Action of the endothelin receptor (ETA) antagonist BQ-123 on forearm blood flow in young normotensive subjects

Abstract

Endothelin-1 (ET-1) has been proposed to contribute to the regulation of vascular tone in humans. BQ-123, an ET(A) receptor antagonist, has also been reported to increase forearm blood flow (FBF) in vivo; however, the efficacy of BQ-123 as an antagonist of ET-1 has not been evaluated in the forearm. The present study investigated the effects of BQ-123 on changes in FBF in response to ET-1 and noradrenaline (NA; norepinephrine), taking into account the possible influence of vasodilator effects of BQ-123 on responses to vasoconstrictors. Six subjects (age 25-34 years) participated in a double-blind randomized study. FBF was measured by forearm occlusion plethysmography. Drugs were infused intra-arterially into the non-dominant arm (study arm) on four separate occasions; the non-infused arm was used as a control. The effects of BQ-123 (50 nmol/min for 60 min, or 300 nmol/min for 5 min followed by saline for 55 min) were compared with the effects of infusion of sodium nitroprusside (SNP; 12 nmol/min for 60 min) or saline on vasoconstriction induced by ET-1 (10 pmol/min for 7 min) and NA (120 pmol/min for 7 min). Infusion of BQ-123 at either dose did not significantly increase FBF, whereas SNP increased FBF by 134% (P=0.03). ET-1 significantly reduced FBF, and this effect was almost completely inhibited by both doses of BQ-123, but was unaffected by SNP. NA also reduced FBF, and this action was unaffected by BQ-123 or SNP. The data show that BQ-123 is a selective ET-1 antagonist, but do not confirm a major role for ET-1 in influencing resting forearm vascular tone in young normotensive subjects.

Skeletal Muscle Vascular Function: A Counterbalance of Insulin Action

“…Several studies have shown that ECE inhibitors and ET‐1 receptor antagonists reduce systemic blood pressure comparably in hypertensive and normotensive states . However, other studies have reported reduction in blood pressure in response to ET‐1 blocking only in hypertensive adults and animal models, whereas no effect was seen with normotensive conditions . Accordingly, some investigators have suggested that ET‐1 has a pathological role rather than a physiological role.…”

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

“…27 An increase of the flow ratio during ET-receptor blockade indicates vasodilation in the leg vascular bed, suggesting a relevant role for endogenous ET-1 in the regulation of baseline vascular tone. Blood flow, vascular resistance, and blood flow ratio were analyzed over the last 10 minutes, where ET-receptor blockade reached its maximal effect (Figure 1) 28,29 …”

“…2,3,28 The difference in response to ET-receptor blockade between forearm and leg vascular bed suggests that ET-1 has a different physiological effect on the lower limbs than on the upper limbs in healthy subjects. Recently, Newcomer et al 30 reported significantly different responses for human forearm and leg vascular beds to endotheliumdependent (acetylcholine and substance P) and -independent (sodium nitroprusside) stimuli.…”