N(N)-nicotinic blockade as an acute human model of autonomic failure.
Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N(N)-nicotinic receptors with intravenous trimethaphan (6+/-0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32+/-3 years, 68+/-4 kg, 171+/-5 cm). N(N)-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1+/-0.12 nmol/L (180+/-20 pg/mL) at baseline to 0.23+/-0.05 nmol/L (39+/-8 pg/mL) with trimethaphan (P<.001). There was a more than 16-fold increase in plasma vasopressin (P<.01) and no change in plasma renin activity. We conclude that blockade of N(N)-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N(N)-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N(N)-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.
Jordan
J
J
Autonomic Dysfunction Center, Vanderbilt University, Nashville, Tenn 37232-2195, USA.
Shannon
J R
JR
Black
B K
BK
Lance
R H
RH
Squillante
M D
MD
Costa
F
F
Robertson
D
D
D000328:Adult; D001341:Autonomic Nervous System / Q000503:physiopathology*; D001794:Blood Pressure / Q000502:physiology; D002395:Catecholamines / Q000502:physiology; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D018733:Nicotinic Antagonists / Q000008:administration & dosage*; D011978:Receptors, Nicotinic / Q000502:physiology*; D014294:Trimethaphan / Q000008:administration & dosage*
D002395:Catecholamines; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D014294:Trimethaphan