Chronic inhibition of endothelium-derived nitric oxide synthesis causes coronary microvascular structural changes and hyperreactivity to serotonin in pigs

Akira Ito, Kensuke Egashira, Toshiaki Kadokami, Yoshihiro Fukumoto, Tsuneo Takayanagi, Ryuichi Nakaike, Takeshi Kuga, Katsuo Sueishi, Hiroaki Shimokawa, Akira Takeshita

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Abstract

Background: Endothelium-derived nitric oxide (NO) is believed to regulate myocardial perfusion and structural changes in the vascular wall. Our objective was to determine whether chronic inhibition of NO synthesis causes structural and functional changes in coronary arteries. Methods and Results: Coronary vasomotor response was studied in pigs before and after chronic oral administration of the NO synthesis antagonist N(ω)-nitro-L-arginine methyl ester (L-NAME) 30 mg · kg-1 · d-1 for 2 weeks. Chronic L-NAME treatment increased (P<.01) arterial pressure but did not alter baseline coronary brood flow (CBF), epicardial coronary diameter, or heart rate. Chronic L-NAME treatment augmented (P<.01) the decrease in CBF in response to intracoronary serotonin (30 μg/kg) from 5±14% to 40±5% but did not alter the CBF response to prostaglandin F(2α). The serotonin-induced decrease in CBF after acute L-NAME administration was still less before (1.3±0.4%) than after chronic L-NAME treatment(51±6%). Chronic L-NAME treatment attenuated the increase in CBF with bradykinin (100 ng/kg) but did not alter the CBF response to nitroglycerin (10 μg/kg). Compared with intact pigs without L- NAME treatment, L-NAME treated pigs had significant thickening of the media in the microvessels (diameter, <300 μm) but not in the large epicardial vessels. Chronic intracoronary infusion of L-NAME at 3 mg · kg-1 · d-1 for 2 weeks, which did not produce arterial hypertension, caused similar microvascular medial thickening. Conclusions: These results indicate that chronic administration of L-NAME caused coronary microvascular structural changes and hyperreactivity to serotonin in pigs in vivo, suggesting an important role of defective NO synthesis in coronary microvascular disorders.

Original languageEnglish
Pages (from-to)2636-2644
Number of pages9
JournalCirculation
Volume92
Issue number9
DOIs
Publication statusPublished - Nov 1 1995

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Ito, A., Egashira, K., Kadokami, T., Fukumoto, Y., Takayanagi, T., Nakaike, R., Kuga, T., Sueishi, K., Shimokawa, H., & Takeshita, A. (1995). Chronic inhibition of endothelium-derived nitric oxide synthesis causes coronary microvascular structural changes and hyperreactivity to serotonin in pigs. Circulation, 92(9), 2636-2644. https://doi.org/10.1161/01.CIR.92.9.2636