The Functional Shift of Endothelin Receptor Subtypes in Dogs with Heart Failure Produced by Rapid Ventricular Pacing

Tadano, Kiyoshi; Hosokawa, Akio; Fukuroda, Takahiro; Nishikibe, Masaru

doi:10.1097/01.fjc.0000166291.72324.eb

Cited by 8 publications

(8 citation statements)

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“…Our measurements of plasma ET-1 are consistent with values reported in human (1,6,13,20,24) and animal heart failure (3,22,25). Our larger dose of ET-1 (4.0 ng⅐ kg Ϫ1 ⅐min Ϫ1 ) is close to the upper limit of the pathophysiological range of ET-1 plasma levels reported earlier.…”

Section: Discussionsupporting

confidence: 80%

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Okajima

Parent

Thorin

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Lavallée. Pathophysiological plasma ET-1 levels antagonize ␤-adrenergic dilation of coronary resistance vessels in conscious dogs. Am J Physiol Heart Circ Physiol 287: H1476 -H1483, 2004. First published June 17, 2004 10.1152/ajpheart.00297.2004.-On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K ϩ (KATP) channel opening, which is pivotal in ␤-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair ␤-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O2 consumption (MV O2) increased, the disproportionate rise in coronary sinus (CS) PO2 indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with ␤-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the PO 2-MV O2 and CBF-MV O2 relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET A receptor blocker, prevented reduction of the slope of PO2-MV O2 and CBF-MV O2 relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of PO 2-MV O2 and CBF-MV O2 relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K ATP channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired ␤-adrenergic dilation of resistance coronary vessels through an ET A receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K ATP channels to impair ␤-adrenergic coronary dilation. endothelin-1; coronary blood flow; dobutamine; ATP-dependent potassium channels; myocardial oxygen consumption PLASMA ENDOTHELIN (ET)-1 levels are elevated in human heart failure (1,6,13,20,24) and pulmonary hypertension (33). The pulmonary circulation acts as the primary source of circulating ET-1 (5, 24). Even if local ET-1 activity is increased in failing hearts (2), circulating ET-1 is still being extracted by the heart, which acts as a consumer, rather than a producer, of circulating ET-1 (5, 24). In humans, increases in circulating ET-1 levels within the pathophysiological range led to decreases in coronary sinus (CS) blood flow and venous blood O 2 saturation, consistent with coronary constriction (19). In normal conscious pigs (14, 15) and dogs (26), blockade of ET-1 receptors led to increases in coronary venous blood O 2 saturation. Thus ET-1 activity may reach the threshold for altering myocard...

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Section: Discussionsupporting

confidence: 80%

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Okajima

Parent

Thorin

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…This is in accordance with a study in pigs with pacing‐induced heart failure, which showed that ET A receptor mRNA and ET A binding are increased (Ergul et al 2001). Similarly, data in dogs showed that, whereas pulmonary vasoconstriction in response to exogenous ET is predominantly mediated through the ET B receptor in normal dogs, there is an ET A ‐mediated component in dogs with pacing‐induced heart failure (Tadano et al 2004). Conversely, Docherty & MacLean (1998) investigated the effect of ET on isolated pulmonary arterioles in animals with MI using ET receptor agonists and antagonists, and found no contribution of the ET A receptor to pulmonary vasoconstriction in either normal rabbits or rabbits with MI.…”

Section: Discussionmentioning

confidence: 98%

Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

Houweling¹,

Merkus²,

Sorop³

et al. 2006

The Journal of Physiology

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We previously observed that pulmonary hypertension secondary to myocardial infarction (MI) in swine is characterized by elevated plasma endothelin (ET) levels and pulmonary vascular resistance (PVR). Consequently, we tested the hypothesis that an increased ET-mediated vasoconstrictor influence contributes to secondary pulmonary hypertension after MI and investigated the involvement of ET A and ET B receptor subtypes. Chronically instrumented swine with (MI swine; n = 25) or without (normal swine; n = 19) MI were studied at rest and during treadmill exercise (up to 4 km h -1 ), in the absence and presence of the ET A antagonist EMD 122946 or the mixed ET A /ET B antagonist tezosentan. In normal swine, exercise caused a small decrease in PVR. ET A blockade had no effect on PVR at rest or during exercise. Conversely, ET A /ET B blockade decreased PVR but only during exercise (at 4 km h -1 , from 3.0 ± 0.1 to 2.3 ± 0.1 mmHg min l -1 ; P ≤ 0.05). MI increased pulmonary arterial pressure and PVR both at rest and during exercise (both P ≤ 0.05). The increased pulmonary arterial pressure correlated with the increased plasma ET levels in resting MI swine (r = 0.71; P ≤ 0.01). Furthermore, the pulmonary vasoconstrictor response to ET-1 infusion was enhanced after MI (P ≤ 0.05). ET A /ET B blockade decreased PVR in MI swine from 3.6 ± 0.3 to 3.1 ± 0.5 mmHg min l -1 at rest and from 3.4 ± 0.3 to 2.4 ± 0.2 mmHg min l -1 during exercise at 4 km h -1 (both P ≤ 0.05). This increased response to mixed ET A /ET B blockade in MI compared to normal swine appeared to be the result of an increased ET A -mediated vasoconstriction, as ET A blockade decreased PVR in MI swine from 3.4 ± 0.4 to 2.8 ± 0.2 mmHg min l -1 at rest and from 3.1 ± 0.3 to 2.6 ± 0.2 mmHg min l -1 at 4 km h -1 (both P ≤ 0.05). In conclusion, increased plasma ET levels together with increased pulmonary resistance vessel responsiveness to ET result in an exaggerated pulmonary vasoconstrictor influence of ET in swine with a recent MI. This vasoconstrictor influence is the result of an emergent tonic ET A -mediated vasoconstriction in addition to the exercise-induced ET B -mediated vasoconstriction that is already present in normal swine. Congestive heart failure is the only major cardiovascular disorder of which the incidence has increased over the past decade, and this is principally due to a reduction in mortality associated with acute myocardial infarction (MI) (Colucci & Braunwald, 2001). The loss of viable myocardial tissue after MI causes left ventricular dysfunction leading to an increase in left ventricular filling pressure and neurohumoral activation particularly during exercise (Colucci & Braunwald, 2001;Haitsma et al. 2001;van der Velden et al. 2004;Merkus et al. 2005). The increase in left ventricular filling pressure is transmitted backwards into the pulmonary circulation, resulting in pulmonary congestion and an increase in pulmonary arterial blood pressure, thereby elevating right ventricular afterload (van Kats et al. 2000;Haitsma et al. 2001). The res...

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“…Although improvements in peripheral vascular function have been observed following exercise regimens in human HF (18,22,43,53), the impact of exercise on the coronary vasculature has not been studied. Functional inadequacies of the peripheral and coronary vasculature, including altered reactions to mediators of vasoconstriction, such as ET-1, are well established in HF (8,21,32,33,46,49), implying exercise-dependent benefits extending to the coronary vasculature could directly impact LV function in HF. Much of the available literature demonstrates blunted coronary responsiveness to ET-1, as seen in a dog model of HF (8), and also following myocardial infarction in swine (35).…”

Section: Discussionmentioning

confidence: 99%

“…coronary circulation; vascular smooth muscle; potassium channels; heart failure CORONARY VASCULAR DYSFUNCTION is a hallmark feature of the progression to heart failure (HF). Altered responsiveness to mediators of vascular tone, such as endothelin-1 (ET-1), have been observed and may contribute to this phenomena (8,21,32,33,46,49). Impaired coronary vascular function can have profound effects on myocardial oxidative capacity and function and may play a significant role in the inability of the failing heart to respond to situations of increasing stress.…”

mentioning

confidence: 99%

Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca²⁺-sensitive K⁺ current in miniature swine with LV hypertrophy

Emter

Tharp²,

Ivey³

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Emter CA, Tharp DL, Ivey JR, Ganjam VK, Bowles DK. Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca 2ϩ -sensitive K ϩ current in miniature swine with LV hypertrophy. Am J Physiol Heart Circ Physiol 301: H1687-H1694, 2011. First published August 12, 2011 doi:10.1152/ajpheart.00610.2011.-Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance (P Ͻ 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ETA) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K ϩ currents (IKϩ) in coronary smooth muscle cells. Raising internal Ca 2ϩ from 200 to 500 nM increased Ca 2ϩ -sensitive K ϩ current in HF-TR and control, but not HF animals. In conclusion, an ETA-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca 2ϩ -sensitive IKϩ was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca 2ϩ -sensitive IKϩ, illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy. coronary circulation; vascular smooth muscle; potassium channels; heart failure CORONARY VASCULAR DYSFUNCTION is a hallmark feature of the progression to heart failure (HF). Altered responsiveness to mediators of vascular tone, such as endothelin-1 (ET-1), have been observed and may contribute to this phenomena (8,21,32,33,46,49). Impaired coronary vascular function can have profound effects on myocardial oxidative capacity and function and may play a significant role in the inability of the failing heart to respond to situations of increasing stress. The mechanism by which this occurs remains unclear. Considerable evidence exists indicating that profound modulation of both cardiomyocyte and smooth muscle cell electrophysiological phenotype are involved in cardiovascular disease (36, 47, 51). Calcium-activated K ϩ (K Ca...

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The Functional Shift of Endothelin Receptor Subtypes in Dogs with Heart Failure Produced by Rapid Ventricular Pacing

Cited by 8 publications

References 0 publications

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca²⁺-sensitive K⁺ current in miniature swine with LV hypertrophy

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The Functional Shift of Endothelin Receptor Subtypes in Dogs with Heart Failure Produced by Rapid Ventricular Pacing

Cited by 8 publications

References 0 publications

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs

Role of endothelin receptor activation in secondary pulmonary hypertension in awake swine after myocardial infarction

Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca2+-sensitive K+ current in miniature swine with LV hypertrophy

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Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca²⁺-sensitive K⁺ current in miniature swine with LV hypertrophy