Large conductance Ca(2+)-activated K(+) channel (BKCa) activating properties of a series of novel N-arylbenzamides: Channel subunit dependent effects.

Large conductance calcium activated potassium channels (BKCa) are fundamental in the control of cellular excitability. Thus, compounds that activate BKCa channels could provide potential therapies in the treatment of pathologies of the cardiovascular and central nervous system. A series of novel N-arylbenzamide compounds, and the reference compound NS1619, were evaluated for BKCa channel opener properties in Human Embryonic Kidney (HEK293) cells expressing the human BKCa channel α-subunit alone or α+ß1-subunit complex. Channel activity was determined using a non-radioactive Rb(+) efflux assay to construct concentration effect curves for each compound. All N-arylbenzamide compounds and NS1619 evoked significant (p <0.05) concentration related increases in Rb(+) efflux both in cells expressing α-subunit alone or α+ß1-subunits. Co-expression of the ß1-subunit modified the Rb(+) efflux responses, relative to that obtained in cells expressing the α-subunit alone, for most of the N-arylbenzamide compounds, in contrast to NS1619. The EC40 values of NS1619, BKMe1 and BKOEt1 were not significantly affected by the co-expression of the BKCa channel α+ß1-subunits. In contrast, 5 other N-arylbenzamides (BKPr2, BKPr3, BKPr4, BKH1 and BKVV) showed a significant (p <0.05) 2- to 10-fold increase in EC40 values when tested on the BKCa α+ß1-subunit expressing cells compared to BKCa α-subunit expressing cells. Further, the Emax values for BKPr4, BKVV and BKH1 were lower in the BKCa channel α+ß1-subunit expressing cells. In conclusion, the N-arylbenzamides studied, like NS1619, were able to activate BKCa channels formed of the α-subunit only. The co-expression of the ß1-subunit, however, modified the ability of certain compounds to active the channel leading to differentiated pharmacodynamic profiles.

Hyperprolactinemia--a review of recent clinical advances.

Since the radioimmunoassay for serum prolactin became available eight years ago, prolactin has become a hormone of considerable clinical interest. An elevated serum prolactin concentration is the most frequent hormone marker for pituitary tumors. Secreted in excess, prolactin causes dysfunction of the hypothalamic-pituitary axis, the gonads, and the adrenal cortex. In women, menstrual disturbances, galactorrhea, infertility, and hirsutism result. Impotence, oligospermia, and decreased libido are common in men. These metabolic abnormalities attributed to prolactin excess are corrected when prolactin concentrations are lowered by either medical or surgical therapy. The availability of effective therapy mandates early recognition and proper management of the patient with hyperprolactinemia.

Oat-bran intake selectively lowers serum low-density lipoprotein cholesterol concentrations of hypercholesterolemic men.

To evaluate selected metabolic effects of plant fibers, we fed control and oat-bran diets in an alternating sequence to eight men with previously documented hypercholesterolemia. The two solid diets differed only in the inclusion of 100 g of oat bran in the test diet. We randomized diet sequences and the measured intakes of carbohydrate, protein, fat, and cholesterol were virtually identical on the two diets. Serum total cholesterol concentrations were stable on control diets whereas a progressive reduction was observed in seven men on oat-bran diets. On oat-bran diets, average reductions in serum total cholesterol concentrations were 13% (p less than 0.01, N = 8); plasma low-density lipoprotein cholesterol concentrations were 14% lower (p less than 0.05) while high-density lipoprotein cholesterol concentrations were not changed. Fasting and postprandial serum glucose, insulin, and triglyceride concentrations were similar on the two diets. Fecal excretion of total bile acids was 54% higher (p less than 0.001) on oat-bran diets than on control diets but neutral steroid excretion was slightly lower while on oat bran. Palatable and inexpensive high-fiber foods such as oat bran may have a role in the treatment of certain patients with hypercholesterolemia.

Colour flow and spectral Doppler imaging after papaverine-induced penile erection in 220 impotent men: study of temporal patterns and the importance of repeated sampling, velocity asymmetry and vascular anomalies.

Of 220 impotent men studied, 52 demonstrated venous leakage, 85 had arterial insufficiency and 65 showed normal vascular response. Persistent diastolic velocity > 7 cm/s diagnosed venous leakage with a sensitivity of 94% and a specificity of 69%, using cavernosography as the reference standard. Using clinical response as the reference standard maximal systolic velocity of 30 cm/s identified normal penile arterial response with a sensitivity of 96% and specificity of 82%. There was a good correlation between penile arterial insufficiency and a strong history of arteriopathy. Time to peak systole > 0.1 s was a reliable predictor of arteriogenic impotence and Pulsatility Index (PI) < 300 was discovered only in patients with either venous leakage or arteriogenic impotence. Peak systolic velocity (Tmax) occurred between 5.2 and 6.5 min after injection, and diastolic velocity was minimal at 9 min with only the normal responders showing reversed diastolic flow. However, 22% had a delayed response (Tmax range 1-18 min). Velocity asymmetry was equally common in the three groups and unilateral sampling would have misdiagnosed 6% of patients studied. Vascular anomalies were seen in 13%, particularly a single feeding artery, dorsal vein flow or collateral arterial flow.

Use of fluoxetine, a selective serotonin-uptake inhibitor, in the treatment of obesity: a dose-response study (with a commentary by Michael Weintraub).

Pharmacologic measures which increase serotonergic activity in the brain decrease food consumption and lead to decreased weight in animals. Fluoxetine, an inhibitor of serotonin reuptake, decreases food intake in animals and is associated with weight loss in depressed and otherwise healthy obese patients. To determine the most effective daily fixed dose which causes weight loss in nondepressed obese patients, fluoxetine (10, 20, 40 or 60 mg) or placebo was administered once daily for 8 weeks to 655 patients consisting primarily of women (mean age 40 years, mean weight 95 kg). Diet and activity were not controlled. The placebo-treated patients lost 0.6 +/- 2.3 kg. With the 60-mg fluoxetine dose, patients lost an average of 4.0 +/- 3.9 kg (P less than 0.001), with intermediate responses at the lower doses. Weight loss was proportional to the initial body mass index (weight/height squared). There were no statistically significant differences between any fluoxetine treatment group and placebo for discontinuations from the study. There were statistically significant dose-dependent increases in reports of asthenia, somnolence and sweating. Thus, fluoxetine 60 mg daily appears to be potentially effective for use in weight reduction.