A 3-month double-blind cross-over study of the effect of benazepril and hydrochlorothiazide on functional class in symptomatic mild heart failure.

The non-sulfhydryl selective angiotensin-converting enzyme inhibitor benazepril (20 mg daily) was compared with hydrochlorothiazide (50 mg daily) in post-infarction (6-24 months) patients with symptomatic (NYHA functional class 2) mild heart failure. No concomitant drug therapy was given. The study had a double-blind cross-over design with 3-month treatment periods. Both drugs were well tolerated, and both caused a similar reduction in systolic blood pressure. Heart rate was higher with the diuretic. Benazepril improved the NYHA functional class in 17 out of 29 (59%) patients, whereas one patient improved with hydrochlorothiazide (P = 0.0004). With regard to global efficacy score, benazepril was also superior. Thus, angiotensin-converting enzyme inhibitors may be superior to diuretics as first-choice therapy in symptomatic mild heart failure.     

The treatment of hypertension

1 A 'retrospective' of the development of the drug treatment of hypertension is presented from the early days of ganglion blockers to the present time together with a review of the evidence of benefit from treatment.
2 Current issues and debates are summarised including shortfalls in the control of hypertension in populations, difficulties surrounding the measurement of blood pressure, disagreement on the levels of blood pressure to treat, the goal blood pressures to aim at, issues surrounding lifestyle measures such as the low salt diet and low intensity exercise, and treatment with diuretics and with calcium antagonists.
3 A 'perspective' is presented on some avenues for progress in the years ahead. These will include the identification of genetic markers to determine the hypertensive individuals with the greatest risk of death and of cardiovascular complications.     

Felodipine or Hydrochlorothiazide/Triamterene for Treatment of Hypertension in the Elderly: Effects on Blood Pressure, Hypertensive Heart Disease, Metabolic and Hormonal Parameters

Trenkwalder P, Plaschke M, Aulehner R, Lydtin H. Felodipine or Hydrochlorothiazide/Triamterene for Treatment of' Hypertension in the Elderly: Effects on Blood Pressure, Hypertensive Heart Disease, Metabolic and Hormonal Parameters.

The aim of the study was to compare the antihypertensive efficacy of either felodipine or the diuretic combination hydrochlorothiazide/triamterene in a group (n = 65) of elderly (≥70 years) hypertensives (office blood pressure ≥ 60/95 mmHg) with special regard to ambulatory blood pressure monitoring, hypertensive heart disease and metabolic parameters. This was a randomized, double-blind study with a treatment period of 6 months. Reduction of office and 24-hr ambulatory blood pressure was comparable with both treatment regimens; after 6 months, 18 of 29 patients in the felodipine group (62%) and 20 of 27 patients in the diuretic group (74%; p = 0.4) were controlled. While episodes of ischemic type ST-segment depression were significantly reduced in the felodipine group (from 49 to 9 episodes), there was no significant change in the diuretic group (from 24 to 21 episodes). Both regimens decreased left ventricular wall thickness, but the decline in left ventricular muscle mass index was significant only for felodipine. Felodipine did not induce any change in metabolic or hormonal parameters; the diuretic combination significantly increased serum creatinine, uric acid, plasma renin activity, and plasma prorenin. Thus, the antihypertensive efficacy of felodipine and the diuretic combination was comparable in elderly hypertensives; only felodipine, however, improved parameters of hypertensive heart diesease and showed a neutral metabolic and hormonal profile.     

A comparison of three diuretic regimens in heart failure

Abstract. Eight patients with mild heart failure were treated in random order for 1 week with 2 mg bumethanide at 0800 and 1200 (treatment I) h, 1 mg bumethanide at 0800, 1200, 1800, 2200 (treatment 2) and 5 mg bendroflumethiazide at 0800 and 1800 (treatment 3) h. The 'quality of life' did not differ significantly between the three treatment periods. At the presumed trough of the diuretic effect the circulating blood volume was largest during treatment 1; it was 6.3% smaller during treatment 2 ( P< 0.02) and 6.7%) lower during treatment 3 (P<0.05). In comparison with treatment 1, the maximal increase in rate-pressure product during physical exercise was 24.6% higher in treatment 3. Compared with treatment 1 the area under the curve (AUC) for plasma lactate during physical exercise was 14% lower during treatment 2 (P<0.05) and 18% lower during treatment 3 (P<0.01). These findings suggest that the type of program for diuretic therapy influences the magnitude of inevitable diurnal fluctuations in body fluids, the ability of the heart to work and the ability of the body to adjust to the oxygen demand.     

Substrate specificity of the luminal Na+-dependent sulphate transport system in the proximal renal tubule as compared to the contraluminal sulphate exchange system

The efflux of [³⁵S]sulphate from the lumen of the proximal renal tubule into tubular cells of rats was measured by the stop-flow tubular-lumen microperfusion technique. The transport parameters obtained and the apparent K _i values of competing substrates were compared with those of the contraluminal influx of [³⁵-S]sulphate from the interstitium into tubular cells. For the luminal sulphate efflux a K _m(l, SO ₄ ^2– ) of 0.8 mmol/l and a J _max(l, SO ₄ ^2– ) of 0.2 pmol s^–1 cm^–1 were found. The corresponding contraluminal values were K _m(cl,SO ₄ ^2– ) 1.4 mmol/l and J _max(cl, SO ₄ ^2– ) 1.2 pmol s^–1 cm^–1. Omission of Na⁺ from the perfusates reduced the luminal efflux of sulphate by 83%, while the contraluminal influx of sulphate was not changed. Increase in HCO ₃ ^– concentration inhibited both luminal efflux and contraluminal influx of sulphate, while a change of pH from 6.0 to 8.0 was without effect. Comparing the apparent K _i(SO ₄ ^2– ) values for luminal and contraluminal sulphate transport, a relationship close to 11 was seen for some inorganic substrates with tetrahedral molecular structure (thio-sulphate, sulphate, molybdate and selenate). The same holds for phosphate, while for oxalate the contraluminal K _i(SO ₄ ^2– ) value was lower than the luminal one (1.2 and 4.5 mmol/l). Some of the dicarboxylates and disulphonates tested show the same affinity to the luminal Na⁺-dependent sulphate transporter and the contraluminal sulphate exchange system, whereas most of the benzene carboxylate and benzenesulphonate derivatives tested exhibit higher luminal than contraluminal k _i values. The inhibitory potency increased with rising numbers of substituents on the benzene ring. This effect was more pronounced for the contraluminal sulphate transporter. In general, only disulphonates and analogues as well as similarly structured compounds (5-sulphosalicylate, 2-hydroxy-5-nitrobenzenesulphonate, eosine-5-isothiocyanate) have a good inhibitory potency toward the luminal sulphate transporter [apparent K _i 0.9–3.1 mmol/l]. All the tested sulphamoyl and phenoxy diuretics, and fluorescein and phenolphthalein dyes showed no or a smaller inhibitory potency to the luminal sulphate transport system than to the contraluminal. The most effective inhibitors of both sulphate transport systems are 8-anilino-1-naphthalenesulphonate, orange G, and H₂-DIDS. The data indicate that the Na⁺-dependent luminal and the Na⁺-independent contraluminal sulphate transport systems accommodate a similar spectrum of anionic substrates, whereby the inhibitory potency against the luminal Na⁺-dependent sulphate transport system is identical or smaller than against the contraluminal transporter.     

Isolated perfused rabbit colon crypts: stimulation of Cl− secretion by forskolin

The aim of this study was to characterize ion conductances and carrier mechanisms of isolated in vitro perfused rabbit colonic crypts. Crypts were isolated from rabbit colon mucosa and mounted on a pipette system which allowed controlled perfusion of the lumen. In non-stimulated conditions basolateral membrane voltage (V _b1) was –65±1 mV (n=240). Bath Ba²⁺ (1 mmol/ l) and verapamil (0.1 mmol/l) depolarized V _b1 by 21±2 mV (n=7) and 31±1 (n=4), respectively. Lowering of bath Cl^– concentration hyperpolarized V _b1 from –69±3 to –75±3 mV (n=9). Lowering of luminal Cl^– concentration did not change V _b1. Basolateral application of loop diuretics (furosemide, piretanide, bumetanide) had no influence on V _b1 in non-stimulated crypts. Forskolin (10^–6 mol/l) in the bath depolarized V _b1 by 29±2 mV (n=54) and decreased luminal membrane resistance. In one-third of the experiments a spontaneous partial repolarization of V _b1 was seen in the presence of forskolin. During forskolin-induced depolarization basolateral application of loop diuretics hyperpolarized V _b1 significantly and concentration dependently with a potency sequence of bumetanide > piretanide furosemide. Lowering bath Cl^– concentration hyperpolarized V _b1. Lowering of luminal Cl^– concentration from 120 to 32 mmol/l during forskolin-induced depolarization led to a further depolarization of V_b1 by 7±2 mV (n=10). We conclude that V_b1 of rabbit colonic crypt cells is dominated by a K⁺ conductance. Stimulation of the cells by forskolin opens a luminal Cl^– conductance. Basolateral uptake of Cl^– occurs via a basolateral Na⁺ : 2Cl^– : K⁺ cotransport system.     

Serotonin antagonists and vascular protection

Summary There is very suggestive evidence for a role of serotonin release from platelets in the mechanisms for platelet aggregation, arterial thrombosis, and arterial spasm. These effects are mediated via the 5HT₂ receptor and are specifically antagonized by ketanserin. The recently published PACK study was a randomized controlled trial of the effects of ketanserin in patients with intermittent claudication. The purpose of the trial was to discover whether ketanserin treatment would reduce the incidence of atherosclerotic complications such as myocardial infarction or stroke. An unexpected adverse interaction between ketanserin and potassium-losing diuretics was observed, causing an excess of deaths in the group taking this combination of drugs. The intention-to-treat analysis showed no overall difference between ketanserin and placebo in terms of cardiovascular complications. Withdrawal of patients taking potassium-losing diuretics left insufficient numbers of patients in the study to answer the original question. However, the on-treatment analysis excluding those taking the combination suggested strongly, although did not prove, that ketanserin reduced thrombotic episodes by about 25%. It is concluded that the risks of interactions between many drugs and potassium-losing diuretics make the use of the latter undesirable. Further studies on ketanserin, possibly combined with thromboxane A₂ inhibitors, seem highly desirable.     

氯化钾缓释片对充血性心力衰竭104例的保钾疗效

充血性心力衰竭患者１０４例（正在使用地高辛加排钾利尿剂）随机均分为氯化钾缓释片（Ｓｌｏｗ－Ｋ）及普通氯化钾片（ＲＫＣｌ）２组进行保钾治疗２ｗｋ,而后改换进入另１组作自身对照。结果：Ｓｌｏｗ－Ｋ组治疗１ｗｋ末血钾即显著增加,服药承受性较好;ＲＫＣｌ组治疗２ｗｋ末血钾才显著增加,且服药承受性较差,不良反应高达２６．９％。＊Ｐ＜０．０１。±２８９ｍｇ／ｄ）。在验证过程中所用利尿剂剂量不变。３观察项目服药前测血钾（Ｋ）、钠（Ｎａ）、氯（Ｃｌ）、肌酐（Ｃｒ）、尿素氮（ＢＵＮ）和心电图。服药后每１ｗｋ复查Ｋ,Ｎａ,Ｃｌ和心电图,每２ｗｋ加复查Ｃｒ和ＢＵＮ。结果Ｓｌｏｗ－Ｋ组１０４例患者全部完成研究。ＲＫＣｌ组在研究过程中共脱落１３例（其中坚持出院者３例,心衰严重救治无效而死亡３例,因胃肠道不良反应难以耐受而改服Ｓｌｏｗ－Ｋ导致研究中断者７例）,故能完成统计分析者为９１例。血清电解质治疗前后的变化２组治疗前的血Ｋ＋参数总体看来尚属正常范围,可能是由于在住院后短时间内测定血Ｋ＋,．所用排Ｋ＋利尿剂时间不长的关系。其中只有５例的血Ｋ＋在２－３ｍｍｏｌ／Ｌ的低水平。加服Ｓｌｏｗ－Ｋ片或ＲＫＣｌ片后,均能有效地使患者的血Ｋ＋提升?     

Diuretic-related hypokalaemia: the role of diuretics,potassium supplements,glucocorticoids and β2-adrenoceptor agonists

All 5,047 consecutive inpatients admitted to the Internal Medicine Division of a teaching hospital (Zieglerspital, Berne) between 1982 and 1985 were registered in accordance with the CHDM (Comprehensive Hospital Drug Monitoring) questionnaire of adverse drug reactions (ADRs). Of them, 2,439 were treated with at least one potassium losing diuretic. The hospital records of the patients were reviewed with particular regard to serum potassium levels, and on the basis of this evaluation, the patients were assigned to four different diuretic treatment groups, and the incidence of hypokalaemia related to diuretic treatment was estimated. The overall rate of occurrence of hypokalaemia was 21.1% at a serum potassium level <3.5 mmol·1^–1, and 3.8% <3.0 mmol·1^–1. Hypokalaemia of less than 3.5 mml·1^–1 developed 24.9% (217/870) of patients treated with potassium losing diuretics alone; in 19.7% (101/513) treated with potassium losing diuretics in conjunction with potassium substitution, in 15.1% (66/438) treated with a combination of diuretics (potassium losing with potassium sparing), and in 20.0% (12/60) treated with combined diuretics and potassium substitution. Only the differences between the first and the two subsequent groups were statistically significant. The overall incidence of hypokalaemia below 3.0+mmol·1^–1 was significantly lower in the patients on combined diuretics without potassium substitution than in the patients on potassium losing diuretics with potassium substitution.Oral or parenteral administration of glucocorticoids (prednisone 5 to 2,000 mg/d) was a significant risk factor for hypokalaemic events. ₂-Adrenoceptor agonists had not effect. The patient's age, sex, renal function and numbers of drugs received were evaluated in a multivariate analysis, in order to take into account their influence on the risk of developing hypokalaemia. The number of drugs above 12 (and, less importantly, female sex) was the main risk factor for this ADR.The comparison between hypokalaemia and hyperkalaemia in this group of inpatients showed the significance of reduced renal function in the occurrence of hyperkalaemia.