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.
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
H
H
Shirahase
Y
Y
Uehara
K
K
Wada
H
H
Shimaji
T
T
Ishimitsu
Y
Y
Hashizume
M
M
Kanda
S
S
Nakamura
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