Diuretics prime plant immunity in Arabidopsis thaliana.

Plant activators are agrochemicals that activate the plant immune system, thereby enhancing disease resistance. Due to their prophylactic and durable effects on a wide spectrum of diseases, plant activators can provide synergistic crop protection when used in combination with traditional pest controls. Although plant activators have achieved great success in wet-rice farming practices in Asia, their use is still limited. To isolate novel plant activators applicable to other crops, we screened a chemical library using a method that can selectively identify immune-priming compounds. Here, we report the isolation and characterization of three diuretics, bumetanide, bendroflumethiazide and clopamide, as immune-priming compounds. These drugs upregulate the immunity-related cell death of Arabidopsis suspension-cultured cells induced with an avirulent strain of Pseudomonas syringae pv. tomato in a concentration-dependent manner. The application of these compounds to Arabidopsis plants confers disease resistance to not only the avirulent but also a virulent strain of the pathogen. Unlike salicylic acid, an endogenous phytohormone that governs disease resistance in response to biotrophic pathogens, the three diuretic compounds analyzed here do not induce PR1 or inhibit plant growth, showing potential as lead compounds in a practical application.

Changes in urinary enzyme levels following the use of antihypertensive agents in patients with essential hypertension.

When choosing antihypertensive agents for the treatment of hypertension, it is necessary to consider the predisposition of individuals to renal damage, which may be associated with the long-term effect of such agents. In this respect, this study examined the effect of two commonly used antihypertensive drugs (Brinerdin and Minizide) on renal function over 24 months in patients diagnosed as having essential hypertension. We utilized urinary enzyme studies, which are indicators of subtle renal dysfunction. Other parameters of glomerular and tubular function were also determined in the pretreatment period, as well as during and at the end of treatment of 28 patients (16 males and 12 females) with therapeutic doses of Brinerdin and 22 patients (12 males and 10 females) with conventional doses of Minizide. During the follow-up period, blood pressure (BP) fell from a mean of 160/108 +/- 9/4 (SD) mmHg to 130/90 +/- 7/4 on Brinerdin and from a mean of 160/106 +/- 5/2 (SD) mmHg to 130/90 +/- 8/5 on Minizide. There was no significant difference in the levels of BP between the patients taking Minizide and those taking Brinerdin before, during, and at the end of treatment. Significant elevation (p < 0.05) of the levels of urinary protein, lactate dehydrogenase (LDH), and N-acetyl-B-D-glycosaminidase (NAG) was observed in patients on Minizide during treatment, and these levels remained elevated during the latter part of the study. Normotensive, untreated, age- and sex-matched control subjects showed no such urinary parameter changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinicopharmacological reappraisal of the potency of diuretics.

From a clinicopharmacological standpoint, the urinary excretory potency of diuretics should be assessed comparatively on the basis of the changes in 24-hour natriuresis, with respect to 24-hour natriuresis after placebo, caused by single oral doses administered to healthy adult subjects who are in habitual and steady-state external sodium balance. The potency of various formulations of loop (e.g., furosemide), of early distal tubular (e.g., the thiazides), and of potassium-retaining diuretics, as well as of several combinations of diuretics, has been evaluated in a series of studies. Two formulations of loop diuretics (muzolimine 20 mg and torasemide 2.5 mg) are definitely nondiuretic. The majority of the other formulations of loop diuretics studied are, in general, comparatively less potent than most of the common formulations of early distal tubular diuretics studied. As a general rule, most common formulations of early distal tubular diuretics are at least not less potent than the majority of common formulations of loop diuretics. Hydrochlorothiazide 25 mg and furosemide 80 mg have similar potencies. Loop diuretics increase mean renal sodium output strikingly within the first few (0-6) hours after dosing, but this forced excretion is followed by a rebound with respect to postplacebo mean urinary sodium flow; the rebound usually takes place between 6 and 24 hours after dosing. However, no rebound in mean urinary sodium flow occurs during the 24 hours following a single dose of a distal tubular diuretic; these substances increase urinary sodium excretion with lower maximal intensity but more protractedly than loop diuretics.(ABSTRACT TRUNCATED AT 250 WORDS)

[The principles of left-right hemispheric interactions of pharmacological preparations exemplified by Brinaldix]. / Nekotorye printsipy levo-pravopolusharnykh vzaimodeistvii farmakologicheskikh preparatov na primere brinal'diksa.

The effect of 4-chlor-N-(cys-2,6-dimethyl peridine)-3-sulfomoin-benzamide as an anti-hypertensive drug on left-to-right hemisphere interactions was studied on experimental animals. Its effect on hemispheres was shown to be asymmetrical. The most effective action of the drug was demonstrated on the left hemisphere of rats differing in their trends of interhemispheric interactions.

Diuretic agents related to indapamide. III--Synthesis and pharmacological activity of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydroisoquinolines.

A series of N-(4-chloro-3-sulfamoylbenzamido)-1,2,3,4-tetrahydroquinoline++ + (IV-1) and isoquinoline (IV-2) have been synthesized and their diuretic and antihypertensive activities evaluated. While none of the test compounds was found to be provided with antihypertensive properties, most of them displayed a diuretic activity comparable to (IV-2 a) or higher (IV-1 a,b) (IV-2 c) than those of indapamide and clopamide, taken as reference drugs.

Interaction of cyclosporine-A with the renin-angiotensin system in canine veins.

Responses of canine saphenous veins to bradykinin and angiotensin and the effect of cyclosporine-A were investigated both in conscious dogs in vivo and on ring preparations from canine saphenous veins in vitro. In vivo local infusion of bradykinin into the saphenous vein elicited dose-dependent reduction in compliance, i.e., venoconstriction, whereas local infusion of angiotensin elicited dose-dependent venodilatation, which was markedly enhanced during blockade of endogenous thromboxane A2 synthesis by dazoxiben (2.5 mg/kg i.v.). The venoconstrictor response to bradykinin was attenuated after oral administration of both the thiazide-like diuretic clopamide (0.5 mg/kg) or cyclosporine-A (30 mg/kg), and by concomitant local infusion of cyclosporine-A (1-10 micrograms/min). Systemic i.v. infusion of the renin inhibitor H-77 (0.1 mg/kg/h) reversed the inhibition of bradykinin by both clopamide and cyclosporine-A. In vitro bradykinin elicited relaxation at low (0.1-10 nmol/l) but constriction at higher concentrations. The venoconstrictor response to bradykinin was resistant to blockade of thromboxane A2 synthesis and only partially attenuated after selective blockade of cyclooxygenase or lipoxygenase. Concomitant blockade of both lipoxygenase and cyclooxygenase activity by nordihydroguaiaretic acid (NDGA 10-30 mumol/l) nearly abolished the contractile response thereby enhancing the relaxant component of the bradykinin effect. Angiotensin II also elicited biphasic responses of partially contracted venous rings. Concomitant blockade of both lipoxygenase and cyclooxygenase by NDGA (10 mumol/l) again attenuated the contractile component of the angiotensin effect thereby unmasking the venodilator activity which could be inhibited by the angiotensin II receptor blocker saralasin (0.01-1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

[Hemodynamic effects of hydrochlorothiazide, propranolol and a combination of pindolol and clopamide in patients with essential hypertension]. / Efectos hemodinámicos de la hidroclorotiacida, el propranolol y la asociación pindolol-clopamida en hipertensos esenciales.

To characterize the haemodynamic effects of diuretics, betablockers and the association of both, 24 hypertensive patients, stages I-II WHO criteria, were studied. Two haemodynamic studies were performed, before under placebo and after two month of active drug therapy. Seven patients received propranolol (PPL) (160-240 mg/day); 7 patients, hydrochlorothiazide (HCT) (150-100 mg/day), and 10 a combined fixed dose of pindolol (PDL) and clopamide (CLP): PDL 10 mg, CLP 5 mg per tablet, each patient receiving one to three tablets according blood pressure response. The haemodynamic study was performed with percutaneous intravenous flow-directed. Swan-Ganz catheter, associated with direct puncture of femoral artery and measuring cardiac output by thermodilution. Arterial pressure was significantly reduced on PPL (p less than 0.05) and PDL-CLP (p less than 0.01) groups, but not in the HCT group. The cardiac index was reduced by PPL (p less than 0.05) but not by HCT and PDL-CLP. The systemic vascular resistance was only reduced in the PDL-CLP group (p less than 0.05). The use of a betablocker with intrinsic sympathetic activity (ISA) (pindolol) in association with a thiazide diuretic (clopamide) seems to induce a favourable change in systemic resistance without a deleterious change in cardiac output as occurred with propranolol.

Efecto de la combinación pindolol-clopamida en el tratamiento de la hipertensión leve y moderada: un estudio multicéntrico / Effect of combined pindolol-clopamide in essential and moderate hypertension therapy: a multicentric study

En el presente estudio se reporta el efecto antihipertensivo de la combinación Pindolol + Clopamida vs placebo, en grupos paralelos, con distribución al azar, en un grupo de pacientes hipertensos leves y moderados que asistieron a los Servicios de Medicina Vial del Estado Carabobo. El estudio duró ocho semanas, con exámenes clínicos cada dos semanas. La dosis de Pindolol + Clopamida fue de 1 tableta (10 mg y 5 mg respectivamente). El grupo de pacientes seleccionados perteneció mayormente al sexo masculino (19 pacientes de 20 pacientes en las edades de 30 y 49 años en el grupo placebo; y 16 pacientes de 20 pacientes en las edades de 30 y 49 años en el grupo Pindolol + Clopamida). En el grupo que recibió el tratamiento activo, en el 60% de los pacientes los valores tensionales se normalizaron al final del tratamiento y en el 40% hubo reducciones apreciables, pero no alcanzaron la normalidad. En el grupo placebo apenas hubo descenso a la normalidad en el 20% de los pacientes. Nosotros concluimos que la combinación Pindolol + Clopamida es util en la terapia de la Hipertensión leve y moderada y exhibe excelente tolerancia

Inhibition of the Cl-/NaCO3- anion exchanger by xipamide in human red blood cells.

The mechanism of action of classical loop diuretics of the 2- or 3-amino-5-sulfamoylbenzoic acid and (aryloxy)acetic acid families involves competition with chloride for a common site on the (Na+, K+, 2Cl-) co-transport system. However this is not the mechanism of action of some high-ceiling diuretics like muzolimine, MK 473, xipamide, indapamide and clopamide, which are not carboxylic acids. We evaluated three of these latter diuretics (xipamide, muzolimine and clopamide) for their inhibitory effects on five ion transport systems in human red blood cells: (i) Cl(-)-dependent (Na+, K+) co-transport, (ii) (NaCO3-/Cl-) anion exchanger, (iii) (Cl-, K+) co-transport, (iv) Na+, K+ pump and (v) Na+: Li+ counter-transport; and on one ion channel the Ca2+-dependent, K+ channel. All erythrocyte transport pathways were resistant to the three diuretics studied (IC50 of 10(-3) M or higher) with one remarkable exception, the (NaCO3-/Cl-) anion exchanger. This transport system was inhibited by xipamide (IC50 of 2.5 +/- 0.4 X 10(-5) M, mean +/- S.D. of five experiments) and less potently by muzolimine (IC50 of 1.1 +/- 0.3 X 10(-4) M, mean +/- S.D. of three experiments). Clopamide only inhibited the anion exchanger at high concentrations (IC50 of about 10(-3) M). Xipamide, the most potent diuretic in this test, was at least one order of magnitude more active than furosemide, ethacrynic acid, hydrochlorothiazide and amiloride. Inhibition of the anion carrier could be involved in the diuretic action (inhibition of CO2-stimulated NaCl absorption in the TAL) and/or in the antihypertensive action (inhibition of net NaCO3- influx and secondarily of Ca2+ influx through Na+: Ca2+ exchange in vascular smooth muscle cells of xipamide).

Clopamide: plasma concentrations and diuretic effect in humans.

Clopamide pharmacokinetics were determined after oral doses of 5, 10, and 20 mg in normal volunteers. Maximum plasma concentrations occurred within 2 hours and were followed by a monoexponential decline with an elimination half-life of approximately 10 hours. There was an approximately linear relationship between dose and the AUC. Urinary sodium, chloride, and potassium excretion rates indicated that the peak diuretic activity corresponded with peak plasma drug concentrations and probably continued for 12 to 24 hours. There was little difference between the total sodium and chloride output after each dose of clopamide, suggesting that 5 mg may have been close to the top of the dose-response curve. Chlorothiazide, 500 mg, caused less sodium and chloride output with similar potassium loss. During chronic administration to patients with hypertension, hypokalemia was more marked with clopamide, 10 mg daily, than with clopamide, 5 mg, or chlorothiazide, 500 mg daily.

Effects of single doses of two antihypertensive rauwolfia-diuretic combinations on urinary excretion.

In a double-blind placebo-controlled investigation, 14 healthy adult male volunteers were studied to assess and compare the urinary effects of acute single doses of two antihypertensive formulations containing: hydroflumethiazide 50 mg, Rauwolfia serpentina 50 mg and potassium chloride 625 mg (HFRK) (Rautrax-50; Squibb Laboratories); and clopamide 5 mg, reserpine 0.1 mg and dihydroergocristine 0.5 mg (CRE) (Brinerdin; Sandoz Products). Both significantly increased mean 24-hour urinary outputs of fluid, Cl-, Na+, K+ and Mg2+. CRE increased creatinine and decreased Ca2+ output. After dosing, times to maximal urinary flow of fluid, Cl-, Na+, Ca2+ and creatinine were shortened by HFRK and CRE and those corresponding to K+, Mg2+, phosphate and urate were unaffected. Both formulations thus acted mainly through their diuretic constituents.

Renal tubular secretion and effects of chlorothiazide, hydrochlorothiazide and clopamide: a study in the avian kidney.

The relationship between renal tubular secretion and saluretic effects of two thiazides (chlorothiazide and hydrochlorothiazide) and clopamide was studied using a modified Sperber technique. The distribution of carbonic anhydrase in the avian kidney was studied by a histochemical method. The modified Sperber technique allows an absolute estimation of the tubular excretion efficiency of a substance, as determined by its True Tubular Excretion Fraction (TTEF). The TTEF values were for chlorothiazide 59%, hydrochlorothiazide 22% and clopamide 10%. Thus, they were all actively secreted by renal tubular cells; most likely through organic anion transport since novobiocin markedly reduced the TTEF values. After infusion of the diuretics into the renal portal system on one side there was only a small ipsilateral excess natriuresis and chloruresis, in spite of their different tubular excretion efficiencies. For hydrochlorothiazide, and especially for chlorothiazide the saluretic effect therefore appears to be largely independent of the tubular fluid concentration of the diuretic and primarily evoked from the peritubular side of the avian nephron. This is a sharp contrast to the primarily luminally induced saluretic effects of furosemide, ethacrynic acid and piretanide. Only chlorothiazide caused an ipsilateral excess excretion of potassium and bicarbonate, probably due to inhibition of carbonic anhydrase since similar effects were seen after acetazolamide. This effect was coupled to tubular secretion of the diuretic, and probably reflects an inhibition of carbonic anhydrase in cortical distal tubules, where the enzyme is present in the apical region of most cells and could be reached by chlorothiazide present in the tubular fluid.

[Potassium metabolism during antihypertensive treatment with beta-receptor blocker and diuretic treatment]. / Kaliumhaushalt bei antihypertensiver Therapie mit beta-Rezeptorenblocker-Saluretika-Kombinationen.

In a controlled, prospective, cross-over study 15 patients with essential hypertension received for four weeks either a combination of beta-receptor blocker and diuretic (twice 10 mg pindolol and 5 mg clopamide daily) or of three drugs: beta-receptor blocker, diuretic and sodium-preserving diuretic (twice daily 10 mg timolol, 25 mg hydrochlorothiazide and 2.5 mg amiloride). Both drug combinations produced quantitatively comparable and definite blood pressure lowering from 162/102 mmHg to 128/82 and 130/82, or 130/84 and 127/82, respectively, after two and four weeks. A significant fall in serum potassium from 4.24 to 3.77 and 3.92 mmol/l occurred with the combined two drugs but not the combination of three. With the two-drug combination renal potassium excretion was significantly raised at one of two control points in time. Heart rate remained constant with the two-drug treatment but fell significantly on three-drug administration. There were more side effects with the two-drug preparation. Combinations of beta-receptor blockers and diuretics are thus by no means potassium neutral but can cause renal potassium loss, fall in serum potassium and hypokalaemia. For this reason combining potassium-sparing diuretic with beta-receptor blocker and diuretics is reasonable and justified.

[A field study with the combination of Pindolol and Clopamid in antihpertensive therapy (author's transl)]. / Der Kombinationstyp Betarezeptorenblocker/Diuretikum in der antihypertensiven Therapie.

In a field study comprising 678 patients with arterial hypertension efficacy and tolerance of the stable combination VKB 105 consisting of 10 mg Pindolol (Visken) and 5 mg Clopamid (Brinaldix) were investigated. Treatment with 1--2 tablets of VKB per day resulted in a successful therapy in 94% of all patients corresponding on the average to a reduction in blood pressure to 145/85 mm Hg within 14 days. In mean arterial pressures ranging between 120 and 170 mm Hg a positive linear relationship between the individual initial value and the hypotensive effect of the combination could be observed. A controlled omission trial disclosed qualitatively the respective contribution to the effect of the two components Pindolol and Clopamid. With a systematic case control of the serum potassium under the combined therapy with VKB 105 and during a monotherapy with Clopamid and antihypokalaemic effect of Pindolol could be demonstrated diminishing the tendency for potassium loss. The result revealed a far-reaching potassium neutrality of diuresis-depending stimulation of renin by the beta-receptor blocker. In 61 patients altogether subjective side-effects could be recorded, such as vertigo (5%), palpitations (2.8%), fatigue (2%), insomina (1.9%), nausea (1.7%) and vomiting (0.8%). Laboratory controls gave no indication for clinically relevant changes.

The influence of ethacrynic acid, hydrochlorothiazide and clopamide on the renal excretion of chloramphenicol and its metabolites.

Simultaneous administration of chloramphenicol (1 g orally) and ethacrynic acid (150 mg orally), hydrochlorothiazide (25 mg orally) or clopamide (40 mg orally) increased the urinary excretion of chloramphenicol and its metabolites (aryl amines and total nitro compounds). The administration of diuretics did not change the time course of serum concentrations of substances under study. Since the urinary excretion of chloramphenicol and its metabolites is a urine flow-dependent process, the influence of the tested diuretics can be explained as a consequence of decreased tubular water reabsorption.