ABSTRACT
Diuretics have been used for decades in the treatment of hypertension. Its efficacy has been demonstrated in numerous clinical trials. It is well known that the reduction in cardiovascular risk is a consequence of the reduction in blood pressure levels regardless of the drug used, but thiazide diuretics continue to be first-line drugs, especially in low doses and combined with other drugs. The debate on the advantages of using chlorthalidone or hydrochlorothiazide continues, however hydrochlorothiazide is drug most used and for which there is greater availability. The association with potassium-sparing diuretics increases the effectiveness and reduces the adverse reactions of thiazides. A new group of drugs, close to potassium-sparing diuretics, that antagonise aldosterone synthase are showing promising results as antihypertensives. There are no significant differences between men and women regarding the antihypertensive effect of thiazide diuretics.
Subject(s)
Antihypertensive Agents , Diuretics , Hypertension , Humans , Hypertension/drug therapy , Diuretics/adverse effects , Diuretics/administration & dosage , Diuretics/therapeutic use , Diuretics/pharmacology , Antihypertensive Agents/adverse effects , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Sodium Chloride Symporter Inhibitors/adverse effects , Sodium Chloride Symporter Inhibitors/therapeutic use , Sodium Chloride Symporter Inhibitors/administration & dosage , Sodium Chloride Symporter Inhibitors/pharmacology , Hydrochlorothiazide/adverse effects , Hydrochlorothiazide/administration & dosage , Hydrochlorothiazide/therapeutic use , Chlorthalidone/administration & dosage , Chlorthalidone/therapeutic use , Chlorthalidone/adverse effects , Female , Male , Drug Therapy, CombinationABSTRACT
Hyponatremia is the most common disorder of electrolyte imbalances. It is necessary to develop new type of diuretics to treat hyponatremia without losing electrolytes. Urea transporters (UT) play an important role in the urine concentrating process and have been proved as a novel diuretic target. In this study, rat and mouse syndromes of inappropriate antidiuretic hormone secretion (SIADH) models were constructed and analyzed to determine if UTs are a promising drug target for treating hyponatremia. Experimental results showed that 100 mg/kg UT inhibitor 25a significantly increased serum osmolality (from 249.83 ± 5.95 to 294.33 ± 3.90 mOsm/kg) and serum sodium (from 114 ± 2.07 to 136.67 ± 3.82 mmol/L) respectively in hyponatremia rats by diuresis. Serum chemical examination showed that 25a neither caused another electrolyte imbalance nor influenced the lipid metabolism. Using UT-A1 and UT-B knockout mouse SIADH model, it was found that serum osmolality and serum sodium were lowered much less in UT-A1 knockout mice than in UT-B knockout mice, which suggest UT-A1 is a better therapeutic target than UT-B to treat hyponatremia. This study provides a proof of concept that UT-A1 is a diuretic target for SIADH-induced hyponatremia and UT-A1 inhibitors might be developed into new diuretics to treat hyponatremia.
Subject(s)
Hyponatremia , Inappropriate ADH Syndrome , Membrane Transport Proteins , Mice, Knockout , Urea Transporters , Animals , Male , Mice , Rats , Disease Models, Animal , Diuretics/pharmacology , Hyponatremia/drug therapy , Hyponatremia/metabolism , Inappropriate ADH Syndrome/drug therapy , Inappropriate ADH Syndrome/metabolism , Membrane Transport Proteins/metabolism , Mice, Inbred C57BL , Osmolar Concentration , Rats, Sprague-Dawley , Sodium/metabolismABSTRACT
Rice bean [Vigna umbellata (Thunb.) Ohwi and Ohashi], an annual legume in the genus Vigna, is a promising crop suitable for cultivation in a changing climate to ensure food security. It is also a medicinal plant widely used in traditional Chinese medicine; however, little is known about the medicinal compounds in rice bean. In this study, we assessed the diuretic effect of rice bean extracts on mice as well as its relationship with the contents of eight secondary metabolites in seeds. Mice gavaged with rice bean extracts from yellow and black seeds had higher urinary output (5.44-5.47 g) and water intake (5.8-6.3 g) values than mice gavaged with rice bean extracts from red seeds. Correlation analyses revealed significant negative correlations between urine output and gallic acid (R = -0.70) and genistein (R = -0.75) concentrations, suggesting that these two polyphenols negatively regulate diuresis. There were no obvious relationships between mice diuresis-related indices (urine output, water intake, and weight loss) and rutin or catechin contents, although the concentrations of both of these polyphenols in rice bean seeds were higher than the concentrations of the other six secondary metabolites. Our study findings may be useful for future research on the diuretic effects of rice bean, but they should be confirmed on the basis of systematic medical trials.
Subject(s)
Diuretics , Polyphenols , Seeds , Animals , Mice , Diuretics/pharmacology , Seeds/chemistry , Polyphenols/pharmacology , Polyphenols/analysis , Male , Plant Extracts/pharmacology , Vigna/chemistry , Gallic Acid/pharmacology , Genistein/pharmacology , Catechin/pharmacology , Catechin/analysis , Rutin/pharmacology , Rutin/analysis , Diuresis/drug effectsABSTRACT
The pathophysiology behind sodium retention in heart failure with preserved ejection fraction (HFpEF) remains poorly understood. We hypothesized that patients with HFpEF have impaired natriuresis and diuresis in response to volume expansion and diuretic challenge, which is associated with renal hypo-responsiveness to endogenous natriuretic peptides. Nine HFpEF patients and five controls received saline infusion (0.25 mL/kg/min for 60 min) followed by intravenous furosemide (20 mg or home dose) 2 h after the infusion. Blood and urine samples were collected at baseline, 2 h after saline infusion, and 2 h after furosemide administration; urinary volumes were recorded. The urinary cyclic guanosine monophosphate (ucGMP)/plasma B-type NP (BNP) ratio was calculated as a measure of renal response to endogenous BNP. Wilcoxon rank-sum test was used to compare the groups. Compared to controls, HFpEF patients had reduced urine output (2480 vs.3541 mL; p = 0.028), lower urinary sodium excretion over 2 h after saline infusion (the percentage of infused sodium excreted 12% vs. 47%; p = 0.003), and a lower baseline ucGMP/plasma BNP ratio (0.7 vs. 7.3 (pmol/mL)/(mg/dL)/(pg/mL); p = 0.014). Patients with HFpEF had impaired natriuretic response to intravenous saline and furosemide administration and lower baseline ucGMP/plasma BNP ratios indicating renal hypo-responsiveness to NPs.
Subject(s)
Furosemide , Heart Failure , Kidney , Natriuretic Peptide, Brain , Sodium , Stroke Volume , Humans , Heart Failure/physiopathology , Heart Failure/metabolism , Male , Female , Aged , Pilot Projects , Furosemide/pharmacology , Furosemide/administration & dosage , Sodium/metabolism , Sodium/urine , Natriuretic Peptide, Brain/blood , Natriuretic Peptide, Brain/metabolism , Kidney/metabolism , Kidney/physiopathology , Kidney/drug effects , Middle Aged , Natriuresis/drug effects , Diuretics/pharmacology , Diuretics/administration & dosage , Cyclic GMP/metabolism , Cyclic GMP/urine , Aged, 80 and overABSTRACT
Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely ß-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Antihypertensive Agents , Hypertension , Humans , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/pharmacology , Hypertension/drug therapy , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Calcium Channel Blockers/therapeutic use , Calcium Channel Blockers/pharmacology , Animals , Adrenergic beta-Antagonists/therapeutic use , Adrenergic beta-Antagonists/pharmacology , Diuretics/therapeutic use , Diuretics/pharmacology , Mineralocorticoid Receptor Antagonists/therapeutic useABSTRACT
Thiazide and thiazide-like diuretics (thiazides) belong to the most frequently prescribed drugs worldwide. By virtue of their natriuretic and vasodilating properties, thiazides effectively lower blood pressure and prevent adverse cardiovascular outcomes. In addition, through their unique characteristic of reducing urine calcium, thiazides are also widely employed for the prevention of kidney stone recurrence and reduction of bone fracture risk. Since their introduction into clinical medicine in the early 1960s, thiazides have been recognized for their association with metabolic side effects, particularly impaired glucose tolerance, and new-onset diabetes mellitus. Numerous hypotheses have been advanced to explain thiazide-induced glucose intolerance, yet underlying mechanisms remain poorly defined. Regrettably, the lack of understanding and unpredictability of these side effects has prompted numerous physicians to refrain from prescribing these effective, inexpensive, and widely accessible drugs. In this review, we outline the pharmacology and mechanism of action of thiazides, highlight recent advances in the understanding of thiazide-induced glucose intolerance, and provide an up-to-date discussion on the role of thiazides in kidney stone prevention.
Subject(s)
Kidney Calculi , Thiazides , Humans , Kidney Calculi/chemically induced , Kidney Calculi/prevention & control , Thiazides/therapeutic use , Thiazides/adverse effects , Thiazides/pharmacology , Animals , Glucose Intolerance/chemically induced , Sodium Chloride Symporter Inhibitors/adverse effects , Sodium Chloride Symporter Inhibitors/therapeutic use , Diuretics/adverse effects , Diuretics/pharmacology , Diuretics/therapeutic useABSTRACT
Understanding the function of the kappa opioid receptor (KOP) is crucial for the development of novel therapeutic interventions that target KOP for the treatment of pain, stress-related disorders and other indications. Activation of KOP produces diuretic effects in rodents and man. Sex is a vital factor to consider when assessing drug response in pre-clinical and clinical studies. In this study, the diuretic effect of the KOP agonist, U50488 (1-10 mg/kg), was investigated in both adult female and male Wistar rats that were either normally hydrated or water-loaded. The KOP antagonist norbinaltorphimine (norBNI, 10 mg/kg) was administered 24 h prior to U50488 to confirm the involvement of KOP. U50488 elicited a significant diuretic response at doses ≥ 3 mg/kg in both female and male rats independent of hydration status. U50488 diuretic effects were inhibited by norBNI pre-administration. Water-loading reduced data variability for urine volume in males, but not in females, compared with normally hydrated rats. Sex differences were also evident in U50488 eliciting a significant increase in sodium and potassium ion excretion only in males. This may suggest different mechanisms of U50488 diuretic action in males where renal excretion mechanisms are directly affected more than in females.
Subject(s)
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer , Diuresis , Rats, Wistar , Receptors, Opioid, kappa , Animals , Receptors, Opioid, kappa/agonists , Receptors, Opioid, kappa/metabolism , Male , Female , Diuresis/drug effects , 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology , Rats , Sex Factors , Diuretics/pharmacology , Naltrexone/pharmacology , Naltrexone/analogs & derivatives , Sodium/urine , Sodium/metabolism , Organism Hydration Status/drug effects , Potassium/urine , Potassium/metabolism , Dose-Response Relationship, Drug , Narcotic Antagonists/pharmacologyABSTRACT
This study aimed to explore the diuretic activity of linalyl acetate (LA). LA is an essential oil, it is an integral phyto-constituent of various plants. In this study, acute and chronic diuretic activities were explored by measuring the levels of different electrolytes and pH in the urine of experimental rats. Rats were divided into five groups. The control group was given 10 mg/kg normal saline, the treated group was given 10 mg/kg furosemide, and the remaining 3 groups received different doses of LA including 25, 50, and 75 mg/kg through intraperitoneal route, to determine its diuretic potential. Urine volume for acute diuretic activity was measured for 6 hours however for chronic diuretic activity was measured for 6 days. For a comparative study of LA with a control group and treated group with reference drug, diuretic index was used. Moreover, the underlying mechanism of the diuretic activity was also explored by comparing atropine, L-NAME, and indomethacin. The results of each group with 6 rats in each group were obtained by ± standard error of the mean of every group. Analysis of Variance (ANOVA) was used for statistical analysis. Results revealed that the LA 75 mg/kg dose showed comparable results as of furosemide. Moreover, this study revealed the involvement of muscarinic receptors to produce diuresis in comparison with atropine with very little involvement of prostanoids and no effect on NO pathway induced by indomethacin and L-NAME respectively. It is concluded that LA possess anti-diuretic potential. Muscarinic receptors might be involved in producing diuretic effects.
Subject(s)
Diuretics , Furosemide , Monoterpenes , Rats , Animals , Furosemide/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Diuretics/pharmacology , Indomethacin/pharmacology , Atropine/pharmacology , Plant Extracts/pharmacology , Receptors, MuscarinicABSTRACT
Chronic angiotensin II (ANG II) infusion is an experimental model that induces hypertension in rodents. The natriuresis, diuresis, and blood pressure responses differ between males and females. This is perhaps not unexpected, given the rodent kidney, which plays a key role in blood pressure regulation, exhibits marked sex differences. Under normotensive conditions, compared with males, the female rat nephron exhibits lower Na+/H+ exchanger 3 (NHE3) activity along the proximal tubule but higher Na+ transporter activities along the distal segments. ANG II infusion-induced hypertension induces a pressure natriuretic response that reduces NHE3 activity and shifts Na+ transport capacity downstream. The goals of this study were to apply a computational model of epithelial transport along a rat nephron 1) to understand how a 14-day ANG II infusion impacts segmental electrolyte transport in male and female rat nephrons and 2) to identify and explain any sex differences in the effects of loop diuretics, thiazide diuretics, and K+-sparing diuretics. Model simulations suggest that the NHE3 downregulation in the proximal tubule is a major contributor to natriuresis and diuresis in hypertension, with the effects stronger in males. All three diuretics are predicted to induce stronger natriuretic and diuretic effects under hypertension compared with normotension, with relative increases in sodium excretion higher in hypertensive females than in males. The stronger natriuretic responses can be explained by the downstream shift of Na+ transport load in hypertension and by the larger distal transport load in females, both of which limit the ability of the distal segments to further elevate their Na+ transport.NEW & NOTEWORTHY Sex differences in the prevalence of hypertension are found in human and animal models. The kidney, which regulates blood pressure, exhibits sex differences in morphology, hemodynamics, and membrane transporter distributions. This computational modeling study provides insights into how the sexually dimorphic responses to a 14-day angiotensin II infusion differentially impact segmental electrolyte transport in rats. Simulations of diuretic administration explain how the natriuretic and diuretic effects differ between normotension and hypertension and between the sexes.
Subject(s)
Angiotensin II , Hypertension , Natriuresis , Sodium-Hydrogen Exchanger 3 , Animals , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/physiopathology , Male , Female , Sodium-Hydrogen Exchanger 3/metabolism , Natriuresis/drug effects , Diuretics/pharmacology , Blood Pressure/drug effects , Sex Factors , Computer Simulation , Sodium/metabolism , Rats , Sodium Chloride Symporter Inhibitors/pharmacology , Sex Characteristics , Disease Models, Animal , Diuresis/drug effects , Sodium Potassium Chloride Symporter Inhibitors/pharmacology , Kidney/metabolism , Kidney/drug effects , Kidney/physiopathologySubject(s)
Antihypertensive Agents , Chlorthalidone , Hypertension , Renal Insufficiency, Chronic , Humans , Chlorthalidone/administration & dosage , Chlorthalidone/pharmacology , Hypertension/drug therapy , Hypertension/physiopathology , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/complications , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacology , Antihypertensive Agents/adverse effects , Diuretics/administration & dosage , Diuretics/pharmacology , Drug Resistance , Evidence-Based MedicineABSTRACT
It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250 mg; n = 9), furosemide (20 mg; n = 10) or amiloride (10 mg; n = 7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ , and renal function were then monitored for up to 8 h post-treatment. The peak diuretic response occurred 2 h (99.4 ± 14.8 mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1 h (196.5 ± 12.3 mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue P O 2 ${P_{{{\mathrm{O}}_{\mathrm{2}}}}}$ fell from 40.1 ± 3.8 mmHg at baseline to 17.2 ± 4.4 mmHg at 3 h and to 20.5 ± 5.3 mmHg at 6 h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8 h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.
Subject(s)
Acetazolamide , Amiloride , Diuretics , Furosemide , Kidney Cortex , Kidney Medulla , Animals , Furosemide/pharmacology , Acetazolamide/pharmacology , Amiloride/pharmacology , Diuretics/pharmacology , Sheep , Female , Kidney Cortex/drug effects , Kidney Cortex/metabolism , Kidney Medulla/drug effects , Kidney Medulla/metabolism , Oxygen/metabolism , Hemodynamics/drug effects , Oxygen Consumption/drug effectsABSTRACT
In this case report, a high dose of torsemide (6mg/kg, every 12 hours for 3 days followed by 12mg/kg, every 12 hours for 4 days) was administered orally to a horse with congestive heart failure (CHF) and atrial fibrillation. Blood samples for measurement of plasma torsemide concentrations were obtained one hour after each drug administration. Pharmacodynamic effects of oral torsemide were evaluated by daily physical examination, electrocardiography, and serum biochemistry. The horse tolerated administration of torsemide. A decrease in ventral oedema and venous congestion was subjectively noted at day 7. Torsemide plasma concentration markedly increased at day 5 (peak concentration of 15.41 µg/mL). Evidence of an increase in renal markers was observed throughout the study period. Electrolyte measurements revealed mild hyponatremia and hypochloremia, and moderate hypokalaemia. No electrocardiographic changes related to torsemide administration were observed. After seven days of treatment, the horse was euthanised due to his disease stage and poor prognosis. Results indicate that torsemide was absorbed after oral administration and was well tolerated in this horse. Furthermore, clinical improvement in this single case indicates that torsemide might be utilized as an oral alternative to furosemide in the management of equine patients in CHF. The high doses of torsemide used in this case report should be reserved for cases without clinical response to lower doses and with close monitoring of electrolytes and renal function parameters. Further investigation of torsemide clinical efficacy and safety in horses with CHF with a larger cohort and prolonged administration is warranted.
Subject(s)
Atrial Fibrillation , Heart Failure , Horse Diseases , Horses , Animals , Torsemide/therapeutic use , Sulfonamides/therapeutic use , Sulfonamides/pharmacology , Diuretics/pharmacology , Diuretics/therapeutic use , Atrial Fibrillation/drug therapy , Atrial Fibrillation/veterinary , Heart Failure/drug therapy , Heart Failure/veterinary , Horse Diseases/drug therapyABSTRACT
Hypertension leads to water-electrolyte disturbances and end-organ damage. Betaine is an osmolyte protecting cells against electrolyte imbalance and osmotic stress, particularly in the kidneys. This study aimed to evaluate tissue levels and hemodynamic and renal effects of betaine in normotensive and hypertensive rats. Betaine levels were assessed using high-performance liquid chromatography-mass spectrometry (HPLC-MS) in normotensive rats (Wistar-Kyoto, WKYs) and Spontaneously Hypertensive rats (SHRs), a model of genetic hypertension. Acute effects of IV betaine on blood pressure, heart rate, and minute diuresis were evaluated. Gene and protein expression of chosen kidney betaine transporters (SLC6a12 and SLC6a20) were assessed using real-time PCR and Western blot. Compared to normotensive rats, SHRs showed significantly lower concentration of betaine in blood serum, the lungs, liver, and renal medulla. These changes were associated with higher urinary excretion of betaine in SHRs (0.20 ± 0.04 vs. 0.09 ± 0.02 mg/ 24h/ 100g b.w., p = 0.036). In acute experiments, betaine increased diuresis without significantly affecting arterial blood pressure. The diuretic response was greater in SHRs than in WKYs. There were no significant differences in renal expression of betaine transporters between WKYs and SHRs. Increased renal excretion of betaine contributes to decreased concentration of the protective osmolyte in tissues of hypertensive rats. These findings pave the way for studies evaluating a causal relation between depleted betaine and hypertensive organ damage, including kidney injury.
Subject(s)
Betaine , Hypertension , Rats , Animals , Betaine/pharmacology , Betaine/metabolism , Rats, Inbred WKY , Diuretics/pharmacology , Renal Elimination , Hypertension/genetics , Kidney/metabolism , Rats, Inbred SHR , Blood Pressure , Electrolytes/metabolismABSTRACT
OBJECTIVES: The diuretic and kidney protective effect of the 3-demethyl-2-geranyl-4-prenylbellidifoline (DGP) were evaluated in rats. METHODS: The normotensive (NTR) and spontaneously hypertensive rats (SHR) received, once a day for 7 days, oral treatment with DGP (0.1 mg/kg), hydrochlorothiazide (10 mg/kg), or vehicle (10 ml/kg). Urine, blood, and kidney samples were collected for further analysis. KEY FINDINGS: The urine and Na+ elimination content were significantly higher in the groups that received DGP. Furthermore, a Ca2+-sparing action was detected in the urine of DGP-treated groups, which was consistent with the reduction in calcium oxalate crystal formation. Relevantly, the treatment did not change the parameters examined in the blood. Concerning the renal analyses, DGP treatment recovered the morphological damages of the kidney corpuscle area of SHR. In addition to the differences observed between the NTR and SHR vehicle groups, DGP augmented the amount of reduced glutathione and the activity of glutathione S-transferase GST while reducing the catalase and N-acetyl-ß-D-glucosaminidase activity and nitrite levels. CONCLUSION: Together, this study displayed the prolonged diuretic action of DGP and its natriuretic, Ca2+-sparing, and antiurolytic effects. The antioxidative and anti-inflammatory effects of DGP were evidenced in SHR kidneys, opening perspectives for further studies regarding the benefits of this xanthone.
Subject(s)
Hypertension , Xanthones , Rats , Animals , Diuretics/pharmacology , Hypertension/drug therapy , Calcium , Kidney , Rats, Inbred SHR , Blood Pressure , Xanthones/pharmacologyABSTRACT
Resistant hypertension is defined as not achieving sufficient control of blood pressure (BP), that is, maintaining BP values equal to or above 140/90 mm Hg when using 3 antihypertensive drugs, including diuretics, properly combined and at maximum doses. The uncontrolled treated hypertension should be confirmed in outofoffice BP measurements, preferably with 24hour ambulatory BP monitoring. Demographic and clinical characteristics indicate that patients with resistant hypertension are older than the general population of patients with arterial hypertension and more often suffer from comorbidities. When resistant hypertension is suspected, it is necessary to assess whether optimal pharmacotherapy has been prescribed, including appropriate combinations of antihypertensive drugs and diuretics at appropriate doses. It is also important to exclude parallel use of drugs that may have unfavorable interactions leading to an increase in BP. A common cause of pseudoresistant hypertension is a patient's failure to comply with therapeutic recommendations, including a lack of lifestyle changes and nonadherence to the prescribed medication regimen. An important step in management of resistant hypertension is targeted screening with diagnostic tests for secondary hypertension. Expanding of the drug therapy beyond a 3drug regimen should include a mineralocorticoid receptor antagonist, in particular spironolactone. In selected patients, devicebased hypertension treatment might be considered.
Subject(s)
Antihypertensive Agents , Hypertension , Humans , Antihypertensive Agents/therapeutic use , Hypertension/diagnosis , Hypertension/drug therapy , Diuretics/therapeutic use , Diuretics/pharmacology , Blood Pressure , Spironolactone/pharmacology , Spironolactone/therapeutic useSubject(s)
Diuretics , Heart Failure , Humans , Diuretics/pharmacology , Acetazolamide/pharmacology , Acetazolamide/therapeutic use , ChloridesABSTRACT
BACKGROUND: Previous studies indicate the renal vasodilating effects of boldine, an alkaloid found in Peumus boldus. However, its potential to induce diuresis still needs to be studied. METHODS: Wistar rats were used and the urine volume was noted for 8 h and further studied. RESULTS: The acute treatment at 0.1 and 0.3 mg/kg of boldine showed a diuretic, natriuretic, and Ca2+-sparing effect in rats without changing the urinary elimination of K+and Cl-. When boldine was given in combination with hydrochlorothiazide, there was an increase in urinary volume compared to the vehicle group. However, this was not different from the treatments in its isolated form. Urine Ca2+values ââremained low but were not enhanced by this association. The excretion of Na+and Cl- was significantly increased compared to the group that received only vehicle or boldine. On the other hand, although the association of amiloride plus boldine did not result in a diuretic effect, the increase in Na+and the reduction in K+excretion were significantly potentiated. Furthermore, in the presence of the non-selective muscarinic receptor antagonist atropine, boldine showed reduced capacity to increase urinary volume, maintaining the natriuretic and Ca2+-sparing effect, besides a very evident K+-sparing action. Similar results were obtained in the presence of the non-selective cyclooxygenase inhibitor indomethacin. Furthermore, boldine showed an ex vivo antiurolithiasis activity, reducing calcium oxalate's precipitation and crystallization. CONCLUSIONS: This study reveals the diuretic, natriuretic, Ca2+-sparing, and antiurolithiatic effects of boldine, an action possibly related to muscarinic receptor activation and prostanoid generation.
Subject(s)
Aporphines , Diuretics , Rats , Animals , Diuretics/pharmacology , Calcium , Rats, Wistar , Aporphines/pharmacology , Sodium , Receptors, MuscarinicABSTRACT
Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) is a protein kinase that inactivates eEF2, a protein that mediates a peptidyl-tRNA translocation during an elongation step of protein synthesis. We have previously shown that eEF2K was involved in pathogenesis of essential and pulmonary hypertension. A484954 (7-amino-1-cyclopropyl-3-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carboxamide), a selective eEF2K inhibitor, is a membrane permeable small molecule. We have previously shown that A484954 lowered blood pressure and induced diuretic effects in spontaneously hypertensive rats (SHR) due to an increase in renal blood flow. Here we aimed to reveal mechanisms underlying the diuretic effects of A484954 in SHR. A484954-induced diuresis and increase in urinary Na+ excretion were inhibited by N (G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor. A484954 increased mRNA expression of angiotensin type 2 receptor (AT2R) and nuclear factor-erythroid 2-related factor 2 (Nrf2). In summary, we for the first time revealed that A484954 induces diuresis in SHR at least partly via the activation of NO/Nrf2/AT2R pathway.