Effects of chronic neutral endopeptidase inhibition in rats with cyclosporine-induced hypertension.
OBJECTIVE
Cyclosporine (CysA), a potent immunosuppressant, is associated with hypertension and nephrotoxicity. Neutral endopeptidase (NEP) degrades vasoactive peptides, including the natriuretic peptides and endothelin-1 (ET-1). We conducted the present study to determine whether or not the NEP inhibitor, ecadotril, prevents cyclosporine-induced hypertension and to clarify the mechanisms responsible for the hypotensive effects of ecadotril.


METHODS
We studied the chronic effects of ecadotril (30 mg/kg per day) on blood pressure; the production of ET-1 and C-type natriuretic peptide (CNP); endothelial nitric oxide synthase (eNOS) activity; and the expression of messenger RNA (mRNA), for each substance in blood vessels of CysA-induced hypertensive rats.


RESULTS
CysA (25 mg/kg per day) given for 4 weeks increased the blood pressure from 116 +/- 14 mmHg to 159 +/- 15 mmHg, in rats. This increase was blunted by the co-administration of ecadotril (blood pressure: 134 +/- 14 mmHg). CysA increased plasma NEP activity. CysA increased the production of ET-1 and the expression of ET-1 mRNA without affecting CNP synthesis and endothelin converting enzyme (ECE)-1 mRNA expression. CysA decreased the eNOS activity and eNOS mRNA levels. Addition of the NEP inhibitor decreased the synthesis of ET-1 and ET-1 mRNA levels and increased the eNOS activity and the eNOS mRNA levels. Vascular CNP synthesis and ECE-1 mRNA expression in rats treated with ecadotril did not differ from those in rats treated with CysA and ecadotril.


CONCLUSIONS
These results indicate that chronic NEP inhibition may prevent the CysA-induced hypertension by decreasing local ET-1 synthesis and partly increasing vascular nitric oxide production.
Takeda
Y
Y
Second Department of Internal Medicine, School of Medicine, Kanazawa University, Japan.
Inaba
S
S
Furukawa
K
K
Fujimura
A
A
Miyamori
I
I
Mabuchi
H
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015139:Blotting, Southern; D016572:Cyclosporine / Q000633:toxicity*; D015342:DNA Probes / Q000737:chemistry; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D020098:Natriuretic Peptide, C-Type / Q000097:blood / Q000235:genetics; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000097:blood / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D016133:Polymerase Chain Reaction; D011480:Protease Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D015244:Thiorphan / Q000031:analogs & derivatives* / Q000494:pharmacology*
D015342:DNA Probes; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D020098:Natriuretic Peptide, C-Type; C049331:racecadotril; D016572:Cyclosporine; D015244:Thiorphan; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D015260:Neprilysin