Reduced natriuretic response to acute sodium loading in COMT gene deleted mice.
BACKGROUND
The intrarenal natriuretic hormone dopamine (DA) is metabolised by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). Inhibition of COMT, as opposed to MAO, results in a potent natriuretic response in the rat. The present study in anaesthetized homozygous and heterozygous COMT gene deleted mice attempted to further elucidate the importance of COMT in renal DA and sodium handling. After acute intravenous isotonic sodium loading, renal function was followed.


RESULTS
COMT activity in heterozygous mice was about half of that in wild type mice and was zero in the homozygous mice. MAO activity did not differ between the genotypes. Urinary sodium excretion increased 10-fold after sodium loading in wild type mice. In heterozygous and homozygous mice, the natriuretic effects of sodium loading were only 29 % and 39 %, respectively, of that in wild type mice. Arterial pressure and glomerular filtration rate did not differ between genotypes. Baseline norepinephrine and DA excretions in urine were elevated in the homozygous, but not in heterozygous, COMT gene deleted mice. Urinary DA excretion increased after isotonic sodium loading in the wild type mice but not in the COMT gene deleted mice.


CONCLUSIONS
Mice with reduced or absent COMT activity have altered metabolism of catecholamines and are unable to increase renal DA activity and produce normal natriuresis in response to acute sodium loading. The results support the hypothesis that COMT has an important role in the DA-mediated regulation of renal sodium excretion.
Dept of Medical Cell Biology, University of Uppsala, Biomedical Centre, Uppsala, Sweden. cecilia.odlind@physiology.uu.se
Cecilia
C
Odlind
Ilkka
I
Reenilä
Pekka T
PT
Männistö
Risto
R
Juvonen
Staffan
S
Uhlén
Joseph A
JA
Gogos
Maria
M
Karayiorgou
Peter
P
Hansell
D015102:3,4-Dihydroxyphenylacetic Acid / Q000652:urine; D000818:Animals; D001794:Blood Pressure / Q000235:genetics / Q000502:physiology; D002394:Catechol O-Methyltransferase / Q000172:deficiency* / Q000235:genetics*; D002395:Catecholamines / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000502:physiology / Q000652:urine; D005260:Female; D017353:Gene Deletion; D005919:Glomerular Filtration Rate / Q000235:genetics / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D007552:Isotonic Solutions / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008995:Monoamine Oxidase / Q000378:metabolism; D009318:Natriuresis / Q000235:genetics* / Q000502:physiology; D012964:Sodium / Q000378:metabolism*
D002395:Catecholamines; D007552:Isotonic Solutions; D015102:3,4-Dihydroxyphenylacetic Acid; D012964:Sodium; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D004298:Dopamine