Pollock
David M
DM
D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D002908:Chronic Disease; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000494:pharmacology* / Q000627:therapeutic use; D006861:Hydrogen Peroxide / Q000652:urine; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000187:drug effects; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D000975:Antioxidants; D003497:Cyclic N-Oxides; D018002:Receptors, Bradykinin; D013113:Spin Labels; D013481:Superoxides; D000804:Angiotensin II; C075750:8-epi-prostaglandin F2alpha; D004656:Enalapril; C065679:icatibant; D015237:Dinoprost; D006861:Hydrogen Peroxide; D001920:Bradykinin; C001803:tempol