Chlorotyrosine exerts renal effects and antagonizes renal and gastric responses to atrial natriuretic peptide.
3-Chloro-L-tyrosine (3CT) is an inhibitor of tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. In vivo inhibition of tyrosine hydroxylase results in lower catecholamine levels. 3CT (0.5 mg/kg), administered as a bolus i.v. to anesthetized uninephrectomized rats, elicited increases of 72% and 44% in urinary sodium concentration and volume, respectively, whereas a dose of 1 mg/kg caused increases of 27% and 29%. 3CT, 1 mg/kg, resulted in a 2-fold increase in plasma aldosterone (ALD); 0.5 mg/kg was without significant effect. At a dose of 1 mg/kg 3CT significantly antagonized the renal effects of atrial natriuretic peptide (ANP) (1.5 micrograms kg-1 min-1 by intrarenal infusion), expressed as an enhanced excretion of urine volume (102 +/- 14 vs. 70 +/- 11 microliters/min) and sodium (16.1 +/- 1.8 vs. 11.5 +/- 1.7 microEq/min) and increased osmolar clearance (171 +/- 12 vs. 144 +/- 13 microliters/min). A dose of 0.5 mg/kg of 3CT did not produce these same responses to ANP. The increased urine flow caused by 3CT may reflect reduced norepinephrine synthesis. The inverse dose-effect relationship of 3CT on urine flow rate may result from concomitant depletion of dopamine (DA) and elevated circulating ALD. The antagonism of 3CT on responses to ANP is not at the receptor level, because 3CT did not compete for [125I] ANP binding or inhibit ANP-stimulated guanylate cyclase in kidney cell membranes. It was proposed that the reduced basal sympathetic and renal DA tone, together with the elevated ALD level, account for this antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)
Chen
Q M
QM
Department of Pharmacology and Therapeutics, University of Manitoba, Faculty of Medicine, Winnipeg, Canada.
Smyth
D D
DD
McKenzie
J K
JK
Glavin
G B
GB
Gu
J G
JG
Geiger
J D
JD
LaBella
F S
FS
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D002552:Cerebral Ventricles; D004231:Diuresis / Q000187:drug effects; D004789:Enzyme Activation; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009318:Natriuresis / Q000187:drug effects; D011188:Potassium / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors*
D014443:Tyrosine; D009320:Atrial Natriuretic Factor; D014446:Tyrosine 3-Monooxygenase; D006162:Guanylate Cyclase; D011188:Potassium; C087259:3-chlorotyrosine