Muscle sympathetic nerve activity and renal responsiveness to atrial natriuretic factor during the development of hepatic ascites.
OBJECTIVE
Sodium retention in cirrhosis has been attributed to an imbalance between vasoconstrictive antinatriuretic forces such as the sympathetic nervous system and vasodilatory natriuretic agents such as atrial natriuretic factor (ANF). With the development of refractory ascites, cirrhotic patients become unresponsive to the natriuretic effect of ANF. Animal data suggest that the sympathetic nervous system plays a key role in mediating the refractoriness to ANF. We therefore studied the relationship between sympathetic nerve activity (SNA) and the natriuretic response to ANF in normal subjects and cirrhotic patients. We also attempted to localize the intrarenal site of refractoriness to ANF by lithium clearance.


METHODS
Twenty-six patients with biopsy-proven cirrhosis and seven age- and sex-matched normal volunteers were studied after a week of 20 mmol/day sodium intake and no diuretics. Muscle SNA was recorded from the peroneal nerve (microneurography) and correlated with responsiveness to a 2-hour ANF infusion. Lithium clearance was used as a marker of sodium reabsorption proximal to the intramedullary collecting duct, the main site of ANF action. Plasma norepinephrine, renin, and aldosterone levels were also determined. Patients were categorized into three groups: nine patients free of ascites (by ultrasonography), five ascitic patients who responded to a 2-hour ANF infusion (i.e., had a natriuretic response to ANF above 0.83 mmol/hour), and 12 ascitic patients who did not respond.


RESULTS
Muscle SNA was greatly increased in the ascitic nonresponder patients compared with the normal subjects (64 +/- 4 versus 27 +/- 7 bursts/minute, p less than 0.001), moderately increased in ascitic responders (47 +/- 6 bursts/minute, p less than 0.05), but not significantly increased in nonascitic patients with cirrhosis (34 +/- 5 bursts/minute). SNA was positively correlated with plasma norepinephrine levels (r = 0.69; p less than 0.005) and inversely correlated with peak sodium excretion during the ANF infusion (r = -0.63; p less than 0.001). Plasma renin activity and aldosterone were markedly elevated in ascitic nonresponders, and normal in ascitic responders and nonascitic patients. Lithium clearance was reduced in ascitic patients compared with nonascitic patients, did not change after the ANF infusion, and correlated inversely with SNA (r = -0.61; p less than 0.01).


CONCLUSIONS
These results support the concept that the sympathetic nervous system is a factor in renal sodium handling in cirrhosis, especially in the initiation of sodium retention and the development of refractory ascites. Refractoriness to ANF might be explained, at least in part, by increased neurally mediated sodium reabsorption proximal to the intramedullary collecting duct, the main site of ANF action.
Morali
G A
GA
Department of Medicine, University of Toronto, Ontario, Canada.
Floras
J S
JS
Legault
L
L
Tobe
S
S
Skorecki
K L
KL
Blendis
L M
LM
D000328:Adult; D000450:Aldosterone / Q000097:blood; D001201:Ascites / Q000097:blood / Q000150:complications / Q000378:metabolism*; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage / Q000097:blood / Q000502:physiology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008094:Lithium / Q000378:metabolism; D008103:Liver Cirrhosis / Q000097:blood / Q000150:complications / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009132:Muscles / Q000294:innervation*; D009638:Norepinephrine / Q000097:blood; D012083:Renin / Q000097:blood; D012720:Severity of Illness Index; D012964:Sodium / Q000378:metabolism* / Q000652:urine; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D014883:Water-Electrolyte Imbalance / Q000097:blood / Q000150:complications / Q000378:metabolism*
D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D008094:Lithium; D012964:Sodium; D012083:Renin; D009638:Norepinephrine