NADPH oxidase inhibition attenuates oxidative stress but not hypertension produced by chronic ET-1.
Experiments were conducted to test the hypothesis that hypertension produced by chronic ET-1 infusion is mediated by NADPH oxidase-dependent superoxide production. Mean arterial pressure (MAP) was continuously monitored in male Sprague Dawley rats by telemetry. After baseline measurements, rats were placed on a high-salt diet (8% NaCl) and osmotic minipumps were implanted to infuse ET-1 (5 pmol/kg per minute intravenous) for 12 days. Control rats were maintained on the high-salt diet only. Separate groups of rats were also infused with ET-1 and given the superoxide dismutase mimetic, tempol (1 mmol/L), or the NADPH oxidase inhibitor, apocynin (1.5 mmol/L), in the drinking water. Infusion of ET-1 significantly increased MAP when compared with baseline values (132+/-3 versus 114+/-2 mm Hg, P<0.05). Neither tempol nor apocynin treatment had any effect on the increase in MAP produced by ET-1 when compared with baseline values (127+/-5 versus 113+/-2 and 130+/-3 versus 115+/-2 mm Hg, respectively). Plasma 8-isoprostane, an indicator of oxidative stress, was significantly increased in ET-1-infused rats compared with rats on a high-salt diet alone (128+/-33 versus 51+/-5 pg/mL; P<0.05). Both tempol and apocynin treatment significantly attenuated the ET-1-induced increase in plasma 8-isoprostane (72+/-10 and 61+/-6 pg/mL, respectively). Similarly, ET-1 infusion also significantly increased aortic superoxide production (chemiluminescence and dihydroethidium staining techniques), which was prevented by both tempol and apocynin. These data provide evidence that chronic ET-1 infusion increases vascular NADPH oxidase-dependent superoxide production but does not account for chronic ET-1-induced hypertension.
Elmarakby
Ahmed A
AA
Department of Pharmacology, Medical College of Georgia, Augusta 30912-2500, USA.
Loomis
E Dabbs
ED
Pollock
Jennifer S
JS
Pollock
David M
DM
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004334:Drug Administration Schedule; D019332:Endothelin-1 / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D007260:Infusion Pumps; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000098:Acetophenones; D000975:Antioxidants; D003497:Cyclic N-Oxides; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D013113:Spin Labels; D013481:Superoxides; C056165:acetovanillone; D019255:NADPH Oxidases; C001803:tempol