Taming the "sleeping giant": the role of endothelin-1 in the regulation of skeletal muscle blood flow and arterial blood pressure during exercise

Abstract

The cardiovascular response to exercise is governed by a combination of vasodilating and vasoconstricting influences that optimize exercising muscle perfusion while protecting mean arterial pressure (MAP). The degree to which endogenous endothelin (ET)-1, the body's most potent vasoconstrictor, participates in this response is unknown. Thus, in eight young (24 ± 2 yr), healthy volunteers, we examined leg blood flow, MAP, tissue oxygenation, heart rate, leg arterial-venous O(2) difference, leg O(2) consumption, pH, and net ET-1 and lactate release at rest and during knee extensor exercise (0, 5, 10, 15, 20, and 30 W) before and after an intra-arterial infusion of BQ-123 [ET subtype A (ET(A)) receptor antagonist]. At rest, BQ-123 did not evoke a change in leg blood flow or MAP. During exercise, net ET-1 release across the exercising leg increased approximately threefold. BQ-123 increased leg blood flow by ~20% across all work rates (changes of 113 ± 76, 176 ± 83, 304 ± 108, 364 ± 130, 502 ± 117, and 570 ± 178 ml/min at 0, 5, 10, 15, 20, and 30 W, respectively) and attenuated the exercise-induced increase in MAP by ~6%. The increase in leg blood flow was accompanied by a ~9% increase in leg O(2) consumption with an unchanged arterial-venous O(2) difference and deoxyhemoglobin, suggesting a decline in intramuscular efficiency after ET(A) receptor blockade. Together, these findings identify a significant role of the ET-1 pathway in the cardiovascular response to exercise, implicating vasoconstriction via the ET(A) receptor as an important mechanism for both the restraint of blood flow in the exercising limb and maintenance of MAP in healthy, young adults.

Fig. 1.

Experimental protocol. Arrows indicate points at which leg blood flow was recorded and arterial and venous blood samples were obtained. KE, knee extensor.

Fig. 2.

Leg blood flow (top), mean arterial pressure (MAP; middle), and leg vascular conductance (bottom) at rest and exercise during continuous infusion of saline and BQ-123. The intensity-dependent increase in leg blood flow and vascular conductance were enhanced, along with an attenuation in the MAP response during endothelin (ET) subtype A (ET_A) receptor inhibition. *Significant difference from saline (P < 0.05).

Fig. 3.

BQ-123-induced changes in leg blood flow (top), MAP (middle), and leg vascular conductance (bottom) at rest and during exercise. The contribution of the ET_A receptor to leg vascular tone and MAP was enhanced only during exercise in an intensity-dependent manner. +Significant difference from BQ-induced changes at rest (P < 0.05).

Fig. 4.

Leg blood flow and MAP at multiple time points in the exercise time control trial. No significant differences were observed between measurements at rest or at equivalent exercise intensities.