Infarction alters both the distribution and noradrenergic properties of cardiac sympathetic neurons

Abstract

Regional changes occur in the sympathetic innervation of the heart after myocardial infarction (MI), including loss of norepinephrine (NE) uptake and depletion of neuronal NE. This apparent denervation is accompanied by increased cardiac NE spillover. One potential explanation for these apparently contradictory findings is that the sympathetic neurons innervating the heart are exposed to environmental stimuli that alter neuronal function. To understand the changes that occur in the innervation of the heart after MI, immunohistochemical, biochemical, and molecular analyses were carried out in the heart and stellate ganglia of control and MI rats. Immunohistochemistry with panneuronal markers revealed extensive denervation in the left ventricle (LV) below the infarct, but sympathetic nerve fibers were retained in the base of the heart. Western blot analysis revealed that tyrosine hydroxylase (TH) expression (normalized to a panneuronal marker) was increased significantly in the base of the heart and in the stellate ganglia but decreased in the LV below the MI. NE transporter (NET) binding sites, normalized to total protein, were unchanged, except in the LV, where [3 H]nisoxetine binding was decreased. TH mRNA was increased significantly in the left and right stellate ganglia after MI, while NET mRNA was not. In the base of the heart, increased TH coupled with no change in NET may explain the increase in extracellular NE observed after MI. Coupled with substantial denervation in the LV, these changes likely contribute to the onset of cardiac arrhythmias. tyrosine hydroxylase; norepinephrine transporter; myocardial infarction THE CARDIAC SYMPATHETIC INNERVATION travels from the base to the apex of the heart, and cardiac sympathetic function is altered in a region-specific manner after myocardial infarction (MI). Noradrenergic transmission is retained in the heart basal to the coronary ligature (4, 17), but 90 min after the loss of blood flow, transmission is decreased or absent in the infarct zone and in noninfarcted myocardium apical to the occlusion (4, 17, 18). These changes include the loss of nerve-stimulated effective refractory period shortening (4, 17) and denervation supersensitivity apical to the infarction (18). Decreased cardiac (4,16,22) and increased interstitial (1, 19) and plasma (22, 24) norepinephrine (NE) are also observed acutely after infarction due primarily to efflux of NE through the NE transporter (NET) (33).Loss of noradrenergic function in the infarct zone and in peri-infarct myocardium is retained for weeks or months after infarction. This is revealed by decreased accumulation of metaiodobenzylguanidine (9, 10, 14, 23) and NE (22), the absence of effective refractory period shortening on nerve stimulation (4), and the loss of catecholamine-containing nerve fibers in the left ventricle (LV) apical to the infarction (4). The loss of noradrenergic function, coupled with the absence of catecholamine-containing nerve fibers, is thought to be due to denervation of the infarct and peri-infarct z...

Sympathetic hyperinnervation and inflammatory cell NGF synthesis following myocardial infarction in rats

“…Although the present study confirms peri-infarct hyperinnervation (Cao, et al, 2000a;Cao, et al, 2000b), other studies have reported reduced cardiac sympathetic innervation after infarction (Barber, et al, 1983;Igawa, et al, 2000;Li, et al, 2004). These differences may be related to the extent of infarction as larger infarcts can result in frank congestive heart failure, and this has been linked to cardiac NGF depletion and diminished sympathetic axon density (Kaye, et al, 2000;Qin, et al, 2002).…”

“…Following ischemia-reperfusion, for example, an acute neurochemical change occurs in sympathetic innervation as a consequence of inflammatory cytokine release (Li, et al, 2004). Denervation in the apex of the heart after ischemia-reperfusion can also occur as the infarct may disrupt passage of sympathetic nerves (Barber, et al, 1983).…”

“…After occlusion, infusion of NGF into coronary arteries can prevent this postischemic denervation (Abe, et al, 1997). Denervation is heterogeneous however; indeed seven days after ischemia-reperfusion, sympathetic hyperinnervation foci along with denervated myocardium are also present in the peri-infarct region (Li, et al, 2004). In ischemiareperfusion models therefore, in parallel with denervation, hyperinnervation may also occur.…”

“…Postmortem analyses of infarcted human myocardium show abnormal increases in numbers of sympathetic axons adjacent to the site of injury (Cao, et al, 2000a). Ischemic injury appears to be the cause of the remodeling, as coronary artery ligation induces hyperinnervation in dogs (Lai, et al, 2000;Zhou, et al, 2004) and rats (Ahonen, et al, 1975;Paessens and Borchard, 1980;Holmgren, et al, 1981;Vracko, et al, 1990;Kaye, et al, 2000;Li, et al, 2004). Through enhanced norepinephrine-mediated myocardial depolarization, abnormally increased sympathetic nerve density may be proarrhythmogenic and represent a significant factor in post-infarct sudden cardiac death.…”

Structural changes of the human superior cervical ganglion following ischemic stroke

“…Experimental investigations of rat cardiac sympathetic neurons following myocardial infarction revealed that infarction altered both the distribution and noradrenergic properties of cardiac sympathetic neurons. Apparent sympathetic denervation of the heart after myocardial infarction is accompanied by the loss of norepinephrine uptake and the depletion of neuronal norepinephrine (9,10). Another experimental study revealed that target deprivation produced by visual cortex ablation caused the death of geniculate neurons in the dorsal lateral geniculate nucleus by an apoptotic process after axotomy (11).…”