(Circulation. 2001;103:1992.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Flow-Induced Dilation of Human Coronary Arterioles
Important Role of Ca2+-Activated K+ Channels
From the VA Medical Center, the Department of Medicine, and the Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee (H.M., Y.L., F.R.L., D.D.G.); the VA Medical Center, Iowa City, and the Department of Internal Medicine and Anesthesia, University of Iowa College of Medicine, Iowa City (R.E.W.); and the 2nd Department of Internal Medicine, Akita University, Akita, Japan (T.S., M.M.).
Correspondence to David D. Gutterman, MD, Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail dgutt{at}mcw.edu
Background—Flow-induced vasodilation (FID) is a physiological mechanism for regulating coronary flow and is mediated largely by nitric oxide (NO) in animals. Because hyperpolarizing mechanisms may play a greater role than NO in the microcirculation, we hypothesized that hyperpolarization contributes importantly to FID of human coronary arterioles.
Methods and
Results—Arterioles from atria or ventricles
were cannulated for videomicroscopy. Membrane potential of vascular
smooth muscle cells (VSMCs) was measured simultaneously.
After constriction with endothelin-1, increases in flow induced an
endothelium-dependent vasodilation.
N
-Nitro-L-arginine
methyl ester
10-4 mol/L
modestly impaired FID of arterioles from patients without
coronary artery disease (CAD), whereas no inhibition was seen
in arterioles from patients with CAD. Indomethacin
10-5 mol/L was
without effect, but 40 mmol/L KCl attenuated maximal FID.
Tetraethylammonium
10-3 mol/L but
not glibenclamide
10-6 mol/L
reduced FID. Charybdotoxin
10-8 mol/L
impaired both FID (15±3% versus 75±12%,
P<0.05) and
hyperpolarization (-32±2 mV [from -28±2 mV
after endothelin-1] versus -42±2 mV [-27±2 mV],
P<0.05). Miconazole
10-6 mol/L or
17-octadecynoic acid
10-5 mol/L
reduced FID. By multivariate analysis, age was
an independent predictor for the reduced
FID.
Conclusions—We conclude that shear stress induces endothelium-dependent vasodilation, hyperpolarizing VSMCs through opening Ca2+-activated K+ channels in human coronary arterioles. In subjects without CAD, NO contributes to FID. NO and prostaglandins play no role in patients with CAD; rather, cytochrome P450 metabolites are involved. This is consistent with a role for endothelium-derived hyperpolarizing factor in FID of the human coronary microcirculation.
Key Words: blood flow • vasodilation • microcirculation
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