RESUMEN
During the urine storage phase, tonically contracting urethral musculature would have a higher energy consumption than bladder muscle that develops phasic contractions. However, ischaemic dysfunction is less prevalent in the urethra than in the bladder, suggesting that urethral vasculature has intrinsic properties ensuring an adequate blood supply. Diameter changes in rat or mouse urethral arterioles were measured using a video-tracking system. Intercellular Ca2+ dynamics in arteriolar smooth muscle (SMCs) and endothelial cells were visualised using NG2- and parvalbumin-GCaMP6 mice, respectively. Fluorescence immunohistochemistry was used to visualise the perivascular innervation. In rat urethral arterioles, sympathetic vasoconstrictions were predominantly suppressed by α,ß-methylene ATP (10 µM) but not prazosin (1 µM). Tadalafil (100 nM), a PDE5 inhibitor, diminished the vasoconstrictions in a manner reversed by N-ω-propyl-l-arginine hydrochloride (l-NPA, 1 µM), a neuronal NO synthesis (nNOS) inhibitor. Vesicular acetylcholine transporter immunoreactive perivascular nerve fibres co-expressing nNOS were intertwined with tyrosine hydroxylase immunoreactive sympathetic nerve fibres. In phenylephrine (1 µM) pre-constricted rat or mouse urethral arterioles, nerve-evoked vasodilatations or transient SMC Ca2+ reductions were largely diminished by l-nitroarginine (l-NA, 10 µM), a broad-spectrum NOS inhibitor, but not by l-NPA. The CGRP receptor antagonist BIBN-4096 (1 µM) shortened the vasodilatory responses, while atropine (1 µM) abolished the l-NA-resistant transient vasodilatory responses. Nerve-evoked endothelial Ca2+ transients were abolished by atropine plus guanethidine (10 µM), indicating its neurotransmitter origin and absence of non-adrenergic non-cholinergic endothelial NO release. In urethral arterioles, NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions pre- and post-synaptically to restrict arteriolar contractility. KEY POINTS: Despite a higher energy consumption of the urethral musculature than the bladder detrusor muscle, ischaemic dysfunction of the urethra is less prevalent than that of the bladder. In the urethral arterioles, sympathetic vasoconstrictions are predominately mediated by ATP, not noradrenaline. NO released from parasympathetic nerves counteracts sympathetic vasoconstrictions by its pre-synaptic inhibition of sympathetic transmission as well as post-synaptic arteriolar smooth muscle relaxation. Acetylcholine released from parasympathetic nerves contributes to endothelium-dependent, transient vasodilatations, while CGRP released from sensory nerves prolongs NO-mediated vasodilatations. PDE5 inhibitors could be beneficial to maintain and/or improve urethral blood supply and in turn the volume and contractility of urethral musculature.
Asunto(s)
Uretra , Vasoconstricción , Animales , Femenino , Uretra/inervación , Uretra/fisiología , Uretra/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Ratones , Arteriolas/efectos de los fármacos , Arteriolas/fisiología , Arteriolas/metabolismo , Ratas , Ratones Endogámicos C57BL , Ratas Sprague-Dawley , Sistema Nervioso Simpático/fisiología , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
The attenuation of glomerular hyperfiltration is posited to be a principal mechanism underlying the kidney protective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in diabetic kidney disease. Notably, the impact of SGLT2 inhibitors on kidney hemodynamic function has been posited to vary between type 1 and type 2 diabetes. The study by Wada et al. documents that in an animal model of type 2 diabetes, SGLT2 inhibitors mitigate glomerular hyperfiltration predominantly through afferent arteriolar constriction, a process mediated by the adenosine/A1 receptor pathway. This observation is consistent with mechanisms identified in type 1 diabetes, arguing for similar methods in type 1 and 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Hemodinámica , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/fisiopatología , Nefropatías Diabéticas/etiología , Ratas , Hemodinámica/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Riñón/irrigación sanguínea , Transportador 2 de Sodio-Glucosa/metabolismo , Arteriolas/efectos de los fármacos , Arteriolas/fisiopatología , Investigación Biomédica TraslacionalRESUMEN
The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, and 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Tasa de Filtración Glomerular , Glomérulos Renales , Ratas Zucker , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Masculino , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/fisiopatología , Glomérulos Renales/patología , Glomérulos Renales/irrigación sanguínea , Tasa de Filtración Glomerular/efectos de los fármacos , Ratas , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/tratamiento farmacológico , Nefropatías Diabéticas/fisiopatología , Hemodinámica/efectos de los fármacos , Xantinas/farmacología , Arteriolas/efectos de los fármacos , Arteriolas/fisiopatología , Antagonistas del Receptor de Adenosina A1/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Transportador 2 de Sodio-Glucosa/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Sorbitol/análogos & derivadosRESUMEN
BACKGROUND: We previously found that cardioplegic arrest and cardiopulmonary bypass are associated with altered coronary arteriolar response to serotonin in patients undergoing cardiac surgery. In this study, we investigated the effects of hypertension on coronary microvascular vasomotor tone in response to serotonin and alterations in serotonin receptor protein expression in the setting of cardioplegic arrest and cardiopulmonary bypass. METHODS: Coronary arterioles were dissected from harvested pre- and post-cardioplegic arrest and cardiopulmonary bypass right atrial tissue samples of patients undergoing cardiac surgery with normotension, well-controlled hypertension, and uncontrolled hypertension. Vasomotor tone was assessed by video-myography, and protein expression was measured with immunoblotting. RESULTS: Pre-cardioplegic arrest and cardiopulmonary bypass, serotonin induced moderate relaxation responses of coronary arterioles in normotension and well-controlled hypertension patients, whereas serotonin caused moderate contractile responses in uncontrolled hypertension patients. Post-cardioplegic arrest and cardiopulmonary bypass, serotonin caused contractile responses of coronary arterioles in all 3 groups. The post-cardioplegic arrest and cardiopulmonary bypass contractile response to serotonin was significantly higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups (P < .05). Pre-cardioplegic arrest and cardiopulmonary bypass, expression of the serotonin 1A receptor was significantly lower in the uncontrolled hypertension group compared with the well-controlled hypertension and normotension groups (P = .01 and P < .001). Serotonin 1B receptor expression was higher in the uncontrolled hypertension group compared with the normotension or well-controlled hypertension groups post-cardioplegic arrest and cardiopulmonary bypass (P = .03 and P = .046). CONCLUSION: Uncontrolled hypertension is associated with an increased coronary contractile response of coronary microvessels to serotonin and altered serotonin receptor protein expression after cardioplegic arrest and cardiopulmonary bypass. These findings may contribute to a worse postoperative coronary spasm and worsened recovery of coronary perfusion in patients with uncontrolled hypertension after cardioplegic arrest and cardiopulmonary bypass and cardiac surgery.
Asunto(s)
Puente Cardiopulmonar , Vasos Coronarios , Hipertensión , Serotonina , Humanos , Puente Cardiopulmonar/efectos adversos , Masculino , Femenino , Serotonina/metabolismo , Serotonina/farmacología , Hipertensión/fisiopatología , Hipertensión/metabolismo , Hipertensión/etiología , Persona de Mediana Edad , Anciano , Vasos Coronarios/fisiopatología , Arteriolas/metabolismo , Arteriolas/fisiopatología , Arteriolas/efectos de los fármacos , Paro Cardíaco Inducido/efectos adversos , Vasoconstricción/efectos de los fármacos , Receptores de Serotonina/metabolismo , Vasodilatación/efectos de los fármacosRESUMEN
OBJECTIVES: We investigated the influence of sildenafil on cardiac contractility and diastolic relaxation and examined the distribution of phosphodiesterase-5 in the hearts of hypertensive rats that were treated with by NG-nitro-L-arginine methyl ester (L-NAME). METHODS: Male Wistar rats were treated with L-NAME and/or sildenafil for eight weeks. The Langendorff method was used to examine the effects of sildenafil on cardiac contractility and diastolic relaxation. The presence and location of phosphodiesterase-5 and phosphodiesterase-3 were assessed by immunohistochemistry, and cGMP plasma levels were measured by ELISA. RESULTS: In isolated hearts, sildenafil prevented the reduction of diastolic relaxation (dP/dt) that was induced by L-NAME. In addition, phosphodiesterase-5 immunoreactivity was localized in the intercalated discs between the myocardial cells. The staining intensity was reduced by L-NAME, and sildenafil treatment abolished this reduction. Consistent with these results, the plasma levels of cGMP were decreased in the L-NAME-treated rats but not in rats that were treated with L-NAME + sildenafil. CONCLUSION: The sildenafil-induced attenuation of the deleterious hemodynamic and cardiac morphological effects of L-NAME in cardiac myocytes is mediated (at least in part) by the inhibition of phosphodiesterase-5.
Asunto(s)
Animales , Masculino , Ratas , Inhibidores Enzimáticos/uso terapéutico , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , NG-Nitroarginina Metil Éster/uso terapéutico , /farmacología , Piperazinas/farmacología , Sulfonas/farmacología , Arteriolas/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , /sangre , /metabolismo , Diástole , Ensayo de Inmunoadsorción Enzimática , Corazón/fisiopatología , Hipertensión/enzimología , Hipertensión/fisiopatología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Purinas/farmacología , Ratas Wistar , Factores de TiempoRESUMEN
OBJECTIVE: Normal endothelial cells respond to shear stress by elongating and aligning in the direction of fluid flow. Hyperglycemia impairs this response and contributes to microvascular complications, which result in deleterious effects to the endothelium. This work aimed to evaluate cheek pouch microvessel morphological characteristics, reactivity, permeability, and expression of cytoskeleton and extracellular matrix components in hamsters after the induction of diabetes with streptozotocin. METHODS: Syrian golden hamsters (90-130 g) were injected with streptozotocin (50 mg/kg, i.p.) or vehicle either 6 (the diabetes mellitus 6 group) or 15 (the diabetes mellitus 15 group) days before the experiment. Vascular dimensions and density per area of vessels were determined by morphometric and stereological measurements. Changes in blood flow were measured in response to acetylcholine, and plasma extravasation was measured by the number of leakage sites. Actin, talin, α-smooth muscle actin, vimentin, type IV collagen, and laminin were detected by immunohistochemistry and assessed through a semiquantitative scoring system. RESULTS: There were no major alterations in the lumen, wall diameters, or densities of the examined vessels. Likewise, vascular reactivity and permeability were not altered by diabetes. The arterioles demonstrated increased immunoreactivity to vimentin and laminin in the diabetes mellitus 6 and diabetes mellitus 15 groups. DISCUSSION: Antibodies against laminin and vimentin inhibit branching morphogenesis in vitro. Therefore, laminin and vimentin participating in the structure of the focal adhesion may play a role in angiogenesis. CONCLUSIONS: Our results indicated the existence of changes related to cell-matrix interactions, which may contribute to the pathological remodeling that was already underway one week after induction of experimental diabetes.
Asunto(s)
Animales , Cricetinae , Masculino , Diabetes Mellitus Experimental/patología , Laminina/ultraestructura , Vasodilatadores/farmacología , Vimentina/ultraestructura , Acetilcolina/farmacología , Arteriolas/efectos de los fármacos , Arteriolas/patología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Mejilla/irrigación sanguínea , Modelos Animales de Enfermedad , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Histamina/farmacología , Laminina/metabolismo , Mesocricetus , Microvasos/efectos de los fármacos , Microvasos/patología , Distribución Aleatoria , Factores de Tiempo , Vimentina/metabolismoRESUMEN
Os autores relatam o caso de uma paciente de 33 anos de idade, que apresentou um quadro de dor precordial em repouso, com remissäo espontânea. A cinecoronariografia realizada na ocasiäo revelou vasos absolutamente normais, assim como a movimentaçäo do ventrículo esquerdo. Sessenta e três dias após o sintoma inicial, a doente voltou a referir dor precordial, agora persistente, e que evoluiu para o infarto do miocárdio. A coronariografia demonstrou obstruçäo total da artéria descendente anterior e area discinética em regiäo anterior do ventrículo esquerdo. Os autores interpretam o quadro como decorrente de espasmo coronariano, salientando que o fenômeno espático pode ser persistente, acometer segmentos relativamente extensos dos vasos e atingir tal magnitude que suplante a açäo de drogas coronariodilatadoras, representando um potencial mecanismo de isquemia miocárdica
Asunto(s)
Humanos , Femenino , Adulto , Vasoconstricción/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Ergonovina/análogos & derivados , Arteriolas/efectos de los fármacos , Enfermedad Coronaria/etiología , Vasos Coronarios/patología , Modelos AnatómicosRESUMEN
Foi estudada, em animal de experimentaçäo (cäo), a vasomotricidade das arteríolas intramiocárdicas, após a administraçäo de ergotrate (maleato de ergometrina). Foi avaliada a resposta vasomotora da rede arterial coronária, através de moldes plásticos e pelo exame histológico e mesoscópico, de cortes corados pela hematoxilina-eosina, tricrômico de Masson, Weighert-Moure e azo-carmin. Verificou-se uma intensa constriçäo arteriolar, nos coraçöes previamente injetados com ergotrate, caracterizada pelo desaparecimento da "penugem", que representa os pequenos vasos nos moldes plásticos e pela reduçäo do lume vascular e espessamento da parede arteriolar, nos exames histológicos. Concluiu-se que a vasoconstriçäo arteriolar, expressa nos diferentes procedimentos de estudo, pode traduzir a potencialidade dos pequenos vasos intramiocárdicos, de produzir espasmo vascular em condiçöes patológicas específicas, e representarem mecanismo eventual de isquemia miocárdica
Asunto(s)
Animales , Perros , Vasoconstricción/efectos de los fármacos , Enfermedad Coronaria/etiología , Vasos Coronarios/efectos de los fármacos , Ergonovina/análogos & derivados , Arteriolas/efectos de los fármacos , Vasos Coronarios/patología , Modelos AnatómicosRESUMEN
Después de perfundir la arteria mesentérica anterior de la rata y sus ramas con una solución de Tyrode sin Ca, que agora el Ca extracelular, es posible provocar contracciones mediante la inyección "en bolo" de Noradrenalina (NA), Adrenalina (AD), Serotonina (ST) y Vasopresina (VP). La infusión continua de NA produce un efecto vasoconstrictor sostenido cuando el líquido intersticial contiene Ca, pero declina cuando ést falta. Todos a la solución perfusora privada de Ca. Estos no se recuperan, perfundiendo una solución sin Ca, pero rápidamente si ésta lo contiene. Tanto el La3+ como el EDTA no ingresan a la célular muscular, sino que desplazan al Ca fijado al plasmalema, que pone en marcha el mecanismo contráctil. Cuando éste falta, los agonistas carecen del Ca que lleva su mensaje al interior de la célula y son, por lo tanto, inefectivos. Este Ca mensajero membranal es reemplazado por el Ca iónico extracelular, pero no por el Ca intracelular. Esta interpretación permite explicar el "efecto dual" de la NA, que postula que los efectos breves o fásicos se deberían a la liberación de Ca intracelular, mientras que los sostenidos o tónicos al ingreso de Ca extracelular. Cuando el medio no contiene Ca, los agonistas son capaces de provocar vasoconstricción a partir de Ca fijado a la membrana celular. Como éste no es repuesto, si el medio carece de Ca, las respuestas vasoconstrictoras delcina y acaban agotándose (AU)
Asunto(s)
Ratas , Animales , Estudio Comparativo , Membrana Celular/metabolismo , Espacio Extracelular/metabolismo , Vasoconstricción/efectos de los fármacos , Arteriolas/efectos de los fármacos , Calcio/farmacología , Arterias , Mesenterio/irrigación sanguínea , Lantano/farmacología , Calcio/metabolismo , Vasopresinas/farmacología , Interacciones Farmacológicas , Neurotransmisores/farmacologíaRESUMEN
Después de perfundir la arteria mesentérica anterior de la rata y sus ramas con una solución de Tyrode sin Ca, que agora el Ca extracelular, es posible provocar contracciones mediante la inyección "en bolo" de Noradrenalina (NA), Adrenalina (AD), Serotonina (ST) y Vasopresina (VP). La infusión continua de NA produce un efecto vasoconstrictor sostenido cuando el líquido intersticial contiene Ca, pero declina cuando ést falta. Todos a la solución perfusora privada de Ca. Estos no se recuperan, perfundiendo una solución sin Ca, pero rápidamente si ésta lo contiene. Tanto el La3+ como el EDTA no ingresan a la célular muscular, sino que desplazan al Ca fijado al plasmalema, que pone en marcha el mecanismo contráctil. Cuando éste falta, los agonistas carecen del Ca que lleva su mensaje al interior de la célula y son, por lo tanto, inefectivos. Este Ca mensajero membranal es reemplazado por el Ca iónico extracelular, pero no por el Ca intracelular. Esta interpretación permite explicar el "efecto dual" de la NA, que postula que los efectos breves o fásicos se deberían a la liberación de Ca intracelular, mientras que los sostenidos o tónicos al ingreso de Ca extracelular. Cuando el medio no contiene Ca, los agonistas son capaces de provocar vasoconstricción a partir de Ca fijado a la membrana celular. Como éste no es repuesto, si el medio carece de Ca, las respuestas vasoconstrictoras delcina y acaban agotándose
Asunto(s)
Ratas , Animales , Arteriolas/efectos de los fármacos , Calcio/farmacología , Membrana Celular/metabolismo , Espacio Extracelular/metabolismo , Vasoconstricción , Arterias , Calcio/metabolismo , Interacciones Farmacológicas , Lantano/farmacología , Mesenterio/irrigación sanguínea , Neurotransmisores/farmacología , Vasopresinas/farmacologíaRESUMEN
The aim of this study was evaluate the effects of a single, 10 min, intravenous infusion of a hyperonic NaCl solution [2.400 mOsm/l; infused volume 0.35 ñ 0.03 ml (SEM) on the hamster cheek pouch microcirculation during normovolemia and after acute bleeding to a hypotension level of about 40 mmHg. Upon bleeding, the arterial pressure dropped to 39 µ 1 mmHg, arterioles > 40 -m constricted 12 ñ 3% (from their control value), arterioles < 40 µm dilated 6 ñ 2%, venules stayed largely unchanged, while RBC velocity and volume flow decreased 57 ñ 7% in all vessels. Durign the subsequent hypertonic NaCl infusion, the arterial pressure increased rapidly to a new steady state level of 66 ñ 3 mmHg. After the infusion, the large arterioles stayed constricted 11 ñ 1% and the small arterioles dilated 7 ñ 1% for a 1-h observation period. The venules constricted iniatially by 6 ñ 2% and returned to control diameter in 30-40 min. RBC velocity and calculated volume flow returned to the pre-hemorrhage cotrol values in about 10 min for the arterioles and in 40 min for the venules. An identical hypertonic infusion given to normovolemic hamsters caused no significant alterations of the measured variables
Asunto(s)
Animales , Femenino , Cricetinae , Presión Sanguínea/efectos de los fármacos , Mejilla/irrigación sanguínea , Solución Salina Hipertónica/farmacología , Arteriolas/efectos de los fármacos , Velocidad del Flujo Sanguíneo , Infusiones Intravenosas , Microcirculación/efectos de los fármacos , Choque/fisiopatología , Factores de TiempoRESUMEN
Várias drogas têm sido utilizadas em neurocirurgia para evitar o aumento da pressäo intracraniana e o espasmo de vasos cerebrais. O diazóxido, um agente hipotensor de açäo direta sobre a musculatura lisa dos vasos ainda näo foi estudado. Dessa maneira resolvemos pesquisar os efeitos dessa droga, administrada por via venosa (3 mg.kg-1) sobre a pressäo intracraniana e o diâmetro dos vasos piais em 16 cäes. Os animais foram divididos em dois grupos de 8. No grupo 1 foi estudado o efeito do diazóxido sobre a pressäo intracraniana, medida através de uma agulha colocada na cisterna magna, ligada a um transdutor e a um fisiógrafo. Ao mesmo tempo se registrava a pressäo arterial e se media o pH, PaO2 e PaCO2, nos tempos 1 (antes) 2,3 e 4 (1,15 e 30 min) após a injeçäo da droga. No grupo 2, media-se o diâmetro de arteríolas e vênulas piais através de uma perfuraçäo na regiäo craniana parieto-temporal e fotografia dos vasos piais nos mesmos tempos empregados no grupo anterior. Eram realizadas também medidas da pressäo arterial e dos gases sangüíneos. Observou-se que o diazóxido determina hipotensäo arterial logo após a sua injeçäo venosa, que persiste por 30 minutos. Ao mesmo tempo induz aumento significante do diâmetro das arteríolas piais. Näo há variaçäo significante da pressäo intracraniana e das vênulas piais. Esses resultados sugerem a possibilidade do uso dessa droga na profilaxia e no tratamento de espasmos vasculares cerebrais