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A J Drake-Holland and MIM Noble. Excessive vasoconstriction in denervated myocardium due to denervation
supersensitivity to noradrenaline. Medical Physiology Online, 13 Feb 2008, available from
http://www.medicalphysiologyonline.org
Medical Physiology Online
Exploring the logic of life
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of Pharmacy, Robert Gordon University, Aberdeen, AB10 1FR, 2Cardiovascular Medicine, Dept of
Medicine and Therapeutics, University of Aberdeen Medical School, Foresterhill, Aberdeen, AB25 2ZN.
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Prof. AJ Drake-Holland, School of Pharmacy, Robert Gordon University, Aberdeen, AB10
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1FR, E-mail: [email protected]. Prof M I M Noble can be reached at [email protected]
[Received 25 January 2008; first decision 1 February 2008;
revised, accepted and published 13 Feb 2008]
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Cannon’s law states that a chronically denervated structure is supersensitive to the neurotransmitter it is
normally regulated by. However, the present consensus is that myocardial arteriolar resistance vessels are
not supersensitive to noradrenaline following chronic sympathetic denervation of the heart. We present an
extended interpretation of results of a published study in which the volume of distribution of radiolabeled
hydroxyephedrine and blood flow were measured in innervated and denervated regions of the same canine
heart using positron emission tomography. For a given amount of noradrenaline, myocardial blood flow was
lower in denervated than innervated myocardium, indicating denervation supersensitivity. This finding has
implications for patients with cardiac autonomic neuropathy.
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HED – hydroxyephedrine; MBF – myocardial blood flow; PET – positron emission tomography; and Vd –
volume of distribution
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A J Drake-Holland and MIM Noble. Excessive vasoconstriction in denervated myocardium due to denervation
supersensitivity to noradrenaline. Medical Physiology Online, 13 Feb 2008, available from
http://www.medicalphysiologyonline.org
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It is well established that activation of α-adrenergic receptors causes an increase in coronary vascular
resistance [1-4]. Noradrenaline released from sympathetic nerve terminals as well as exogenously
administered noradrenaline administration cause coronary vasoconstriction mediated by ά adrenergic
receptors, coronary vasodilation mediated by ß-adrenergic receptors, and coronary vasodilatation secondary
to metabolic autoregulatory mechanisms accompanying an increase in heart rate and myocardial
contractility. Chronically denervated organs are supersensitive to the neurotransmitter by which they are
normally regulated – “Cannon’s Law” [5]. As Cannon’s law applies particularly to heart rate and contractility
effects [6, 11], it is not easy to study whether it also applies to coronary vascular responses as these are
concomitantly affected by changes in heart rate and myocardial contractility. Additional difficulty arises from
the fact that myocardial vascular resistance is heterogeneous so that if only global values are calculated, false
conclusions could be drawn. In this paper, we present our reinterpretation of data from a study published
recently by Rimoldi et al [7] in which the required discrete measurements were made in canine hearts with
chronic regionally denervated myocardium.
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The paper by Rimoldi et al [7] was published in a nuclear medicine journal so that the discussion presented
here (which we think is of clinical importance) was not addressed earlier. The authors were able to make
measurements of myocardial blood flow (MBF) with positron emission tomography (PET). The intact dogs (n
= 9) were sleeping under a dose regime of α-chloralose less than that required for surgical anaesthesia, the
sedation being required so that the animal rested without motion, other than respiration, within the PET
scanner. Rimoldi et al [7] measured the heterogeneity of MBF as well as sympathetic innervation. MBF was
measured with oxygen-15-labeled water (H215O). The radioisotope
11C-hydroxyephedrine
(11C-HED) is
handled by cells in the same way as noradrenaline; sympathetic innervation was estimated from the volume
11C-HED.
of distribution (Vd) of
As the study protocol did not include the administration of a ß-adrenergic
antagonist, we needed to consider theoretical arguments presented below.
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The methods used by Rimoldi et al [7] provided data on differences in the amount of noradrenaline as well as
blood flow in different parts of the myocardium. As the perfusion pressure is the same everywhere (the
different parts are in the same heart), blood flow is inversely related to resistance to flow. If there were no
sympathetic vascular tone or if the vasoconstrictor and vasodilator effects of α and ß adrenergic receptors
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A J Drake-Holland and MIM Noble. Excessive vasoconstriction in denervated myocardium due to denervation
supersensitivity to noradrenaline. Medical Physiology Online, 13 Feb 2008, available from
http://www.medicalphysiologyonline.org
respectively were equal, then, a statistically significant relationship between content of norepinephrine and
myocardial blood flow would not be expected. If ß–adrenergic tone dominated over α-adrenergic tone, a
positive correlation between local noradrenaline content and blood flow would be expected. On the other
hand, if α-adrenergic vasoconstrictor tone predominated, there would be an inverse relationship between
local noradrenaline content and blood flow.
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It was found that local MBF in various regions within innervated tissue was inversely related to 11C-HED; i.e.,
higher the local noradrenaline content, less the blood flow. The regression equation for this inverse
relationship between MBF and the Vd of 11C-HED is as follows: MBF =1.772 – 0.01 [Vd of HED]; r = 0.72, P =
0.02. This relationship was then compared with that in the denervated part of the heart, where, again, an
inverse relationship was found: MBF = 1.363 – 0.03 [Vd of HED]; r = 0.80, P = 0.01. A comparison of the two
regression lines by analysis of covariance indicated that the positions of these lines were significantly
different (F = 10.8, P = 0.005); i.e., myocardial blood flow for a given Vd of HED was lower in denervated
tissue compared to innervated tissue.
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The interpretation presented here takes into account the theoretical considerations alluded to above. The
11C-HED
inverse relationship between MBF and the Vd of
is interpreted as indicating vasoconstriction
mediated by α-adrenergic receptors outweighs vasodilation mediated by ß-adrenergic receptors in both
innervated and denervated myocardium. We assume, in the unfortunate absence of results following
administration of a ß-adrenergic antagonist, that the proportion of ß to α effects are similar in the two
situations, and that the lower MBF for a given amount of noradrenaline is caused by the supersensitivity of
coronary resistance vessels to noradrenaline. An alternative explanation might be that a ß–adrenergic
vasodilatory contribution to the relationship between norepinephrine content in sympathetic postganglionic
neurons and MBF in the innervated tissue disappears in denervated tissue due to downregulation of ßadrenergic receptors. However there is no evidence of downregulation according to the results of study of the
distribution of the β-adrenergic receptor ligand, 11C-CGP 12177 [7], a finding similar to that of Van der Vusse
et al [8].
Supersensitivity has been denied in the case of coronary vasculature in chronic regionally denervated hearts
because the application of noradrenaline did not alter pressor responses in isolated epicardial arteries [9].
However, epicardial arteries are not resistance vessels and would be subject to the in vitro changes caused by
the perfusion conditions. The only study we could identify from amongst similar studies of resistance vessels
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A J Drake-Holland and MIM Noble. Excessive vasoconstriction in denervated myocardium due to denervation
supersensitivity to noradrenaline. Medical Physiology Online, 13 Feb 2008, available from
http://www.medicalphysiologyonline.org
was a paper suggesting increased MBF in response to intracoronary norepinephrine after ventricular
sympathectomy [10]. However, this may have been secondary to the increased inotropic effect and increased
demand for flow accompanying administration of norepinephrine.
Classic studies of cardiac denervation have involved a surgical technique [6, 11-13] that removed sympathetic
as well as parasympathetic innervation (as is also the case in transplanted hearts). In such chronically
denervated preparations, the increased response to noradrenaline is a well accepted phenomenon: a
tachycardic response is certainly present [6] and so is an increase in myocardial contractility [11], both
confirmed in the study by Drake et al [12]. The heightened contractility response was confirmed using the
alternative method of selective regional sympathetic denervation with phenol [9]. This method [14] also
revealed supersensitivity of the shortening effect of noradrenaline on effective refractory period [15-17].
Supersensitivity following chronic sympathetic denervation of the heart is not accompanied by upregulation
of ß-adrenergic receptors [7, 8, 17]. Supersensitivity has been ascribed to lack of reuptake of norepinephrine
from denervated myocardium following degeneration of sympathetic postganglionic neurons [13]. Thus, an
increase in tissue noradrenaline has a greater effect on the adrenergic receptors in target tissues. Hammond
et al [18] also think that adrenergic denervation supersensitivity in the myocardium depends on a postreceptor mechanism but that it is not linked with increased cyclic AMP production. It would be extraordinary
if supersensitivity of the heart rate response [6] and of the contractility response [11, 13], which are present,
was not accompanied by supersensitivity of arterioles in the same tissue. We are not aware of an exception to
Cannon’s law of denervation.
The clinical implication of our interpretation, if correct, is that a heightened vasoconstrictor response to
noradrenaline (circulating noradrenaline and or noradrenaline diffusing from neighbouring innervated
regions [17]) reaching chronically denervated myocardial resistance vessels would increase the susceptibility
of denervated myocardium (for example in patients with cardiac autonomic neuropathy [19-20] or patients
with transplanted hearts) to ischemia.
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Dr.O.E.Rimlodi and Prof. P.Camici kindly agreed to allow us to discuss these results from their laboratory, in
which we participated. The study was supported by the Coronary Thrombosis Trust, UK.
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none declared
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A J Drake-Holland and MIM Noble. Excessive vasoconstriction in denervated myocardium due to denervation
supersensitivity to noradrenaline. Medical Physiology Online, 13 Feb 2008, available from
http://www.medicalphysiologyonline.org
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The prepublication record for this manuscript MPO-005-2008 containing the draft
manuscript and editor’s comments can be accessed at http://www.medicalphysiologyonline.org
This is an open access article distributed
under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by-ncsa/3.0/
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