Preventive effect of iganidipine on renal and cerebral injuries in salt-induced hypertension.
Iganidipine, a new water-soluble calcium antagonist, was administered at a nonhypotensive dose (NHD) of 0.3 mg/kg/day, a moderate-hypotensive dose (MHD) of 1.0 mg/kg/day, and a sustained-hypotensive dose (SHD) of 3.0 mg/kg/day to Dahl salt-sensitive (Dahl-S) rats fed a high-salt diet for 8 weeks. The effects on survival, and on renal and cerebral injuries, were then examined. Iganidipine completely prevented hypertensive death at the SHD and tended to increase the survival at the NHD and MHD. Iganidipine reduced glomerulosclerosis and renal arterial and tubular injuries in a dose-dependent manner. Iganidipine at the SHD, but not NHD or MHD, improved plasma creatinine, serum urea nitrogen, and glomerular filtration rate. Iganidipine at all doses examined increased the urinary prostaglandin (PG) I2 and PGE2, but not PGF2alpha or thromboxane B2, and decreased plasma angiotensin II (AII) level and renin activity. The renal glomerular, tubular, and arterial injuries were significantly correlated with blood pressure (r = 0.56 to 0.80) and plasma AII level (r = 0.50 to 0.71) but not with urinary prostanoids. Iganidipine also reduced the incidence of cerebral infarction. The infarction area was slightly and significantly correlated with urinary PGI2 (r = 0.42) and PGE2 (r = 0.41) but not with blood pressure or plasma AII. In conclusion, iganidipine prevented renal and cerebral injuries in Dahl-S rats. In addition to the reduced blood pressure, the reduction of plasma AII and the increase of vasodilatory prostanoids may also partially contribute to the renal and cerebral protective effects of iganidipine.
Shirahase
H
H
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Japan.
Wada
K
K
Uehara
Y
Y
Nakamura
S
S
Ichikawa
A
A
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015777:Eicosanoids / Q000652:urine; D005919:Glomerular Filtration Rate; D005923:Glomerulosclerosis, Focal Segmental / Q000473:pathology / Q000517:prevention & control; D006973:Hypertension / Q000150:complications*; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D018377:Neurotransmitter Agents / Q000097:blood; D010879:Piperazines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D011919:Rats, Inbred Strains; D012077:Renal Artery / Q000473:pathology; D051437:Renal Insufficiency / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D017673:Sodium Chloride, Dietary
D002121:Calcium Channel Blockers; D015777:Eicosanoids; D018377:Neurotransmitter Agents; D010879:Piperazines; D011725:Pyridines; D017673:Sodium Chloride, Dietary; C108540:iganidipine