Blood pressure and endocrine effects of single doses of CS-866, a novel angiotensin II antagonist, in salt-restricted hypertensive patients.
OBJECTIVE
This study was conducted to assess the dose-response relationship of the new angiotensin II (Ang II) antagonist CS-866 on blood pressure and on endocrine parameters in hypertensive patients with an activated renin-angiotensin system.


METHODS
Following a four-way crossover protocol, two groups of eight patients with mild-to-moderate hypertension received a sodium-restricted diet (60 mmol daily) and ingested single doses of 2.5, 10 and 40 mg or 5, 20 and 80 mg of CS-866, respectively, or placebo. Twenty-four hour ambulatory blood pressure measurements, plasma renin activity (PRA), Ang II and concentrations of RNH-6270, the pharmacologically active metabolite of CS-866, were monitored up to 24 h after medication.


RESULTS
CS-866 was well tolerated. There was a significant decrease in 24 h diastolic blood pressure (DBP) at all doses of CS-866 above 5 mg. Increasing doses of CS-866 from 2.5 to 10 mg and from 5 to 20 mg lowered the mean 24 h DBP and DBP AUC(0-24h) values considerably more than increasing doses from 10 to 40 mg and from 20 to 80 mg, respectively. The mean 24 h DBP was lowered by 6.9 and 8.4 mmHg after oral doses of 10 and 20 mg CS-866, respectively, compared with placebo and by 8.9 mmHg after 80 mg CS-866. The drug increased PRA and Ang II concentrations in plasma, maximum concentrations of which occurred within 3 h post-dose. The highest RNH-6270 concentrations were also found at the first post-dose measurement 3 h after administration of CS-866.


CONCLUSIONS
The new Ang II receptor antagonist CS-866 is effective and well tolerated. In salt-restricted hypertensive patients, CS-866 lowered blood pressure and increased PRA and Ang II concentrations at low doses. A single oral dose of 10-20 mg CS-866 resulted in almost maximal effects.
Püchler
K
K
Sankyo Europe GmbH, Düsseldorf, Germany.
Nussberger
J
J
Laeis
P
P
Witte
P U
PU
Brunner
H R
HR
D000284:Administration, Oral; D000328:Adult; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000097:blood; D057911:Angiotensin Receptor Antagonists; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D018660:Blood Pressure Monitoring, Ambulatory; D018592:Cross-Over Studies; D004039:Diet, Sodium-Restricted; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000178:diet therapy / Q000188:drug therapy*; D007093:Imidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D000068557:Olmesartan Medoxomil; D011863:Radioimmunoassay; D012083:Renin / Q000097:blood; D012449:Safety; D013777:Tetrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D000068557:Olmesartan Medoxomil; D012083:Renin