(Circulation. 1995;92:2636-2644.)
© 1995 American Heart Association, Inc.
Articles |
Chronic Inhibition of Endothelium-Derived Nitric Oxide Synthesis Causes Coronary Microvascular Structural Changes and Hyperreactivity to Serotonin in Pigs
From the Research Institute of Angiocardiology and Cardiovascular Clinic and the First Department of Pathology (K.S.), Kyushu University School of Medicine, Fukuoka, Japan.
Correspondence to Kensuke Egashira, MD, PhD, The Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.
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
-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 blood 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 F2
. 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.
Key Words: microcirculation • endothelium-derived factors • nitric oxide • coronary disease • remodeling
This article has been cited by other articles:
 |
|
 |
|
  K. K. Naka, A. C. Tweddel, S. N. Doshi, J. Goodfellow, and A. H. Henderson Flow-mediated changes in pulse wave velocity: a new clinical measure of endothelial function Eur. Heart J., February 1, 2006; 27(3): 302 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Masaki, B. Takase, K. Satomura, T. Akima, Y. Matsushima, H. Hosaka, A. Hamabe, A. Kurita, and F. Ohsuzu Provocation of Microvessel Spasm by Low-Dose Acetylcholine in Patients with Suspected Coronary Artery Disease: Two Case Reports Angiology, March 1, 2005; 56(2): 211 - 216. [Abstract] [PDF]
|
|
|
|
 |
|
 H. Hong, S. Aksenov, X. Guan, J. T. Fallon, D. Waters, and C. Chen Remodeling of Small Intramyocardial Coronary Arteries Distal to a Severe Epicardial Coronary Artery Stenosis Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2059 - 2065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Fitch, R. Vergona, M. E. Sullivan, and Y.-X. Wang Nitric oxide synthase inhibition increases aortic stiffness measured by pulse wave velocity in rats Cardiovasc Res, August 1, 2001; 51(2): 351 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rodriguez-Porcel, A. Lerman, E. L. Ritman, S. H. Wilson, P. J. M. Best, and L. O. Lerman Altered Myocardial Microvascular 3D Architecture in Experimental Hypercholesterolemia Circulation, October 24, 2000; 102(17): 2028 - 2030. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Miyao, K. Kugiyama, H. Kawano, T. Motoyama, H. Ogawa, M. Yoshimura, T. Sakamoto, and H. Yasue Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina J. Am. Coll. Cardiol., August 1, 2000; 36(2): 432 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Shi, F. Hu, W. Kassouf, and R. P. Michel Altered reactivity of pulmonary vessels in postobstructive pulmonary vasculopathy J Appl Physiol, January 1, 2000; 88(1): 17 - 25. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Usui, K. Egashira, S. Kitamoto, M. Koyanagi, M. Katoh, C. Kataoka, H. Shimokawa, and A. Takeshita Pathogenic Role of Oxidative Stress in Vascular Angiotensin-Converting Enzyme Activation in Long-Term Blockade of Nitric Oxide Synthesis in Rats Hypertension, October 1, 1999; 34(4): 546 - 551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. W. Watts and G. D. Fink 5-HT2B-receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H944 - H952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Goodfellow, M. F Bellamy, S. T Gorman, M. Brownlee, M. W Ramsey, M. J Lewis, D. P Davies, and A. H Henderson Endothelial function is impaired in fit young adults of low birth weight Cardiovasc Res, December 1, 1998; 40(3): 600 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F Bellamy, J. Goodfellow, A. C Tweddel, F. D.J Dunstan, M. J Lewis, and A. H Henderson Syndrome X and endothelial dysfunction Cardiovasc Res, November 1, 1998; 40(2): 410 - 417. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Katoh, K. Egashira, M. Usui, T. Ichiki, H. Tomita, H. Shimokawa, H. Rakugi, and A. Takeshita Cardiac Angiotensin II Receptors Are Upregulated by Long-Term Inhibition of Nitric Oxide Synthesis in Rats Circ. Res., October 5, 1998; 83(7): 743 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tomita, K. Egashira, M. Kubo-Inoue, M. Usui, M. Koyanagi, H. Shimokawa, M. Takeya, T. Yoshimura, and A. Takeshita Inhibition of NO Synthesis Induces Inflammatory Changes and Monocyte Chemoattractant Protein-1 Expression in Rat Hearts and Vessels Arterioscler. Thromb. Vasc. Biol., September 1, 1998; 18(9): 1456 - 1464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Usui, T. Ichiki, M. Katoh, K. Egashira, and A. Takeshita Regulation of Angiotensin II Receptor Expression by Nitric Oxide in Rat Adrenal Gland Hypertension, September 1, 1998; 32(3): 527 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tomita, K. Egashira, Y. Ohara, M. Takemoto, M. Koyanagi, M. Katoh, H. Yamamoto, K. Tamaki, H. Shimokawa, and A. Takeshita Early Induction of Transforming Growth Factor-ß via Angiotensin II Type 1 Receptors Contributes to Cardiac Fibrosis Induced by Long-term Blockade of Nitric Oxide Synthesis in Rats Hypertension, August 1, 1998; 32(2): 273 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Takemoto, K. Egashira, H. Tomita, M. Usui, H. Okamoto, A. Kitabatake, H. Shimokawa, K. Sueishi, and A. Takeshita Chronic Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade : Effects on Cardiovascular Remodeling in Rats Induced by the Long-term Blockade of Nitric Oxide Synthesis Hypertension, December 1, 1997; 30(6): 1621 - 1627. [Abstract] [Full Text]
|
|
|
|
|
|
H. Kawaguchi, W. S. Shin, Y. Wang, M. Inukai, M. Kato, Y. Matsuo-Okai, A. Sakamoto, Y. Uehara, Y. Kaneda, and T. Toyo-oka In Vivo Gene Transfection of Human Endothelial Cell Nitric Oxide Synthase in Cardiomyocytes Causes Apoptosis-Like Cell Death : Identification Using Sendai Virus–Coated Liposomes Circulation, May 20, 1997; 95(10): 2441 - 2447. [Abstract] [Full Text]
|
|
|
|
|
|
T. Kadokami, K. Egashira, K. Kuwata, Y. Fukumoto, T. Kozai, H. Yasutake, T. Kuga, H. Shimokawa, K. Sueishi, and A. Takeshita Altered Serotonin Receptor Subtypes Mediate Coronary Microvascular Hyperreactivityin Pigs With Chronic Inhibitionof Nitric Oxide Synthesis Circulation, July 15, 1996; 94(2): 182 - 189. [Abstract] [Full Text]
|
|