Antagonism of the Cardiodepressant Effects of Adenosine during Acute Hypoxia

Cummings, J. R.; Kaplan, Justin L.; Gao, Erhe; Clas, Dawn; Dalsey, William C.; Garavilla, Lawrence de

doi:10.1111/j.1553-2712.2000.tb02034.x

Cited by 9 publications

(4 citation statements)

References 26 publications

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“…The overall baseline values found for MAP are in accordance with what has been reported elsewhere (13). It has been shown that inspired hypoxia leads to a drop in MAP, which was present but nonsignificant in our study.…”

Section: Blood Pressuressupporting

confidence: 93%

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The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude

Radiloff

Zhao

Boico

et al. 2012

Journal of Applied Physiology

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Decreased physical performance is a well-known consequence of rapid ascent to high altitude. Hypoxic pulmonary vasoconstriction (HPV) potentially limits cardiac output and systemic blood flow, thus preventing successful adaptation to rapid ascent. We hypothesized that pharmacological enhancement of the heart rate with theophylline, combined with reversal of HPV via endothelin blockade, could increase exercise performance at high altitude. Female Sprague-Dawley rats were treated with combinations of 1) theophylline, 2) the endothelin receptor antagonists sitaxsentan/ambrisentan, and/or 3) phosphodiesterase-5 inhibitor sildenafil and exposed to either a simulated high altitude (4,267 m) or 12% oxygen. Exercise capacity, peripheral blood flow, hemodynamics, and pulmonary leak were examined. Combination treatment with theophylline and endothelin blockade, but not with the respective single compounds, significantly prolonged run-to-fatigue time under simulated high altitude. No such efficacy was found when theophylline was combined with sildenafil. Neither theophylline nor sitaxsentan or their combination influenced breathing rates and hemoglobin oxygen saturation. Whereas under hypoxia, theophylline significantly increased muscular blood flow, and sitaxsentan increased tissue oxygenation, the combination improved both parameters but in a reduced manner. Under hypoxia, the combination treatment but not the single compounds significantly enhanced pulmonary arterial pressure compared with controls (13.1 ± 6.3 vs. 11.9 ± 5.2 mmHg), whereas mean arterial pressure remained unaffected. Pulmonary wet-to-dry weight ratios were unaffected by combination treatment. We conclude that concomitant dosing with a cardiac stimulant and endothelin antagonist can partially reverse loss of physical performance capacity under hypobaric hypoxia, independent from improving blood oxygen saturation.

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Section: Blood Pressuressupporting

confidence: 93%

“…This discrepancy is probably due to the effect of ketamine anesthesia. Whereas conscious mammals, including humans and rats, react to inspired hypoxia with an increase in heart rate, hypoxia-in conjunction with ketamine anesthesia-generally appears to reverse this reaction (13,36,47).…”

Section: Pulmonary Wdrmentioning

confidence: 99%

The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude

Radiloff

Zhao

Boico

et al. 2012

Journal of Applied Physiology

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“…This dose of NPC-205 was the most effective dose in prolonging survival and maintaining HR and dP/dt in a prior study of hypoxic cardiac insufficiency. 8 Measures. The main efficacy outcome was survival duration, which was the time (in minutes) after the onset of hypoxia until dP/dt reached zero.…”

Section: Methodsmentioning

confidence: 99%

“…b-adrenergic drugs also may be rendered inefficacious by high levels of Ado, which, via the A 1 AdoR, exert an anti-badrenergic effect. Preinsult treatment with NPC-205 8 and postinsult treatment with KW-3902, 9 both novel selective A 1 AdoR antagonists, have recently been shown to prolong survival by attenuating hypoxic cardiac insufficiency. Selective A 1 AdoR antagonists, because of their potential advantages over adrenergic drugs and promising results to date, warrant further study in models of low-flow states.…”

mentioning

confidence: 99%

Adenosine A₁Antagonism Attenuatesβ-adrenergic-resistant Sudden Hypoxic Cardiac Insufficiency

Gao

Kaplan

Victain

et al. 2005

Academic Emergency Medicine

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Objectives: In states such as hypoxia, shock, and cardiac arrest, compromised systemic oxygenation or perfusion appears to induce cardiac insufficiency that can be resistant to b-adrenergic drugs. Elevated levels of adenosine may mediate such b-adrenergic-resistant cardiac insufficiency via the adenosine A 1 receptor (A 1 AdoR). The objective of this study was to test the hypothesis that selective A 1 AdoR antagonism attenuates hypoxic cardiac insufficiency more efficaciously than b 1 -adrenergic agonism or nonselective adenosine antagonism. Methods: Rats were paralyzed and ventilated to a pCO 2 level of 35-40 mm Hg. Ten minutes before hypoxia (inspired O 2 concentration = 5%), rats were treated intravenously with one of the following: 0.1 mg/kg BG-9719 (n = 9), 10 mg/kg NPC-205 (n = 10; BG-9719 and NPC-205 are selective A 1 AdoR antagonists, with durations of action of 30-60 minutes and 60-90 minutes, respectively), 10 mg/kg aminophylline (n = 12), 5 mg/kg/min dobutamine (n = 11), or control solutions. These drug doses maximized survival duration in dose-response studies.Results: Before hypoxia, cardiac work was increased more by aminophylline and dobutamine than by BG-9719. Mean (6SEM) duration of survival (in minutes) after hypoxia increased from ,13 (control solutions) to 13.8 (61.4) (dobutamine), 20.0 (61.6) (aminophylline), 31.7 (64.6) (BG-9719), and 40.5 (67.5) (NPC-205) (p , 0.0001). Heart rate and dP/dt decreased rapidly after hypoxia, but decreases were attenuated with BG-9719 and NPC-205 compared with dobutamine (p , 0.05) and tended toward attenuation with aminophylline. Conclusions: BG-9719 and NPC-205 improved survival duration, heart rate, and left ventricular contractility during hypoxia more efficaciously than dobutamine and possibly aminophylline. Selective A 1 AdoR antagonists warrant further study as alternatives to b-adrenergic agonists in hypoxia, shock, and cardiac arrest, in which compromised systemic perfusion or oxygenation impairs cardiac output.

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Techniques for Supraventricular Tachycardias

Minczak¹

2010

Clinical Procedures in Emergency Medicine

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Antagonism of the Cardiodepressant Effects of Adenosine during Acute Hypoxia

Cited by 9 publications

References 26 publications

The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude

The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude

Adenosine A₁Antagonism Attenuatesβ-adrenergic-resistant Sudden Hypoxic Cardiac Insufficiency

Techniques for Supraventricular Tachycardias

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Antagonism of the Cardiodepressant Effects of Adenosine during Acute Hypoxia

Cited by 9 publications

References 26 publications

The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude

The combination of theophylline and endothelin receptor antagonism improves exercise performance of rats under simulated high altitude

Adenosine A1Antagonism Attenuatesβ-adrenergic-resistant Sudden Hypoxic Cardiac Insufficiency

Techniques for Supraventricular Tachycardias

Contact Info

Product

Resources

About

Adenosine A₁Antagonism Attenuatesβ-adrenergic-resistant Sudden Hypoxic Cardiac Insufficiency