Abstract-Hypertension in blacks is more prevalent and less often controlled than the hypertension of other ethnic groups.We sought to explore the benefit of adding inhibitors of the epithelial sodium channel (ENaC), an aldosterone-regulated site of sodium reabsorption in the distal nephron, to the antihypertensive regimen of black hypertensive patients. In a prospective, randomized, placebo-controlled, double-blind clinical trial, we used a 2-by-2 factorial design with 4 treatment groups: amiloride (a direct inhibitor of ENaC), spironolactone (an aldosterone receptor antagonist), the combination of both drugs, and placebo. The subjects (nϭ98) had an elevated blood pressure despite treatment that included a diuretic and a calcium channel blocker; the level of plasma renin activity was Յ0.56 ng/L per second. The primary end points were changes from baseline in systolic and diastolic blood pressure over a 9-week period of treatment. The reductions in systolic and diastolic blood pressures (mm Hg) were, respectively, 9.8Ϯ1.6 (SE) and 3.4Ϯ1.0 for amiloride (PϽ0.001) and 4.6Ϯ1.6 (Pϭ0.006) and 1.8Ϯ1.0 for spironolactone (Pϭ0.07). Treatment with either amiloride or spironolactone or the combination was well tolerated; no patient experienced hyperkalemia. In a substudy, plasma endothelin-1 levels were observed to decrease after 3 weeks of treatment with spironolactone (PϽ0.001), consistent with a non-ENaC-related potential benefit of spironolactone. In conclusion, treatment with either amiloride or spironolactone can provide an additional reduction in blood pressure in blacks already receiving conventional antihypertensive therapy.
PR1 cells are a prolactin (PRL)-secreting cell line derived from a pituitary lactotroph tumor found in 17-estradiol-treated Fischer 344 rats. We examined the effect of estrogen on cell proliferation and PRL synthesis under various culture conditions. Estrogen, at extremely low concentrations, induces cell proliferation in this cell line, whereas antiestrogen inhibits proliferation. Interestingly, the proliferation response is much more sensitive than the PRL response because 0.01 pM estradiol or diethylstilbestrol induces half-maximal growth induction [Ϸ0.1% estrogen receptor (ER) occupancy is required], whereas 0.01 nM concentration is required for half-maximal PRL induction (Ϸ50% ER occupancy is required). The proliferation response is not as sensitive to antiestrogen as the PRL response, because 10 nM concentration of the pure antiestrogen ICI 182,780 could not inhibit 1 nM estradiol-or diethylstilbestrol-induced proliferation. The same concentration of ICI 182,780 decreased PRL secretion to 1% of estradiol-or diethylstilbestrol-induced prolactin secretion suggesting a possible dichotomy of ER control of proliferation and PRL synthesis. The K d of ER binding in these cells is about 3 ؋ 10 ؊11 M. These results with the PR1 cells extend previous studies in other estrogenregulated systems and suggest that only a small pool of ER is required for cell proliferation in contrast with the regulation of expression of specific genes. They also raise questions as to how a dimeric receptor functions when only one ligand site is occupied or when both an estrogen and an antiestrogen occupy one dimer.Estrogen is a physiological regulator of both replication and prolactin (PRL) synthesis in pituitary lactotrophs. Pituitaries of the Fischer 344 (F344) rat strain form tumors in response to 6-10 weeks of estrogen treatment (1-3). The GH3 cell line was derived from the radiation-induced MtT͞W5 transplantable pituitary tumor (4), and the GH4C1 cell line was subcloned from the GH3 cell line (5, 6). These cell lines are somatolactotrophs that secrete both PRL and growth hormone and in some cases proliferate on estrogen treatment (7-9). However, the response of these cell lines has been variable, with some investigators reporting no effect or negative effects of estrogen on proliferation (9-12), whereas others reported estrogen-stimulated proliferation (13, 14).In the above-mentioned research, replication was more sensitive than PRL synthesis to estrogen. GH4C1 pituitary tumor cell growth was 10-fold more sensitive to estrogen than PRL mRNA accumulation (14). GH3 cells showed maximum cell growth at 0.01 nM 17-estradiol (E2), whereas only half-maximal PRL production occurred at the same concentration (13). These data, although interesting, did not lead to any additional studies.We have studied the relationship between estrogen-induced cell proliferation and PRL expression by using a newly established pituitary cell line (PR1) from E2-treated F344 female rats (15). The cell growth response in this cell line is 1,000-fold mor...
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