Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats.
Pulmonary hypertension (PH) causes right ventricular (RV) hypertrophy and, according to the extent of pressure overload, eventual heart failure. We tested the hypothesis that the mechanical stress in PH-RV impairs the vasoreactivity of the RV coronary microvessels of different sizes with increased superoxide levels. Five-week-old male Sprague-Dawley rats were injected with monocrotaline (n=126) to induce PH or with saline as controls (n=114). After 3 wk, coronary arterioles (diameter = 30-100 microm) and small arteries (diameter = 100-200 microm) in the RV were visualized using intravital videomicroscopy. We evaluated ACh-induced vasodilation alone, in the presence of N(omega)-nitro-L-arginine methyl ester (L-NAME), in the presence of tetraethylammonium (TEA) or catalase with or without L-NAME, and in the presence of SOD. The degree of suppression in vasodilation by L-NAME and TEA was used as indexes of the contributions of endothelial nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), respectively. In PH rats, ACh-induced vasodilation was significantly attenuated in both arterioles and small arteries, especially in arterioles. This decreased vasodilation was largely attributable to reduced NO-mediated vasoreactivity, whereas the EDHF-mediated vasodilation was relatively robust. The suppressive effect on arteriolar vasodilation by catalase was similar to TEA in both groups. Superoxide, as measured by lucigenin chemiluminescence, was significantly elevated in the RV tissues in PH. SOD significantly ameliorated the impairment of ACh-induced vasodilation in PH. Robust EDHF function will play a protective role in preserving coronary microvascular homeostasis in the event of NO dysfunction with increased superoxide levels.
Kajiya
Masahito
M
Department of Cardiovascular Physiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 5-1 Shikata-cho, 2-chome, Okayama, 700-8558, Japan. mkajiya@md.okayama-u.ac.jp
Hirota
Masanori
M
Inai
Yousuke
Y
Kiyooka
Takahiko
T
Morimoto
Taro
T
Iwasaki
Tatsuo
T
Endo
Kousuke
K
Mohri
Satoshi
S
Shimizu
Juichiro
J
Yada
Toyotaka
T
Ogasawara
Yasuo
Y
Naruse
Keiji
K
Ohe
Tohru
T
Kajiya
Fumihiko
F
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001685:Biological Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008833:Microcirculation / Q000378:metabolism / Q000503:physiopathology; D018715:Microscopy, Video; D016686:Monocrotaline; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D001685:Biological Factors; D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D013481:Superoxides; D009599:Nitroprusside; D009569:Nitric Oxide; D019789:Tetraethylammonium; D016686:Monocrotaline; D002374:Catalase; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester