Radiation induces endothelial dysfunction in murine intestinal arterioles via enhanced production of reactive oxygen species.
OBJECTIVE
Endothelial dysfunction and vascular dysregulation contribute to the pathological effects of radiation on tissues. The objectives of this study were to assess the acute effect of irradiation on acetylcholine (Ach)-induced dilation of gut submucosal microvessels.


RESULTS
Rats were exposed in vivo to 1 to 9 cGy in 3 fractions per week on alternate days for 3 successive weeks for a total dose of up to 2250 cGy. Submucosal microvessels were isolated after varying levels of irradiation. Diameters of isolated vessels were measured using videomicroscopy, and the dose-response relationship to Ach was determined. Dihydroethidine and 2', 7'-dichlorodihydrofluorescein diacetate fluorescent probes were used to assess reactive oxygen species (ROS) production. After constriction (30% to 50%) with endothelin, dilation to graded doses of Ach (10(-9)-10(-4) M) was observed in control vessels (maximal dilation [MD] 87+/-3%; n=7). However, Ach-induced dilation was reduced in vessels from irradiated rats (MD=3+/-9%; n=7; P= or <0.05 versus controls). Significant increases in superoxide and peroxides were observed in irradiated microvessels. Irradiated microvessels pretreated with superoxide dismutase-mimetic demonstrated significant improvement in Ach-induced vasodilation compared with irradiation alone, suggesting that superoxide contributes to impaired dilation to Ach after irradiation.


CONCLUSIONS
Radiation induces acute microvascular dysfunction in the resistance arterioles of the intestine. Enhanced ROS contribute to this dysfunction and therefore may represent a novel therapeutic target to minimize radiation toxicity in the gut.
Hatoum
Ossama A
OA
Division of Cardiovascular Medicine, Froedtert Memorial Lutheran Hospital, VA Medical Center, Medical College of Wisconsin, Milwaukee, WI, USA. ohatoum@mcw.edu
Otterson
Mary F
MF
Kopelman
Doron
D
Miura
Hiroto
H
Sukhotnik
Igor
I
Larsen
Brandon T
BT
Selle
Rebecca M
RM
Moulder
John E
JE
Gutterman
David D
DD
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D016166:Free Radical Scavengers / Q000494:pharmacology; D007422:Intestines / Q000098:blood supply; D008665:Metalloporphyrins / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D011833:Radiation Injuries, Experimental / Q000378:metabolism* / Q000473:pathology*; D011837:Radiation-Protective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013113:Spin Labels; D014652:Vascular Diseases / Q000378:metabolism* / Q000473:pathology*; D014664:Vasodilation / Q000187:drug effects / Q000528:radiation effects; D014665:Vasodilator Agents / Q000494:pharmacology
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; D013113:Spin Labels; D014665:Vasodilator Agents; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D009569:Nitric Oxide; D000109:Acetylcholine; C001803:tempol