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 acetylcholine may be related to decreased endothelial release of nitric oxide, interaction with peripheral alpha-adrenergic transmission, or production of cyclooxygenase-dependent vasoconstricting substances. The extent to which each of these mechanisms contributes to the reduced vasodilatory response to acetylcholine in patients with congestive heart failure is not known.


RESULTS
Thirty-one patients with congestive heart failure (New York Heart Association functional class II-III) and five age-matched normal subjects were studied. Regional vascular responses in the forearm to infusions of acetylcholine, an endothelium-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 and after regional alpha-adrenergic blockade with intra-arterial phentolamine (25 micrograms/min) and systemic cyclooxygenase with oral indomethacin (50 mg). Administration of phentolamine significantly increased resting baseline forearm blood flow in 11 patients with congestive heart failure (2.9 +/- 0.4 to 5.4 +/- 0.8 mL.min-1.100 mL-1) and normal subjects (4.6 +/- 0.3 to 11.3 +/- 2.1 mL.min-1.100 mL-1). Before administration of phentolamine, intra-arterial infusions of acetylcholine 10(-7), 10(-6), and 10(-5) mol/L increased forearm blood flow 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 subjects. After administration of phentolamine, the vasodilatory responses to intra-arterial infusions of acetylcholine and nitroglycerin did not change in either patients or normal subjects. Administration of indomethacin 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). Administration of indomethacin significantly increased the vasodilatory response to infusion of acetylcholine by an average of 39% in patients with congestive heart failure but did not change the vasodilatory response to acetylcholine in normal subjects. In patients with congestive heart failure, baseline forearm blood flow and the vasodilatory responses 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
The reduced vasodilatory response to intra-arterial infusion of acetylcholine in patients with congestive heart failure probably results from several coexistent abnormalities in peripheral vascular function, including abnormal production of cyclooxygenase-dependent vasoconstricting factor, impaired endothelial release of nitric oxide, and decreased vascular smooth muscle responsiveness to cyclic GMP-mediated vasodilation.
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461.
S D
SD
Katz
M
M
Schwarz
J
J
Yuen
T H
TH
LeJemtel
D000109:Acetylcholine / Q000008:administration & dosage / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016232:Endothelins / Q000502:physiology*; D005260:Female; D005542:Forearm / Q000098:blood supply; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology*; D005996:Nitroglycerin / Q000494:pharmacology; D010646:Phentolamine / Q000494:pharmacology; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D016861:Cyclooxygenase Inhibitors; D016232:Endothelins; D011942:Receptors, Adrenergic, alpha; D009569:Nitric Oxide; D005996:Nitroglycerin; D000109:Acetylcholine; D007213:Indomethacin; D010646:Phentolamine