Respuesta de los autores: Empleo de diuréticos y empagliflozina: ¿contraindicados? / Diuretics and empagliflozin use: authors' reply

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Mechanisms underlying the diuretic effect of Gomphrena celosioides Mart. (Amaranthaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Gomphrena celosioides (Amaranthaceae) is a native medicinal plant found in Mato Grosso do Sul State that is used for treating urinary tract and kidney stones. This study aimed to evaluate the diuretic effects of ethanolic extract from G. celosioides (EEGC) on acute and extended diuresis to provide a pharmacological basis for its use in traditional medicine. AIM OF THE STUDY: To evaluate the diuretic and natriuretic activity of EEGC and its mechanism of action in an animal model. MATERIALS AND METHODS: EEGC (30, 100 and 300mg/kg) was orally administered in male Wistar rats, and urinary excretion was measured at intervals of up to 8h after administration. To evaluate participation of the nitric oxide (NO), prostaglandin and bradykinin pathways in its effect, respective inhibitors were also administered together with effectives doses of EEGC and compared with control groups. A 7-day model with daily administration and urine measurement was also carried out. RESULTS: Oral administration of doses of 100 and 300 significantly increased urine output after 8h compared to the control group. It was observed this effect is dependent on the NO, prostaglandin and bradykinin pathways because their inhibitors reduced the diuretic effects of EEGC. Moreover, after 7 days of treatment, the effect was sustained and a decrease in serum aldosterone was observed in the extract group. CONCLUSION: According to the results, G. celosioides extract showed diuretic and natriuretic effects associated with more than one mechanism of action. Considering that all diuretic drugs are currently available for the treatment of volume and electrolyte disturbances, especially hypertensive status, the present results may have clinical relevance and open new possibilities for the development of new natural diuretics from G. celosioides.

Prednisolone attenuates improvement of cardiac and skeletal contractile function and histopathology by lisinopril and spironolactone in the mdx mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an inherited disease that causes striated muscle weakness. Recently, we showed therapeutic effects of the combination of lisinopril (L), an angiotensin converting enzyme (ACE) inhibitor, and spironolactone (S), an aldosterone antagonist, in mice lacking dystrophin and haploinsufficient for utrophin (utrn(+/-);mdx, het mice); both cardiac and skeletal muscle function and histology were improved when these mice were treated early with LS. It was unknown to what extent LS treatment is effective in the most commonly used DMD murine model, the mdx mouse. In addition, current standard-of-care treatment for DMD is limited to corticosteroids. Therefore, potentially useful alternative or additive drugs need to be both compared directly to corticosteroids and tested in presence of corticosteroids. We evaluated the effectiveness of this LS combination in the mdx mouse model both compared with corticosteroid treatment (prednisolone, P) or in combination (LSP). We tested the additional combinatorial treatment containing the angiotensin II receptor blocker losartan (T), which is widely used to halt and treat the developing cardiac dysfunction in DMD patients as an alternative to an ACE inhibitor. Peak myocardial strain rate, assessed by magnetic resonance imaging, showed a negative impact of P, whereas in both diaphragm and extensor digitorum longus (EDL) muscle contractile function was not significantly impaired by P. Histologically, P generally increased cardiac damage, estimated by percentage area infiltrated by IgG as well as by collagen staining. In general, groups that only differed in the presence or absence of P (i.e. mdx vs. P, LS vs. LSP, and TS vs. TSP) demonstrated a significant detrimental impact of P on many assessed parameters, with the most profound impact on cardiac pathology.

Assessing the effects of non-steroidal anti-inflammatory drugs on antihypertensive drug therapy using post-marketing surveillance database.

BACKGROUND: Antihypertensive and non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat many common diseases. However, it has been suspected that interactions between these drugs exist. Here, we assessed the interactions between non-selective NSAIDs and several classes of antihypertensive drugs. METHODS: The study design was a cohort study using "The Antihypertensive Drug Database," which is a collection of data accumulated from Drug Use Investigations. Subjects newly starting antihypertensive drug therapy were identified in the database. We compared the "User" group, who were co-administered NSAIDs, with the "Non-user" group, who were not. The outcome measure was the change in systolic blood pressure from the baseline after 2 months of treatment. We estimated the non-adjusted and adjusted differences in the change in systolic blood pressure between the "User" and "Non-user" groups. RESULTS: Data were collected for a total of 1,204 subjects, of whom 364 were prescribed beta blockers, 60 were prescribed diuretics, 628 were prescribed angiotensin-converting enzyme inhibitors, and 152 were prescribed calcium channel blockers. The adjusted difference in the change in systolic blood pressure between the User (n = 301) and Non-user (n = 903) groups was 2.88 mmHg (95% confidence interval: 0.89, 4.87); thus, systolic blood pressure in the Non-User group decreased further from the baseline than that in the User group. In subjects administered beta blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers, the corresponding differences were 0.37 mmHg (-3.24, 3.98), 6.11 mmHg (-3.16, 15.37), 3.85 mmHg (1.16, 6.66), and 3.50 mmHg (-2.03, 9.02). CONCLUSION: The effectiveness of antihypertensive drugs was attenuated by the co-administration of NSAIDs. The differences in the effects of NSAIDs varied with different classes of antihypertensive drugs.

Analogues of arginine vasopressin modified in position 2 and 3 with conformationally constrained dipeptide fragments.

This study describes the synthesis and some pharmacological properties of ten new analogues of arginine vasopressin (AVP) containing a conformationally constrained dipeptide fragment in the N-terminal part of their molecules. Amino acid residues in positions 2 and 3 of AVP and some of its agonistic analogues were replaced with -Phe-Phe and D-Phe-D-Phe, dipeptides having a -CH2-CH2- link bridging two nitrogens. All the new peptides were tested for vasopressor and antidiuretic activities. Four peptides with pA2 values ranging from 5.96 to 7.21 turned out to be weak or moderately potent V1a antagonists. The results supplied new information about the structure-activity relationship of AVP analogues. As some of these were unexpected, they point to the need for caution when extrapolating previously known effects of modifications to analogues having conformationally constrained fragments in their molecules.

[Study on prescriptions of gutianquan capsule by orthogonal experiment].

OBJECTIVE: To study optimum ingredient of prescriptions of Gutianquan capsule. METHODS: The study was carried out with orthogonal design. The optimum ingredient were studied by anti-diuretic action on rats and sedative-hypnosis action on mice. RESULTS: The composition of Gutianquan capsules should be the best one of the original prescription of Sangpiaoxiao Pulvis. CONCLUSION: Orthogonal design can be used to study prescription of the traditional Chinese medicine.

Contributions of saturable active secretion, passive transcellular, and paracellular diffusion to the overall transport of furosemide across adenocarcinoma (Caco-2) cells.

Furosemide permeation across Caco-2 cells was investigated to determine if previously reported directional differences in transport rates are due to a saturable, energy dependent process. In addition, studies were carried out to determine the route of permeation for this drug. By comparing apical (A) to basolateral (B) and B to A directional transport across Caco-2 cells, a saturable, nonlinear component to furosemide transport was observed. Transport in the secretory direction was fit to yield the following apparent parameters K(m) = 63 +/- 28 microM, V(max) = 436 +/- 137 pmol/cm(2)h, and P(app) = 3.7 +/- 0.9 x 10(-7) cm/s. Evidence of energy dependence was demonstrated using both metabolic inhibition, and transport against a diffusion gradient methods. Disruption of tight junctions by use of the calcium chelator, EGTA, caused a significant increase in furosemide transport (twofold and 12-fold increases in B to A and A to B, respectively) indicating the importance of the paracellular route. We conclude that furosemide secretion from Caco-2 cells is the result of saturable active transport and passive diffusion that has a significant paracellular component.

Antagonistic control of fluid secretion by the Malpighian tubules of Tenebrio molitor: effects of diuretic and antidiuretic peptides and their second messengers.

Fluid secretion by insect Malpighian tubules is controlled by haemolymph-borne factors. The mealworm Tenebrio molitor provides the first known example of antagonistic interactions between endogenous neuropeptides acting on Malpighian tubules. The two corticotropin-releasing-factor (CRF)-related diuretic peptides previously isolated from Tenebrio molitor, Tenmo-DH(37) and Tenmo-DH(47), were found to stimulate Tenebrio molitor tubules in vitro in a dose-dependent manner with EC(50) values of 0.12 nmol l(-1) and 26 nmol l(-1) respectively. However, no synergistic or additive effect was observed when these two peptides were tested simultaneously. We then investigated antagonism between second messengers: dose-response curves were constructed for stimulation of Tenebrio molitor tubules by cyclic AMP and their inhibition by cyclic GMP. When both cyclic nucleotides were included in the bathing Ringer, the stimulatory effect of cyclic AMP was neutralised by cyclic GMP. Similarly, the stimulatory effect of Tenmo-DH(37) was reversed on addition of an antidiuretic peptide (Tenmo-ADF), which was recently isolated from Tenebrio molitor and acts via cyclic GMP. The cardioacceleratory peptide CAP(2b), originally isolated from Manduca sexta, also increases intracellular cyclic GMP levels and inhibited fluid secretion by Tenebrio molitor tubules, with an EC(50) value of 85 nmol l(-1). This inhibitory effect was reversed by Tenmo-DH(37). Endogenous diuretic and antidiuretic peptides, effective at low concentrations and acting via antagonistic second messengers, have the potential for fine control of secretion rates in the Malpighian tubules of Tenebrio molitor.

Attenuation by phenylbutazone of the renal effects and excretion of frusemide in horses.

The objectives of this study were to determine the effect of phenylbutazone premedication on the pharmacokinetics and urinary excretion of frusemide in horses; and on frusemide-induced changes in urinary electrolyte excretion. Six Standardbred mares were used in a 3-way crossover design. The pharmacokinetics and renal effects of frusemide (1 mg/kg bwt i.v.) were studied with and without phenylbutazone premedication (8.8 mg/kg bwt per os 24 h before, followed by 4.4 mg/kg bwt i.v. 30 min before frusemide administration). A control (saline) treatment was also studied. Administration of frusemide without phenylbutazone led to diuresis, natriuresis, kaliuresis and chloruresis, and altered the ratio of sodium:chloride excretion from 0.4 to 1.0 in the first hour of diuresis. When frusemide and phenylbutazone were administered, sodium and chloride excretion in the first hour were significantly (P<0.05) reduced by 40 and 32%, respectively, when compared to frusemide administrationwithout phenylbutazone. The fractional clearance of sodium and chloride was also significantly reduced. Potassium excretion, potassium fractional clearance and the ratio of sodium to chloride excretion were not affected by administration of phenylbutazone. During peak diuresis, phenylbutazone did not affect the efficiency of frusemide with respect to electrolyte excretion. The plasma disposition of frusemide was not affected by phenylbutazone. However, the renal excretion of frusemide decreased by approximately 25%. We conclude that the decreased urinary excretion of frusemide by phenylbutazone led to an attenuation of frusemide-induced increases in urinary excretion of sodium and chloride. Since the efficiency of frusemide was not affected by phenylbutazone, we conclude that phenylbutazone attenuates the renal excretion of frusemide without inhibiting the intrarenal activity of frusemide in horses.

NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics.

BACKGROUND: Both diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, in particular among the elderly. The use of NSAIDs may decrease the efficacy of diuretics and induce congestive heart failure (CHF) in patients treated with diuretics. OBJECTIVE: To investigate the risk of CHF associated with combined use of diuretics and NSAIDs in patients older than 55 years. METHODS: We conducted a study in a base cohort of 10,519 recipients of diuretics and NSAIDs identified in the PHARMO database during the period from 1986 through 1992. The incidence density of hospitalizations for CHF during exposure to both diuretics and NSAIDs (index) was compared with that during exposure to diuretics only (reference). RESULTS: We found an overall increased risk of hospitalization for CHF during periods of concomitant use of diuretics and NSAIDs compared with use of diuretics only (crude relative risk, 2.2; 95% confidence interval, 1.7-2.9). After adjusting for cofactors including age, sex, history of hospitalization, and drug use, a 2-fold increased risk remained (relative risk, 1.8; 95% confidence interval, 1.4-2.4). CONCLUSION: Use of NSAIDs in elderly patients taking diuretics is associated with a 2-fold increased risk of hospitalization for CHF, especially in those with existing serious CHF.

Inhibition by xipamide of amiloride-induced acidification in cultured rat cardiocytes.

The diuretic drug xipamide improves myocardial relaxation in hypertensive patients with left ventricular hypertrophy, but its mechanism of action is unknown. Here, xipamide was tested in cultured rat heart myogenic H9c2 cells and newborn cardiomyocytes for its effects on cell acidification (and Ca2+ mobilization). In H9c2 cells, blocking Na+/H+ exchange with amiloride (2 mM) provoked cell acidification with rate = 0.82 +/- 0.17 pH units/h (n = 6). Xipamide 1 microM maximally inhibited 50 +/- 7% (n = 9) of cell acidification. The action of xipamide required the presence of HCO3- and was antagonized by the HCO3(-)-transport blocker DIDS (4,4'-diisothiocyanostilbene-2.2'-disulfonic acid). Conversely, the carbonic anhydrase (EC 4.2.1.1) inhibitor acetazolamide failed to prevent xipamide action. Finally, xipamide was without significant effect on the Ca2+ signals induced by endothelin-1, vasopressin or the Ca2+ ionophore ionomycin. In newborn rat cardiomyocytes, xipamide reduced amiloride-induced cell acidification at similar concentrations as in H9c2 cardiocytes, but with a slightly higher extent of maximal inhibition (70-80%). In conclusion, xipamide reduced amiloride-dependent cell acidification in the rat heart myogenic H9c2 cell line and in newborn rat cultured cardiomyocytes. This action of xipamide seems to be related to a complex interaction with DIDS-sensitive HCO3- movements. Prevention of cell acidification by xipamide could be involved in the beneficial effects of this compound in myocardial relaxation and left ventricle filling in hypertensive patients with left ventricular hypertrophy.

Influence of L-naphthylalanine in position 3 of AVP and its analogues on their pharmacological properties.

We describe the synthesis and pharmacological properties of two series of analogues: one which consists of three peptides having L-1-naphthylalanine in position 3 and the second composed of analogues substituted in position 3 with L-2-naphthylalanine. All peptides were tested in bioassays for pressor and antidiuretic activities. We also checked the uterotonic activity in vitro. We observed that the activity of counterparts in both series is, in two cases, strikingly different. One of the new analogues, [(L-2-Nal)3,(D-Arg)8]VP is among the most potent antagonists of the vasopressor response to AVP. Moreover, it is the first potent V1 antagonist devoid of antiuterotonic activity. This analogue was designed without modification of position 1, which was previously thought to be essential for substantial pressor antagonism. Two other peptides, [Mpa1;(L-2-Nal)3;(D-Arg)8]VP and [Mpa1,(L-1-Nal)3,D-Arg)8]VP, are highly potent V2 agonists. The second analogue is highly selective. With the exception of [(L-2-Nal)3]AVP, which showed weak antioxytocic activity, (L-Nal)3 modification resulted in the almost complete removal of interaction of our analogues with oxytocic receptors in vitro. Our results suggest that position 3 in AVP and its analogues is important not only for binding and recognition as previously though, but also for pressor, antidiuretic and uterotonic activities. We also assume that the hindering effect caused by bulky naphthyl moiety has a significant impact on the bioactive conformations of molecules which contain Nal residue, and can thus influence their interaction with V1, V2 and oxytocic receptors.

Antagonism of metergoline on the diuretic effect of cyclazocine and U-50488 drugs with a kappa agonist activity.

In rats receiving a normal saline load of 2.5 ml/100 g, sc, (moderately hydrated rats), injections of the serotonin (5-HT) antagonist, metergoline (0.25-1-4 mg/kg), resulted in a dose-dependent decrease in the urine output induced by a dose of 8 mg/kg of cyclazocine (a benzomorphan derivative, mixed kappa and sigma agonist) at the 2-h time period. The antagonist effect of metergoline (1 mg/kg) on cyclazocine doses ranging from 0.25 to 8 mg/kg, was observed only at 2 mg/kg higher doses. Other 5-HT receptor blockers, methysergide, pizotifen, cyproheptadine, caused a significant degree of antagonism. In rats receiving a saline load and a water load of 5.5 ml/100 g, ip (hyperhydrated rats), metergoline (1 mg/kg) completely antagonized the diuretic effect of cyclazocine (8 mg/kg) at the 4-h and 5-h time periods. Similarly, metergoline (1 and 4 mg/kg) administered in moderately hydrated rats, markedly decreased at the 2-h time period, the urine output produced by 5 mg/kg of U-50488 (a non benzomorphan derivative, highly selective kappa agonist), and in hyperhydrated rats, completely suppressed, at the 4-h and 5-h time periods the drug-induced diuresis. Metergoline administered alone had no effect on urine output in moderately hydrated rats or in hyperhydrated rats. These results suggest the hypothesis that 5-HT may be involved in the complex mechanisms of kappa agonist-induced diuresis in rats.

[Antagonistic properties of tetra-substituted analog of vasopressin with selective antidiuretic effects]. / Antagonisticheskie svoistva chetyrekhzameshchennogo analoga vazopressina s selektivnym antidiureticheskim deistviem.

Biological properties of a novel vasopressin analogue were investigated. It was found that this analogue has no vasopressor and oxytocic activities but it exhibits a selective antidiuretic effect which is weaker than that of adiuretin (DDAVP). Novel analogue inhibits vasopressor, oxytocic and antidiuretic effects caused by arginine--vasopressin. The usefulness of novel compound as a pharmacological tool--vasopressin antagonist is suggested.

Antidiuretic activity of terlipressin (triglycyl-lysine vasopressin)--role of pressure natriuresis.

Terlipressin (triglycyl-lysine vasopressin TP), a "hormonogen" analogue, was introduced in gastroenterology for its low and protracted vasopressor action, reducing bleeding from gastrointestinal tract. Its antidiuretic activity, estimated originally in ethanol-anaesthetized rats (Sawyer's method) was claimed to be equally low and protracted. We performed several series of antidiuretic tests on conscious rats (Burn's method) with the following results. TP in low doses of 0.05-1.0 micrograms/kg exhibited typical dose-dependent antidiuretic effect. In the dose of 0.2 micrograms/kg, the dynamics of urine and sodium excretion did not differ from that after equivalent dose of lysine vasopressin and equipotent dose of DDAVP. The antidiuretic potency of TP (estimated by parallel line assay) was 175.0 U/mg. TP in doses of 5.0 and 20.0 micrograms/kg exhibited limited diuresis and marked natriuresis. High osmolality and sodium content were present in all portions of excreted urine. The discrepancy between previous and our results concerning antidiuretic activity of TP and the role of pressure natriuresis for overall renal action of TP are discussed.

Attenuation of azosemide's action in the loop of Henle of rat kidney by nonsteroidal anti-inflammatory drugs.

The purpose of the present study, which was performed in anaesthetized rats, was to clarify whether the nonsteroidal anti-inflammatory drugs (NSAIDs) indomethacin and meclofenamate interact with the diuretic action of the new loop diuretic azosemide (Luret, CAS-27589-33-9). Since azosemide's diuretic action shows a lower onset and a more prolonged duration as compared to classical loop diuretics it was also tested whether azosemide's tubular action is mediated by an active metabolite. The results demonstrate that azosemide, when infused directly into the lumen of superficial loops of Henle, dose-dependently diminished the loops sodium and chloride reabsorption. A half-maximum effect was observed at an azosemide concentration of 3 x 10(-6) mol/l. These results clearly prove that the diuretic effect of azosemide is exerted by the drug itself and does not require metabolism to an active metabolite. Luminal application of the drug also dose-dependently increased early distal sodium and chloride concentrations, indicating that the drug's tubular action is located in the thick ascending limb of Henle's loop. Indomethacin and meclofenamate blunted the diuretic, natriuretic and chloruretic response to azosemide, and microperfusion experiments on single loops of Henle revealed an attenuation by NSAIDs of azosemide's inhibitory action on the loops sodium and chloride reabsorption. The quantitative extent of this interaction was nearly identical to that observed previously for the NSAID-furosemide interaction.

Effects of an aldose reductase inhibitor on organic osmotic effectors in rat renal medulla.

Renal medullary cells use sorbitol, betaine, and other organic compounds as osmotic effectors (osmolytes) to balance high extracellular NaCl. Excess sorbitol is also implicated in diabetes complications in several organs including kidneys. To study regulation of renal sorbitol, male Wistar rats were given an aldose reductase inhibitor, sorbinil, at 40 mg.kg-1.day-1 in food to block sorbitol formation from glucose. Inner medullas of kidneys were analyzed for osmolytes by high-performance liquid chromatography and atomic absorption. Animals on sorbinil had significantly reduced medullary sorbitol contents in a group on ad libitum water for 10 days (2.7 mmol/kg wet wt compared with 4.8 in controls) and in an antidiuretic group kept 7 days and an additional 3 days without water (3.8 mmol/kg wet wt compared with 7.2 in antidiuretic controls). In both groups, betaine contents were significantly elevated (9.2 mmol/kg wet wt compared with 5.5 in ad libitum water controls: 6.4 mmol/kg wet wt compared with 4.2 in antidiuretic controls). No other osmolytes differed. Total contents of nonurea organic osmolytes maintained a constant ratio to sodium contents; thus increased betaine concomitant with decreased sorbitol may have maintained constant cell volume. In contrast, in animals kept 21 days on sorbinil, there were significant decreases in urea and inositol contents. However, there were no significant differences in sorbitol or betaine compared with controls, suggesting a compensating increase in sorbitol production or in sorbinil removal.