What rare autonomic disorders can teach us about human cardiovascular pharmacology.

Normal cardiovascular regulation requires intact baroreflex regulation. The efferent portion of the baroreflex arc, which is composed of parasympathetic and sympathetic nerves, is particularly important in this regard. Autonomic failure ensues when the efferent arc is interrupted. Neuronal degeneration within the brain or in the periphery,1,2 enzymatic defects in catecholamine synthesis,3 and autoimmune disorders4 can be causative. Common to all of these syndromes is debilitating orthostatic and postprandial hypotension. Some patients are unable to stand for more than a few seconds before presyncopal symptoms occur. Trivial stimuli, such eating, taking a hot shower, moderate physical exertion, or drinking small amounts of alcohol, can elicit hypotension in these patients. Less recognized is the fact that many autonomic failure patients are hypertensive in the supine position.5 Cardiovascular studies in autonomic failure patients can serve several purposes. First, these studies can provide deeper insight into human physiology and cardiovascular pharmacology, given the extreme phenotype exhibited by the patients. Many patients resemble laboratory “lesioned animals” or “knockout” models in their underlying pathology. Second, cardiovascular studies in autonomic failure patients may provide clues regarding treatment of orthostatic and postprandial hypotension. Finally, studies on supine hypertension in autonomic failure patients may provide mechanisms relevant to “garden variety” essential hypertension. Indeed, techniques to dissect autonomic cardiovascular regulation in rare patients with severe autonomic failure could be successfully applied to more common cardiovascular ailments. One of the more puzzling findings in autonomic failure patients is that, even in severely affected patients, loss of efferent sympathetic function is rarely complete. Some residual efferent nerves appear to be disconnected from central nervous system input, making them truly “autonomic.” Residual sympathetic efferent fibers can be engaged through physiological and pharmacological stimuli. For example, when autonomic-failure patients drink 16 oz of tap water, blood pressure increases profoundly.6 The pressor response appears to be mediated through activation of an osmosensitive spinal sympathetic reflex mechanism7,8 and also occurs in healthy older subjects, albeit to a lesser degree.6 Residual sympathetic nerves can be exploited in the treatment of orthostatic and postprandial hypotension. Shibao et al9 manipulated residual sympathetic activity with yohimbine or pyridostigmine and with a combination of both drugs in patients with severe autonomic failure. The primary goal was gauging influences of these interventions on standing blood pressure. Yohimbine raises sympathetic activity through -2 adrenoreceptor inhibition in the brain. In addition, yohimbine attenuates -2 adrenoreceptor–mediated feedback inhibition of norepinephrine release from adrenergic nerve terminals in peripheral tissues.10 Pyridostigmine increases acetylcholine availability through acetylcholine esterase inhibition. Because acetylcholine is the main neurotransmitter mediating fast transmission in autonomic ganglia, pyridostigmine raises postganglionic adrenergic nerve activity among other actions. Both yohimbine and pyridostigmine have been applied previously in the treatment of symptomatic orthostatic hypotension when responses to nonpharmacological treatments were insufficient.11,12 Shibao et al9 included patients with peripheral and with central autonomic failure. Pure autonomic failure and Parkinson disease patients with autonomic failure composed the peripheral autonomic failure group. Most of the patients with probable central autonomic failure had multiple system atrophy. The main finding in the study was that yohimbine was more effective than pyridostigmine in improving orthostatic hypotension. Surprisingly, the combined use of yohimbine and pyridostigmine was not better than yohimbine alone. In patients with intact baroreflex regulation, moderate yohimbine and pyridostigmine doses hardly raise blood pressure. Why then does blood pressure increase in patients with autonomic failure when given these compounds? That sympathetic stimulants such as yohimbine, pyridostigmine, or water cause more norepinephrine release in autonomic failure patients than in subjects with intact sympathetic nerves is highly unlikely. Indeed, water drinking increases plasma norepinephrine similarly in autonomic failure patients and in healthy subjects.6,13 Thus, a similar increase in endogenous norepinephrine produces a much greater blood pressure increase in patients. Autonomic failure patients are also extremely hypersensitive to exogenous -adrenergic agonists.14 Similar increases in the sensitivity to -adrenoreceptor agonists ensue when sympathetic and parasympathic efferents are acutely interrupted through ganglionic blockade. Loss of baroreflex blood pressure buffering and increased vascular sensitivity may contribute to the pressor hypersensitivity.15 All of these observations are relevant for physicians caring for patients with autonomic failure because they directly The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany. Correspondence to Jens Jordan, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail [email protected] (Hypertension. 2010;56:811-813.) © 2010 American Heart Association, Inc.