IMPAIRED ACETYLCHOLINE-MEDIATED VASODILATION IN PATIENTS WITH CONGESTIVE-HEART-FAILURE - ROLE OF ENDOTHELIUM-DERIVED VASODILATING AND VASOCONSTRICTING FACTORS

Background. The vasodilatory response to intra-arterial administration of acetylcholine is reduced in patients with congestive heart failure compared with that of normal subjects. The reduced response to acetyl choline may be related to decreased endothelial release of nitric oxid e, interaction with peripheral alpha-adrenergic transmission, or produ ction of cyclooxygenase-dependent vasoconstricting substances. The ext ent to which each of these mechanisms contributes to the reduced vasod ilatory response to acetylcholine in patients with congestive heart fa ilure is not known. Methods and Results. Thirty-one patients with cong estive heart failure (New York Heart Association functional class II-I II) and five age-matched normal subjects were studied. Regional vascul ar responses in the forearm to infusions of acetylcholine, an endothel ium-dependent vasodilator (10(-7) to 10(-5) mol/L) and nitroglycerin, an endothelium-independent vasodilator (10(-6) mol/L) in the brachial artery were determined with venous occlusion plethysmography before an d after regional alpha-adrenergic blockade with intra-arterial phentol amine (25 mug/min) and systemic cyclooxygenase inhibition with oral in domethacin (50 mg). Administration of phentolamine significantly incre ased resting baseline forearm blood flow in 11 patients with congestiv e heart failure (2.9+/-0.4 to 5.4+/-0.8 mL . min-1 . 100 mL-1) and nor mal subjects (4.6+/-0.3 to 11.3+/-2.1 mL . min-1 . 100 mL-1). Before a dministration of phentolamine, intra-arterial infusions of acetylcholi ne 10(-7), 10(-6), and 10(-5) mol/L increased forearm blood How to 4.0 +/-1.0, 6.0+/-1.7, and 16.1+/-4.0 mL . min-1 . 100 mL-1, respectively, in patients with congestive heart failure and to 14.7+/-6.2, 20.2+/-4 .7, and 38.7+/-7.9 mL . min-1 . 100 mL-1, respectively, in normal subj ects. After administration of phentolamine, the vasodilatory responses to intra-arterial infusions of acetylcholine and nitroglycerin did no t change in either patients or normal subjects. Administration of indo methacin did not alter resting forearm blood flow in 15 patients with congestive heart failure (2.7+/-0.4 to 2.7+/-0.4 mL . min-1 . 100 mL-1 ) or normal subjects (4.6+/-0.3 to 5.4+/-0.8 mL . min-1 . 100 mL-1). A dministration of indomethacin significantly increased the vasodilatory responses to infusions of acetylcholine by an average of 39% in patie nts with congestive heart failure but did not change the vasodilatory response to acetylcholine in normal subjects. In patients with congest ive heart failure, baseline forearm blood flow and the vasodilatory re sponses to intra-arterial infusions of acetylcholine and nitroglycerin were significantly less than those of normal subjects both before and after administration of phentolamine and indomethacin. Conclusions. T he reduced vasodilatory response to intra-arterial infusion of acetylc holine in patients with congestive heart failure probably results from several coexistent abnormalities in peripheral vascular function, inc luding abnormal production of cyclooxygenase-dependent vasoconstrictin g factor, impaired endothelial release of nitric oxide, and decreased vascular smooth muscle responsiveness to cyclic GMP-mediated vasodilat ion.