Attenuation of exercise-induced myocardial ischemia in dogs with recruitment of coronary vasodilator reserve by nifedipine.

Heusch, Gerd; Guth, Brian D.; Seitelberger, Rainald; Ross, John

doi:10.1161/01.cir.75.2.482

Cited by 85 publications

(22 citation statements)

References 49 publications

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“…Larger, controlled trials looking at the effect of ␣-blockade in patients with chronic stable angina are lacking and are probably worthwhile only with agents that do not block presynaptic ␣ 2 -adrenoceptors and thus do not increase norepinephrine release but are nevertheless effective at postsynaptic ␣ 2 -adrenoceptors, which appear more important than ␣ 1 -adrenoceptors in mediating ␣-adrenergic coronary vasoconstriction. Such requirements are well met by calcium antagonists that may counteract ␣-adrenergic coronary constriction in both the experimental 64 and clinical setting. 65 …”

Section: ␣-Adrenergic Coronary Vasoconstriction During Interventionsmentioning

confidence: 99%

α-Adrenergic Coronary Vasoconstriction and Myocardial Ischemia in Humans

et al. 2000

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Abstract-The use of quantitative coronary angiography, combined with Doppler and PET, has recently been directed at the study of ␣-adrenergic coronary vasomotion in humans. Confirming prior animal experiments, there is no evidence of ␣-adrenergic coronary constrictor tone at rest. Again confirming prior experiments, responses to ␣-adrenoceptor activation are augmented in the presence of coronary endothelial dysfunction and atherosclerosis, involving both ␣ 1 -and ␣ 2 -adrenoceptors in epicardial conduit arteries and microvessels. Such augmented ␣-adrenergic coronary constriction is observed during exercise and coronary interventions, and it is powerful enough to induce myocardial ischemia and limit myocardial function. Recent studies indicate a genetic determination of ␣ 2 -adrenergic coronary constriction. (Circulation. 2000;101:689-694.)Key Words: coronary disease Ⅲ ischemia Ⅲ microcirculation Ⅲ nervous system Ⅲ receptors, adrenergic, alpha U nder normal circumstances, small coronary arteries and arterioles with a diameter of Ͻ300 m are the principal determinants of coronary vascular resistance. 1 These vessels receive autonomic innervation, and their diameter is altered by activation of these nerves. 2 In animal experiments, there is little ␣-adrenergic coronary vasomotor tone at rest, and the increase in coronary blood flow during sympathetic activation is only somewhat blunted. When the coronary circulation, however, is impaired by hypercholesterolemia, 3 endothelial dysfunction, 4 exhaustion of autoregulation, 5 or severe coronary stenosis, 6,7 ␣-adrenergic vasoconstriction becomes unrestrained and powerful enough to reduce coronary blood flow and initiate myocardial ischemia. 8 Both ␣ 1 -and ␣ 2 -adrenoceptors mediate coronary vasoconstriction, and there is a gradient with ␣ 1 -adrenoceptors more predominant in larger vessels and a reverse gradient with ␣ 2 -adrenoceptors more predominant in the microcirculation. 5,9 Surprisingly, isolated coronary arterioles of a size that constricts in vivo to ␣ 1 -adrenoceptor activation are unresponsive in vitro, 10 and cardiomyocytes on ␣ 1 -adrenergic activation release endothelin, which causes arteriolar constriction. 11 In the past, the study of ␣-adrenergic coronary vasoconstriction in humans has been limited by a lack of adequate techniques to quantify coronary blood flow and myocardial perfusion. In the last decade, quantitative coronary angiography has allowed quantification of the diameter of coronary arteries to Ϸ0.5 mm. Study of the human coronary microcirculation is indirect 12 and relies on parameters such as coronary flow velocity, measured invasively with Doppler flow probes, or myocardial blood flow, quantified noninvasively with PET. 13 Recently, these techniques have become widely available and directed toward the study of ␣-adrenergic coronary vasoconstriction in humans. Moreover, selective ␣ 1 -and ␣ 2 -agonists and -antagonists are now available for clinical use. The antagonist approach is used to study the endogenous ␣-adrenergic coronary vasocon...

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Section: ␣-Adrenergic Coronary Vasoconstriction During Interventionsmentioning

confidence: 99%

α-Adrenergic Coronary Vasoconstriction and Myocardial Ischemia in Humans

et al. 2000

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“…This is not necessarily a disadvantage: Because the coronary reserve distal to a severe stenosis on a coronary artery is already exhausted [37], calcium-channel blockers will particularly dilate intact coronary arteries, thus inducing a flow redistribution and "stealing" blood flow from the ischemic region [30]. This latter property was challenged after it had been demonstrated that calciumchannel blockers could also preferentially increase ischemic subendocardial blood flow [38].…”

Section: Effect On Myocardial Oxygen Demand-supply Balancementioning

confidence: 99%

Effect of a bradycardic agent on the isolated blood-perfused canine heart

Schipke

Harasawa

Sugiura

et al. 1991

Cardiovasc Drug Ther

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Bradycardic agents could limit the consequences of myocardial ischemia via two mechanisms: by decreasing myocardial oxygen demand (MVO2) and by increasing diastolic coronary blood flow (CBF). We investigated whether the benzazepinone UL-FS 49 affects only sinus node cells or also smooth muscle and/or myocardial cells. To avoid confounding interactions with the periphery, we performed experiments on 11 isolated, blood-perfused canine hearts. Injection of UL-FS 49 (1 mg/kg i.c.) significantly reduced heart rate (HR) from 104 +/- 7 to 93 +/- 7 min-1 (mean +/- SEM) and increased stroke volume (n = 6: 9.8 +/- 1.1 vs. 13.2 +/- 1.6 ml), so that cardiac output remained unchanged (n = 6: 1.1 +/- 0.1 vs. 1.2 +/- 0.1 l/min). The contractile state, assessed by isovolumic peak systolic pressure, was unaltered by UL-FS 49 (n = 5: 72 +/- 6 vs. 72 +/- 6 mmHg). At a constant coronary arterial pressure (CAP) of 80 mmHg, mean CBF was slightly decreased (102 +/- 11 vs. 97 +/- 10 ml/[min.100 g]) by UL-FS 49, such that mean coronary resistance remained unchanged (0.9 +/- 0.1 vs 1.0 +/- 0.1 mmHg.min.100 g/ml). The slight decreases in arteriovenous oxygen content difference (n = 6: 6.6 +/- 0.7 vs. 6.5 +/- 0.7 ml/100 ml) and in CBF lead to a calculated, significant decrease in MVO2 (n = 6: 6.9 +/- 0.5 vs. 6.0 +/- 0.4 ml.100 g/min). In conclusion, UL-FS 49 at the dose used decreases MVO2 by reducing HR in isolated canine hearts. In the absence of negative inotropic and vasodilating effects, cardiac output is maintained via increased stroke volume, and CAP will likely be preserved in situ. Thus, this specific bradycardic agent could be useful in treating ischemic myocardial disease.

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“…Whereas some vasodilating drugs (e.g., dipyridamole, chromo,mr) are prone to induce a coronary steal phenomenon [33,34], calcium antagonists such as nifedipine increase blood supply to both the uncompromised myocardium and the poststenotic ischemic regions [35,36]. In clogs, nisoldipine enhanced coronary collateral flow to poststenotic regions with a comparable distribution to the epicardial and endocardial layers [37 I.…”

Section: Discussionmentioning

confidence: 99%

Vasodilatory effects of nisoldipine on coronary arteries—Correlation with plasma levels

Jost

Rafflenbeul

Mogwitz

et al. 1990

Cardiovasc Drug Ther

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Vasomotion of angiographically normal and stenotic epicardial coronary arteries was analyzed up to 15 minutes after the onset of an intravenous infusion (4 minutes) of 0.5 mg (13 patients, group A) or 1 mg nisoldipine (13 patients, group B). After both doses the maximal increase of the mean diameters of normal coronary segments was achieved not before the 15th minute, averaging 11 +/- 6% in group A (p less than 0.001) and 18 +/- 9% in group B (p less than 0.001). Eleven of 15 and 8 of 9 coronary stenoses in groups A and B dilated to 5-80% and 15-70%, respectively. The nisoldipine concentration reached maximal levels at the end of the infusion (fourth minute) with an average of 8 +/- 4 ng/ml and 17 +/- 7 ng/ml in groups A and B, respectively. A significant correlation between nisoldipine plasma levels and dilation of normal coronary segments was obtained only with the individual maxima of these parameters and only in group A (p less than 0.01). The hysteresis of the coronary dilation in relation to the drug plasma levels may be due to the high receptor affinity of nisoldipine. In either group nisoldipine provoked a persistent increase in coronary sinus oxygen saturation (p less than 0.01) and a substantial and prolonged drop in systolic and diastolic aortic pressure (p less than 0.001). Both doses of nisoldipine induced a rise in heart rate (p less than 0.01) and a slight drop in the rate-pressure product (p less than 0.05).

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Attenuation of exercise-induced myocardial ischemia in dogs with recruitment of coronary vasodilator reserve by nifedipine.

Cited by 85 publications

References 49 publications

α-Adrenergic Coronary Vasoconstriction and Myocardial Ischemia in Humans

α-Adrenergic Coronary Vasoconstriction and Myocardial Ischemia in Humans

Effect of a bradycardic agent on the isolated blood-perfused canine heart

Vasodilatory effects of nisoldipine on coronary arteries—Correlation with plasma levels

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