Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans

Wray, D. Walter; Nishiyama, Steven K.; Donato, Anthony J.; Sander, Mikael; Wagner, Peter D.; Richardson, Russell S.

doi:10.1152/ajpheart.00867.2007

Cited by 52 publications

(46 citation statements)

References 55 publications

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“…Consequently, it has been proposed that endothelin blockade may be useful to improve exercise capacity in these patients. 68 And more recently, it has been shown that the phosphodiesterase-5 inhibitor sildenafil improves ventilatory and aerobic efficiencies in heart failure patients by improving muscle perfusion and endothelial activity. 69 What is particularly striking is that these are the same classes of vasodilators that have been shown to increase exercise performance in patients with PAH.…”

Section: Vasodilators and Their Effects On The Ergoreflexmentioning

confidence: 99%

The Effects of Vasodilators in Pulmonary Hypertension

Rich

2009

Circ: Heart Failure

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W hen primary pulmonary hypertension (PPH) was first described in the medical literature, it was characterized from a cardiac catheterization on a young woman who had an elevated pulmonary arterial pressure of unknown origin which, after the intravenous administration of acetylcholine, promptly fell. 1 The sentinel description of this phenomenon led to the acceptance of PPH as a medical entity in which inappropriate pulmonary vasoconstriction was a central feature. 2 Since then many series of patients with PPH (now referred to as idiopathic pulmonary arterial hypertension [IPAH]) have been published which document a variable ability to respond to acute vasodilator challenge. Although, the approach to therapy has emphasized the initial classification of responder or nonresponder, most patients demonstrate only a small decrease in pulmonary pressure (PAP) in response to vasodilators. 3 However, vasodilators are widely prescribed in patients who are nonresponders, based on clinical trials that established the response to a 6-minute walk (6 MW) test as the primary end point. 4 The consistent improvement in 6 MW reflects the complexity of exercise intolerance, which may be strongly influenced not only by cardiopulmonary factors, but by peripheral factors such as the muscle ergoreflex. 5 Who is a Responder?In the current era, patients with PAH 6 who undergo acute vasoreactivity testing at the time of diagnosis are classified as responders or nonresponders based on the change in PAP from select agents. 7 The definition of a responder has changed many times, the most recent being a fall in the mean PAP of at least 10 mm Hg to a level below 40 mm Hg without any fall in cardiac output. 4 However, the response is in reality a continuum, and not an all or none phenomenon. It is notable that in 2 large series of patients who were deemed acute responders, the characteristic of those who had near perfect survival on calcium blockers (CCB) for up to 18 years had an acute fall in mean PAP of 39% and an acute fall in pulmonary vascular resistance (PVR) of 50%. 3,8 It is remarkable how similar the experiences from the 2 series are, supporting the validity of the observations. Who is a Nonresponder?The majority of patients with IPAH are nonresponders. Although this implies lack of vasoreactivity, this is clearly not the case. In an observational study of patients with IPAH who were monitored with a pulmonary artery catheter over 6 hours without an intervention, considerable variability was noted in the PAP (Ϯ8%) and PVR (Ϯ13%), suggesting that changing vasomotor tone is common in these patients. 9 In the 2 series on long-term calcium blocker therapy, the nonresponders also had an acute fall in mean PAP and PVR, but of a lesser magnitude than the responder group. In one series, the fall in PAP was 8%, and fall in PVR was 17%. 8 In the other, nonresponders were noted to have a fall in PVR of less than 20%. 3 Thus, the characterization of a patient as a nonresponder actually means a minimal response, not lack of response. Although the...

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Section: Vasodilators and Their Effects On The Ergoreflexmentioning

confidence: 99%

The Effects of Vasodilators in Pulmonary Hypertension

Rich

2009

Circ: Heart Failure

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“…Although the mechanisms governing this event are far from certain, there exists evidence in humans for a reduction in the effectiveness of both adrenergic [31][32][33] and nonadrenergic 18,34 vasoconstrictor pathways to facilitate the requisite hyperemic response. The potential involvement of endogenous Ang II in the regulation of exercise hyperemia is supported by the acute increase in circulating Ang II during exercise, 35 as well as the profound hemodynamic effect seen when AT 1 receptor blockade is applied during exercise.…”

Section: Ang Ii-mediated Vasoconstriction During Exercisementioning

confidence: 99%

Angiotensin II in the Elderly

et al. 2008

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Abstract-Exercise hyperemia is attenuated in the elderly, which may be attributed to local vasoregulatory pathways within the skeletal muscle vasculature. Therefore, we sought to determine whether healthy aging is associated with changes in angiotensin II (Ang II) receptor sensitivity through measurements of leg blood flow in resting and exercising skeletal muscle. In 12 (nϭ6 young, 24Ϯ1 years; nϭ6 older, 68Ϯ3 years) healthy volunteers, we determined changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of Ang II (0.8 ng/mL of leg blood flow per minute). Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20% and 40% of the maximal work rate (WR max ). At rest, Ang II infusion decreased leg blood flow to a greater extent in older (Ϫ61Ϯ8%) subjects compared with younger subjects (Ϫ31Ϯ5%). Compared with rest, Ang II-mediated vasoconstriction (leg blood flow) during exercise was diminished in both older and younger subjects at 20% (older: Ϫ7Ϯ5%; younger: Ϫ21Ϯ2%) and 40% WR max (older: Ϫ5Ϯ4%; younger: Ϫ9Ϯ3%). These data identify a clear age-related hypersensitivity to Ang II in the resting leg, which may contribute to the recognized decrement in leg blood flow in this cohort. However, the diminished vasoconstriction to Ang II during exercise suggests that the elevation in Ang II type 1 receptor sensitivity documented at rest does not contribute significantly to the blunted exercise hyperemia experienced with advancing age. Key Words: basic science Ⅲ elderly Ⅲ blood flow regulation Ⅲ exercise Ⅲ angiotensin receptors A ngiotensin II (Ang II) acts as a potent endogenous vasoconstrictor through binding to the Ang II type 1 (AT 1 ) receptor on arteriolar vascular smooth muscle. With advancing age, there is a notable decline in plasma renin activity 1 accompanied by small decrements in circulating Ang II 2 and an increase in AT 1 receptor density. 3,4 However, the functional consequence of this age-related adaptation of the renin-angiotensin system on the peripheral circulation is not well understood. Although the pressor response to systemic Ang II infusion is elevated with age, 5 no age-specific adaptation in AT 1 receptor sensitivity has been observed with local, intra-arterial Ang II infusion in the arm. 6 Together, these studies indicate a general decline in renin-angiotensin system function with age but with uncertainty as to the impact of these changes on end-organ function and skeletal muscle hemodynamics.AT 1 receptor sensitivity to Ang II in the elderly may be especially important in the context of underlying changes in autonomic function. It is well established that elevated vasoconstrictor tone as a consequence of high sympathetic nerve activity is present in healthy, older adults, 7-9 despite a reduction in the sensitivity of postjunctional adrenergic vascular receptors. 10 This capacity for sustained sympathetic vasoconstriction in the face of reduced adrenergic responsivenes...

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“…In healthy volunteers [14], intravenous ET-1 administration causes a reduction in leg blood flow at rest without a reduction in the common femoral artery diameter, suggesting an effect on distal resistance vessels. Exercise blunts the ET-1-mediated vasoconstriction in an intensity-dependent manner [14]. However, as suggested previously [13], the exercise-induced 'lysis' of ET-1-mediated vasoconstriction might be modulated in conditions with higher circulating ET-1 levels or modified receptor responsiveness such as obesity, hypertension, HF and COPD.…”

Section: Discussionmentioning

confidence: 94%

“…ET-1 and CT-proET-1 are surrogates of vascular tone and probably systemic vascular resistance [37,38]. In healthy volunteers [14], intravenous ET-1 administration causes a reduction in leg blood flow at rest without a reduction in the common femoral artery diameter, suggesting an effect on distal resistance vessels. Exercise blunts the ET-1-mediated vasoconstriction in an intensity-dependent manner [14].…”

Section: Discussionmentioning

confidence: 99%

“…ET-receptor-A-mediated vasoconstriction accounts at least in part for the impaired vasodilatory response to exercise in hypertensive subjects [13], and ET-1 seems also to be involved in the regulation of leg blood flow during exercise in healthy subjects [14]. High ET-1 could be related to low peak VO 2 in at least two ways: first, by a relationship with increased systemic vascular resistance and thereby reduced cardiac output, and second, by a relationship with low arterio-venous oxygen extraction due to impaired perfusion of the working musculature.…”

Section: Introductionmentioning

confidence: 99%

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B‐type natriuretic peptide and C‐terminal‐pro‐endothelin‐1 for the prediction of severely impaired peak oxygen consumption

Maeder

Brutsche

Staub

et al. 2009

Journal of Internal Medicine

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Objective. To assess the utility of B-type natriuretic peptide (BNP) and C-terminal-pro-endothelin-1 (CTproET-1) to predict a severely impaired peak oxygen consumption (peak VO 2 , < 14 mL kg )1 min )1 ) in patients referred for cardiopulmonary exercise testing.Design. Cross-sectional study.Setting. Tertiary care center.Methods. Peak VO 2 , BNP and CT-proET-1 were assessed in 141 consecutive patients referred for cardiopulmonary exercise testing.Results. B-type natriuretic peptide [median (interquartile range) 48 (38-319) vs. 33 (15-86) pg mL )1 ; P = 0.002] and vs. 60 (52-74) pmol L )1 ; P < 0.001] were higher in patients with a peak VO 2 < 14 mL kg )1 min )1 (n = 30) than in those with a peak VO 2 ‡ 14 mL kg )1 min )1 (n = 111). CT-pro-ET-1 had a higher area under the receiver-operator-characteristics curve (AUC) to predict a peak VO 2 < 14 mL kg )1 min )1 than BNP (0.79 vs. 0.68; P = 0.04). The optimal BNP cut-off of 37.2 pg mL )1 had a sensitivity of 80% and a specificity of 56%. The optimal CT-proET-1 cut-off of 74.4 pmol L )1 had a sensitivity of 80% and specificity of 76%. A five-item score composed of body mass index, diabetes, forced expiratory volume within the first second, alveolo-arterial oxygen pressure difference, and BNP had an AUC of 0.88 to predict a peak VO 2 < 14 mL kg )1 min )1 . Adding CT-proET-1 to the score resulted in an AUC of 0.92.Conclusions. C-terminal-pro-endothelin-1 is superior to BNP for the prediction of a peak VO 2 < 14 mL kg )1 min )1 in patients referred for CPET. A score incorporating body mass index, diabetes status, spirometry, blood gases, BNP and CT-proET-1 improves the prediction of a peak VO 2 < 14 mL kg )1 min )1 based on single biomarkers.

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Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans

Cited by 52 publications

References 55 publications

The Effects of Vasodilators in Pulmonary Hypertension

The Effects of Vasodilators in Pulmonary Hypertension

Angiotensin II in the Elderly

B‐type natriuretic peptide and C‐terminal‐pro‐endothelin‐1 for the prediction of severely impaired peak oxygen consumption

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