Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after beta-adrenergic blockade.

Yusuf, Salim; Theodoropoulos, Stergios; Mathias, Christopher J.; Dhalla, Nazir; Wittes, Janet; Mitchell, Andrew; Yacoub, Magdi H.

doi:10.1161/01.cir.75.4.696

Cited by 132 publications

(24 citation statements)

References 20 publications

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“…The mechanism seems to be an increase in myocardial /-receptor density and/or affinity. [36][37][38] There is also evidence that vigorously exercise-trained normal subjects and even postmyocardial infarction patients develop a significant reduction in effort-induced levels of serum norepinephrine.394 Measurements of circulating catecholamines were not made in the present study, but if such a reduction occurred as a result of our training regimen, it could explain the training bradycardia seen in the eight highly compliant subjects. Another possibility is that the high compliers experienced a "downregulation" in sensitivity of cardiac /3-adrenoreceptors.…”

mentioning

confidence: 79%

Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation.

et al. 1988

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confidence: 79%

Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation.

et al. 1988

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“…Isoproterenol infusions were performed essentially as described by Yusuf et al 13 Subjects rested supine for at least 30 minutes before the start of the study. Heart rate was determined at least twice during the control period (separated by 3 minutes) and until subsequent determinations differed by less than 2 beats/min.…”

Section: Isoproterenol Infusionmentioning

confidence: 99%

Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization.

et al. 1989

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The mechanism responsible for the attenuated heart rate (HR) response to exercise in patients with congestive heart failure (CHF) was investigated in 46 normal subjects and 59 patients with CHF stratified by peak exercise oxygen consumption (Vo2). The peak exercise HR and the increment in HR from rest to peak exercise were decreased in CHF patients, and both correlated strongly with peak Vo2 (r=0.810, p<0.0001; r=0.863, p <0.0001, respectively). Peak exercise norepinephrine level (NE) and the increment in NE from rest to peak exercise were not attenuated in CHF patients. Resting NE was elevated in CHF patients and correlated inversely with peak Vo2 (r=-0.595, p<0.001). However, no significant correlation occurred between peak Vo2 and either peak exercise NE or the exercise increment in NE. The ratio of the exercise increments in HR and NE, an indirect index of sinoatrial node sympathetic responsiveness, was markedly reduced in CHF patients and was inversely related to the severity of exercise impairment. Likewise, the HR response to a graded isoproterenol infusion was markedly reduced in CHF patients. Age-matching of normal subjects and CHF patients did not affect the foregoing observations. Infusion of CHF patients with the phosphodiesterase inhibitor milrinone caused a significant increase in the ratio of the exercise increments in HR and NE. These data strongly suggest that the attenuated HR response to exercise in CHF patients is due, at least in part, to postsynaptic desensitization of the 8-adrenergic receptor pathway. (Circulation 1989;80:314-323) P eak heart rate response to exercise is determined primarily by the magnitude of increase in sympathetic drive to the heart and the ability of f-adrenergic receptors in the sinoatrial node to respond to catecholamines. In patients with congestive heart failure (CHF), the chronotropic response to peak exercise is reduced and may contribute significantly to the impaired cardiac output response to exercise.1-4The mechanism responsible for a reduced chronotropic response to exercise in patients with CHF is not known. Although it is known that both the reflex stimulation of sympathetic nervous system

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“…(Circulation 1989;79:344-349) W e have reported that rabbit and rat heterotopic cardiac allografts analyzed 4 weeks after transplantation have increased f3-adrenergic receptor density and increased isoproterenol-stimulated adenylate cyclase activity presumably due to denervation.1 An increase in cardiac 8-adrenergic sensitivity or 8-receptor density has also been described in several other animal species after denervation of the heart.2-5 Although the heart of human cardiac transplant recipients has been shown to be denervated,6-8 early studies with small numbers of subjects did not demonstrate increased sensitivity to catecholamines.9-1 In contrast, two recent studies have reported increased sensitivity of the transplanted human heart to ,Badrenergic stimulation. 12,13 Increased sensitivity to sympathomimetic amines may result from changes occurring either before or after the presynaptic nerve ending.14 When supersensitivity results from changes occurring before the synapse, it is classically termed "supersensitivity of presynaptic origin. "'15 An example of supersensitivity of presynaptic origin is the adrenergic supersensitivity produced by cocaine's inhibition of the neuronal uptake mechanism.14,15 When supersensitivity results from changes occurring after the synapse, such as an increase in adrenergic receptor density, it is termed "supersensitivity of postsynaptic origin.…”

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confidence: 99%

Beta-adrenergic supersensitivity of the transplanted human heart is presynaptic in origin.

Gilbert¹,

Eiswirth²,

Mealey³

et al. 1989

Circulation

108

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An increase in cardiac P-adrenergic sensitivity or 8-receptor density or both has been described in several animal species after denervating the heart. The transplanted human heart is also denervated and, therefore, may exhibit supersensitivity to /3-adrenergic agonists and an increase in .3-adrenergic receptor density. In 16 patients examined 1-3 months after orthotopic cardiac transplantation, /3-adrenergic receptor density measured by [t211]iodocyanopindolol binding in endomyocardial biopsy specimens was not significantly different in transplant recipients compared with normal controls (transplant=1,429±199, control=1,728±263 fmol/g wet wt; p=NS). However, when normalized to Lowry protein, the ['25lliodocyanopindolol in ,8-adrenergic receptor density in biopsy tissue from transplant recipients was significantly lower than in tissue from controls (transplant=58.1+6.2, control=93.5+13.4 fmol/g Lowry protein; p = 0.011). Atrial sinus node activity of the denervated donor heart and the innervated atrial cuf of the native recipient heart could be detected on the surface electrocardiogram in six patients. In these six patients, the heart rate response to graded infusions of epinephrine (taken up by the adrenergic nerve terminals) and isoproterenol (not taken up by the adrenergic nerve terminals) was measured. The epinephrine dose-response curve in transplanted donor atria was significantly to the left of the native recipient atrial dose-response curve (p < 0.0001). The isoproterenol dose-response curves for native and transplanted atria were not different. We conclude that myocardial 3-adrenergic receptors are not increased in human orthotopic cardiac allografts and that there is no evidence for /3-receptor-mediated supersensitivity of postsynaptic origin. However, human orthotopic cardiac allografts exhibit adrenergic supersensitivity of the sinus node to agents that are ordinarily removed by the neuronal uptake system. This supersensitivity is, therefore, presynaptic in origin and should increase the response of the transplanted heart to circulating epinephrine or norepinephrine. (Circulation 1989;79:344-349) W e have reported that rabbit and rat heterotopic cardiac allografts analyzed 4 weeks after transplantation have increased f3-adrenergic receptor density and increased isoproterenol-stimulated adenylate cyclase activity presumably due to denervation.1 An increase in cardiac 8-adrenergic sensitivity or 8-receptor density has also been described in several other animal species after denervation of the heart.2-5 Although the heart of human cardiac transplant recipients has been shown to be denervated,6-8 early studies with small numbers of subjects did not demonstrate From the Utah Cardiac Transplant Program, Salt Lake City, Utah.

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Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after beta-adrenergic blockade.

Cited by 132 publications

References 20 publications

Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation.

Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation.

Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization.

Beta-adrenergic supersensitivity of the transplanted human heart is presynaptic in origin.

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