Resistance to renal denervation therapy — Identification of underlying mechanisms by analysis of differential DNA methylation
The sympathetic nervous system regulates many different target tissues in the somatic and visceral domains of the body in a differentiated manner, indicating that there exist separate sympathetic pathways that are functionally defined by their target cells. Signals generated by central integration and channelled through the preganglionic neurons into the final sympathetic pathways are precisely transmitted through the para- and prevertebral ganglia and at the neuroeffector junctions to the effector cells. Neurophysiological recordings of activity in postganglionic neurons in skin and muscle nerves using microneurography in human subjects and in skin, muscle and visceral nerves, using conventional recording techniques in anaesthetized animals, clearly show that each type of sympathetic neuron exhibits a discharge pattern that is characteristic for its target cells and, therefore, its function. These findings justify labelling the neurons as muscle vasoconstrictor, cutaneous vasoconstrictor, sudomotor, lipomotor, cardiomotor, secretomotor neurons, etc. The discharge patterns monitor aspects of the central organization of the respective sympathetic system in the neuraxis and forebrain. They can be dissected into several distinct reflexes (initiated by peripheral and central afferent inputs) and reactions connected to central signals (related to respiration, circadian and other rhythms, command signals generated in the forebrain, etc). They are functional markers for the sympathetic final pathways. These neurophysiological recordings of the discharge patterns from functionally identified neurons of sympathetic pathways in the human and in animals are the ultimate reference for all experimental investigations that aim to unravel the central organization of the sympathetic systems. The similarities of the results obtained in the in vivo studies in the human and in animals justify concluding that the principles of the central organization of sympathetic systems are similar, if not identical, at least in the neuraxis, in both species. Future progress in the analysis of the central neuronal circuits that are associated with the different final sympathetic pathways will very much depend on whether we are able to align the human models and the animal models. Human models using microneurography have the advantage to work under awake conditions. The activity in the postganglionic neurons can be correlated with various other (afferent, centrally generated) signals, effector responses, perceptions, central changes monitored by imaging methods, etc. However, human models have considerable limitations. Animal models can be divided into in vivo models and various types of reduced in vitro models. Animal models allow using various methodological approaches (e.g., neurophysiological, pharmacological, modern anatomical tracing methods; behavioural animal models; transgenic animals), which cannot be used in the human. Interaction of the research performed in the human and animals will allow to design animal models that are relevant for diseases in which the sympathetic nervous systems is involved and to trace down the underlying pathophysiological mechanisms. The scientific questions to be asked are formulated on the basis of clinical observations resulting in testable hypotheses that are investigated in the in vivo human and animal models. Results obtained in the in vivo models lead to the formulation of hypotheses that are testable in reduced in vivo and particularly in vitro animal models. Microneurographic recordings from sympathetic postganglionic fibres in the human will keep its place in the analysis of the sympathetic nervous system in health and disease although only relatively few laboratories in the world will be able to keep the standards and expertise to use this approach. Experimental investigation of the organization of the sympathetic nervous system in animal models has changed dramatically in the last 15 years. The number of in vitro models and the methodological diversity have increased. In vivo experimentation on larger animals has almost disappeared and has been replaced by experimentation on rats, which became the species for practically all types of studies on the central organization of the sympathetic nervous system.