Restoration of endothelial cell function by chronic cicletanine treatment in Dahl salt-sensitive rats with salt-induced hypertension.
The effects of chronic cicletanine (CICL) treatment on endothelial cell function were investigated in Dahl salt-sensitive (Dahl S) rats. Forty-four six-week-old Dahl S rats were divided into four groups: i) 10 Dahl S rats fed a low-salt (0.3% NaCl) diet and given vehicle, ii) 12 Dahl S rats fed a high-salt (4% NaCl) diet and given vehicle, iii) 11 low-dose (10 mg/kg body weight/d) CICL-treated Dahl S rats fed a high-salt diet, and iv) 11 high-dose (30 mg/kg body weight/d) CICL-treated Dahl S rats fed a high-salt diet. The rats were maintained on the respective salt regimen for 12 wk and treated with cicletanine for the last 6 wk, after which various parameters of endothelial cell function were determined. Systolic blood pressure, measured by the tail-cuff method, was reduced significantly by high-dose cicletanine (223 vs. 195 mmHg, p < 0.01). Scanning electron microscopy revealed that high-dose CICL attenuated endothelial injury in the aorta of Dahl S rats. Arterial lesions in the heart and glomerulosclerosis in the kidney were significantly reduced by treatment with high-dose CICL. Moreover, prostacyclin (PGI2) and prostaglandin E2 (PGE2) generation in the aortic wall was significantly increased by 28% (p < 0.005) and by 149% (p < 0.001), respectively, by high-dose CICL. Nitric oxide (NO) generation in the aortic walls was significantly increased by high-dose CICL (0.38 vs. 15.4 pmol/cm2/30 min, p < 0.001). This effect was accompanied by a 47% increase in cGMP synthesis in the vascular walls. In contrast, the synthesis of PGI2, PGE2, and NO in the kidney slices did not differ significantly among the four experimental groups. In addition, the generation of vasodilatory substances inversely correlated with the score of vascular lesions in the heart and kidney. The results suggested that the blood pressure reduction by chronic cicletanine treatment in Dahl S rats is associated with an improvement in endothelial cell function. The increased release of vasodilatory substances from endothelial cells may contribute to the blood pressure reduction and attenuation of vascular injury observed with cicletanine treatment.
Hirawa
N
N
Second Department of Medicine, University of Tokyo, Japan.
Uehara
Y
Y
Kawabata
Y
Y
Akie
Y
Y
Ichikawa
A
A
Funahashi
N
N
Goto
A
A
Omata
M
M
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001835:Body Weight; D004039:Diet, Sodium-Restricted; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D011464:Epoprostenol / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000178:diet therapy / Q000188:drug therapy*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008855:Microscopy, Electron, Scanning; D009569:Nitric Oxide / Q000378:metabolism; D009924:Organ Culture Techniques; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012965:Sodium Chloride / Q000009:adverse effects; D014665:Vasodilator Agents / Q000378:metabolism
D000959:Antihypertensive Agents; D011725:Pyridines; D014665:Vasodilator Agents; D009569:Nitric Oxide; D012965:Sodium Chloride; C038068:cicletanine; D011464:Epoprostenol; D015232:Dinoprostone