cyclic-gmp and Dizziness

This multicentre, double-blind, placebo-controlled, parallel-group study determined the efficacy and safety of GW660511 200 mg, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in mild-to-moderate hypertensive patients (diastolic blood pressure (DBP), > or =90 and < or =109 mm Hg; systolic blood pressure (SBP), > or =150 and < or =180 mm Hg). After a single-blind 2- to 4-week placebo run-in period, 123 patients (aged 18-65 years) were randomized to either placebo (n=62) or to active treatment (n=61) consisting of two consecutive 3-day dose titration periods of GW660511X 50 mg once daily and 100 mg once daily followed by GW660511X 200 mg once daily for 14 days. GW660511X 200 mg significantly lowered (baseline and placebo-corrected) both trough mean cuff SBP (-8.00 mm Hg, P=0.002) and DBP (-5.38 mm Hg, P=0.003). GW660511X 200 mg significantly reduced placebo-corrected mean 24-h and daytime but not night-time ambulatory SBP and DBP. Over the 0-24 h time period following GW660511X 200 mg, there were significant (P<0.001) reductions in serum ACE activity and significant (P<0.001) increases in plasma ANP concentration compared with placebo in terms of both peak and trough effects. In addition, treatment with GW660511X 200 mg significantly (P=0.003) increased (placebo-corrected, 1.52-fold) urinary excretion of cGMP over the 0-24 h interval. Treatment-related adverse events were experienced by 43% of the patients administered GW660511X 200 mg and 44% of those dosed with placebo with headache the most commonly reported. In conclusion, GW660511X 200 mg is an effective antihypertensive in mild-to-moderate hypertensive patients with potent effects on biological markers of ACE and NEP inhibition.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dizziness; Double-Blind Method; Female; Headache; Humans; Hypertension; Male; Middle Aged; Neprilysin; Peptidyl-Dipeptidase A; Placebos; Thiazoles; Treatment Outcome

This study reports the effects of a short-term (60 min) low-dose (20 ng x kg(-1) x min(-1)) infusion of synthetic urodilatin (URO) in patients with liver cirrhosis. URO is a natriuretic peptide. A total of 15 cirrhotic patients with ascites and nine without ascites participated in a randomized, double-blind, placebo-controlled study in a crossover design. Renal hemodynamics were estimated by a clearance technique using radioactive tracers, and tubular handling of sodium was evaluated by the lithium clearance method. The renal effects of URO were characterized by a significant increase in urine sodium excretion rate (UNa) and urine flow rate (V) in the cirrhotic patients without ascites (UNa: 173%; V: 94%) and with ascites (UNa: 219%, P < 0.01; V: 42%, P < 0.01) when compared with placebo infusions. Fractional excretion of sodium increased significantly, indicating a tubular effect of URO on sodium handling. Filtration fraction, lithium clearance (a marker of end-proximal fluid delivery), and fractional excretion of lithium increased, fractional proximal tubular sodium reabsorption decreased, and absolute proximal tubular sodium reabsorption remained unchanged, suggesting increased delivery of isotonic fluid from the proximal tubule during URO infusion. In addition, a significant decrease in fractional distal tubular sodium reabsorption contributed to the natriuresis. In conclusion, URO improved sodium and urine output in cirrhotic patients with and without ascites by enhancing fluid delivery from the proximal tubules in addition to inhibiting fractional sodium reabsorption in the distal nephron.

Topics: Adult; Ascites; Atrial Natriuretic Factor; Cyclic GMP; Diuretics; Dizziness; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Infusions, Intravenous; Kidney Tubules; Lithium; Liver Cirrhosis; Male; Middle Aged; Natriuresis; Peptide Fragments; Renal Plasma Flow, Effective; Renin-Angiotensin System; Second Messenger Systems