Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator.

Cooke, John P.; Rossitch, Eugene; Andon, N.; Loscalzo, Joseph; Dzau, Victor J.

doi:10.1172/jci115481

Cited by 479 publications

(240 citation statements)

References 33 publications

Supporting

Mentioning

229

Contrasting

Unclassified

Order By: Relevance

“…44 Flow-mediated vasodilation is endothelium dependent, 44 -45 leading to the release of an endothelium-derived relaxing factor (EDRF), nitric oxide. 46 In the present study, despite an increase in coronary blood flow secondary to the increase in myocardial metabolic demand evoked by the cold pressor test, we did not observe any dilation of the coronary arteries in HTN patients, suggesting an impaired flowinduced vasodilation. Impaired endothelium-dependent dilation of the forearm vasculature has been demonstrated in HTN patients (assessed by the responses to acetylcholine, an endothelium-dependent vasodilator), related to decreased EDRF release.…”

Section: -43contrasting

confidence: 73%

Coronary artery constriction caused by the cold pressor test in human hypertension.

et al. 1994

View full text Add to dashboard Cite

Hypertensive patients with angiographically normal coronary arteries may have myocardial ischemia when metabolic demand increases. Abnormal epicardial coronary artery vasomotion in response to sympathetic stimulation may contribute to ischemia in such patients. We studied the vasomotor response of smooth coronary arteries to a cold pressor test in 10 hypertensive patients without other risk factors and in 9 control subjects. Vessel dimensions were measured by quantitative angiography, and blood flow was calculated using an intracoronary Doppler catheter in the left anterior descending coronary artery. In response to cold pressor stimulation, arteries of control subjects dilated 13.0±5.9% (P<.001), and they constricted 8.2±8.5% in hypertensive patients (P<.001). Rate-pressure product increased from 9466±1677 to 12 547±2367 beats per minute (bpm) • mm Hg in control subjects (P<.001) and from 13 720±1823 to 17 353±2037 bpm • mm Hg in hypertensive A ngina-like chest pain or thallium defects consis-/\ tent with myocardial ischemia can occur in _Z A. patients with hypertension and angiographically normal coronary arteries. 1 -2 Abnormal maximal coronary vasodilator reserve 13 and/or disturbances of coronary vasomotion 4 -5 may constitute mechanisms responsible for myocardial ischemia in these patients. The vascular endothelium, by releasing relaxing and constricting factors, 67 and the sympathetic nervous system are major regulators of vascular tone. Furthermore, endothelium is a modulator of the contractile agonist effects of sympathetic activation. In experimental hypertension, morphological changes develop in arterial endothelial cells. 8 In hypertensive rats, endothelial destruction is associated with increased constriction of large vessels in response to norepinephrine infusion. 910 In isolated pig and dog coronary arteries, norepinephrine is a more powerful vasoconstrictor in the absence of endothelium.11 In hypertensive patients (HTN patients), impairment of endothelium-dependent dilation of coronary epicardial and resistance vessels has been evidenced, The aim of the present study was to assess the effects of sympathetic stimulation on vasomotion of epicardial coronary arteries in HTN patients with angiographically normal coronary arteries. We studied the response to a cold pressor test, which activates the sympathetic nervous system and induces dilation of angiographically normal coronary arteries in control subjects. 15 We measured coronary artery diameters by quantitative angiography and used intracoronary Doppler to measure blood flow velocity. Methods Patient SelectionTen HTN patients and 9 control normotensive subjects undergoing diagnostic coronary angiography for evaluation of chest pain were studied. Control subjects had a supine systolic blood pressure lower than 140 mm Hg and a diastolic blood pressure lower than 90 mm Hg. All HTN patients had a well-established history of elevated blood pressure higher than 140/90 mm Hg, with at least four sets of readings taken at 1-week intervals. Hyper...

show abstract

Section: -43contrasting

confidence: 73%

Coronary artery constriction caused by the cold pressor test in human hypertension.

et al. 1994

View full text Add to dashboard Cite

show abstract

“…Perfusion of rabbit iliac arteries at varying flow rates induced proportional increases in vessel diameter, which were antagonized by N°-methyl-L-arginine. 230 BaCl 2 and antagonists of the calcium-activated K + channel (charybdotoxin, iberiotoxin) also blocked flow-mediated vasodilation. 230 When cultured endothelial cells were added to a flow chamber containing a vascular ring without endothelium and were stimulated subsequently by flow, they relaxed the vascular ring, and this relaxation is inhibited by Ba 2+ , tetraethylammonium ion, or charybdotoxin.…”

Section: Mechanically Evoked [Ca 2+ ] and Conductance Changesmentioning

confidence: 89%

Intracellular calcium, currents, and stimulus-response coupling in endothelial cells.

1993

View full text Add to dashboard Cite

Vascular endothelium appears to be a unique organ. It not only responds to numerous hormonal and chemical signals but also senses changes in physical parameters such as shear stress, producing mediators that modulate the responses of numerous cells, including vascular smooth muscle, platelets, and leukocytes. In many cases, the initial response of endothelial cells to these diverse signals involves elevation of cytosolic Ca 2+ and activation of Ca 2+-dependent enzymes, including nitric oxide synthase and phospholipase A 2 . Both the release of Ca 2+ from intracellular stores, most likely the endoplasmic reticulum, and the influx of Ca 2+ from the extracellular space contribute to the [Ca 2+ ]| increase. The most important trigger for Ca 2+ release is inositol 1,4,5 -trisphosphate, which is generated by the action of phospholipase C, a plasmalemmal enzyme activated in many cases by the receptor-G protein cascade. Ca 2+ influx appears to be related to the activity of receptor-G protein-enzyme complex and to the degree of fullness of the endoplasmic reticulum but does not involve voltage-gated Ca 2+ channels. The magnitude of the Ca 2+ influx depends on the electrochemical gradient, which is modulated by the membrane potential, V m . Under basal conditions, V m is dominated by a large inward rectifier K + current. Some stimuli, e.g., acetylcholine, have been shown to hyperpolarize V m , thus increasing the electrochemical gradient for Ca 2+ , which appears to be modulated by activation of Ca 2+ -dependent K + and CI" currents. However, the lack of potent and specific blockers for many of the described or postulated channels (e.g., nonselective cation channel, Ca 2+ -activated Cl~ channel) makes an estimation of their effect on endothelial cell function rather difficult. involved in the contraction of endothelial cells and the increased permeability of microvessels in response to inflammatory agents (for review, see Reference 19). Thus, a detailed knowledge of intracellular Ca 2+ homeostasis is essential for our understanding of the physiology, pathophysiology, and pharmacology of endothelial cells. The following sections review the importance of the endothelium in various disease states and the mechanisms underlying cytoplasmic Ca 2+ regulation under basal and stimulated conditions. Importance of the Endothelium in VariousDisease States Increased systemic vascular tone, which is thought to result from enhanced circulating hormones (e.g., norepinephrine, angiotensin II), is among the most common hemodynamic findings in patients with heart failure. 20 However, heightened vasoconstriction correlates poorly with the plasma levels of these substances. 20 The poor correlation could possibly be explained by the involvement of local, endothelium-dependent factors, such as an imbalance of endothelium-derived relaxing and contracting factors.21 " 23 This view is supported by numerous studies conducted in isolated vascular segments as well as in intact laboratory animals and human subjects in a variety of disease states, i...

show abstract

“…Fujii et al (1992) found that compared to mesenteric arteries taken from control, normotensive (WKY) rats, those from hypertensive (SHR) rats showed a reduction in ACh-mediated relaxation, which was probably due to loss of endothelium-dependent hyperpolarization. Also, Melkumyants et al (1992) found no role for NO in endothelium-dependent arterial dilatation to increased flow in the hindquarters of the cat, although in an isolated endothelial cell model of flow-induced release of vasoactive factors, Cooke et al (1991) reported that flow activated a Ca2"-dependent K+ channel in endothelial cells that lead to release of NO (see also Lamontagne et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Evidence for differential roles of nitric oxide (NO) and hyperpolarization in endothelium‐dependent relaxation of pig isolated coronary artery

Kilpatrick

Cocks

1994

British J Pharmacology

117

View full text Add to dashboard Cite

1 The possible roles of endothelial and smooth muscle cell hyperpolarization and nitric oxide (NO) in endothelium-dependent relaxation were examined in isolated rings of pig right coronary artery. 2 The effects of hyperpolarization were prevented with high K+ (30-125 mM), isotonic Krebs solutions. Functional antagonism due to high K+-induced smooth muscle contraction was prevented with 0.3 gM nifedipine (in all treatments, for consistency). All rings were contracted with the thromboxanemimetic U46619, (1-100 nM) to bring them to an initial active force of within 30-50% of maximum contraction.3 High K+ had no effects on the sensitivity (EC") or time course of endothelium-dependent (substance P, SP; bradykinin, BK; calcimycin, A23187) and -independent (sodium nitroprusside, SNP) agents.Maximum relaxations (R.,) to SP, BK and A23187 were reduced significantly by approximately 20% but only with 125 mM K+.

show abstract

Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator.

Cited by 479 publications

References 33 publications

Coronary artery constriction caused by the cold pressor test in human hypertension.

Coronary artery constriction caused by the cold pressor test in human hypertension.

Intracellular calcium, currents, and stimulus-response coupling in endothelial cells.

Evidence for differential roles of nitric oxide (NO) and hyperpolarization in endothelium‐dependent relaxation of pig isolated coronary artery

Contact Info

Product

Resources

About