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1.
J Urol ; 181(3): 1444-51, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19157444

RESUMEN

PURPOSE: Urodynamics have been traditionally recorded in anesthetized or conscious animals implanted with a bladder catheter that is used to artificially fill the bladder while measuring intravesicular bladder pressure. Anesthesia alters the urodynamics and in the conscious state this methodology requires that the dogs be tethered/restrained, which evokes stress and limits the period of continuous urodynamic assessment. A more physiological and chronic method of evaluating pharmacological responses on urodynamics is necessary. MATERIALS AND METHODS: Adult female beagle dogs were surgically instrumented with radiotelemetry transmitters enabling urodynamic/hemodynamic recordings. Telemetered urodynamics were compared to those measured in anesthetized dogs receiving bladder infusion of saline. The response to diuresis with furosemide (Intervet, Millsboro, Delaware) and the M3 selective antimuscarinic darifenacin (Matrix Laboratories, Hyderabad, India) were evaluated. RESULTS: Saline infused, anesthetized dogs demonstrated lower peak micturition pressure and higher threshold pressure than conscious, freely moving telemetered dogs. In telemetered dogs a single dose of furosemide increased voiding frequency and average urine volume per void. Darifenacin decreased peak voiding pressure without affecting voiding frequency. CONCLUSION: Telemetry provides the potential to significantly decrease animal use while enabling the continuous monitoring of urodynamics under more physiological conditions without tethering or artificial filling. In addition, this new model facilitates evaluation of the chronic efficacy of new urological therapies.


Asunto(s)
Telemetría , Urodinámica , Animales , Perros , Femenino
2.
Am J Physiol Renal Physiol ; 295(2): F507-14, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18508878

RESUMEN

Nonsteroidal anti-inflammatory cyclooxygenase inhibitors that function to reduce prostaglandin E2 (PGE2) production have been widely reported as effective agents in models of urinary bladder overactivity. We therefore investigated a potential role for the PGE2 receptor, EP3, in urinary bladder function by performing conscious, freely moving cystometry on EP3 receptor knockout (KO) mice. EP3 KO mice demonstrated an enhanced bladder capacity compared with wild-type (WT) mice ( approximately 185% of WT) under control conditions, based on larger voided and infused bladder volumes. Infusion of the EP3 receptor agonist GR63799X into the bladder of WT mice reduced the bladder capacity. This was ineffective in EP3 KO mice that demonstrated a time-dependent increase in bladder capacity with GR63799X, an effect similar to that observed with vehicle in both genotypes. In addition, infusion of PGE2 into WT mice induced bladder overactivity, an effect that was significantly blunted in the EP3 KO mice. The data reported here provide the first evidence supporting a functional role for EP3 receptors in normal urinary bladder function and implicate EP3 as a contributor to bladder overactivity during pathological conditions of enhanced PGE2 production, as reported previously in overactive bladder patients.


Asunto(s)
Dinoprostona/metabolismo , Receptores de Prostaglandina E/metabolismo , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria/patología , Vejiga Urinaria/fisiopatología , Ácido Acético , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Prostaglandinas E Sintéticas/farmacología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Prostaglandina E/efectos de los fármacos , Receptores de Prostaglandina E/genética , Subtipo EP3 de Receptores de Prostaglandina E , Vejiga Urinaria Hiperactiva/inducido químicamente
3.
J Pharmacol Exp Ther ; 326(2): 432-42, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18499743

RESUMEN

The transient receptor potential (TRP) vanilloid 4 (TRPV4) member of the TRP superfamily has recently been implicated in numerous physiological processes. In this study, we describe a small molecule TRPV4 channel activator, (N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), which we have used as a valuable tool in investigating the role of TRPV4 in the urinary bladder. GSK1016790A elicited Ca2+ influx in mouse and human TRPV4-expressing human embryonic kidney (HEK) cells (EC50 values of 18 and 2.1 nM, respectively), and it evoked a dose-dependent activation of TRPV4 whole-cell currents at concentrations above 1 nM. In contrast, the TRPV4 activator 4alpha-phorbol 12,13-didecanoate (4alpha-PDD) was 300-fold less potent than GSK1016790A in activating TRPV4 currents. TRPV4 mRNA was detected in urinary bladder smooth muscle (UBSM) and urothelium of TRPV4+/+ mouse bladders. Western blotting and immunohistochemistry demonstrated protein expression in both the UBSM and urothelium that was absent in TRPV4-/- bladders. TRPV4 activation with GSK1016790A contracted TRPV4+/+ mouse bladders in vitro, both in the presence and absence of the urothelium, an effect that was undetected in TRPV4-/- bladders. Consistent with the effects on TRPV4 HEK whole-cell currents, 4alpha-PDD demonstrated a weak ability to contract bladder strips compared with GSK1016790A. In vivo, urodynamics in TRPV4+/+ and TRPV4-/- mice revealed an enhanced bladder capacity in the TRPV4-/- mice. Infusion of GSK1016790A into the bladders of TRPV4+/+ mice induced bladder overactivity with no effect in TRPV4-/- mice. Overall TRPV4 plays an important role in urinary bladder function that includes an ability to contract the bladder as a result of the expression of TRPV4 in the UBSM.


Asunto(s)
Leucina/análogos & derivados , Contracción Muscular/efectos de los fármacos , Sulfonamidas/farmacología , Canales Catiónicos TRPV/agonistas , Vejiga Urinaria/efectos de los fármacos , Urodinámica/efectos de los fármacos , Urotelio/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Femenino , Leucina/farmacología , Masculino , Ratones , Ratones Noqueados , Estructura Molecular , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Forboles/farmacología , Canales Catiónicos TRPV/genética , Canales Catiónicos TRPV/fisiología , Vejiga Urinaria/metabolismo , Urotelio/metabolismo
5.
J Pharmacol Exp Ther ; 323(1): 202-9, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17626794

RESUMEN

Functional studies have demonstrated that adrenoceptor agonist-evoked relaxation is mediated primarily by beta3-adrenergic receptors (ARs) in human bladder. Thus, the use of selective beta3-AR agonists in the pharmacological treatment of overactive bladder is being explored. The present studies investigated the effects of a novel selective beta3-AR agonist, (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid (GW427353; solabegron) on bladder function in the dog using in vitro and in vivo techniques. GW427353 stimulated cAMP accumulation in Chinese hamster ovary cells expressing the human beta3-AR, with an EC50 value of 22 +/- 6 nM and an intrinsic activity 90% of isoproterenol. At concentrations of 10,000 nM, GW427353 produced a minimal response in cells expressing either beta1-ARs or beta2-ARs (maximum response <10% of that to isoproterenol). In dog isolated bladder strips, GW427353 evoked relaxation that was attenuated by the nonselective beta-AR antagonist bupranolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol (SR59230A) (reported to have beta3-AR antagonist activity). The relaxation was unaffected by atenolol, a selective beta1-AR antagonist, or (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118551), a selective beta2-AR antagonist. GW427353 increased the volume required to evoke micturition in the anesthetized dog following acetic acid-evoked bladder irritation, without affecting the ability of the bladder to void. GW427353-evoked effects on bladder parameters in vivo were inhibited by bupranolol. The present study demonstrates that selective activation of beta3-AR with GW427353 evokes bladder relaxation and facilitates bladder storage mechanisms in the dog.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/farmacología , Compuestos de Anilina/farmacología , Benzoatos/farmacología , Relajación Muscular/efectos de los fármacos , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Vejiga Urinaria/efectos de los fármacos , Micción/efectos de los fármacos , Ácido Acético , Agonistas Adrenérgicos beta/uso terapéutico , Compuestos de Anilina/uso terapéutico , Animales , Benzoatos/uso terapéutico , Compuestos de Bifenilo , Células CHO , Cricetinae , Cricetulus , AMP Cíclico/metabolismo , Modelos Animales de Enfermedad , Perros , Femenino , Humanos , Músculo Liso/efectos de los fármacos , Músculo Liso/inervación , Reflejo , Vejiga Urinaria/inervación , Vejiga Urinaria/metabolismo , Vejiga Urinaria Hiperactiva/metabolismo , Vejiga Urinaria Hiperactiva/fisiopatología
6.
Am J Physiol Regul Integr Comp Physiol ; 293(1): R299-305, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17395790

RESUMEN

Spontaneous and induced uterine contractions in the rat were found to be inhibited by a novel and selective oxytocin receptor antagonist GSK221149A (3R,6R)-3-Indan-2-yl-1-[(1R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]-6-[(1S)-1-methylpropyl]-2,5-piperazinedione. GSK221149A displayed nanomolar affinity (K(i) = 0.65 nM) for human recombinant oxytocin receptors with >1,400-fold selectivity over human V1a, V1b, and V2 receptors. GSK221149A had similar affinity (K(i) = 4.1 nM) and selectivity for native oxytocin receptors from rat and produced a functional, competitive block of oxytocin-induced contractions in isolated rat myometrial strips with a pA(2) value of 8.18. Intravenous administration of GSK221149A produced a dose-dependent decrease in oxytocin-induced uterine contractions in anesthetized rats with an ID(50) = 0.27 +/- 0.60 mg/kg (corresponding plasma concentrations were 88 ng/ml). Oral administration of GSK221149A (5 mg/kg) was effective in inhibiting oxytocin-induced uterine contractions after single and multiple (4-day) dosing. Spontaneous uterine contractions in late-term pregnant rats (19-21 days gestation) were significantly reduced by intravenous administration of 0.3 mg/kg of GSK221149A. These results provide further evidence that selective oxytocin receptor antagonism may offer an effective treatment for preterm labor.


Asunto(s)
Oxitocina/antagonistas & inhibidores , Oxitocina/farmacología , Piperazinas/farmacología , Receptores de Oxitocina/antagonistas & inhibidores , Contracción Uterina/fisiología , Anestesia , Animales , Unión Competitiva/efectos de los fármacos , Células CHO , Línea Celular , Cricetinae , Cricetulus , Femenino , Humanos , Paridad , Embarazo , Ratas , Ratas Sprague-Dawley , Receptores de Vasopresinas/efectos de los fármacos , Transfección , Vasopresinas/farmacología
7.
Br J Pharmacol ; 148(2): 154-61, 2006 May.
Artículo en Inglés | MEDLINE | ID: mdl-16547526

RESUMEN

Non-selective cyclooxygenase (COX) inhibitors exert effects on lower urinary tract function in several species. The exact contributions of COX-1 and COX-2 isozymes have not been studied much. The present studies investigated the effects of non- and selective COX inhibitors on bladder irritation in the cat.Chloralose-anaesthetised female cats were catheterised through the bladder dome for cystometric evaluation of bladder responses to intravesical infusion of saline or acetic acid. Bladder capacity, voiding efficiency, threshold pressure, and reflex-evoked bladder contraction amplitude and duration were measured. The cat COX selectivity of the doses of inhibitors examined was determined using an in vitro whole-blood assay and analysis of plasma levels. Pretreatment with indomethacin or ketoprofen (non-selective COX inhibitors; 0.3 mg kg(-1) i.v.) inhibited acetic acid-evoked irritation (characterised by a decrease in bladder capacity in vehicle pretreated animals). FR-122047 (selective COX-1 inhibitor), NS-398 and nimesulide (selective COX-2 inhibitors; 1 and 3 mg kg(-1) i.v.) had no effects on bladder irritation. Analysis of plasma levels of the doses examined and determination of COX-1 and COX-2 inhibition in cat whole blood confirmed the reported selectivity of these compounds in this species. The present studies suggest that dual COX inhibition is required to attenuate acetic acid-evoked bladder irritation in the cat.


Asunto(s)
Ciclooxigenasa 1/sangre , Ciclooxigenasa 2/sangre , Inhibidores de la Ciclooxigenasa/farmacología , Enfermedades de la Vejiga Urinaria/tratamiento farmacológico , Ácido Acético/administración & dosificación , Ácido Acético/toxicidad , Anestesia , Animales , Gatos , Relación Dosis-Respuesta a Droga , Femenino , Indometacina/farmacología , Cetoprofeno/farmacología , Masculino , Nitrobencenos/farmacología , Piperazinas/farmacología , Reflejo Anormal/efectos de los fármacos , Cloruro de Sodio/administración & dosificación , Cloruro de Sodio/farmacología , Sulfonamidas/farmacología , Tiazoles/farmacología , Enfermedades de la Vejiga Urinaria/inducido químicamente , Enfermedades de la Vejiga Urinaria/fisiopatología
8.
Pharmacology ; 69(1): 7-11, 2003 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12886024

RESUMEN

In the present study, we demonstrate that the intravenous infusion of endothelin-1 (3 and 10 ng/kg/min) causes a decrease in the mean micturition volume of rats in addition to an increase in mean arterial pressure. These effects are blocked by both the ET(A)/ET(B)-non-selective and the ET(A)-selective endothelin antagonists SB 217242 and SB 247083 respectively (both 30 mg/kg). However, it was also observed that the ET(B)-selective agonist sarafotoxin 6c (3 and 10 ng/kg/min) had similar effects on both mean arterial pressure and micturition volume. Initial experiments indicated that spontaneously hypertensive rats have a much lower mean micturition volume than normal rats. Binding studies comparing the total number and ratio of ET(A)/ET(B) receptors in spontaneously hypertensive, Wister-Kyoto and Sprague-Dawley rats revealed no significant differences in receptor expression. However, the magnitude of the response to endothelin-1 was greater in spontaneously hypertensive versus normal rats.


Asunto(s)
Endotelinas/farmacología , Vejiga Urinaria/fisiología , Animales , Benzofuranos/farmacología , Ácidos Carboxílicos/farmacología , Relación Dosis-Respuesta a Droga , Hipertensión/inducido químicamente , Hipertensión/complicaciones , Hipertensión/fisiopatología , Indanos/farmacología , Infusiones Intravenosas , Masculino , Contracción Muscular/efectos de los fármacos , Propionatos/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Micción/efectos de los fármacos , Trastornos Urinarios/inducido químicamente , Trastornos Urinarios/fisiopatología
9.
J Pharmacol Exp Ther ; 301(3): 987-92, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12023529

RESUMEN

Two endogenous receptors for the potent smooth muscle-stimulating peptide neuromedin U (NmU) have recently been identified and cloned. Pharmacological, binding, and expression studies were conducted in an attempt to determine the receptor(s) involved in the smooth muscle-stimulating effects of NmU. The NmU peptides caused a concentration-dependent contraction of canine isolated urinary bladder. NmU did not have this same effect in the urinary bladder from rat, guinea pig, rabbit, mouse, or ferret. Although NmU had no effect on canine uterus it did cause contraction of canine stomach, ileum, and colon. As well as causing contraction of canine bladder in vitro, NmU administered systemically resulted in a significant increase in urinary bladder pressure in vivo. High-affinity binding sites for NmU were identified in canine bladder. The four NmU peptides porcine NmU-8, rat NmU-23, human NmU-25, and porcine NmU-25 displaced (125)I-NmU-25 binding with similar K(i) values (0.08-0.24 nM). A different binding profile was revealed in human embryonic kidney-293 cells transiently expressed with the canine NmU-2 receptor where porcine NmU-8 (K(i) = 147.06 nM) was much less potent than the other NmU peptides. Using TaqMan, expression of NmU-1 was detected in human urinary bladder, small intestine, colon, and uterus. Expression of NmU-2 was much lower or absent in these human tissues and undetectable in canine bladder and stomach. The results of this study reveal significant species differences in the activity of NmU. The contractile activity in human and canine smooth muscle seems to be mediated by the recently cloned NmU-1 receptor.


Asunto(s)
Proteínas de la Membrana , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Neuropéptidos/metabolismo , Receptores de Neurotransmisores , Animales , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Línea Celular , Perros , Evaluación Preclínica de Medicamentos/métodos , Femenino , Hurones , Cobayas , Humanos , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Neuropéptidos/farmacología , Conejos , Ratas , Receptores de Superficie Celular/biosíntesis , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Útero/efectos de los fármacos , Útero/metabolismo
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