Resistance to salt-induced hypertension in catechol-O-methyltransferase-gene-disrupted mice.
BACKGROUND
Previous studies have indicated that catechol-O-methyltransferase (COMT) can modulate renal dopaminergic tone.


OBJECTIVE
To test the hypothesis that COMT blockade protects from salt-induced hypertension.


METHODS
COMT gene-disrupted (-/-) mice and wild-type controls received a high-sodium diet (NaCl 6%) for 3 weeks. Blood pressure and heart rate were recorded by radiotelemetry. Tissue and urine samples were assessed by light microscopy and high-performance liquid chromatography. The effects of nitecapone treatment were also examined. Systolic blood pressure and heart rate during normal sodium diet were similar in COMT (-/-) and wild-type mice. The high-sodium diet increased night-time systolic and diastolic blood pressures in wild-type mice, whereas blood pressure in COMT (-/-) mice remained unaltered. In wild-type mice, the sodium-induced increase in blood pressure was completely normalized by treatment with the COMT inhibitor, nitecapone. At baseline, 24-h urinary excretion of levodopa (L-DOPA), dopamine and noradrenaline was increased by 145, 85 and 74%, respectively, in COMT (-/-) mice compared with wild-type controls. In COMT (-/-) and wild-type mice, a high-sodium diet increased urinary L-DOPA excretion by 405 and 660% (reflected as 102 and 212% increases in dopamine excretion), respectively. The absolute amounts of urinary L-DOPA and dopamine remained 60 and 20% greater in COMT (-/-) mice. The high-sodium diet did not influence renal cortical COMT activity.


CONCLUSIONS
Our findings suggest that COMT deficiency in mice increases the availability of L-DOPA, leading to enhanced dopaminergic tone, which may be associated with resistance to salt-induced hypertension. The findings of the present study also underline the importance of COMT in the regulation of blood pressure, sodium excretion and renal dopaminergic tone.
Helkamaa
Teemu
T
Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
Männistö
Pekka T
PT
Rauhala
Pekka
P
Cheng
Zhong Jian
ZJ
Finckenberg
Piet
P
Huotari
Marko
M
Gogos
Joseph A
JA
Karayiorgou
Maria
M
Mervaala
Eero M
EM
D000818:Animals; D015415:Biomarkers / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002394:Catechol O-Methyltransferase / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D002395:Catecholamines / Q000652:urine; D002940:Circadian Rhythm / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008955:Models, Cardiovascular; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D012982:Sodium, Dietary / Q000008:administration & dosage* / Q000009:adverse effects* / Q000652:urine; D013599:Systole / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects* / Q000235:genetics*; D014664:Vasodilation / Q000187:drug effects
D015415:Biomarkers; D002395:Catecholamines; D012982:Sodium, Dietary; D002394:Catechol O-Methyltransferase