Valsartan in heart failure patients previously untreated with an ACE inhibitor.

OBJECTIVE: To evaluate the effect on cardiac hemodynamic parameters of valsartan in patients with chronic stable congestive heart failure previously untreated with ACE inhibitors. METHODS: After a 2 to 4 week run-in period, 116 adult outpatients were randomized to receive valsartan 40, 80 or 160 mg twice daily, the ACE inhibitor lisinopril 5/10 mg once daily, or placebo. At baseline and after 28 days of treatment, cardiac hemodynamic parameters were measured. Tolerability was assessed by adverse events and by any changes in systolic or diastolic blood pressure, body weight, heart rate, and routine laboratory parameters. RESULTS: For the 12 hour time point (trough), all doses of valsartan reduced mean pulmonary capillary wedge pressure (statistically significant for valsartan 40 mg and 160 mg), decreased systemic vascular resistance (statistically significant for all three valsartan doses and for lisinopril at peak and trough), and increased cardiac output (statistically significant for all three valsartan doses at peak, and for 80 and 160 mg at trough). There were no clinically relevant effects on any safety parameters. CONCLUSIONS: Valsartan has beneficial effects on cardiac hemodynamics, and is generally well tolerated in patients with congestive heart failure not taking ACE inhibitors.

Biogenesis of the yeast vacuole (lysosome). The precursor forms of the soluble hydrolase carboxypeptidase yscS are associated with the vacuolar membrane.

We have studied the structure, biosynthesis, intracellular routing, and vacuolar localization of carboxypeptidase ysCS in the yeast Saccharomyces cerevisiae. Nondenaturing polyacrylamide gel electrophoresis revealed two forms of carboxypeptidase yscS with different electrophoretic mobility. Antibodies specific for carboxypeptidase yscS recognized two glycoproteins of 77- and 74-kDa apparent molecular mass which differ by one N-linked carbohydrate residue. Both observations suggest that carboxypeptidase yscS exists in two catalytically active forms. The enzyme was found to be synthesized as two active high molecular mass precursor forms which are converted to the mature forms with a half-time of 20 min. The mature forms of carboxypeptidase yscS appeared soluble in the vacuolar lumen, while the precursor proteins accumulated tightly associated with the vacuolar membrane. The single hydrophobic domain present at the N terminus is believed to be responsible for the membrane association of the precursor molecules. Double mutants defective in proteinase yscA and proteinase yscB synthesize solely the carboxypeptidase yscS precursor forms. Correct proteolytic cleavage of the precursor forms was performed using purified proteinase yscB in vitro. Sec61, sec18, and sec7 mutants, conditionally defective in the secretory pathway, accumulate carboxypeptidase yscS precursor protein. Thus the carboxypeptidase yscS precursor molecules are delivered to the vacuole in a membrane bound form via the secretory pathway. After assembly into the vacuolar membrane, proteinase yscB presumably cleaves the precursor molecules to release soluble carboxypeptidase yscS forms into the lumen of the vacuole. The proposed mechanism is different from the delivery mechanism found for the other soluble vacuolar hydrolases in yeast.

Carboxypeptidase yscS: gene structure and function of the vacuolar enzyme.

The gene encoding carboxypeptidase yscS in Saccharomyces cerevisiae, CPS1, was cloned by complementation of the cps1-3 mutation. The cloned CPS1 gene, which again enabled a leucine auxotrophic cps1-3 mutant to grow on the modified dipeptide Cbz-Gly-Leu (Cbz, benzyloxycarbonyl) as sole leucine source, was sequenced and found to consist of an open reading frame of 1728 bp encoding a protein of 576 amino acids. The putative protein contains a hydrophobic stretch of 20 amino acids and a putative signal sequence cleavage site. Five putative N-glycosylation sites are also in the protein sequence. This data is consistent with the previous finding of carboxypeptidase yscS being a vacuolar peptidase. Chromosomal disruption of the CPS1 gene completely abolishes carboxypeptidase yscS activity. This protein is yet another member of the peptidases in S. cerevisiae involved in nitrogen metabolism.