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. W e tested whether coronary vasoconstrictor responses are augmented at t he sites of X-ray-induced intimal thickening in Gottingen miniature pi gs. Methods: In 17 pigs, a major branch of the left coronary artery wa s denuded with a balloon catheter. In 10 pigs, the denuded portion of the left coronary artery was selectively irradiated with 15 Gy of X-ra ys twice at 3 and 4 months after denudation (group 1). The remaining 7 pigs were not irradiated (group 2). The effects of intracoronary admi nistration of serotonin, histamine and phenylephrine on the coronary d iameter were studied 3 (3M) and 5 months (5M) after denudation. After the angiographical study at 5M, the vessels were isolated and isometri c tension was measured in an organ chamber. Results: The percent reduc tion in coronary diameter evoked with 10 mu g . kg(-1) of serotonin in creased from 39(s.e.m. 4)% before X-irradiation (3M) to 75(5)% after X -irradiation (5M) in group 1 (P < 0.01), while it did not differ in gr oup 2 [39(6)% at 3M vs. 33(8)% at 5M]. In group 1, serotonin-induced c oronary constriction was frequently accompanied by ischemic ECG change s. Histamine (10 mu g . kg(-1))-induced vasoconstriction was also augm ented 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 serot onin-induced hypercontraction in a dose-dependent fashion. In the in v itro studies, endothelium-dependent relaxation to serotonin was impair ed at the denuded site with (group 1) and without (group 2) X-irradiat ion to a similar extent. Isometric tension of medial smooth muscle dev eloped by serotonin was significantly greater at the denuded site with X-irradiation (group 1) than the control site and the denuded site wi thout X-irradiation (group 2) (P < 0.05). Intimal thickening was signi ficantly greater at the denuded sites with X-irradiation [group 1, 238 (45) mu m] than at the denuded sites without X-irradiation [group 2, 5 8(5) mu m] (P < 0.05). Conclusions: These results indicate that X-irra diation augments the coronary vasoconstrictor responses to autacoids, predominantly to serotonin, and that this augmentation is accompanied by enhanced intimal thickening. Serotonin-induced hypercontraction aft er X-irradiation resulted mainly from the hyperreactivity of medial sm ooth muscle.