Co-administration of sodium hydrosulfide and tadalafil modulates hypoxia and oxidative stress on bladder dysfunction in a rat model of bladder outlet obstruction.

PURPOSE: This study aimed to assess the possible healing effect of combination treatment with a hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS) plus tadalafil on partial bladder outlet obstruction (PBOO)-induced bladder dysfunction. MATERIALS AND METHODS: A total of 75 male Sprague-Dawley rats aged 10-wk and 300-350g were divided into five groups; control; PBOO; PBOO+NaHS (5.6mg/kg/day, i.p., 6-wk); PBOO+tadalafil (2mg/kg/day, oral, 6-wk) and PBOO+NaHS+tadalafil. PBOO was created by partial urethral ligation. 6 weeks after obstruction, the in vitro contractile responses of the detrusor muscle and Western blotting, H2S and malondialdehyde assay were performed in bladder tissues. RESULTS: There was an increase in bladder weight(p<0.001) and a decrease in contractile responses to KCL(p<0.001), carbachol(p<0.01), electrical field stimulation(p<0.05) and ATP (p<0.001) in the detrusor smooth muscle of obstructed rats which was normalized after the combination treatment. Cystathionine γ-lyase and cystathionine ß-synthase, and nuclear factor kappa B protein levels did not significantly differ among groups. The obstruction induced decrement in 3-mercaptopyruvate sulfur transferase protein expression(p<0.001) and H2S levels(p<0.01) as well as increment in protein expressions of neuronal nitric oxide synthase (NO, p<0.001), endothelial NOS (p<0.05), inducible NOS(p<0.001), hypoxia-inducible factor 1-alpha (p<0.01), and malondialdehyde levels (p<0.01), when combined treatment entirely normalized. CONCLUSIONS: Combination therapy has beneficial effects on bladder dysfunction via regulating both H2S and nitric oxide pathways as well as downregulation of oxidative stress and hypoxia. The synergistic effect of H2S and nitric oxide is likely to modulate bladder function, which supports the combined therapy for enhancing clinical outcomes in men with BPH/LUTS.

The Search for New Agonists to P2X7R for Clinical Use: Tuberculosis as a Possible Target.

Treatment for tuberculosis is effective with the use of proper antibiotics, but the number of drug-resistant cases is increasing. Drug resistance occurred in 650,000 cases of the 20 million patients in treatment worldwide in 2011, which demonstrates the necessity of finding new therapeutic approaches. In this context, the search for new medicines and immunomodulators could help reduce the prevalence and incidence of multi-drug-resistant tuberculosis cases. Thus several preclinical studies demonstrate the involvement of the P2X7 receptor (P2X7R) in the control of Mycobacterium tuberculosis (MTB) infection. Adenosine triphosphate (ATP), a natural agonist for P2X7R, promotes MTB death and the induction of apoptosis in monocytes and macrophages infected with MTB via activation of P2X7R by extracellular ATP. In addition, P2X7R activation in the presence of ATP increases the expression of major histocompatibility complex (MHC) class II by macrophages infected with Mycobacterium bovis (BCG) or MTB, which contributes to the generation of the antimicrobial immune response via T cells. Nevertheless, one idea that seems overlooked by the "purinergic community" is the use of the high-conductance channel associated with P2X7R to increase the passage of hydrophilic drugs to the cytoplasm of cells that express the P2X7 pore, a potential method for a drug delivery system. In this work, we propose the use of P2X7 agonists in conjunction with low molecular weight anti-tuberculosis medicines for the treatment of multi-drug-resistant tuberculosis.

In vivo effects of adenosine 5'-triphosphate on rat preneoplastic liver.

The utilization of adenosine 5'-triphosphate (ATP) infusions to inhibit the growth of some human and animals tumors was based on the anticancer activity observed in in vitro and in vivo experiments, but contradictory results make the use of ATP in clinical practice rather controversial. Moreover, there is no literature regarding the use of ATP infusions to treat hepatocarcinomas. The purpose of this study was to investigate whether ATP prevents in vivo oncogenesis in very-early-stage cancer cells in a well characterized two-stage model of hepatocarcinogenesis in the rat. As we could not preclude the possible effect due to the intrinsic properties of adenosine, a known tumorigenic product of ATP hydrolysis, the effect of the administration of adenosine was also studied. Animals were divided in groups: rats submitted to the two stage preneoplasia initiation/promotion model of hepatocarcinogenesis, rats treated with intraperitoneal ATP or adenosine during the two phases of the model and appropriate control groups. The number and volume of preneoplastic foci per liver identified by the expression of glutathione S-transferase placental type and the number of proliferating nuclear antigen positive cells significantly increased in ATP and adenosine treated groups. Taken together, these results indicate that in this preneoplastic liver model, ATP as well as adenosine disturb the balance between apoptosis and proliferation contributing to malignant transformation.

In vivo effects of adenosine 5´-triphosphate on rat preneoplastic liver / Efecto in vivo de adenosina 5´-trifosfato sobre el hígado preneoplásico de la rata

The utilization of adenosine 5´-triphosphate (ATP ) infusions to inhibit the growth of some human and animals tumors was based on the anticancer activity observed in in vitro and in vivo experiments, but contradictory results make the use of ATP in clinical practice rather controversial. Moreover, there is no literature regarding the use of ATP infusions to treat hepatocarcinomas. The purpose of this study was to investigate whether ATP prevents in vivo oncogenesis in very-early-stage cancer cells in a well characterized two-stage model of hepatocarcinogenesis in the rat. As we could not preclude the possible effect due to the intrinsic properties of adenosine, a known tumorigenic product of ATP hydrolysis, the effect of the administration of adenosine was also studied. Animals were divided in groups: rats submitted to the two stage preneoplasia initiation/promotion model of hepatocarcinogenesis, rats treated with intraperitoneal ATP or adenosine during the two phases of the model and appropriate control groups. The number and volume of preneoplastic foci per liver identified by the expression of glutathione S-transferase placental type and the number of proliferating nuclear antigen positive cells significantly increased in ATP and adenosine treated groups. Taken together, these results indicate that in this preneoplastic liver model, ATP as well as adenosine disturb the balance between apoptosis and proliferation contributing to malignant transformation.

La utilización de adenosina 5´-trifosfato (ATP ) para inhibir el crecimiento de algunos tumores en humanos y en animales se basa en la actividad anticancerígena observada en experimentos in vitro e in vivo. El uso del ATP en la práctica clínica es discutido debido a resultados contradictorios. Por otra parte, no existen antecedentes del uso de ATP en el tratamiento de hepatocarcinomas. El objetivo del presente estudio fue determinar si el ATP previene la oncogénesis in vivo en un modelo de preneoplasia hepática murina de dos etapas. Para determinar la probable contribución de la adenosina, producto de la hidrólisis de ATP y descrita como tumorigénica, se estudió también el efecto del nucleósido exógeno sobre los focos preneoplásicos. Los animales se dividieron en grupos: ratas sometidas al modelo de preneoplasia de iniciación/promoción, ratas tratadas con ATP o adenosina intraperitonealmente durante las dos fases del modelo y los correspondientes grupos controles. El número y el volumen de focos preneoplásicos por hígado, identificados por la expresión de la forma placentaria de la glutation S- transferasa de rata y el número de células positivas para el antígeno nuclear proliferante, aumentaron significativamente en los grupos tratados con ATP y adenosina. Los resultados en su conjunto indican que en este modelo preneoplásico, el ATP y la adenosina alteran el balance entre apoptosis y proliferación, contribuyendo a la transformación maligna.

Role of purines on hepatic ischemia-reperfusion lesions in rabbit.

In this work, we evaluate the effects of adenosine 5' triphosphate (ATP) on hepatic lesions caused by ischemia/reperfusion (I/R) in liver rabbit. Rabbits were pretreated with ATP (15 mg/kg IV) or saline solution 0.9% (SS), before the hepatic I/R procedure. We evaluated the effects of ATP on hepatic injury before and after I/R. The warm hepatic I/R procedure caused profound acute liver injury, as indicated by elevated serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels, as well as a high apoptotic cell count. All these changes were attenuate by ATP treatment before the hepatic I/R procedure. These results suggested that ATP exerted protective effects on hepatic I/R lesions in the rabbit. This ATP effect may be related to improved energy metabolism during reperfusion in ischemic livers protecting against functional damage of cellular and subcellular membranes during lipid peroxidation.

[Comparative study between verapamil and adenosine triphosphate in the treatment of paroxysmal supraventricular tachycardia]. / Estudo comparativo entre verapamil e adenosina-trifosfato no tratamento das taquicardias paroxísticas supraventriculares.

PURPOSE: To evaluate the efficacy and safety of intravenous (IV) adenosine-triphosphate (ATP) and verapamil to convert acute episodes of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm. METHODS: Fifty patients with PSVT were randomized in two groups: A) 25 treated with IV bolus of ATP (10 or 20mg), and V) 25 treated with IV verapamil, up to 15mg, during 3min. We evaluated the time delay necessary to convert the arrhytmia, doses, and side-effects. Patients with acute ischemic syndromes (< 3 weeks), severe congestive heart failure, and treatment with dipyridamole or methylxanthine were excluded. RESULTS: There were no differences between the two groups regarding to age, sex, and success rate. The average time till reversal were respectively, 30s and 248s for ATP and verapamil. Ventricular ectopy and general discomfort were observed in 33% of patients receiving ATP, whereas no side-effects occurred in group V. CONCLUSION: ATP is a good option to convert rapidly PSVT to sinus rhythm and, probably, could be the first choice to treat PSVT patients with ventricular dysfunction.

ATP reduces blood loss produced by heparin in cardiopulmonary bypass operations.

It was previously shown that topical application of heparin produces enhanced bleeding from small vessels and capillaries. Adenosine triphosphate at low concentrations is able to dislodge heparin bound to a receptor, counteracting its antihemostatic activity. These results led us to measure the amounts of heparin remaining in the blood after protamine neutralization of the patients subjected to cardiopulmonary bypass operation and to test the topical application of the nucleotide. Adenosine triphosphate at a concentration of 10(-4) mol/L significantly reduces the blood volume (p < 0.005) oozed from the thoracic cavity of the patients (mean, 288 +/- 188 mL) when compared with controls (mean, 564 +/- 288 mL). Adenosine triphosphate at 5 x 10(-5) mol/L reduces the blood loss to a mean of 370 +/- 155 mL in the patients tested (p < 0.08). About 10% of heparin of low molecular weight (< or = 6.0 Kda), which is also found in the oozed blood, is not neutralized by protamine. We suggest that the excessive blood loss of the patients is probably produced by low molecular weight heparins in the commercial preparations that are not neutralized by protamine.

Selective pulmonary vasodilation by low-dose infusion of adenosine triphosphate in newborn lambs.

The systemic and pulmonary vascular effects of adenosine 5'-triphosphate (ATP) were investigated in 12 newborn lambs during normoxia and during alveolar hypoxia (10% oxygen, 5% carbon dioxide, and 85% nitrogen). Lambs had catheters in the descending aorta, main pulmonary artery, and were studied after a 3-day recovery. We infused ATP or an equal volume of saline solution (control) into the right atrial line in doses ranging from 0.01 to 2.5 mumol/kg per minute. In normoxic lambs, ATP caused a significant decrease in pulmonary vascular resistance in doses of 0.08 to 2.5 mumol/kg per minute, and in systemic vascular resistance in doses of 0.3 to 2.5 mumol/kg per minute. Infusion of ATP in hypoxic lambs caused decreases in pulmonary artery pressure and pulmonary vascular resistance in all the doses tested. Systemic vascular resistance decreased, and cardiac output and heart rate increased in doses greater than 0.3 mumol/kg per minute in hypoxic lambs during ATP infusion. The effects of ATP in hypoxic lambs were not blocked by propranolol, indomethacin, or theophylline. Plasma ATP levels in left atrial blood samples did not change significantly during the infusion of ATP. We conclude that ATP is a vasodilator in lambs, and its effects are specific for pulmonary circulation at doses of less than or equal to 0.15 mumol/kg per minute. The vasodilator effects of ATP appear to be independent of P1 purinergic and beta-adrenergic mechanisms, and of prostacyclin synthesis.

Comportamento da polpa dental após pulpotomia e aplicaçäo de trifosfato de adenosina, hidróxido de cálcio e combinaçäo de ambos: estudo histológico em dentes humanos / Behaviour of dental pulps after pulpotomy and application of adenosin three-phosphate, calcium hydroxide and both combination: histological study in human teeth

A finalidade desta pesquisa foi verificar o comportamento da polpa dentária após pulpotomia e proteçäo do remanescente pulporradicular com os seguintes materiais: trifosfato de adenosina e hidróxido de cálcio com e sem tratamento prévio com trifosfato de adenosina. Foram utilizados 80 dentes pré-molares de pacientes com idade de 10 a 16 anos. Decorridos períodos de observaçäo de 7 e 40 dias, os dentes foram extraídos e submetidos à análise radiográfica e histológica. Com base nos resultados obtidos as condiçöes experimentais em que foi realizado este trabalho, pôde-se concluir que: Em relaçäo à análise histopatológica: - o ATP puro se mostrou como um material irritante ao tecido pulpar; - o hidróxido de cálcio associado ou näo às soluçöes de ATP foram bem tolerados pelo tecido pulpar; - o processo de reparo pulpar foi acelerado quando utilizada a soluçäo de ATP näo-tamponada, previamente ao hidróxido de cálcio...