Protective effect of the calcium antagonist NKY-722 against renal and arterial injuries in Dahl salt-sensitive rats.
OBJECTIVE
To study the effect of long-term administration of NKY-722 and nicardipine on renal dysfunction and morphological changes in the kidneys and arteries in Dahl salt-sensitive (Dahl-S) rats.


METHODS
Vehicle, NKY-722 and nicardipine were administered orally to Dahl-S rats fed a high-salt diet for 6 weeks.


METHODS
Systolic blood pressure was measured once a week. At the last week blood and urine were collected and an autopsy was carried out.


RESULTS
NKY-722 (1 mg/kg per day) lowered blood pressure reproducibly for 6 weeks, whereas nicardipine (3 mg/kg per day) showed a similar effect at week 1 only. NKY-722 tended to decrease blood urea-nitrogen, and reduced plasma creatinine and renin activity significantly. NKY-722 increased urine volume, urinary sodium, creatinine and protein excretions, but did not affect urinary N-acetyl-beta-D-glucosaminidase activity significantly. NKY-722 increased the glomerular filtration rate and reduced glomerulosclerosis and renal arterial injury morphologically. Nicardipine did not affect blood or urinary parameters, but reduced glomerular injury significantly. NKY-722 but not nicardipine reduced cerebral arterial injury. A lower dose of NKY-722 (0.3 mg/kg per day) did not affect blood pressure, blood or urinary parameters, but reduced glomerulosclerosis and renal arterial injury significantly. NKY-722 (1 mg/kg per day) and nicardipine (3 mg/kg per day) increased urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and PGE2. NKY-722 but not nicardipine increased the 6-keto-PGF1 alpha:thromboxane B2 ratio in the thoracic aorta.


CONCLUSIONS
NKY-722 improved the renal dysfunction, and reduced glomerular, renal and cerebral arterial injuries in Dahl-S rats. The effect of NKY-722 on glomerulosclerosis and arterial injuries is, at least partly, independent of blood pressure, and is probably related to the effect on eicosanoid metabolism.
Shirahase
H
H
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
Uehara
Y
Y
Wada
K
K
Shimaji
H
H
Ishimitsu
T
T
Hashizume
Y
Y
Kanda
M
M
Nakamura
S
S
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001158:Arteries / Q000187:drug effects* / Q000293:injuries / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002536:Cerebral Arteries / Q000187:drug effects / Q000293:injuries; D004095:Dihydropyridines / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis; D006973:Hypertension / Q000188:drug therapy; D007668:Kidney / Q000187:drug effects* / Q000293:injuries / Q000502:physiology; D008297:Male; D009529:Nicardipine / Q000494:pharmacology; D051381:Rats; D012077:Renal Artery / Q000187:drug effects / Q000293:injuries; D013928:Thromboxane A2 / Q000096:biosynthesis
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C058351:NKY 722; D013928:Thromboxane A2; D009529:Nicardipine; D011464:Epoprostenol