Coronary Vessel Supersensitivity to Noradrenaline in the Presence of Chronic Sympathetic Denervation

Cardiac autonomic neuropathy almost certainly plays an important role in diabetic heart disease according to Draman, et al.[1]. The generally accepted concept of denervation supersensitivity is that, in the chronic absence of the neural innervation, the response of neurotranmiter applied to the organ evokes an exaggerated response when compared with the innervated case. The present analysis explores this phenomenon in the instance of noradrenaline (the neurotransmitter of the sympathetic system) applied to denervated myocardium. Nor adrenaline causes both alpha and beta receptor effects on ventrricular myocardium, the former being vasocontricion, and the latter increased contractility and vasodilation, which may be due to increased blood flow and shear-stress-induced dilation. We here concern ourselves with the dominant alpha-adrenergically mediated vascular constriction. Such supersensitivity has been denied in the case of the coronary vasculature in chronic regionally denervated hearts because the responses of isolated epicardial arteries, to applied nor-adrenaline, are not altered [2]. Classic studies of cardiac denervation involved a surgical technique [3-5] that removed the sympathetic and parasympathetic innervation (as is also the case in transplanted organs). In those preparations the increased response to noradrenaline in chronically denervated tissue is a well-accepted phenomenon that is certainly present in sinus node and myocardium as far as tachycardic responses and contractility responses are concerned [3,4]. Using the alternative method of selective regional sympathetic denervation with phenol, supersensitivity of the shortening effect on effective refractory period by noradrenaline was demonstrated [6,7]. Chronic sympathetic denervation supersensitivity is not accompanied by upregulation of ß-adrenergic receptors [8-10]. The mechanism is thought to be that chronically denervated myocardium lacks the sympathetic neuronal re-uptake mechanism, the neurones having degenerated [5]. Thus, any increase in tissue noradrenaline has a greater effect on the adrenergic receptors of the target tissue. It would be extraordinary if supersensitivity of the heart rate response and of the contractility response were present, but not present Abstract