RESUMO
The testicular capsules of different mammalian species exhibit spontaneous motor activity. In addition, contractions can be mediated by neuronal stimulation or exogenous drug administration. However, the physiological role of testicular capsule motor activity is still not well understood. Nevertheless, there is evidence for putative roles in spermatozoa transport from the testis to the caput epididymis, control of interstitial/intratesticular pressure and testicular blood flow. In this review, we have collated information about the agents that regulate testicular capsule motor activity, their receptors and second messengers as well as the impact of altered testicular capsule function on the male reproductive system. Furthermore, we highlight the knowledge gaps in the physiology and pharmacology of the testicular capsule as indicators of future research directions that may lead to a better understanding of the physiological role of testicular capsule motor activity and its importance in male fertility.
Assuntos
Sistema Nervoso Autônomo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/inervação , Animais , Sistema Nervoso Autônomo/fisiologia , Fertilidade/efeitos dos fármacos , Humanos , Masculino , Pressão , Fluxo Sanguíneo Regional , Motilidade dos Espermatozoides/efeitos dos fármacosRESUMO
Comorbidity of diabetes and hypertension is frequent. Here, we have performed a comparative study in three animal models namely, normotensive Wistar Kyoto (WKY) rats, streptozotocin-induced diabetic rats (STZ), and spontaneously hypertensive rats (SHR). With respect WKY rats, we have found the following alterations in adrenal chromaffin cells from STZ and SHR rats: (1) diminished Ca2+ currents; (2) augmented [Ca2+]c elevations and catecholamine release in cells stimulated with angiotensin II or high K+; (3) unchanged expression of angiotensin II receptors AT1 and AT2; (4) higher density of secretory vesicles at subplasmalemmal sites; (5) mitochondria with lower cristae density that were partially depolarized; and (6) lower whole cell ATP content. These alterations may have their origin in (i) an augmented capacity of the endoplasmic reticulum [Ca2+] store likely due to (ii) impaired mitochondrial Ca2+ uptake; (iii) augmented high-[Ca2+]c microdomains at subplasmalemmal sites secondary to augmented calcium-induce calcium release and to inositol tris-phosphate receptor mediated enhanced Ca2+ mobilization from the endoplasmic reticulum; and (iv) augmented vesicle pool. These alterations seem to be common to the two models of human hypertension here explored, STZ diabetic rats and SHR hypertensive rats.
Assuntos
Sinalização do Cálcio , Catecolaminas/metabolismo , Células Cromafins/metabolismo , Células Cromafins/patologia , Diabetes Mellitus Experimental/patologia , Mitocôndrias/patologia , Animais , Contagem de Células , Masculino , Ratos , Ratos Endogâmicos SHR , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismoRESUMO
It is known that red wine has cardioprotective properties. However, its influence is unknown about purinergic system. Therefore, we study the influence of the treatment with red wine or ethanol in purinergic neurotransmission. We used Wistar Kyoto rats (WKY), diabetic streptozotocin-induced WKY and spontaneously hypertensive rats (SHR), treated with red wine (12.5%) or ethanol (12.5%). The cardiovascular function stimulated with purinergic agonists and systolic blood pressure (SBP) was assessed. In atria of diabetics and SHRs, the P1 receptor response was decreased, unlike the P2 receptor response was increased. Likewise, in aorta the affinity to adenosine (ADO) was decreased from SHRs and diabetics. Furthermore, the P2X function was increased just SHRs. All these alterations were improved after treatment with red wine, resulting in reduction of SBP from diabetics and SHRs, but not when treated with ethanol. This study has important implications, because it is shown that consumption of red wine can improve cardiovascular system by purinergic neurotransmission.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Experimental/fisiopatologia , Hipertensão/tratamento farmacológico , Receptores Purinérgicos/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Vitis , Vinho , Adenosina/metabolismo , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Etanol/farmacologia , Hipertensão/etiologia , Hipertensão/metabolismo , Masculino , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêutico , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Purinérgicos P1/metabolismo , Receptores Purinérgicos P2/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
Histamine is an important modulatory agent of the sympathetic neurotransmission, but its exact action on the testicular capsule or rat vas deferens is not fully understood. The present study sought to further investigate the functional effects of histamine on the neuronal and exogenous noradrenaline-induced contraction of the testicular capsule and rat vas deferens as well as to evaluate the contractile properties of this drug. The testicular capsule or vas deferens from Wistar rats, 3-4 months old, weighing 300-400 g, was isolated and mounted in organ baths for functional experiments. The results indicated that the neuronally evoked contraction of the testicular capsule was affected by histamine (10(-10) to 10(-8) M) with participation of inhibitory (H3 receptors) and excitatory (H1 receptors) receptors. Histamine (10(-7) to 10(-4) M) modulated the field-stimulated vas deferens by excitatory (H2 receptors) and inhibitory (H1 receptors) receptors. Histamine was able to decrease the tonic response for noradrenaline-induced contractions with participation of H1 receptors (testicular capsule) and H3 receptors (vas deferens) followed by nitric oxide generation. At high concentration, histamine exerts contractile effects in both tissues. In the testicular capsule, the histamine-induced contractions were related to H1 receptor activation followed by release of prostaglandins. In contrast, the contractile effects of histamine in the vas deferens were related to H2 receptor activation followed by release of catecholamines from sympathetic nerve endings. Therefore, our results indicate that histamine induced several effects on the sympathetic neurotransmission of rat testicular capsule and vas deferens. These effects are dependent on the concentration used and with participation of multiple histamine receptors.
Assuntos
Histamina/farmacologia , Testículo/efeitos dos fármacos , Ducto Deferente/efeitos dos fármacos , Animais , Estimulação Elétrica , Técnicas In Vitro , Masculino , Óxido Nítrico/fisiologia , Norepinefrina/farmacologia , Ratos Wistar , Receptores Histamínicos/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Testículo/fisiologia , Ducto Deferente/fisiologiaRESUMO
Diabetes augments the risk of hypertension. Although several factors have been implicated in the development of such hypertensive state, we designed this study to investigate blood pressure development, the activity of angiotensin-converting enzyme (ACE) in blood as well as sympathetic neurotransmission in the vas deferens of diabetic rats. We used streptozotocin (STZ)-induced diabetic rats (60 mg/kg) in order to evaluate the systolic blood pressure (SBP), ACE activity and peripheral sympathetic neurotransmission. We observed the following changes of parameters: increase of SBP, decrease of heart rate, augmentation of plasma ACE activity, enhancement of phasic and tonic vas deferens contractions elicited by electrical stimulation at 5 Hz, increase of maximal response to noradrenaline (NA) and decrease of adenosine triphosphate (ATP)-elicited contraction of vasa deferentia. The results reveal that in the development of hypertension in diabetic rats, augmentation of circulating ACE activity precedes the sympathetic dysfunction. Additionally, it seems that the purinergic and noradrenergic neurotransmission is compromised.
Assuntos
Diabetes Mellitus Experimental/complicações , Hipertensão/etiologia , Músculo Liso/inervação , Peptidil Dipeptidase A/sangue , Sistema Nervoso Simpático/fisiopatologia , Ducto Deferente/inervação , Animais , Pressão Sanguínea , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Frequência Cardíaca , Hipertensão/sangue , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Masculino , Contração Muscular , Fármacos Neuromusculares/farmacologia , Ratos , Estreptozocina , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Transmissão Sináptica , Sístole , Fatores de Tempo , Regulação para CimaRESUMO
The term functionomics (Amin 2003, Neumann et al. 2004) refers to a postgenomic integrated Systems Biology (Attur et al. 2002) using a multidimensional approach for cells, tissues and organs. It considers current or future involvement among genomics, proteomics or metabolomics, including the main factors that cause biological responses and modulation under different conditions. Our objective in the present review is to summarize the contemporary understanding of functionomics of smooth muscle pharmacology, based on the results obtained on the pregenomic era during several years in our laboratory. The present approach is based on the knowledge of the dynamics of the receptor system, which comprises a cascade of phenomena, leading from the drug administration to the final biological response. We will describe several conditions in which the final effect is modified, based on perturbations induced on drug absorption, distribution, metabolism, interaction with receptors and mobilization of second messengers, as well as by interactions with a second receptor system. We will also discuss the gaps that need to be fulfilled in order to obtain a clear and better understanding of the receptor system in smooth muscle, and to narrow the bridge between ourknowledge of the function of biological systems, genomics, and other recently introduced areas.
Assuntos
Genômica , Músculo Liso/efeitos dos fármacos , Animais , Humanos , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
The term functionomics (Amin 2003, Neumann et al. 2004) refers to a postgenomic integrated Systems Biology (Attur et al. 2002) using a multidimensional approach for cells, tissues and organs. It considers current or future involvement among genomics, proteomics or metabolomics, including the main factors that cause biological responses and modulation under different conditions. Our objective in the present review is to summarize the contemporary understanding of functionomics of smooth muscle pharmacology, based on the results obtained on the pregenomic era during several years in our laboratory. The present approach is based on the knowledge of the dynamics of the receptor system, which comprises a cascade of phenomena, leading from the drug administration to the final biological response. We will describe several conditions in which the final effect is modified, based on perturbations induced on drug absorption, distribution, metabolism, interaction with receptors and mobilization of second messengers, as well as by interactions with a second receptor system. We will also discuss the gaps that need to be fulfilled in order to obtain a clear and better understanding of the receptor system in smooth muscle, and to narrow the bridge between ourknowledge of the function of biological systems, genomics, and other recently introduced areas.
O termo funcionômica (Amin 2003, Neumann et al. 2004) refere-se a um estudo posgenômico de Biologia de Sistemas (Attur et al. 2002), usando um enfoque multidimensional, dinâmico e simultâneo para células, tecidos e órgãos. Considera o envolvimento presente e futuro da genômica, proteômica e metabolômica incluindo os principais fatores que causam a resposta biológica final e sua modulação em diferentes condições. Nosso objetivo na presente revisão é resumir o nosso conhecimento atual em relação à funcionômica da farmacologia da musculatura lisa, baseada em resultados que obtivemos ainda na era pregenômica, durante vários anos em nosso laboratório. O presente enfoque baseia-se no que sabemos hoje em dia sobre a dinâmica do sistema receptor, que compreende uma cascata de fenômenos, que vão desde a administração de uma droga até a resposta biológica. Descreveremos várias condições nas quais a resposta é modificada, com base em perturbações produzidas na absorção, distribuição e metabolismo de fármacos, interação com receptores, mobilização de segundos mensageiros, bem como interações com um segundo sistema receptor. Discutiremos também o papel da genômica e as inúmeras falhas que devem ser preenchidas, para que se chegue a um conhecimento integrado e cada vez melhor dos sistemas receptores na musculatura lisa e para encurtar a ponte entre as funções do sistema biológico, genômica e outras áreas recentemente introduzidas.
Assuntos
Animais , Humanos , Genômica , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Músculo Liso/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
The inhibitory effect of agmatine on electrically induced contractions was studied in vas deferens of Adra 2a transgenic mice lacking alpha(2A)-adrenoceptors. Agmatine and clonidine caused a concentration-dependent inhibition of twitches. However, while agmatine showed a similar pIC(50) value in control and transgenic mice, the pIC(50) value for clonidine was about 30-fold lower in knockout mice. In both strains, yohimbine shifted the curve for clonidine, but not for agmatine, even when a 100-fold higher concentration of yohimbine was employed. Our results indicate that inhibition by agmatine in mouse vas deferens is not simply due to interactions with alpha(2)-adrenoceptors in our experimental conditions.
Assuntos
Agmatina/farmacologia , Receptores Adrenérgicos alfa 2/fisiologia , Ducto Deferente/efeitos dos fármacos , Animais , Clonidina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Contração Muscular/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Ducto Deferente/fisiologiaRESUMO
Female Wistar rats were treated with the serotonin reuptake inhibitor fluoxetine (10 mg/kg/i.p/day), during pregnancy and breast-feeding, for the study of the corresponding newborn rats. At the end of the preweaning period, the 30-day old litters had their vas deferens removed for testing peripheral sympathetic reactivity, through the following experiments in vitro: (a) concentration-contraction curves for serotonin and for the adrenergic agonists noradrenaline, phenylephrine, clonidine and dopamine or for the indirect agonist tyramine (b) contractions induced by electric field stimulation, as an indicator of sympathetic neurotransmission (c) release of endogenous noradrenaline, measured by real-time determinations on HPLC (d) Ca(+2) time-contraction curves, to check for changes on Ca(+2) translocation. Our results showed that the affinity (pD(2)) for serotonin was strikingly decreased by about 1.5 log units. The pD(2) for adrenergic agonists was decreased by about 0.5 log units, except for dopamine and clonidine. The maximum effects and intrinsic activity were decreased only for dopamine. On the other hand, the response to Ca(+2) and the release of noradrenaline from nerve terminals were not modified. In additional experiments, the mother's body weights were measured, showing a decrease during gestation and a recovery during lactation while the offspring's weights were lower than controls. It is concluded that, besides the alterations on body weights, changes on noradrenergic and serotonergic mechanisms were observed and persisted in the newborn, at least one month after parturition.
Assuntos
Animais Recém-Nascidos/fisiologia , Fluoxetina/farmacologia , Norepinefrina/fisiologia , Prenhez/fisiologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Serotonina/fisiologia , Ducto Deferente/fisiologia , Animais , Bário/farmacologia , Peso ao Nascer/efeitos dos fármacos , Cálcio/farmacologia , Relação Dose-Resposta a Droga , Estimulação Elétrica , Feminino , Crescimento/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Gravidez , Ratos , Ratos WistarRESUMO
In this study, we investigated the effect of aging on intracellular Ca2+ stores, as sarcoendoplasmic reticulum (SR) and mitochondria, and the influence of these compartments on contraction of rat colon smooth muscle [Bitar, K.N., 2003. Aging and neural control of the GI tract V. Aging and gastrointestinal smooth muscle: from signal transduction to contractile proteins. Am. J. Physiol. Gastrointest. Liver. Physiol. 284(1), G1-G7; Marijic, J., Li, Q.X., Song, M., Nishimaru, K., Stefani, E., Toro, L., 2001. Decreased expression of voltage-and Ca2+-activated K+ channels in coronary smooth muscle during aging. Circ. Res. 88, 210-234; Rubio, C., Moreno, A., Briones, A. Ivorra, M.D., D'Ocon, P., Vila, E., 2002. Alterations by age of calcium handling in rat resistance arteries. J. Cardiovasc. Pharmacol. 40(6), 832-840]. Calcium stores and contraction were evaluated by simultaneous measurements of fluorescence and tension in smooth muscle strips loaded with fura-2. Results showed that activation of muscarinic receptors by methylcholine (MCh, 10 microM), induced a greater contraction in aged rats than in adult animals. The inhibition of Ca2+ ATPase by thapsigargin (TG, 1 microM) did not prevent the refilling of SR either in adult or aged rats. MCh, in the presence of TG, induced an increase in transient fluorescence, indicating a release of Ca2+ from TG-insensitive compartment. The mitochondrial uncoupler, FCCP (5 microM), caused a greater increase in intracellular Ca2+ and tension in aged rats, indicating that mitochondria may accumulate more Ca2+ during aging. The present results show that changes in intracellular Ca2+ stores, such as mitochondria and SR, affect contraction and may cause dysfunctions during aging that could culminate in severe alterations of Ca2+ homeostasis and cell damage.