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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:325.)
© 2007 American Heart Association, Inc.

Vascular Biology

A Causal Role for Endothelin-1 in the Vascular Adaptation to Skeletal Muscle Deconditioning in Spinal Cord injury

Dick H.J. Thijssen; Reinier Ellenkamp; Miriam Kooijman; Peter Pickkers; Gerard A. Rongen; Maria T.E. Hopman; Paul Smits

From the Department of Physiology, Institute of Fundamental and Clinical Movement Sciences (D.H.J.T., R.E., M.K., M.T.E.H.); and the Departments of Pharmacology-Toxicology (P.P., G.A.R., P.S.), Internal Medicine (G.A.R., P.S.), and Intensive Care (P.P.), Radboud University Nijmegen Medical Centre, Netherlands.

Correspondence to Paul Smits, MD, PhD, Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, Geert Grooteplein-Noord 21, 6525 EZ, Nijmegen, Netherlands. E-mail P.Smits{at}pharmtox.umcn.nl

Objective— Endothelin-1 (ET-1) contributes to the increased peripheral resistance in heart failure and hypertension. Physical inactivity is associated with cardiovascular disease and characterized by increased vascular tone. In this study, we assess the contribution of ET-1 to the increased vascular tone in the extremely deconditioned legs of spinal cord-injured (SCI) individuals before and after exercise training.

Methods and Results— In 8 controls and 8 SCI individuals, bilateral thigh blood flow was measured by plethysmography before and during the administration of an ET_A/ET_B-receptor blocker into the femoral artery. In SCI, this procedure was repeated after 6 weeks of electro-stimulated training. In a subset of SCI (n=4), selective ET_A-receptor blockade was performed to determine the role of the ET_A-receptors. In controls, dual ET-receptor blockade increased leg blood flow at the infused side (10%, P<0.05), indicating a small contribution of ET-1 to leg vascular tone. In SCI, baseline blood flow was lower compared with controls (P=0.05). In SCI, dual ET-receptor blockade increased blood flow (41%, P<0.001). This vasodilator response was significantly larger in SCI compared with controls (P<0.001). The response to selective ET_A-receptor blockade was similar to the effect of dual blockade. Electro-stimulated training normalized baseline blood flow in SCI and reduced the response to dual ET-receptor blockade in the infused leg (29%, P=0.04).

Conclusion— ET-1 mediates the increased vascular tone of extremely inactive legs of SCI individuals by increased activation of ET_A-receptors. Physical training reverses the ET-1-pathway, which normalizes basal leg vascular tone.

We examined the contribution of endothelin-1 to leg vascular tone in controls and in spinal cord injury (representing inactivity), before and after 6-weeks training. Endothelin-1 is responsible for the increased leg vascular tone in spinal cord injury. Interestingly, 6 weeks cycling training normalized leg vascular tone, partially mediated by the reduced contribution of endothelin-1.

Key Words: endothelin receptor • endothelium • exercise • cardiovascular disease • paraplegia

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