Assessment of renin dependency of hypertension with a dipeptide renin inhibitor.
To evaluate the participation of the renin-angiotensin system in sustaining hypertension, we administered the specific dipeptide renin inhibitor enalkiren (A-64662) to 18 patients with essential hypertension. Ascending intravenous bolus doses (0.03, 0.1, 0.3, and 1.0 mg/kg) of the inhibitor were each given at 45-minute intervals to patients maintained on an ad libitum sodium diet who were studied while in bed in the semirecumbent posture. Enalkiren produced marked decreases in plasma renin activity (PRA) that were still evident 8 hours after completion of dosing. Systolic and diastolic blood pressures were decreased in a dose-dependent fashion without an effect on heart rate. Repetition of this procedure after patients were subjected to sodium depletion by 1 week of thiazide treatment produced amplified decreases in blood pressure. Despite the short plasma half-life of the inhibitor, these blood pressure-lowering effects were sustained for 4-8 hours when compared with parallel placebo administration in the same patients. Both the baseline PRA and the inhibitor-induced changes in PRA correlated significantly with blood pressure changes during the unstimulated and the sodium-depleted studies. However, effects of the inhibitor on diastolic blood pressure in the latter study correlated most closely with actual increases in renin produced by diuretic pretreatment. Thus, this specific renin inhibitor has demonstrated the dependency of blood pressure on the renin-angiotensin system even during basal conditions in hypertensive patients. Moreover, renin response to sodium depletion appears to be an attribute that additionally characterizes individual hypertensive patients.
Hypertension Center, Veterans Administration Medical Center, Long Beach, CA 90822.
M A
MA
Weber
J M
JM
Neutel
I
I
Essinger
H N
HN
Glassman
R S
RS
Boger
R
R
Luther
D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood; D004151:Dipeptides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000627:therapeutic use; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011187:Posture; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology*; D012982:Sodium, Dietary / Q000008:administration & dosage; D000092502:Renin Inhibitors
D000450:Aldosterone; D004151:Dipeptides; D006852:Hydrochlorothiazide; D012083:Renin; D012982:Sodium, Dietary; D000092502:Renin Inhibitors; C056622:enalkiren