Relation between dose of bendrofluazide,antihypertensive effect,and adverse biochemical effects.

OBJECTIVE--To determine the relevant dose of bendrofluazide for treating mild to moderate hypertension. DESIGN--Double blind parallel group trial of patients who were given placebo for six weeks and then randomly allocated to various doses of bendrofluazide (1.25, 2.5, 5, or 10 mg daily) or placebo for 12 weeks. SETTING--General practices in Zealand, Denmark. PATIENTS--257 Patients with newly diagnosed or previously treated hypertension, aged 25-70, who had a mean diastolic blood pressure of 100-120 mm Hg after receiving placebo for six weeks. MAIN OUTCOME MEASURES--Reduction in diastolic blood pressure and changes in biochemical variables (potassium, urate, glucose, fructosamine, total cholesterol, apolipoprotein A I, apolipoprotein B, and triglyceride concentrations). RESULTS--All doses of bendrofluazide significantly reduced diastolic blood pressure to the same degree (10-11 mm Hg). Clear relations between dose and effect were shown for potassium, urate, glucose, total cholesterol, and apolipoprotein B concentrations. The 1.25 mg dose increased only urate concentrations, whereas the 10 mg dose affected all the above biochemical variables. CONCLUSION--The relevant range of doses of bendrofluazide to treat mild to moderate hypertension is 1.25-2.5 mg a day. Higher doses caused more pronounced adverse biochemical effects including adverse lipid effects. Previous trials with bendrofluazide have used too high doses.     

Atenolol and bendrofluazide in hypertension.

The effect of atenolol, a new beta-1-adrenergic receptor blocking agent, was studied in a double-blind cross-over trial in 24 carefully selected hypertensive outpatients. After a four-week run-in period on matching placebo each patient received atenolol 200 mg/day, atenolol 400 mg/day, a combination of atenolol 200/mg day with bendrofluazide 5 mg/day, and bendrofluazide 5 mg/day alone, according to a random sequence. Atenolol at either dose produced a significantly greater reduction in all blood pressure levels except standing systolic pressure than bendrofluazide alone. There was no statistically significant difference between the effects of the two atenolol doses on either blood pressure or pulse rate. The addition of bendrofluazide to atenolol resulted in a further significant lowering of the blood pressure. A significant effect of thiazide on weight was noted. The study shows that atenolol, a cardioselective beta-blocker of similar potency to propranolol in animals but without membrane-stabilizing or partial agonist acitivity, is an effective and well-tolerated hypotensive agent.     

Comparison of chlorthalidone and spironolactone in low--renin essential hypertension.

Nineteen patients with uncomplicated essential hypertension and low activity of plasma renin in response to a change from recumbency to an upright posture along with furosemide administration were given spironolactone, 400 mg/d, or chlorthalidone, 100mg/d, in a double-blind, random-sequence, crossover trial. The sequence of treatments was placebo for 2 months, one active drug for 2 months, placebo again for 1 month and the other active drug for 2 months. With both active treatments the average systolic, diastolic and mean arterial pressures decreased significantly. The two agents were equally efficacious in lowering the blood pressure regardless of the severity of hypertension during placebo treatment. Body weight, 24--hour urinary excretion of sodium, the plasma renin activity and the plasma aldosterone level at the end of the initial placebo period did not allow us to predict the response to either drug. Both drugs reduced the body weight and increased the stimulated plasma renin level activity. Chlorthalidone significantly increased the serum uric acid level and significantly reduced the serum potassium level. Three patients experienced orthostatic dizziness during spironolactone therapy, but no adverse symptoms were observed with chlorthalidone therapy. Thus, spironolactone is an effective alternative to thiazide-type drugs in patients with low-renin essential hypertension.     

Effect of the glutathione S-transferase inhibitor, tienilic acid, on biliary excretion of sulphobromophthalein

Tienilic acid, a phenoxyacetic acid diuretic, reduces the amount of total sulphobromophthalein (BSP) excretion in the isolated perfused rat liver (IPRL). This reduction was primarily by reduction in excretion of conjugated BSP, with excretion of unchanged BSP being relatively unaffected. TA also reduces the amount of conjugated BSP formed in vitro, indicating that its effect in the IPRL may be by means of inhibiting the glutathione S-transferase enzymes involved in the formation of the conjugate. It would appear that a reduction in the biliary excretion of BSP cannot be taken to be an indication of reduced liver function in a general sense.     

Contribution of atenolol,bendrofluazide, and hydrallazine to management of severe hypertension.

The efficacy of various combinations of atenolol, bendrofluazide, and hydraliazine given twice daily was assessed in a double-blind trial on 39 patients with moderate to severe essential hypertension. Concurrent treatment with all three drugs proved most effective and produced a mean reduction in blood pressure of 43/31 mm Hg. In the dosage used, hydrallazine affected only the diastolic blood pressure, and when added to either bendrofluazide or bendrofluazide plus atenolol it produced a further mean reduction in pressure of 6 mm Hg. Once-daily treatment with atenolol and bendrofluazide was as effective in reducing blood pressure as the same combination given twice daily, and the hypotensive effect was still present at least 24 hours after the last dose of tablets. A combined tablet of atenolol and bendrofluazide taken once daily would be a simple regimen to follow and would provide almost as much hypotensive effect as a twice-daily regimen incorporating a modest dose of hydrallazine. The hypotensive effect of atenolol was equal to that of bendrofluazide on systolic pressure but significantly better than that of bendrofluazide on diastolic pressure. Atenolol reduced plasma renin and urate concentrations but increased plasma potassium levels. The biochemical effects of atenolol, therefore, may be an advantage over those of bendrofluazide when deciding on first-line treatment for essential hypertension.     

Central antihypertensive properties of muscimol and related gamma-aminobutyric acid agonists and the interaction of muscimol with baroreceptor reflexes.

The central antihypertensive properties of four gamma-aminobutyric acid (GABA) analogs were characterized in anesthetized cats with implanted intracerebroventricular cannulae. An intracerebroventricular infusion (icv) of muscimol, 0.1--0.5 microgram/min (total dose: 1--5 micrograms, icv), substantially reduced mean arterial pressure and slightly reduced heart rate. The compound was not hypotensive at 5 micrograms, iv (total dose) and only slightly hypotensive after an intracisternal injection (5 micrograms). Kojic amine (2-aminomethyl-5-hydroxy-4H-pyran-4-one) and baclofen were also hypotensive following an intracerebroventricular infusion, but they were less active than muscimol. GABA, at 15--150 micrograms/min, icv (total dose, 150--1500 micrograms, icv), was not hypotensive by itself and unlike muscimol its activity was not enhanced in cats pretreated with nipecotic acid, an uptake inhibitor of GABA. The ability of muscimol to interfere with baroreceptor reflexes was considered in experiments in which reflex vasoconstrictor (carotid occlusion) and reflex vasodilatation (acute elevation in mean arterial pressure with norepinephrine) was measured in the perfused hindlimb of cats previously prepared with intracerebroventricular cannulae. Muscimol significantly attenuated the response to bilateral carotid occlusion and completely abolished reflex vasodilatation. The results suggest that GABA agonists and analogs may regulate blood pressure centrally and, through an interaction with the central nervous system, may attenuate baroreceptor reflexes.     

一株降血压功能乳酸菌在模拟胃肠环境中抗性的研究

目的研究具有降血压功能乳酸菌DM9057株对pH、胆汁盐、胃蛋白酶及胰蛋白酶的耐受性。方法以MRS为基础培养基,模拟胃肠环境。结果 DM9057在pH2~3、胆汁盐浓度0.1%~0.3%、胃蛋白酶0.592~1.482μg/mL和胰蛋白酶14.24~72.32 U/g的条件下,37℃培养4 h,活菌数均能达到107CFU/mL以上。结论乳酸菌DM9057能顺利通过胃肠道,达到促进健康的作用。     

Comparison of antihypertensive activity of beta-blocking drugs during chronic treatment.

The hypotensive activity of five beta-adrenoceptor antagonists with different ancillary pharmacological properties was compared in a randomised double-blind factorial trial in 25 untreated patients with stable, uncomplicated essential hypertension. In doses that produced similar reductions in exercise tachycardia all drugs had similar blood-pressure lowering activity, greater on systolic than diastolic pressure and greatest during exercise. With the exception of vasodilator activity the possession of any particular combinaton of ancillary pharmacological properties did not significantly influence the specific antihypertensive activity of these compounds.     

Comparison of solubility properties of alpha-paramyosin, beta-paramyosin and acid-extracted paramyosin.

The solubility properties of paramyosin in the zones of pH and ionic strength in which aggregation occurs were initially studied using preparations isolated by a method originally described by Bailey (Bailey, K. (1956), Pubbl. Stn. Zool. Napoli 29, 26). Other preparations yielding apparently different protein components have been described by Hodge (Hodge, A.J. (1952), Proc. Natl. Acad. Sci., U.S.A. 38, 850) using acid conditions, and Stafford and Yphantis (Stafford, W.F., AND Yphantis, D. (1972), Biochem. Biophys. Res. Commun. 49, 848) have identified alpha-, beta-, and gamma-paramyosin using various times and temperatures of extraction with or without ethylenediaminetetraacetic acid. We have found that acid-extracted paramyosin is very similar if not identical to alpha-paramyosin, but that both acid and alpha forms differ considerably from beta- and gamma-paramyosin. Beta-Paramyosin precipitates abruptly from solution in narrow zone of pH below neutrality, and increases in ionic strength shift the zone of precipitation toward lower pH values. In contrast, both acid and alpha-paramyosin show gradual aggregation with changing pH at lowerionic strength (less than 0.3) but sharp transitions similar to beta-paramyosin at higher ionic strength (greater than 0.3). Transitions were also found at lower pH (ca. 4.0) which were not mirror images of transitions at higher pH (ca. 7.0). Viscosity measurements show that acid extracted paramyosin is close in behavior to a native extract obtained by extraction in mild, nondenaturing media containing mixed antibiotics. Each of these extracts differed considerably from beta-paramyosin. Mild, nonhydrolytic procedures employed by others to remove small, noncovalent bonded components or to separate protein complexes were not effective in converting alpha- to beta-paramyosin. Comparison of extraction procedures strongly supports the suggestion of Stafford and Yphantis that beta- and gamma-paramyosin are hydrolytic products of alpha-paramyosin and that the proteases responsible may be of bacterial origin.     

Comparison of cis and trans fatty acid containing phosphatidylcholines on membrane properties

The ever-increasing amount of trans fatty acids in the human diet has been linked to a variety of afflictions, most notably coronary heart disease and arteriosclerosis. The mechanism of why the replacement of cis fatty acids with their trans counterparts can be detrimental to the health of an individual remains a mystery. Here, we compare the differences in membrane physical properties including molecular dynamics, lateral lipid packing, thermotropic phase behavior, "fluidity", lateral mobility, and permeability between model membranes (lipid monolayers and bilayers) composed of cis- and trans-containing phosphatidylcholines (PCs). The PCs tested have a total of zero, one, two, or four cis (oleic or linoleic) or trans (elaidic or linoelaidic) double bonds. These experiments all confirm the basic hypothesis that trans fatty acids produce membrane properties more similar to those of saturated chains than to those of acyl chains containing cis double bonds; i.e., cis double bonds induce much larger membrane perturbations than trans double bonds.     

Atrial natriuretic peptide, B-type natriuretic peptide, and serum collagen markers after acute myocardial infarction.

Experimental data suggest that atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) act locally as antifibrotic factors in heart. We investigated the interrelationships of natriuretic peptides and collagen markers in 93 patients receiving thrombolytic treatment for their first acute myocardial infarction (AMI). Collagen formation following AMI, evaluated as serum levels of amino terminal propeptide of type III procollagen, correlated with NH(2)-terminal proANP (r = 0.45, P < 0.001), BNP (r = 0.55, P < 0.001) and NH(2)-terminal proBNP (r = 0.50, P < 0.01) on day 4 after thrombolysis. Levels of intact amino terminal propeptide of type I procollagen decreased by 34% (P < 0.001), and levels of carboxy terminal cross-linked telopeptide of type I collagen (ICTP) increased by 65% (P < 0.001). ICTP levels correlated with NH(2)-terminal proBNP (r = 0.25, P < 0.05) and BNP (r = 0.28, P < 0.05) on day 4. Our results suggest that ANP and BNP may act as regulators of collagen scar formation and left ventricular remodeling after AMI in humans. Furthermore, degradation of type I collagen is increased after AMI and may be regulated by BNP.