Effects of Radiation Therapy on Vascular Responsiveness

Abstract

The use of radiation therapy to inhibit vascular proliferative diseases has produced encouraging results in several clinical trials. However, little is known about the possible side effects of radiation on vascular responsiveness. Our goal was to study the in vitro vascular responses of the rabbit aorta to various agonists immediately after several regimens of radiation therapy administered at doses prescribed in clinical protocols and at two different dose rates. High-dose-rate radiation was administered either by brachytherapy, using a gamma source, iridium 192, or an external electron beam producing beta radiation. Low-dose-rate radiation was administered by brachytherapy using a liquid-filled balloon with the beta emitter 32P. Vascular reactivity after the various regimens of irradiation was determined using the organ bath pharmacology assay. Various agonists were applied to the rabbit aorta to produce full cumulative concentration-response curves. Radiation, administered using an external electron beam, did not alter endothelium-dependent relaxation of the aorta induced by acetylcholine. However, the use of a catheter-based system to deliver radiation disrupted the endothelial cell lining of the vessel, causing a lack of relaxation by acetylcholine. Therefore, to compare all modalities of radiation therapy on vascular responsiveness, the agonists used in this study are known to act directly on the smooth muscle. Radiation therapy had no effect on the contractile responses induced by the following agonists: phenylephrine and potassium chloride. Vascular dilatation induced by nitroglycerin, a nitric oxide donor, was unaffected by radiation therapy. The contractile response induced by des-Arg9-bradykinin, a kinin B1 receptor agonist, was significantly increased twofold to threefold by all types of irradiation under study. This enhanced response is attributable to an increase of mRNA levels coding for this receptor. In all cases, radiation therapy did not alter the effective concentration producing 50% of maximal responsiveness (EC50) and did not reduce the vascular responsiveness induced by agonists. Taken together, we conclude that radiation therapy does not hinder endothelium-independent vascular responsiveness and increases the kinin B1 receptor-mediated vasoconstriction.

Relaxation of the isolated human internal anal sphincter by sildenafil

“…The absence of effect of preoperative radiotherapy on the in vitro relaxation to sildenafil may be due to its direct mechanism of action on muscle PDE5, which is unrelated to neural release of mediators. A similar lack of influence of clinical doses of radiation has been reported for directly contracting and relaxing agents in isolated vascular smooth muscle29.…”

Ionizing radiation alters myofilament calcium sensitivity in vascular smooth muscle: potential role of protein kinase C

“…In contrast to the numerous studies demonstrating that irradiation depresses endothelium-dependent vasorelaxation, other investigations have shown that irradiation enhances vascular contractility in an endothelium-independent manner (20,39). This information suggests that, in addition to the indirect effect through a decrease in endothelial-dependent relaxation, a direct effect on vascular contractility may be important in the vascular anomalies induced by irradiation.…”

Cardiac Inflammation after Local Irradiation Is Influenced by the Kallikrein-Kinin System

“…Whole body irradiation with a dose of 2 Gy enhanced immediate B1 receptor expression in the heart (28). Ex vivo beta and gamma irradiation of rabbit aorta induced B1 gene expression within hours after irradiation, and the response to B1 activation was enhanced (29). To our knowledge, this is the first study to examine left ventricular expression of bradykinin receptors several months after irradiation.…”