Aliskiren, a novel orally effective renin inhibitor, provides antihypertensive efficacy and placebo-like tolerability similar to an at1-receptor blocker in hypertensive patients

108A

POSTERS: Antihypertensive Drugs

improvement in BP control without metabolic disturbances. The higher the baseline BP values were the greater the lowering effect was. Key Words: Angiotensin Receptor Blocker, Hypertension, Fixed Combination

P-203 EFFECT OF THIOLS ON PEROXYNITRITE: RELATIONSHIP TO BLOOD PRESSURE CHANGES Harvey C Gonick, Stanislav Shelkovnikov. Medicine/Nephrology, West LA VA Hospital, Los Angeles, CA. Of fundamental concern to physiologists is the equation which links the interaction of nitric oxide (NO) and superoxide (O2.⫺) to the formation of peroxynitrite (ONOO) : NO ⫹ O2⫺.fONOO. ONOO is a potent vasodilator, yet its formation is associated with the onset of hypertension. Thiols react with peroxynitrite to form S-nitrosothiols, thus diminishing the concentration of ONOO ( Schrammel A et al: Free Rad Biol Med 34: 1078, 2003). Previous studies have demonstrated that a thiol, dimercaptosuccinic acid (DMSA), can reduce blood pressure in lead-treated rats and prevent the severe vascular and interstitial changes in salt-treated Dahl SS rats (Khalil-Manesh F et al: Environ Res 65:86,1994; Gonick HC et al: Kidney Int 50:1572,1996), while depletion of the intracellular thiol, glutathione, induces hypertension in normal rats (Vaziri ND et al: Hypertension 36:142, 2000). In this study we have compared the ability of three thiols, cysteine, glutathione, and DMSA, to diminish the concentration of ONOO by: 1) a chemical reaction between ONOO, from 5x10⫺6 M to 10⫺4 M, and thiols, 10⫺4 M, using Ellman’s reagent to measure the SH groups of the thiols; 2) an HPLC method to measure the interaction between ONOO, 10⫺4 M, and norepinephrine (NE), 10⫺6 M, with subsequent modification by thiols, 10⫺4 M. Both phosphate buffer, pH 7.4, and Krebs solution were employed.The results in phosphate buffer are listed in the Table. At 10⫺4 M concentration, ONOO destroyed 90 to 100% of NE, but the reaction was modified by addition of thiols, as indicated in the Table. Results in Krebs solution were the same. Thus depletion of ONOO, a vasodilator, was associated with a fall in blood pressure, rather than a rise.Three possible explanations can be offered: 1) a shift in the equation NO ⫹ O2.⫺fONOO to the right would result in a decrease in O2.⫺, a known vasoconstrictor; 2) ONOO stimulates the formation of a vasoconstrictor such as F-2 isoprostanes ( Romeo JC and Reckelhoff JF: Hypertension 34: 143, 1999); or 3) restoration of depleted glutathione levels to normal by thiols. What is clear is that too much emphasis has been placed on an increase in NO accounting for the reduction in blood pressure following thiol administration. Table. Modification of peroxynitrite by thiols Thiols (10ⴚ4 M)

EC50 for ONOO by spectrophotometry

NE by HPLC (control 10ⴚ6 M)

Cysteine Glutathione DMSA

3.3 ⫻ 10⫺5 M 3.5 ⫻ 10⫺5 M 4.5 ⫻ 10⫺5 M

5.0 ⫻ 10⫺7 M 4.2 ⫻ 10⫺7 M 5.6 ⫻ 10⫺7 M

Key Words: Peroxynitrite, Thiols, Blood Pressure

P-204 ALISKIREN, A NOVEL ORALLY EFFECTIVE RENIN INHIBITOR, PROVIDES ANTIHYPERTENSIVE EFFICACY AND PLACEBO-LIKE TOLERABILITY SIMILAR TO AN AT1-RECEPTOR BLOCKER IN HYPERTENSIVE PATIENTS Alan H Gradman, Roland E Schmieder, Robert L Lins, Yanntong Chiang, Martin P Bedigian. The Western Pennsylvania Hospital, Pittsburgh, PA; University of Erlangen-Nurnberg, Erlangen, Germany; A.C.Z.A. Stuivenberg, Antwerp, Belgium; Cardiovascular and Metabolism Clinical Research, Novartis, East Hanover, NJ. Aliskiren is the first in a new class of orally effective, non-peptide renin inhibitors. This dose-finding study compared the antihypertensive effi-

AJH–May 2004 –VOL. 17, NO. 5, PART 2

cacy and safety of aliskiren with placebo and with the AT1-receptor blocker, irbesartan. The study was a randomized, multi-centre, double-blind, placebocontrolled, active comparator 8 week trial in patients with mild-tomoderate hypertension (mean sitting diastolic blood pressure [DBP] ⱖ95 and ⬍110 mmHg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with either once-daily oral doses of aliskiren (150 mg, 300 mg or 600 mg), irbesartan 150 mg, or placebo. The primary efficacy variable of the study was the change from baseline in trough mean sitting DBP. All doses of aliskiren significantly lowered mean sitting DBP and systolic BP (SBP) compared with placebo. Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting DBP by 9.5 ⫾ 8.0, 12.0 ⫾ 8.5 and 11.7 ⫾ 8.8 mmHg respectively versus 6.5 ⫾ 9.0 mmHg for placebo (p⬍ 0.005 versus placebo). Aliskiren 150 mg, 300 mg, and 600 mg lowered mean sitting SBP by 10.8 ⫾ 12.4, 15.5 ⫾ 13.1 and 15.6 ⫾ 14.3 mmHg respectively versus 5.1 ⫾ 16.2 mmHg for placebo (p⬍ 0.001 versus placebo). The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (9.0 ⫾ 7.9 and 12.5 ⫾ 14.2 mmHg reduction in mean sitting DBP and SBP respectively for irbesartan). The effects on mean sitting DBP of aliskiren 300 mg and 600 mg were significantly greater than those obtained with irbesartan 150 mg (p⬍ 0.05). Aliskiren was comparable to placebo and irbesartan with respect to overall safety and tolerability. The percentage of patients reporting adverse events (AEs) was 26.8%, 36.2% and 33.1% with aliskiren 150 mg, 300 mg and 600 mg respectively, compared with 36.6% for irbesartan and 32.1% for placebo. The number of patients discontinuing therapy due to AEs was similar in all groups (range 2.2–3.9%). The results of this study show that once-daily oral treatment with aliskiren lowers blood pressure effectively and that aliskiren 150 mg is comparable in efficacy to irbesartan 150 mg, with an overall safety and tolerability profile comparable to irbesartan and placebo in patients with mild-to-moderate hypertension. Key Words: Hypertension, Renin Inhibitor, Angiotensin Receptor Blocker

P-205 ADMINISTRATION TIME-DEPENDENT EFFECTS ON AMBULATORY BLOOD PRESSURE OF DOXAZOSIN GITS AS ADDED THERAPY IN UNCONTROLLED HYPERTENSIVE PATIENTS Ramon C Hermida, Carlos Calvo, Diana E Ayala, Maria J Dominguez, Manuel Covelo, Artemio Mojon, Jose R Fernandez, Jose E Lopez. Bioengineering and Chronobiology Labs., University of Vigo, Vigo, Spain; Hypertension and Vascular Risk Unit, Hospital Clinico Universitario, Santiago de Compostela, Spain. Previous studies have shown that a single nighttime dose of Doxazosin (DOX), an alpha-adrenergic antagonist with demonstrated antihypertensive effects, reduces blood pressure (BP) throughout day and night [Am J Hyp. 1994;7:844 – 847]. However, the potential differing effects of DOX on BP as a function of its time of administration have not yet been reported. Accordingly, we investigated the administration time-dependent effects on the 24-hour pattern of BP of the new DOX gastrointestinal therapeutic system (GITS) formulation given as added therapy in hypertensive patients. We studied 62 patients with uncontrolled grade 1–2 essential hypertension (26 men), 58.3⫾11.0 years of age, who were already taken an average of 2.7 drugs. Patients were randomly assigned to receive 4 mg/day DOX GITS either on awakening or before bedtime. BP was measured by ambulatory monitoring at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 consecutive hours at baseline and after 3 months of therapeutic intervention. Physical activity was monitored every minute by wrist actigraphy, and the information used to determine diurnal and nocturnal means of BP for each patient according to individual resting time. After DOX GITS on awak-