ANIMAL MODELS OF AUTONOMIC FAILURE

We will investigate two experimental models of autonomic disorders in rats: 1) the well established postganglionic sympathectomy induced by guanethidine, and 2) a novel model of preganglionic sympathectomy induced by antibodies to acetylcholinesterase. These models will be compared with each other, the results will also be used to assess the degrees of correspondence to patients with pure autonomic failure (PAF) and multiple system atrophy with autonomic failure (MSA). Morphometric studies of the spinal cord and sympathetic ganglia will be performed with NADPH-diaphorase histochemistry and tyrosine hydroxylase immunohistochemistry to define the location and severity of losses of pre- and postganglionic sympathetic neurons. Pharmacologic experiments involving cardiovascular responses to direct and indirectly acting drugs will aid in characterizing the pathophysiology of the animal models for comparison with their human counterparts. Catecholamine release and metabolism will be studied intensively by HPLC determinations on plasma and urine samples obtained at rest and after mild immobilization stress. Resting and stimulated levels of neuropeptides and selected peptide hormones will also be examined. We expect the results taken together will support the view that guanethidine sympathectomy is a good model for PAF, while antibody-induced preganglionic sympathectomy, in its peripheral manifestations, is a close analog of MSA.