Endothelin-1 is an endothelium-derived peptide with powerful vasoconstrictor activity. Previous studies in the forearm circulation of normal volunteers have suggested that endogenous endothelin is physiologically important in regulating basal vascular tone. The endothelin system has been implicated in the pathophysiology of heart failure and hypertension. There is increasing evidence that circulating and tissue levels of endothelin are elevated in patients with coronary artery disease suggesting that endothelin may also be involved in the pathophysiology of atherosclerosis. Atherosclerosis is associated with abnormal endothelial and vasomotor function, but it is not known whether the increase in endothelin activity is functionally important in these phenomena. Furthermore, the majority of endothelin released from blood vessels is abluminal, and thus plasma levels are a poor reflection of tissue activity. Recent development of endothelin receptor antagonists has made it possible to investigate endogenous endothelin activity. In this study, we will investigate whether 1) endogenous coronary endothelin activity is increased, 2) it contributes to abnormal metabolic coronary vasodilation, and 3) endothelial dysfunction improves in patients with atherosclerosis or its risk factors after endothelin receptor type A blockade with BQ-123.STUDY Coronary vasodilation and improvement in endothelial dysfunction with endothelin ETA receptor blockadeThe predominant pressor effect of endothelin-1 (ET-1) is mediated via smooth muscle ETA receptors. ETA receptor antagonism improves endothelial dysfunction in animals. We hypothesized that ET-1, via the ETA receptor, contributes to vasoconstrictor tone and to endothelial dysfunction in human coronary arteries in vivo.Methods: We studied unobstructed coronary arteries(<20% stenosis) of 44 patients with either atherosclerosis (CAD, n=34) or normal coronary arteries and risk factors for CAD. Hemodynamics, epicardial diameter (D), and flow velocity were measured, and coronary vascular resistance (CVR) calculated during intracoronary (i.c.) infusions of acetylcholine (ACH, 1.5-15mcg/min), and sodium nitroprusside (SNP, 10-20mcg/min), and during cold pressor test (CPT), before and after a 60 min i.c. infusion of theETA antagonist BQ-123.Results: BQ-123 produced coronary vasodilation: D increased by 5.6% (p<0.0001), and CVR fell by 12% (p<0.01). Mild systemic and pulmonary vasodilation also occurred. The magnitude of improvement in D and CVR responses to ACH with BQ-123 inversely correlated with the baseline ACH responses (r= -0.44, p=0.006 and r= -0.78, p=0.001 respectively), indicating a greater improvement in those with endothelial dysfunction. Thus, the D response to ACH, corrected for the SNP response, improved in segments that constricted with ACH at baseline (p=0.03), whereas segments that initially dilated with ACH did not change with BQ-123 (p=ns). Similarly, patients with ?abnormal' baseline microvascular dilation with ACH improved after BQ-123 (DCVR from -8% to -23%, p<0.05), whereas patients with 'normal' ACH response remained unchanged (DCVR from -57% to -55%, p=ns). CPT-mediated epicardial vasoconstriction (-2.0%) was reversed after BQ-123 (+1.0%), most notably in dysfunctional segments (from -5.6% to +2.2%, p<0.001). Conclusions: 1) ET-1, acting via the ETA receptor, contributes to basal human coronary vasoconstrictor tone in patients with CAD and risk factors for atherosclerosis. 2) ET-1 contributes to coronary vascular dysfunction during physiologic and pharmacologic testing, which is improved by acute ETA receptor blockade.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL005043-02
Application #
6432729
Study Section
Cell Biology Integrated Review Group (CB)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
United States
Zip Code