RESUMEN
The aim of this paper was to describe and test a social cognitive model of physical activity tailored for adolescent girls. Participants were 1518 girls (aged 13.6 ± 0.02 years) from 24 secondary schools in New South Wales, Australia. Useable accelerometer (≥10 hours day(-1) on at least 3 days) and questionnaire data were obtained from 68% of this sample (N = 1035). Participants completed questionnaires assessing psychological, behavioural, social and environmental correlates of activity. The theoretical model was tested using structural equation modelling in AMOS. The model explaining accelerometer counts per minute was an adequate-to-good fit to the data (Tucker-Lewis Index = 0.89, the comparative fit index = 0.97 and the root mean square of approximation = 0.098; 90% confidence interval = 0.075-0.122) but explained only 5% of the variance in activity. There were significant model pathways from self-efficacy (r = 0.11, P = 0.01), school environment (r = 0.07, P = 0.02) and physical self-worth (r = 0.07, P = 0.04) to accelerometer counts. Although the proposed model provided an adequate-to-good fit to the data, it explained a small portion of the variance. Shared method variance may explain the larger portions of variance explained in previous studies. Future studies are encouraged to evaluate theories of physical activity behaviour change using objective measures of physical activity.
Asunto(s)
Modelos Psicológicos , Actividad Motora , Psicología del Adolescente , Actigrafía , Adolescente , Femenino , Humanos , Nueva Gales del Sur , Educación y Entrenamiento Físico/métodos , Encuestas y CuestionariosRESUMEN
There is growing support to reverse mass incarceration in the United States, especially in the wake of the COVID-19 pandemic. Little is known about what types and scale of community investments are most effective to support mass decarceration. Using a public health prevention framework, we conducted a scoping review to examine community-based programs that reduced criminal legal involvement. We searched PubMed, Embase and three EBSCO databases from 1990 through September 2019 for all experimental or quasi-experimental studies testing interventions pertaining to education, housing, healthcare, employment, or social support services and how they affected an individual's criminal legal outcomes. Our review identified 53 studies that demonstrated the efficacy of early childhood educational interventions and nurse-family partnership programs, post-secondary education for incarcerated students, navigation programs linking incarcerated people to community resources, and peer support upon release to reduce criminal legal system exposure. In concert with legislative action to end mass incarceration, additional research is needed to test interventions designed to achieve mass decarceration which cross multiple domains, interrogate community-level impacts and ascertain long-term outcomes.
RESUMEN
The well-known side effects of anticholinergic compounds used to treat urinary incontinence caused by detrusor overactivity have addressed the interest on other pharmacological intervention. The purpose of the present work was to investigate the possible changes in purinergic and cholinergic components of parasympathetic neurotransmission in obstructed rat bladders with detrusor overactivity, and to examine the effect of the association of suramin, atropine and indomethacin on nerve-mediated responses to electrical field stimulation (EFS). Mechanical responses to exogenous acetylcholine, ATP and substance P were also evaluated. Altered sensitivities to acetylcholine and to the sensory neurotransmitter substance P, but unchanged sensitivity to the stable ATP analogue alpha,beta-methyleneATP were observed in bladders from obstructed rats. Suramin and atropine inhibited purinergic and cholinergic components of the neurogenic responses evoked by EFS in detrusor strips from control and obstructed rats. Interestingly, suramin enhanced the antagonistic effect of atropine on neurogenic responses of detrusor strips at all frequencies of stimulation tested. Our results suggest that the association between an antimuscarinic drug and an antagonist of P2X purinoceptors such as suramin might be helpful to reduce the therapeutic dosage of the antimuscarinic drug, along with its side effects. This approach may be of interest in the therapy of patients with bladder incontinence caused by detrusor overactivity, which do not even respond to a maximal dosage of antimuscarinic drug.
Asunto(s)
Acetilcolina/farmacología , Adenosina Trifosfato/farmacología , Músculo Liso/efectos de los fármacos , Sustancia P/farmacología , Obstrucción del Cuello de la Vejiga Urinaria/fisiopatología , Adenosina Trifosfato/análogos & derivados , Animales , Atropina/farmacología , Agonistas Colinérgicos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Estimulación Eléctrica , Femenino , Técnicas In Vitro , Indometacina/farmacología , Ácidos Mandélicos/farmacología , Agonistas Muscarínicos/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/inervación , Ratas , Ratas Sprague-Dawley , Suramina/farmacología , Uretra/fisiopatología , Vejiga Urinaria/inervaciónRESUMEN
Several studies have provided evidence for a direct effect of 17beta-estradiol on vessel wall via interaction with the constitutively expressed nitric oxide synthase (NOS) by endothelium. The aim of the present study was to investigate the effect of 17beta-estradiol on inducible NOS (NOS II) in primary culture of smooth muscle cells (SMC) from rat aorta. We here prove that 17beta-estradiol decreases the content and activity of NOS II in SMC. This effect appears to be the consequence of ER activation, because: 1) ER alpha and ER beta are expressed in rat aorta SMC grown in culture; 2) low concentrations of hormone modulate NOS II activity; 3) the specific ER alpha antagonist ICI182,780 completely blocks 17beta-estradiol effect. On the other hand, progesterone is deprived of any effect on NOS II content or activity, proving the specificity of 17beta-estradiol effect. In addition, we show that 17beta-estradiol can counteract the increase in NOS II activity following cytokine treatment. The observation could indicate a novel mechanism for the protective effects exerted by these hormones in cardiovascular diseases and atherosclerosis in particular.
Asunto(s)
Estradiol/farmacología , Músculo Liso Vascular/enzimología , Óxido Nítrico Sintasa/biosíntesis , Animales , Aorta , Células Cultivadas , Estradiol/administración & dosificación , Estradiol/análogos & derivados , Antagonistas de Estrógenos/farmacología , Fulvestrant , Masculino , Óxido Nítrico Sintasa de Tipo II , Nitritos/metabolismo , Progesterona/farmacología , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/genética , Receptores de Estrógenos/fisiología , Tamoxifeno/farmacologíaRESUMEN
1. Nitric oxide (NO) is known from previous studies to be the principle transmitter in NANC inhibitory nerves supplying the hamster urethra. However, the identity of the cotransmitter(s) responsible for the responses remaining following block with L-NG-nitroarginine methyl ester (L-NAME) is not known. 2. Electrical field stimulation (EFS) of circular strips of hamster proximal urethra precontracted with arginine vasopressin (AVP 10(-8) M), and in the presence of phentolamine (10(-6) M), propranolol (10(-6) M) and atropine (10(-6) M), caused frequency-dependent relaxation, which was attenuated by suramin (10(-4) M) and reactive blue 2 (RB2; 2 x 10(-4) M), but not by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 10(-4) M), alpha-chymotrypsin (10-50 u ml(-1)) or by the vasoactive intestinal polypeptide (VIP) antagonist, [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP, (5 x 10(-7)-10(-6) M). In the presence of indomethacin (10(-6) M) frequency-dependent relaxations to EFS were enhanced, particularly at the lower frequencies of stimulation. EFS-induced relaxation was blocked by tetrodotoxin (10(-6) M), indicating its neurogenic origin. 3. Exogenous ATP (10(-7)-10(-3) M) produced concentration-related relaxations which were attenuated by the P2-purinoceptor antagonists suramin (10(-4) M) and RB2 (2 x 10(-4) M) but not by PPADS (10(-4) M). ATP-induced relaxations were also reduced significantly by indomethacin (10(-6) M). The inhibitory responses to ATP were urothelium- and NO-independent, since they were not affected by either removal of urothelium or by L-NAME (10(-4) M). 4. Exogenous VIP (10(-9)-10(-7) M) induced concentration-related relaxations which were not affected by urothelium removal, L-NAME (10(-4) M), alpha-chymotrypsin (10-50 u ml(-1)) or by [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP (3 x 10(-7)-10(-6) M). Nevertheless, suramin (10(-4) M) and RB2 (2 x 10(-4) M) but not PPADS (10(-4) M) antagonized the VIP-induced relaxant responses. Calcitonin gene-related peptide (CGRP: 10(-9)-10(-7) M) was devoid of any effect or only elicited a small relaxant response in AVP-precontracted strips. 5. Exogenous prostaglandin E2 (PGE2; 10(-9)-3 x 10(-6) M) and the NO donor, sodium nitroprusside (SNP; 10(-8)-3 x 10(-5) M) elicited concentration-related relaxations on the hamster proximal urethra which were not attenuated by suramin (10(-4) M), RB2 (2 x 10(-4) M), or by PPADS (10(-4) M), indicating a specific inhibitory effect of the antagonists used. 6. In summary, these results are consistent with the view that ATP is an inhibitory transmitter released from inhibitory nerves supplying the NANC relaxation of hamster proximal urethra. The relaxant effect of ATP is NO- and urothelium-independent. The present study did not demonstrate whether VIP is released from parasympathetic nerves during EFS, since both alpha-chymotrypsin and [Lys1, Pro2,5, Arg3,4, Tyr6]-VIP were ineffective on neurogenic responses.
Asunto(s)
Adenosina Trifosfato/farmacología , Uretra/efectos de los fármacos , Péptido Intestinal Vasoactivo/farmacología , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Cricetinae , Dinoprostona/farmacología , Masculino , Mesocricetus , Relajación Muscular/efectos de los fármacos , Óxido Nítrico/farmacología , Nitroprusiato/farmacología , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Suramina/farmacología , Triazinas/farmacología , Uretra/inervación , Uretra/fisiologíaRESUMEN
1. Electrical field stimulation (EFS) of circular strips of hamster proximal urethra caused frequency-dependent relaxations at raised tone. Phentolamine (10(-6) M), propranolol (10(-6) M) and atropine (10(-6) M) were present throughout the experiment. Neurogenic relaxation was attenuated by L-NG-nitroarginine methyl ester (L-NAME) (10(-4) M), was restored by L-arginine (3 x 10(-3) M) but not by D-arginine (3 x 10(-3) M) and completely blocked by tetrodotoxin (10(-6) M). Neurogenic relaxation was also reduced by suramin (10(-4) M) and totally blocked by suramin together with L-NAME. Strips of hamster urethra devoid of urothelium showed little, if any, relaxant response to EFS. 2. An immunohistochemical study showed nitric oxide synthase-immunoreactive nerves in the smooth muscle layers and in the lamina propria, just beneath the urothelium, but no nitric oxide synthase (NOS) staining in the urothelial layer. 3. Noradrenaline elicited a significantly greater contraction in strips without urothelium than in control strips. L-NAME (10(-4) M) did not affect noradrenaline-induced contraction in both control and urothelium-free strips. The contractile response to acetylcholine was not dependent on the presence or absence of urothelium. Nevertheless the response induced by exogenous acetylcholine (10(-3) M) was increased by L-NAME (10(-4) M), both in intact and in urothelium-free strips. 4. Prostaglandin E2 (10(-8)-5 x 10(-6) M) and 2-methyl-thio-ATP (10(-9)-10(-5) M) relaxed proximal urethra. Suramin (10(-4) M) significantly inhibited the relaxation induced by 2-methyl-thio-ATP. The amplitude of these responses was not significantly different between intact and urothelium-free strips and was not blocked by L-NAME (10(-4) M). 5. These results suggest that nitric oxide (NO) is the principal transmitter involved in the non-adrenergic, non-cholinergic (NANC) relaxation of hamster proximal urethra possibly together with another inhibitory transmitter released from nerves. NO can be released from nerves located in the circular smooth muscle layer and in the lamina propria rather than in the urothelium. The reduced neurogenic relaxation in urothelium-free preparations suggests that a NO-dependent inhibitory factor is released from the urothelium. In addition, ATP and prostaglandin E2 may be involved, together with NO, in the urethra during micturition.
Asunto(s)
Uretra/efectos de los fármacos , Animales , Cricetinae , Epitelio/efectos de los fármacos , Epitelio/enzimología , Epitelio/metabolismo , Inmunohistoquímica , Microscopía Electrónica de Rastreo , Contracción Muscular/efectos de los fármacos , NADPH Deshidrogenasa/metabolismo , Óxido Nítrico Sintasa/metabolismo , Uretra/enzimología , Uretra/metabolismoRESUMEN
1. Adenosine-5'-triphosphate (ATP) is known to exert a variety of biological effects via the activation of either ionotropic P2x- or G-protein coupled P2Y-purinoceptor subtypes. In this study the effects induced by ATP and ATP analogues on rat bladder strips were characterized at resting tone and in carbachol-prestimulated tissues. 2. ATP exerted a clear concentration-dependent biphasic response, which was maximal at 1 mM concentration and was characterized by an immediate and transient contraction, followed by a slower sustained relaxation. The receptor mediating contraction was susceptible to desensitization by ATP and by the ATP analogue, alpha,beta-methyleneATP (alpha,beta-meATP) showing the typical features of the P2x-purinoceptor; conversely, ATP-evoked relaxation did not undergo tachyphylaxis following either ATP or alpha,beta-meATP. 3. The slower and sustained relaxant phase seemed to be due to activation of P2Y-purinoceptors, based on responses obtained with the P2Y agonist, 2-methyl-thioATP (2-meSATP) and, more importantly, based on the clear involvement of the G-proteins. In fact, the G-protein activator, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) significantly potentiated and the G-protein blocking agent, guanosine 5'-O-(2-thio-diphosphate) (GDP beta S) completely abolished the ATP-induced relaxation. No effects were exerted by these two G-protein modulators on the ATP-induced contraction. 4. The relaxant component of the ATP response of bladder tissue was not significantly influenced by nitro-benzyl-thioinosine (NBTI) or by 8-phenyltheophylline (8-PT), suggesting that the contribution of the ATP metabolite adenosine to this response was negligible. Moreover, relaxation evoked by ATP and by the adenosine analogue, 5'-N-ethylcarboxamidoadenosine (NECA) was additive.5. Suramin was unable to modify either the relaxant or the contractile responses of bladder strips to ATP. However, when tested on the concentration-response curve to the slowly hydrolysable P2x-agonist alpha,beta-meATP, a rightward shift was detected, suggesting that ATP contractile responses are mediated by suramine-sensitive P2x-purinoceptors.6. Uridine-5'-triphosphate (UTP) only induced a rapid and concentration-dependent contraction of the rat bladder preparation, which was not desensitized by pre-exposure to alpha,beta-meATP, suggesting that UTP responses were not mediated by the 'classical' P2X-purinoceptor.7. It is therefore concluded that both P2x- and P2y-purinoceptors, which mediate ATP-induced contraction and relaxation, respectively, are present in rat bladder. Moreover, removal of epithelium did not affect ATP-elicited contraction, whereas ATP-induced relaxation was significantly augmented. These data suggest that P2x- and P2Y- purinoceptors are localized in smooth muscle cells and that the relaxant response is probably modulated by excitatory factor(s) released by epithelial cells.
Asunto(s)
Adenosina Trifosfato/farmacología , Músculo Liso/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/farmacología , Adenosina-5'-(N-etilcarboxamida) , Animales , Relación Dosis-Respuesta a Droga , Guanosina Trifosfato/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores Purinérgicos P2/efectos de los fármacos , Tioinosina/análogos & derivados , Tioinosina/farmacología , Uridina Trifosfato/farmacología , Vejiga Urinaria/inervación , Vasodilatadores/farmacologíaRESUMEN
1. Purinergic and cholinergic components of parasympathetic neurotransmission and contractile responses to exogenous alpha,beta-methylene ATP, acetylcholine, substance K, substance P, calcitonin gene-related peptide, vasoactive intestinal polypeptide and capsaicin have been investigated in the urinary bladder of hibernating hamsters (4 weeks), cold exposed (4 weeks) and age-matched controls. 2. Electrical field stimulation (EFS) evoked increased frequency-dependent contractions in the detrusor strips from hibernating hamsters compared with those obtained from cold-exposed and age-matched animals. Tetrodotoxin (10(-6) M) completely blocked the frequency-dependent contractions in all groups. 3. The purinergic component of the parasympathetic neurotransmission was not affected in hibernating and cold-exposed animals while the cholinergic component was increased with respect to age-matched animals. The neurogenic response to EFS, still present after incubation with atropine (10(-6) M) and suramin (10(-4) M), was attenuated by indomethacin (10(-6) M) and blocked by tetrodotoxin (10(-6) M). 4. Exogenous administration of alpha,beta-methylene ATP elicited a significantly reduced contraction in strips from hibernating and cold-exposed hamsters relative to age-matched animals. The contractile response to exogenous acetylcholine was greater in the detrusors from hibernating hamsters than in cold-exposed and age-matched animals. Substance K elicited reduced contractions in preparations from hibernating animals compared with cold-exposed and control animals. Calcitonin gene-related peptide, vasoactive intestinal polypeptide, substance P and capsaicin did not elicit any relaxant or contractile response either at resting tone or in carbachol (5 x 10(-7) M)-precontracted tissues. 5. In summary, our findings indicate that 4 weeks of hibernation can significantly increase neurogenic responses in the hamster urinary bladder. This appears to be due to an increase in postjunctional responses to acetylcholine. In contrast, there was a decrease of the postjunctional responses to the parasympathetic cotransmitter ATP and also to the sensory-motor neurotransmitter substance K.
Asunto(s)
Hibernación , Vejiga Urinaria/fisiología , Acetilcolina/farmacología , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/farmacología , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Cricetinae , Estimulación Eléctrica , Masculino , Mesocricetus , Neuroquinina A/farmacología , Sustancia P/farmacología , Transmisión Sináptica/efectos de los fármacos , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/inervación , Péptido Intestinal Vasoactivo/farmacologíaRESUMEN
1. A brief challenge of rat astrocytes with either alpha, beta-methyleneATP (alpha, beta-meATP) or basic fibroblast growth factor (bFGF) resulted, three days later, in morphological differentiation of cells, as shown by marked elongation of astrocytic processes. The P2 receptor antagonist suramin prevented alpha, beta-meATP- but not bFGF-induced astrocytic elongation. Similar effects on astrocytic elongation were also observed with ATP and other P2 receptor agonists (beta, gamma meATP, ADP beta S, 2meSATP and, to a lesser extent, UTP). 2. Pertussis toxin completely abolished alpha, beta-meATP- but not bFGF-induced effects. No effects were exerted by alpha, beta-meATP on cyclic AMP production; similarly, neomycin had no effects on elogation of processes induced by the purine analogue, suggesting that adenylyl cyclase and phospholipase C are probably not involved in alpha, beta-meATP-induced effects (see also the accompanying paper by Centemeri et al., 1997). The tyrosine-kinase inhibitor genistein greatly reduced bFGF- but not alpha, beta-meATP-induced astrocytic elongation. 3. Challenge of cultures with alpha, beta-meATP rapidly and concentration-dependently increased [3H]-arachidonic acid (AA) release from cells, suggesting that activation of phospholipase A2 (PLA2) may be involved in the long-term functional effects evoked by purine analogues. Consistently, exogenously added AA markedly elongated astrocytic processes. Moreover, various PLA2 inhibitors (e.g. mepacrine and dexamethasone) prevented both the early alpha, beta-meATP-induced [3H]-AA release and/or the associated long-term morphological changes, without affecting the astrocytic elongation induced by bFGF. Finally, the protein kinase C (PKC) inhibitor H7 fully abolished alpha, beta-meATP- but not bFGF-induced effects. 4. Both alpha, beta-meATP and bFGF rapidly and transiently induced the nuclear accumulation of Fos and Jun. Both c-fos and c-jun induction by the purine analogue could be fully prevented by pretreatment with suramin. In contrast, the effects of bFGF were unaffected by this P2 receptor antagonist. 5. It was concluded that alpha, beta-meATP- and bFGF-morphological differentiation of astrocytes occurs via independent transductional pathways. For the purine analogue, signalling involves a Gi/G(o) protein-coupled P2Y-receptor which may be linked to activation of PLA2 (involvement of an arachidonate-sensitive PKC is speculated); for bFGF, a tyrosine kinase receptor is involved. Both pathways merge on some common intracellular target, as suggested by induction of primary response genes, which in turn may regulate late response genes mediating long-term phenotypic changes of astroglial cells. 6. These findings implicate P2 receptors as novel targets for the pharmacological regulation of reactive astrogliosis, which has intriguing implications in nervous system diseases characterized by degenerative events.
Asunto(s)
Adenosina Trifosfato/análogos & derivados , Astrocitos/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/farmacología , Adenosina Trifosfato/farmacología , Animales , Ácido Araquidónico/metabolismo , Astrocitos/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Proteína Quinasa C/fisiología , Ratas , Receptores Purinérgicos P2/fisiologíaRESUMEN
1. This study was aimed at characterizing ATP-induced rises in cytosolic free calcium ion, [Ca2+]i, in a population of rat striatal astrocytes loaded with the fluorescent Ca2+ probe Fura2, by means of fluorescence spectrometry. 2. ATP triggered a fast and transient elevation of [Ca2+]i in a concentration-dependent manner. The responses of the purine analogues 2-methylthio-ATP (2-meSATP), adenosine-5'-O-(2-thiodiphosphate) (ADP beta S), as well as uridine-5'-triphosphate (UTP) resembled that of ATP, while alpha, beta-methylene-ATP (alpha, beta-meATP) and beta, gamma-methylene-ATP (beta, gamma-meATP) were totally ineffective. 3. Suramin (50 microM) had only a minor effect on the ATP response, whereas pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) (5 microM) significantly depressed the maximum response. 4. Extracellular Ca2+ did not contribute to the observed [Ca2+]i rise: removing calcium from the extracellular medium (with 1 mM EGTA) or blocking its influx by means of either Ni2+ (1 mM) or Mn2+ (1 mM) did not modify the nucleotide responses. 5. Furthermore, after preincubation with 10 microM thapsigargin, the nucleotide-evoked [Ca2+]i increments were completely abolished. In contrast, 10 mM caffeine did not affect the responses, suggesting that thapsigargin-, but not caffeine/ryanodine-sensitive stores are involved. 6. Both application of the G-protein blocker guanosine-5'-O-(2-thiodiphosphate) (GDP beta S) (1 mM) and preincubation with pertussis toxin (PTx) (350 ng ml-1) partially inhibited the nucleotide-mediated responses. Moreover, the phospholipase C (PLC) inhibitor U-73122, but not its inactive stereoisomer U-73343 (5 microM), significantly reduced the ATP-evoked [Ca2+]i rise. 7. In conclusion, our results suggest that, in rat striatal astrocytes, ATP-elicited elevation of [Ca2+]i is due solely to release from intracellular stores and is mediated by a G-protein-linked P2Y receptor, partially sensitive to PTx and coupled to PLC.
Asunto(s)
Adenosina Trifosfato/farmacología , Astrocitos/metabolismo , Calcio/metabolismo , Animales , Células Cultivadas , Estrenos/farmacología , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Pirrolidinonas/farmacología , Ratas , Receptores Purinérgicos P2/fisiología , Fosfolipasas de Tipo C/fisiología , Uridina Trifosfato/farmacologíaRESUMEN
The in vitro responses of rat urinary bladder, to substance P and capsaicin were studied at 1, 4, 16, and 26 weeks of diabetes induction by streptozotocin. We also studied the role of epithelium in these responses. The results were compared with those obtained in age-matched control rats. The bladder contractile response to exogenous substance P was similar in both groups at all stages (1-26 weeks) studied, whereas the bladder response to capsaicin gradually decreased with the progression of diabetes. Atropine did not inhibit these responses whereas indomethacin slightly reduced substance P- but not capsaicin-induced responses in control and diabetic rats. The removal of epithelium slightly increased the substance P- and capsaicin-induced responses in control tissue; these responses were significantly reduced in tissue excised from diabetic rats. Our results indicate that, in rat urinary bladder, diabetes (1) provokes an impairment of capsaicin-sensitive sensory fibers but not of the cholinergic system even at an early stage (4 weeks) of the disease, (2) has no effect on the sensitivity of smooth muscle cells to substance P, (3) stimulates the release of epithelial contracting factors, partially non-prostanoic. Furthermore epithelium removal impairs acetylcholine-induced contraction in bladder excised from diabetic rats but not in controls.
Asunto(s)
Capsaicina/farmacología , Diabetes Mellitus Experimental/fisiopatología , Músculo Liso/efectos de los fármacos , Sustancia P/farmacología , Vejiga Urinaria/efectos de los fármacos , Acetilcolina/fisiología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Capsaicina/antagonistas & inhibidores , Epitelio/fisiología , Técnicas In Vitro , Masculino , Músculo Liso/fisiopatología , Tamaño de los Órganos/efectos de los fármacos , Prostaglandinas/fisiología , Ratas , Ratas Sprague-Dawley , Sustancia P/antagonistas & inhibidores , Factores de Tiempo , Vejiga Urinaria/fisiopatologíaRESUMEN
Diabetes provokes a greater responsiveness of rat urinary bladder preparations to bradykinin and a greater formation and release of prostaglandin F2 alpha, without affecting prostaglandin E2 release significantly. Inhibition of cyclooxygenase by indomethacin (1 microM) inhibits the contraction elicited by bradykinin and leads to identical contractile responses of control and diabetic urinary bladder strips. Removal of the urinary bladder epithelium does not modify the contractile response evoked by bradykinin in control preparations but significantly decreases the contraction of preparations of diabetic tissues. Quantitatively, the activity of control urinary bladder strips with epithelium and the activity of diabetic preparations without epithelium are the same. More prostaglandin F2 alpha is released into the medium by urinary bladder strips devoid of epithelium in both control and in diabetic rats. These results indicate a role for epithelial cells in the smooth muscle contraction evoked by bradykinin in diabetic rats.
Asunto(s)
Bradiquinina/farmacología , Diabetes Mellitus Experimental/fisiopatología , Vejiga Urinaria/efectos de los fármacos , Animales , Dinoprost/metabolismo , Dinoprostona/metabolismo , Epitelio/efectos de los fármacos , Epitelio/fisiología , Técnicas In Vitro , Indometacina/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Ratas , Ratas Endogámicas , Vejiga Urinaria/fisiologíaRESUMEN
Isolated epithelial layer preparations were obtained from urinary bladders of 4-week streptozotocin-diabetic rats and used for endogenous prostaglandins E(2) and F(2alpha) determination. Tissues were incubated in modified Krebs solution under basal conditions, or in the presence of either indomethacin (5x10(-7) M), ATP (10(-5) and 10(-3) M) or bradykinin (10(-7) and 10(-5) M), and samples of incubation medium were collected at 15 and 30 min. In the presence of indomethacin, the release of prostaglandins in the incubation medium was under the detection limit of the enzyme immunoassay (EIA). The epithelium from diabetic rat urinary bladders was thicker and heavier and the absolute amount of endogenous prostaglandins E(2) and F(2alpha) was higher than for control animals, but when prostaglandin production was expressed as a fraction of tissue weight, it was reduced in diabetic epithelium. ATP and bradykinin has significantly increased the endogenous release of both prostaglandins from the epithelium when compared with the release under basal conditions. This increase was time-dependent and was higher in diabetic than in control tissues. ATP evoked a phasic and tonic contraction in bladder strips that was abolished by epithelium removal. Concentration-response curves for ATP did not differ among groups. Bradykinin evoked a long-lasting tonic contraction that was reduced significantly by epithelium removal in diabetic rat bladders only. Concentration-response curves for prostaglandin E(2) and F(2alpha) in diabetic rat bladder differed significantly from that in controls and epithelium removal did not alter these responses. It is suggested that bradykinin receptors and P2X nucleotide receptors already found in the smooth muscle detrusor might be present in the epithelial layer of the bladder. The prostaglandin-release impairment observed in this study might be responsible, in part, for bladder abnormalities observed in pathological conditions, such as diabetes.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Dinoprost/metabolismo , Dinoprostona/metabolismo , Vejiga Urinaria/metabolismo , Urotelio/metabolismo , Adenosina Trifosfato/farmacología , Animales , Bradiquinina/farmacología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Ensayo de Inmunoadsorción Enzimática , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/patología , Vejiga Urinaria/fisiopatología , Urotelio/efectos de los fármacos , Urotelio/patología , Urotelio/fisiopatologíaRESUMEN
The in vitro responses of longitudinal preparations of rat stomach fundus and ileum to capsaicin at 1, 8, 4, 16 and 26 weeks and to substance P at 1 and 8 weeks from diabetes induction were studied. The results were compared with those obtained in age-matched control rats. The contractile responses to exogenous substance P and capsaicin were not affected in the stomach fundus from diabetic rats. Atropine (1 microM) did not antagonize the substance P-induced response whereas it inhibited about 90% of the capsaicin-induced response in controls and about 60% of the response in diabetic rats. At the resting tone, capsaicin induced a relaxation followed by a contraction in stomach fundus of control rats. Only a contraction was evoked in diabetic rats. In carbachol (0.05-0.1 microM) pre-stimulated strips, a complete restoration of the biphasic response was obtained in the diabetic state. The contractile response elicited by exogenous substance P was not significantly increased in the ileum preparations from diabetic rats; nevertheless the EC50 value for substance P was reduced 8 weeks after the onset of diabetes. The response elicited by capsaicin in the ileum of control rats was also biphasic. The capsaicin-induced contraction was greater in tissue from diabetic rats as compared with controls and relaxation was not evident. An age-related decrease of the contraction was also evident in both groups. Atropine (1 microM) partially antagonized the responses to substance P and capsaicin. The inhibition of the responses with atropine was more evident in control than in diabetic rats. These results suggest that the myogenic actions of several agonists in these two tissues are differently modified in experimental diabetes.
Asunto(s)
Capsaicina/farmacología , Diabetes Mellitus Experimental/fisiopatología , Fundus Gástrico/efectos de los fármacos , Íleon/efectos de los fármacos , Sustancia P/farmacología , Acetilcolina/farmacología , Factores de Edad , Animales , Relación Dosis-Respuesta a Droga , Fundus Gástrico/fisiología , Íleon/fisiología , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , EstreptozocinaRESUMEN
Electrical field stimulation caused frequency-dependent relaxations in precontracted strips of hamster proximal urethra, which were attenuated by L-N(G)-nitroarginine methyl ester (10(-4) M) and completely blocked by tetrodotoxin (10(-6) M). Strips of hamster urethra devoid of urothelium showed reduced relaxant responses to electrical field stimulation which were abolished by L-N(G)-nitroarginine methyl ester (10(-4) M). Western blot analysis showed the presence of a constitutive endothelial nitric oxide synthase in the urothelial layer, suggesting that urothelium may release nitric oxide in response to electrical field stimulation and that this release is blocked by tetrodotoxin. It is suggested that the urothelium may contribute to relaxations of the smooth muscle of hamster urethra produced by nerve stimulation.
Asunto(s)
Óxido Nítrico Sintasa/análisis , Uretra/enzimología , Urotelio/enzimología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Western Blotting , Cricetinae , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Técnicas In Vitro , Masculino , Mesocricetus , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III , Tetrodotoxina/farmacología , Uretra/efectos de los fármacos , Uretra/fisiología , Urotelio/citologíaRESUMEN
Diabetes is associated with gender-specific macrovascular complications arising from increased oxidant stress in the vascular wall. In this study, male and female rats were treated with two structurally unrelated drugs sharing antioxidant properties, lercanidipine and Leucoselect (both 3 mg/kg/day), for 1 week starting 1 day after streptozotocin-diabetes induction. Concentration-response curves to L-nitroarginine methylester (L-NAME), superoxide dismutase and acetylcholine in aortic rings showed significantly greater nitric oxide-mediated relaxation in female compared with male non-diabetic rats. Diabetes increased contractility to noradrenaline and L-NAME in both genders, whereas relaxation to acetylcholine and iloprost were significantly attenuated in females only. Treatment with lercanidipine and Leucoselect restored, at least in part, responses to noradrenaline, acetylcholine and iloprost without affecting those to L-NAME and sodium nitroprusside. Unexpectedly, both drugs impaired superoxide dismutase response in female tissues. In conclusion, female rat aorta is markedly exposed to short-term diabetic vascular injury, which may be prevented by antioxidant treatment.
Asunto(s)
Antioxidantes/farmacología , Diabetes Mellitus Experimental/fisiopatología , Diabetes Mellitus/fisiopatología , Dihidropiridinas/farmacología , Músculo Liso Vascular/efectos de los fármacos , Factores Sexuales , Acetilcolina/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Glucemia/análisis , Diabetes Mellitus/sangre , Femenino , Iloprost/farmacología , Técnicas In Vitro , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/metabolismo , Nitroprusiato/farmacología , Norepinefrina/farmacología , Ratas , Superóxido Dismutasa/farmacología , Vasoconstricción , Vasodilatadores/farmacologíaRESUMEN
Vaccinium myrtillus L. (blueberry) leaf infusions are traditionally used as a folk medicine treatment of diabetes. To further define this therapeutical action, a dried hydroalcoholic extract of the leaf was administered orally to streptozotocin-diabetic rats for 4 days. Plasma glucose levels were consistently found to drop by about 26% at two different stages of diabetes. Unexpectedly, plasma triglyceride (TG) were also decreased by 39% following treatment. Subsequent to the latter observation, possible lipid-lowering properties of the extract were investigated on other models of hyperlipidaemia and ciprofibrate, a well-established hypolipidaemic drug, was used as a reference compound. Both drug reduced TG levels of rats on hyperlipidaemic diet in a dose-dependent fashion. When administered at single doses over the same experimental period, blueberry and ciprofibrate were effective in lowering TG concentrations in ethanol-treated normolipidaemic animals and in genetically hyperlipidaemic Yoshida rats. Unlike ciprofibrate, however, blueberry failed to prevent the rise in plasma TG elicited by fructose and did not affect free fatty acid levels in any of the above experimental conditions. In rats treated with Triton WR-1339, blueberry feeding induced an hypolipidaemic activity one hour after injection but proved to be ineffective at later time points, thus suggesting that its hypolipidaemic action may reflect improved TG-rich lipoprotein catabolism. In addition, ciprofibrate and the extract were tested for antithrombotic activity using a collagen-triggered model of venous thrombosis in diabetic and Yoshida rats. Only ciprofibrate, however, significantly reduced thrombus formation in diabetics, possibly because of its effects on free fatty acid metabolism, whereas no effect was observed in Yoshida rats. In conclusion, the present findings indicate that active consituent(s) of Vaccinium myrtillus L. leaves may prove potentially useful for treatment of dyslipidaemiae associated with impaired TG-rich lipoprotein clearance.
Asunto(s)
Antocianinas/uso terapéutico , Ácido Clofíbrico/análogos & derivados , Diabetes Mellitus Experimental/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Extractos Vegetales/uso terapéutico , Animales , Glucemia/metabolismo , Ácido Clofíbrico/uso terapéutico , Ácidos Grasos no Esterificados/sangre , Ácidos Fíbricos , Masculino , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangre , Vaccinium myrtillusRESUMEN
Diabetes mellitus reduces gender-related differences in the prevalence of cardiovascular disease by fading the vascular protective effects afforded by estrogen in females. However, the impact of estrogen treatment on and the contribution of androgens to vascular function in vessels from male diabetics are largely unknown. We investigated the effects of androgen deficiency and in vivo estrogen treatment by assessing the responsiveness to a number of vasoactive agents and the formation of eicosanoid mediators in aortic rings from intact and castrated streptozotocin-diabetic rats which had been implanted with 17beta-estradiol (E2) or its vehicle for 5 days. Castration was found to attenuate contractility to noradrenaline, to enhance tone-related release of NO, as shown by curves for N-methyl-L-arginine and superoxide dismutase (SOD), and to increase endothelium-dependent relaxation to carbachol and histamine, compared with intact animals. Smooth muscle sensitivity to exogenous NO and platelet thromboxane A2 production were unchanged but prostacyclin release by aortic tissue dropped by about 40% following castration. Treatment with E2 to intact animals still attenuated contractility to noradrenaline and potentiated relaxation to SOD and histamine but affected no other parameters. In contrast, when E2 was administered to castrated animals, responses to SOD, carbachol and histamine were significantly impaired. Thus, androgen deprivation appears to improve vascular function in male diabetic rats, whereas E2 treatment exerts some beneficial effects in intact, but not in castrated animals. Our findings therefore provide new insights into the role of sex hormones in the development of diabetic vascular complications.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Estrógenos/farmacología , Vasoconstricción/efectos de los fármacos , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/fisiología , Plaquetas/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Interacciones Farmacológicas , Eicosanoides/biosíntesis , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Técnicas In Vitro , Masculino , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Norepinefrina/farmacología , Ratas , Ratas Sprague-Dawley , Estreptozocina , Vasoconstrictores/farmacología , omega-N-Metilarginina/farmacologíaRESUMEN
The beneficial effects of estrogen on arterial function in women are well established, whereas studies concerning the vascular role of androgens have produced conflicting results. In the present study, we examined the effects of androgen deprivation and of estrogen treatment on vascular responses in male rats. Vascular reactivity was studied in aortic rings excised from intact and castrated rats, which had been implanted with capsules containing either 17beta-estradiol (E2) or its vehicle for 5 days. Contractile responses to noradrenaline were potentiated by castration and by E2 treatment. Concentration-response curves for N-methyl-L-arginine and superoxide dismutase indicated that the tone-related release of NO increased in tissues from castrated, compared with intact rats, but was not affected by E2 treatment. Endothelium-dependent relaxation elicited by carbachol and histamine were not altered by castration and were attenuated by E2 in preparations from intact, but not from castrated rats. Moreover, aortic prostacyclin release dropped by about 40% after E2 treatment in tissues from both intact and castrated animals. Similarly, smooth muscle sensitivity to NO significantly decreased following castration and E2 treatment, as assessed by responses to sodium nitroprusside. Finally, no differences among groups were detected in platelet thromboxane A2 production. Thus, vascular responses in male rats were not improved by androgen deprivation alone or by E2 treatment, whose effects differed in the presence or absence of androgens. These findings provide evidence for the gender specificity of the vascular effects of estrogen and may be consistent with a beneficial role of physiologic levels of male sex hormones in arterial function.
Asunto(s)
Andrógenos/fisiología , Aorta/efectos de los fármacos , Estradiol/farmacología , Animales , Aorta/fisiología , Eicosanoides/biosíntesis , Técnicas In Vitro , Masculino , Óxido Nítrico/biosíntesis , Norepinefrina/farmacología , Orquiectomía , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/farmacología , Vasoconstricción/efectos de los fármacos , omega-N-Metilarginina/farmacologíaRESUMEN
In an attempt to study the mechanisms by which estrogens affect vascular responses, we utilized aortic preparations from intact and ovariectomized female rats receiving low- and high-dose subcutaneous estrogen treatments. Oil-treated, as well as male rats, served as controls. In ovariectomized females, low-dose 17-beta-estradiol injections (5 microg/kg daily for two days) affected the basal release of nitric oxide, as evaluated by concentration-related curves to superoxide dismutase and N(G)-Methyl-L-arginine acetate, which was found to be greater in 17-beta-estradiol-treated females compared to oil-treated females or males. Conversely, the nitric oxide-related vascular relaxation evoked by acetylcholine and sodium nitroprusside was unchanged. Prostacyclin production was also evaluated. Aortic rings from ovariectomized 17-beta-estradiol-treated females released significantly more prostacyclin than those from oil-treated females. These results point out a possible role for nitric oxide and prostacyclin in the vascular protection brought about by physiological levels of estrogens. When intact females were treated with high doses of ethynilestradiol (100 microg/Kg daily for one month), a component of contraceptive pills, either the basal release of nitric oxide, or acetylcholine-induced relaxation underwent a significant decrease. Likewise, the relaxant responses to sodium nitroprusside were impaired in the aortic rings obtained from ethynilestradiol-treated animals when compared to controls. Similarly, the amount of prostacyclin released from aortic tissues obtained from ethynilestradiol-treated animals was significantly reduced. These results may provide a possible explanation for the higher incidence of cardiovascular disease in women who take contraceptive preparations containing high doses of estrogens.