The lower medication doses delivered by glyburide/metformin tablets provided a significantly greater reduction in A1C than did glyburide co-administered with metformin in patients with type 2 diabetes, especially when baseline A1C >/= 8%.

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The present studies were designed to determine the action of neutral endopeptidase inhibition (NEP-I), an inhibitor of the degradation of atrial natriuretic factor (ANF), in congestive heart failure (CHF). Studies were conducted in two groups of anesthetized dogs with CHF induced by 8 days of rapid right ventricular pacing. Group 1 (n=5) received a specific NEP-I (SQ 28,603) at two doses administered sequentially-30 mg/kg followed by a 60 mg/kg i.v. bolus. Group 2 (n=5) received intravenous infusion of exogenous ANF (100 ng/kg/min) to achieve increases in plasma ANF concentration as observed in group 1. NEP-I resulted in a diuresis and natriuresis (p

1 There are at least two subtypes of vascular endothelin (ET) receptors. Stimulation of the ETA receptors on vascular smooth muscle cells leads to vasoconstriction, whereas activation of the ETB receptors on endothelial cells elicits vasodilatation. Several reports in the literature have suggested the presence of a vasoconstrictor non-ETA receptor on vascular smooth muscle which has pharmacological similarities to the ETB receptor. The present study was undertaken to determine the location of this ETB-like receptor within the vascular system. 2 Fourteen vascular smooth muscle preparations from six species were used to determine the effect of the ETA receptor antagonist, BQ-123, on concentration-response curves elicited by ET-1 and the ability of the ETB receptor agonist, sarafotoxin S6c, to cause contraction. The vessels fell into two categories. One group was sensitive to BQ-123 and insensitive to sarafotoxin S6c and, thus, probably contained ETA receptors. The other group, with vasoconstrictor ETB-like receptors, was insensitive to BQ-123 and sensitive to sarafotoxin S6c. 3 Vessels from cynomolgus monkeys, when studied in vitro, appeared to contain primarily ETA receptors, although the potency of BQ-123 was quite variable, suggesting the possibility of ETA receptor subtypes. In contrast, both ET-1 and sarafotoxin S6c, given as intravenous injections in conscious monkeys, produced transient, equipotent, and dose-related increases in blood pressure. The highest dose of sarafotoxin S6c (1 nmol kg-', i.v.) also caused a marked secondary depressor response (-80± 6 mmHg) that lasted approximately 10 min. The pressor responses suggest that the vasoconstrictor ETB-like receptors are present in cynomolgus monkeys. 4 The data suggest the presence of two distinct vasoconstrictor ET receptor subtypes on smooth muscle cells. The ETA receptors are primarily located on the high pressure side of the circulation. The vasoconstrictor ETB-like receptors appear to be concentrated on the low pressure side.

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A series of 7-(di)alkyl and spirocyclic substituted azepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. Clear structure-activity relationships with respect to both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) activity in vitro were observed. The best in this series, compound 1g, a geminally dimethylated C-7-substituted azepinone, demonstrated excellent blood pressure lowering in animal models. Compound 1g (BMS-189921) is characterized by a good duration of activity and excellent oral efficacy in models relevant to ACE or NEP inhibition, and its activity is comparable to that of the clinically efficacious agent omapatrilat. Consequently this inhibitor has been advanced clinically for the treatment of hypertension and congestive heart failure.

SUMMARY Synthetic atrial natriuretic factor (Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-AspArg-Ile-Gly-Ala-Gln-Ser-GIy-Leu-Gly-Cys-Asn-Ser-Phe-Arg-TVr-COOH [disulfide bond between cysteines]) was infused intravenously into conscious normotensive and deoxycorticosterone, onekidney, one-clip, and two-kidney, one-clip hypertensive rats. Mean arterial pressure, urine volume, and electrolyte excretion rates were measured during a 20-minute infusion of a single dose (ranging from 0-1520 pmol/min) into each animal; 95 to 380 pmol/minute of synthetic atrial natriuretic factor maximally reduced mean arterial pressure by -20 ± 4, -29 ± 2, and -39 ± 7 mm Hg in normotensive, one-kidney, one-clip, and two-kidney, one-clip hypertensive rats, respectively. In deoxycorticosterone rats, a dose of 760 pmol/minute was required to produce the largest depressor response (-58 ± 12 mm Hg). Sodium excretion increased to 8.8 ± 2.5 ^tEq/minute at 760 pmol/minute in normotensive rats, to 6.5 ± 1 . 1 /xEq/minute at 50 pmol/minute in deoxycorticosterone rats, and to 5.8 ± 1 . 5 /xEq/minute at 95 pmol/minute in one-kidney, one-clip animals. The natriuretic effect was consistently greater at all doses of synthetic atrial natriuretic factor in the two-kidney, one-clip hypertensive model, in which the maximum response was 15.3 ± 4.7 /xEq/minute at 190 pmol/minute. The changes in urine volume and excretion rates of potassium and chloride tended to parallel the increases in sodium excretion in each model. Interestingly, the maximally effective hypotensive dose of synthetic atrial natriuretic factor was different from the maximally effective natriuretic dose in all four groups. Even though its exact mechanisms of action remain unclear, synthetic atrial natriuretic factor appears to be an effective hypotensive and natriuretic agent in several models of conscious hypertensive rats. 1 described the biological actions of atnal extracts in anesthetized rats and reported that atnal natriuretic factor (ANF) induced a natriuretic and a hypotensive response. Shortly thereafter, a direct vasorelaxant effect of atrial preparations was demonstrated in isolated vascular smooth muscle strips.2 "* In addition, urinary guanosine cyclic 3',5'-monophosphate (cGMP) excretion and plasma cGMP concentration were elevated following injection of atrial extracts in anesthetized rats.3 A closely related group of active peptides was later isolated from rat 6 " 11 and human 12 atria, and a peptide containing a 26 amino acid sequence was synthesized l3 The structure of the synthetic ANF is as follows: Arg-Arg-Ser-Ser-CysPhe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Gln-Ser-

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