Feedforward sympathetic coronary vasodilation in exercising dogs

Gorman, Mark W.; Tune, Johnathan D.; Richmond, Keith Neu; Feigl, Eric O.

doi:10.1152/jappl.2000.89.5.1892

Cited by 72 publications

(122 citation statements)

References 48 publications

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“…The presence and importance of ␤ 2 -receptors in human coronary arterioles are further underscored by the finding that salbutamol, a ␤ 2 -receptor agonist, also elicited dilation. The present results are also in accord with the recent reports of Gorman and colleagues, 35,36 who demonstrated in exercising dogs a significant role for feedforward ␤-receptor-mediated sympathetic coronary vasodilation.…”

Section: Sun Et Al ␤ 2 -Adrenoceptors In Human Coronary Circulation 553supporting

confidence: 93%

Norepinephrine Elicits β ₂ -Receptor–Mediated Dilation of Isolated Human Coronary Arterioles

et al. 2002

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Background-The exact role of adrenoceptors in norepinephrine (NE)-mediated regulation of the human coronary circulation has yet to be elucidated. Thus, the goals of this study were to characterize the adrenoceptors involved in the responses to NE in isolated human coronary arterioles and small arteries. Methods and Results-Arterioles (nϭ39) and small arteries from the left ventricle of explanted human hearts were isolated and cannulated. Vessels from the hearts of 21 patients were studied: 15 males and 6 females, aged 0.5 to 63 years. Nineteen patients were considered to be New York Heart Association class 4. All hearts exhibited hypertrophy (190Ϯ20%). The passive diameter of arterioles was 167Ϯ8 m (range 97 to 323 m). NE (10 Ϫ7 to 3ϫ10 Ϫ7 mol/L) elicited concentration-dependent dilations (47Ϯ4 m) that were unaffected by endothelium removal, N -nitro-Larginine (10 Ϫ4 mol/L, an NO synthase inhibitor), or practolol (10 Ϫ6 mol/L, a ␤ 1 -receptor blocker). However, administration of propranolol (10 Ϫ5 mol/L, a combined ␤ 1 -and ␤ 2 -blocker) or butoxamine (10 Ϫ6 mol/L, a ␤ 2 -receptor blocker) completely eliminated the NE-induced dilation. Constrictions to NE (2 of 39 vessels) were inhibited by prazosin (10 Ϫ6 mol/L, an ␣ 1 -receptor blocker). Methoxamine (10 Ϫ9 to 10 Ϫ5 mol/L, an ␣ 1 -agonist) had no effect, whereas U44619, a thromboxane mimetic, elicited dose-dependent constriction of vessels. Conclusions-Our data indicate that isolated human coronary arterioles and small arteries dilate to NE via ␤ 2 -receptors on smooth muscle. These findings are important to our understanding of the mechanisms action of NE in the human coronary circulation. (Circulation. 2002;106:550-555.)

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Section: Sun Et Al ␤ 2 -Adrenoceptors In Human Coronary Circulation 553supporting

confidence: 93%

Norepinephrine Elicits β ₂ -Receptor–Mediated Dilation of Isolated Human Coronary Arterioles

et al. 2002

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“…Because changes in myocardial O 2 extraction were abolished by atrial pacing, one might speculate that partial loss of flow-dependent vasodilation contributes to this phenomenon. Concerning atenolol, we cannot also exclude a role for the loss of ␤-adrenoceptor feedforward vasodilation and/or unopposed ␣-adrenoceptor vasoconstriction (10,17) because the relationship between coronary sinus PO 2 and MV O 2 was significantly steeper with atenolol compared with saline (data not shown). Such an effect has been previously reported with propranolol by Heyndrickx et al (14) showing that, for a given level of exercise, the increases in coronary blood flow and oxygen extraction were respectively lower and higher than those expected if these parameters were only controlled through metabolic autoregulation.…”

Section: Discussionmentioning

confidence: 96%

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

Colin

Ghaleh

Monnet

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

132

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Berdeaux. Contributions of heart rate and contractility to myocardial oxygen balance during exercise. Am J Physiol Heart Circ Physiol 284: H676-H682, 2003. First published October 24, 2002 10.1152/ajpheart.00564.2002The respective contributions of heart rate (HR) reduction and left ventricular (LV) negative inotropy to the effects of antianginal drugs are debated. Accordingly, eight instrumented dogs were investigated during exercise at spontaneous and paced HR (250 beats/min) after administration of either saline, atenolol, or ivabradine (selective pacemaker current channel blocker). During exercise, atenolol and ivabradine (both 1 mg/kg iv) similarly reduced HR (Ϫ30% from 222 Ϯ 5 beats/ min), and LV mean ejection wall stress was not altered. LV dP/dtmax was reduced by atenolol but not ivabradine. Diastolic time (DT) was increased by atenolol versus saline (195 Ϯ 6 vs. 123 Ϯ 4 ms, respectively) and to a greater extent by ivabradine (233 Ϯ 11 ms). Myocardial oxygen consumption (MV O2) was lower under ivabradine and atenolol versus saline (6.7 Ϯ 0.6 and 4.7 Ϯ 0.4 vs. 8.1 Ϯ 0.6 ml/min, respectively, P Ͻ 0.05). Under pacing, DT and MV O2 were similar between ivabradine and saline but significantly reduced with atenolol. Thus HR reduction and negative inotropy equally contribute to the reduction in MV O2 during exercise in the normal heart. The negative inotropy limits the increase in DT afforded by HR reduction. metabolic demand; chronotropy; inotropy; diastolic time ALTHOUGH IT IS WELL KNOWN that reductions in heart rate and myocardial contractility are both major mechanisms involved in the antianginal effect of ␤-blockers, the relative contributions of these two parameters to the therapeutic properties of these drugs are still debated. Heart rate reduction is indeed critical to reduce exercise-induced ischemia by increasing subendocardial myocardial blood flows and diastolic perfusion time (12) and by decreasing myocardial oxygen consumption (MV O 2 ). Accordingly, Guth et al. (13) abolished the anti-ischemic effect of atenolol through atrial pacing during exercise-induced ischemia, suggesting that the negative inotropic effect of this ␤-blocker was negligible in this setting. Furthermore, zatebradine and ivabradine, two selective heart rate-reducing agents devoid of any negative inotropic effect, afforded significant anti-ischemic effects during exercise-induced ischemia in conscious dogs (12, 18) and pigs (16). In contrast, Buck et al. (2) reported only a partial attenuation of the beneficial effects of ␤-blockade on myocardial blood flow distribution and dynamic severity of a proximal coronary artery stenosis after atrial pacing. Two clinical trials using zatebradine failed to reveal any antianginal activity secondary to the sole reduction in heart rate (8, 9). However, in these studies, reduction in heart rate might have induced changes in other determinants of MV O 2 , e.g., loading conditions. Furthermore, in these studies, the potential beneficial effects of heart rate reduction on diastolic time, i.e., o...

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“…In microvessels, ␤-adrenergic dilation during exercise serves as a feedforward mechanism to ensure a better match between myocardial oxygen supply and demand (10,11). Gorman et al (11) using a mathematical model to quantitate interstitial norepinephrine levels, estimated that norepinephrine contributed to ϳ25% of CBF responses to exercise through feedforward ␤-adrenergic dilation.…”

Section: Exercise Levelmentioning

confidence: 99%

“…In addition to NO, ␤-adrenergic receptors directly contribute to conductance vessel dilation during exercise, because their blockade leads to a paradoxical constriction sensitive to ␣-adrenergic receptor blockade (2). In resistance vessels, ␤-adrenergic receptor activation causes dilator responses during exercise and serves as a feedforward mechanism (10,11). In contrast, NO is not essential for increasing CBF and ensuring a close match between myocardial oxygen supply and demand during exercise (1,4,24,25).…”

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confidence: 99%

β-Adrenergic receptor blockade impairs NO-dependent dilation of large coronary arteries during exercise

Okajima

Takamura

Véquaud

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Okajima, Masaki, Masayuki Takamura, Philippe Vé -quaud, Robert Parent, and Michel Lavallé e. ␤-Adrenergic receptor blockade impairs NO-dependent dilation of large coronary arteries during exercise. Am J Physiol Heart Circ Physiol 284: H501-H510, 2003. First published October 3, 2002 10.1152/ajpheart.00419.2002-Shear stress-dependent nitric oxide (NO) formation prevents immoderate vascular constriction. We examined whether shear stress-dependent NO formation limits exercise-induced coronary artery constriction after ␤-adrenergic receptor blockade in dogs. Control exercise led to increases (P Ͻ 0.01) in coronary blood flow (CBF) by 38 Ϯ 5 ml/min from 41 Ϯ 5 ml/min and in the external diameter of epicardial coronary arteries (CD) by 0.24 Ϯ 0.03 mm from 3.33 Ϯ 0.20 mm. CD and shear stress were linearly related. After propranolol, CD fell (P Ͻ 0.01) during exercise (0.08 Ϯ 0.03 from 3.23 Ϯ 0.19 mm), and the slope of the relationship between CD and shear stress was reduced (P Ͻ 0.01). This slope was not further altered by the additional blockade of NO formation. In propranolol-treated resting dogs, flow-dependent effects of intracoronary adenosine to mimic exercise-induced increases in shear stress (after propranolol) led to increases (P Ͻ 0.01) in CD (0.09 Ϯ 0.02 from 3.68 Ϯ 0.27 mm). Thus both shear stress-dependent NO formation and ␤-adrenergic receptor activation are required to cause CD dilation during exercise. Suppression of ␤-adrenergic receptor activation leads to impaired shear stress-dependent NO formation and allows ␣-adrenergic constriction to become dominant. nitric oxide; adrenergic receptors; endothelium; shear stress; coronary vessels NITRIC OXIDE (NO) and ␤-adrenergic receptor activation are the major determinants of large epicardial coronary artery dilation during exercise. In those vessels, endothelium-derived NO formation during exercise is a flow-dependent process, secondary to increases in shear stress (20). Preventing the rise in coronary blood flow (CBF) (20), endothelial denudation (3), or blockade of NO formation (27) blunts large epicardial coronary dilation. Therefore, NO-dependent dilation of conductance coronary arteries during exercise may be considered as a secondary phenomenon triggered by the dilation of resistance coronary vessels. In addition to NO, ␤-adrenergic receptors directly contribute to conductance vessel dilation during exercise, because their blockade leads to a paradoxical constriction sensitive to ␣-adrenergic receptor blockade (2). In resistance vessels, ␤-adrenergic receptor activation causes dilator responses during exercise and serves as a feedforward mechanism (10, 11). In contrast, NO is not essential for increasing CBF and ensuring a close match between myocardial oxygen supply and demand during exercise (1,4,24,25).One intriguing observation is the complete failure of the large epicardial coronary artery to dilate during exercise performed after ␤-adrenergic receptor blockade (2). Despite the elevated shear stress caused by the decrease in large epicardial coro...

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Feedforward sympathetic coronary vasodilation in exercising dogs

Cited by 72 publications

References 48 publications

Norepinephrine Elicits β ₂ -Receptor–Mediated Dilation of Isolated Human Coronary Arterioles

Norepinephrine Elicits β ₂ -Receptor–Mediated Dilation of Isolated Human Coronary Arterioles

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

β-Adrenergic receptor blockade impairs NO-dependent dilation of large coronary arteries during exercise

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Feedforward sympathetic coronary vasodilation in exercising dogs

Cited by 72 publications

References 48 publications

Norepinephrine Elicits β 2 -Receptor–Mediated Dilation of Isolated Human Coronary Arterioles

Norepinephrine Elicits β 2 -Receptor–Mediated Dilation of Isolated Human Coronary Arterioles

Contributions of heart rate and contractility to myocardial oxygen balance during exercise

β-Adrenergic receptor blockade impairs NO-dependent dilation of large coronary arteries during exercise

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Norepinephrine Elicits β ₂ -Receptor–Mediated Dilation of Isolated Human Coronary Arterioles

Norepinephrine Elicits β ₂ -Receptor–Mediated Dilation of Isolated Human Coronary Arterioles