Augmentation of coronary responsiveness to serotonin at the site of X-ray-induced intimal thickening in miniature pigs.
OBJECTIVE
X-irradiation is known to enhance atherosclerotic change. We tested whether coronary vasoconstrictor responses are augmented at the sites of X-ray-induced intimal thickening in Göttingen miniature pigs.


METHODS
In 17 pigs, a major branch of the left coronary artery was denuded with a balloon catheter. In 10 pigs, the denuded portion of the left coronary artery was selectively irradiated with 15 Gy of X-rays twice at 3 and 4 months after denudation (group 1). The remaining 7 pigs were not irradiated (group 2). The effects of intracoronary administration of serotonin, histamine and phenylephrine on the coronary diameter were studied 3 (3M) and 5 months (5M) after denudation. After the angiographical study at 5M, the vessels were isolated and isometric tension was measured in an organ chamber.


RESULTS
The percent reduction in coronary diameter evoked with 10 micrograms.kg-1 of serotonin increased from 39(s.e.m. 4)% before X-irradiation (3M) to 75(6)% after X-irradiation (5M) in group 1 (P < 0.01), while it did not differ in group 2 [39(6)% at 3M vs. 33(8)% at 5M[ [39(6)% at 3M vs. 33(8)% at 5M]. In group 1, serotonin-induced coronary constriction was frequently accompanied by ischemic ECG changes. Histamine (10 micrograms.kg-1)-induced vasoconstriction was also augmented but to a smaller degree [47(6)% at 3M vs. 62(4)% at 5M; P < 0.05] in group 1, while it remained unchanged in group 2[52(5)% at 3M vs. 44(7)% at 5M]. Phenylephrine did not cause detectable contraction in either group at 3M or 5M. Methysergide and ketanserin attenuated serotonin-induced hypercontraction in a dose-dependent fashion. In the in vitro studies, endothelium-dependent relaxation to serotonin was impaired at the denuded site with (group 1) and without (group 2) X-irradiation to a similar extent. Isometric tension of medial smooth muscle developed by serotonin was significantly greater at the denuded site with X-irradiation (group 1) than the control site and the denuded site without X-irradiation (group 2) (P < 0.05). Intimal thickening was significantly greater at the denuded sites with X-irradiation [group 1, 238(45) microns] than at the denuded sites without X-irradiation [group 2, 58(5) microns] (P < 0.05).


CONCLUSIONS
These results indicate that X-irradiation augments the coronary vasoconstrictor responses to autacoids, predominantly to serotonin, and that this augmentation is accompanied by enhanced intimal thickening. Serotonin-induced hypercontraction after X-irradiation resulted mainly from the hyperreactivity of medial smooth muscle.
Mitsuoka
W
W
Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Egashira
S
S
Tagawa
H
H
Kuga
T
T
Hayashi
Y
Y
Yamada
A
A
Tomoike
H
H
Nakamura
M
M
Takeshita
A
A
D000818:Animals; D003329:Coronary Vasospasm / Q000139:chemically induced*; D003331:Coronary Vessels / Q000187:drug effects; D004730:Endothelium, Vascular; D006632:Histamine / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008784:Methysergide / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000139:chemically induced*; D010656:Phenylephrine / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature; D017539:Tunica Intima / Q000528:radiation effects*; D014661:Vasoconstriction / Q000187:drug effects; D014965:X-Rays
D012702:Serotonin Antagonists; D010656:Phenylephrine; D012701:Serotonin; D006632:Histamine; D007650:Ketanserin; D008784:Methysergide