RESUMO
Genitourinary syndrome of menopause (GSM) is a highly prevalent, not self-limiting condition displaying a major negative impact on sexual function and emotional well-being. Various non-hormonal and hormonal treatment options are available. Many women consider GSM treatment to be a short-term interval cure rather than a long-term or lifelong treatment. The aim of this systematic literature search was to assess the sustainability of vaginal estrogens for GSM treatment after treatment cessation. We found that objective GSM signs mostly deteriorated within approximately 4 weeks after vaginal estrogen treatment cessation, while vaginal estrogens had a more sustainable impact on subjective GSM symptoms up to 3-6 months. However, overall, scientific evidence on sustainability of vaginal estrogens was low. Thus, GSM treatment should not be considered a short-term interval cure but long-term therapy. Further studies in an internationally harmonized setting (Core Outcomes in Menopause [COMMA]) are needed.
Assuntos
Estrogênios , Menopausa , Feminino , Humanos , Sistema UrogenitalRESUMO
In women, body weight increases with age. Often menopausal hormone therapy (MHT) is blamed for enhancing this effect. In recent years, the debate on bioidentical MHT including micronized progesterone (MP) has increased. Among others, the question has been raised of whether MHT containing MP has an impact on body weight and glucose metabolism. Based on a systematic literature review on the impact of MHT containing MP on body weight, body mass index (BMI), and glucose metabolism, the following conclusions can be drawn: estrogens combined with MP (1) either do not change or reduce body weight in normal weight postmenopausal women, (2) do not change BMI in normal and overweight postmenopausal women, (3) do not change or improve fasting serum glucose levels in (non-)diabetic postmenopausal women, (4) do not change or improve fasting serum insulin levels in (non-)diabetic postmenopausal women, and (5) do not have an impact on serum glycated hemoglobin in postmenopausal diabetic women. This beneficial effect is probably mostly due to the estrogen MHT component.
Assuntos
Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Terapia de Reposição de Estrogênios/efeitos adversos , Glucose/metabolismo , Progesterona/farmacologia , Glicemia/análise , Feminino , Hemoglobinas Glicadas/análise , Humanos , Insulina/sangue , MEDLINE , Menopausa/efeitos dos fármacosRESUMO
OBJECTIVE: Having previously demonstrated release of histamine from mast-cell-deficient rat aorta, the objective of this study was to determine and localize histamine synthesis capability in the aorta by detecting histidine decarboxylase (HDC), the enzyme that catalyzes histamine formation. MATERIALS AND METHODS: Experiments were conducted with nested reverse transcription-polymerase chain reaction (nRT-PCR) to detect HDC mRNA and with immunofluorescence and western blot analysis to detect HDC protein in rat aorta, cultured rat aortic smooth muscle (RASMC) and endothelial cells (RAEC). RESULTS: Gel electrophoresis of nRT-PCR products indicated HDC mRNA in liver, aorta and RASMC but not in RAEC or kidney. Sequence analysis confirmed that the band observed in RASMC was the target HDC amplicon. Immunofluorescence indicated the presence of HDC protein in RASMC and not in RAEC. Western Blot analysis revealed HDC protein (55 kDa) in liver, aorta, RASMC but not in RAEC or kidney. CONCLUSIONS: The results of this study are the first to demonstrate the presence of HDC mRNA and protein in rat aorta and more specifically in RASMC, indicative of their capability to synthesize histamine.
Assuntos
Aorta/citologia , Aorta/enzimologia , Histidina Descarboxilase/genética , Histidina Descarboxilase/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Animais , Western Blotting , Células Cultivadas , Escherichia coli/genética , Imunofluorescência , Músculo Liso Vascular/citologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos F344 , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: The objective of this study was to investigate histamine synthesis capability of human vascular smooth muscle and endothelial cells by detecting histidine decarboxylase (HDC) mRNA. METHODS: HDC catalyzes exclusively the formation of histamine in mammalian cells. Experiments utilizing nested reverse transcription-polymerase chain reaction (nRT-PCR) were conducted to detect the presence of HDC mRNA. Human aortic smooth muscle cells (HAoSMC) and human aortic endothelial cells (HAEC) were cultured and RNA was extracted and amplified using two sets of HDC-specific primers. Rat liver and kidney RNA were isolated and amplified to serve as positive and negative controls, respectively. RESULTS: Gel electrophoresis of HAoSMC, HAEC and liver mRNA revealed bands coinciding with an expected product size of 440 base pairs. Sequence analysis revealed that the observed bands were the appropriate HDC amplicons. CONCLUSIONS: These findings are the first to indicate the presence of HDC mRNA in vascular smooth muscle cells and confirm the presence of HDC mRNA in endothelial cells which is consistent with an ability of these cell types to synthesize histamine in the vascular wall.
Assuntos
Endotélio Vascular/metabolismo , Histidina Descarboxilase/metabolismo , Músculo Liso Vascular/metabolismo , RNA Mensageiro/metabolismo , Animais , Aorta/citologia , Células Cultivadas , Primers do DNA/química , Endotélio Vascular/citologia , Histamina/química , Humanos , Rim/metabolismo , Fígado/metabolismo , RNA/metabolismo , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNARESUMO
We hypothesized that substance P and capsaicin would cause the release of prostaglandin E2 (PGE2) from intrapulmonary bronchi isolated from Sprague-Dawley rats. Substance P (1 microM) caused the release of PGE2, measured with enzyme immunoassay, from the isolated airway segments; PGE2 release was inhibited by the neurokinin (NK)1-receptor antagonist, RP-67580, by inhibition of cyclooxygenase with meclofenamate, and by removal of the epithelium. The release of PGE2 caused by capsaicin (1 microM) was similar in magnitude to that caused by substance P. The capsaicin-induced release of PGE2 was inhibited by desensitization of sensory nerves with capsaicin and by RP-67580, meclofenamate, and epithelial denudation. We conclude that activation of NK1 receptors on epithelium causes release of PGE2, which most likely represents the ultimate mediator of airway smooth muscle relaxation, produced by exogenous neuropeptides and by activation of the sensory nerve inhibitory system. Epithelial damage, such as that seen in asthmatic airways, would disrupt this protective system in the lungs, which could contribute to the development of airway disease.
Assuntos
Brônquios/fisiologia , Capsaicina/farmacologia , Dinoprostona/metabolismo , Músculo Liso/fisiologia , Substância P/farmacologia , Animais , Brônquios/efeitos dos fármacos , Células Epiteliais/fisiologia , Técnicas In Vitro , Indóis/farmacologia , Isoindóis , Masculino , Ácido Meclofenâmico/farmacologia , Modelos Biológicos , Músculo Liso/efeitos dos fármacos , Fibras Nervosas/fisiologia , Antagonistas dos Receptores de Neurocinina-1 , Ratos , Ratos Sprague-DawleyRESUMO
Previous studies in our laboratory and others suggested that activation of 5-HT2 receptors mediates 5-hydroxytryptamine (5-HT)-induced contraction of airway smooth muscle and that this response is dependent in part on endogenous acetylcholine (ACh). The purpose of the present study was to confirm a role for 5-HT2 receptors and endogenous ACh in 5-HT-induced contraction of rat bronchi. In this study, we examined the effects of 5-HT2 receptor antagonists (ketanserin and LY53857), acetylcholinesterase inhibitors (physostigmine and neostigmine), and a muscarinic receptor alkylating agent [propylbenzilylcholine mustard (PBCM)] on contractile responses evoked by 5-HT and the 5-HT2 receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT). Concentration-response curves generated in isolated rat intrapulmonary bronchi in response to 5-HT and alpha-Me-5-HT were superimposable. Inhibition of acetylcholinesterase by physostigmine or neostigmine potentiated contractile responses elicited by 5-HT and alpha-Me-5-HT. Alkylation of muscarinic receptors with PBCM decreased maximal responses elicited by 5-HT or alpha-Me-5-HT in a concentration-dependent manner. Maximum contraction attained with exogenous ACh was decreased by PBCM in a concentration-dependent manner and, at the highest concentration evaluated, ACh-induced contractions were abolished. 5-Hydroxytryptamine-induced contraction was inhibited competitively by low concentrations of the 5-HT2-receptor selective antagonist, ketanserin; higher concentrations abolished contractile responses to the amine. The inhibition of 5-HT-induced contractile responses by another 5-HT2-receptor selective antagonist, LY53857, was non-competitive in nature. Together, the results suggest that 5-HT contracts rat airways directly by activating 5-HT2 receptors located on airway smooth muscle and indirectly by activation of 5-HT2 receptors on parasympathetic nerve endings to cause release of ACh. The potential physiological implication of these findings is that 5-HT released in inflammatory conditions such as asthma may play a role in causing bronchoconstriction by releasing ACh or by augmenting release of ACh from activated cholinergic nerves.
Assuntos
Brônquios/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Antagonistas Muscarínicos/farmacologia , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/análogos & derivados , Serotonina/farmacologia , Análise de Variância , Animais , Broncoconstrição , Relação Dose-Resposta a Droga , Masculino , Músculo Liso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/fisiologiaRESUMO
This study was initiated to test the hypothesis that histamine can act as an endothelium-derived contracting factor in bovine isolated intrapulmonary vein. The effects of calcium ionophore, calcimycin (A23187), on isometric tension were compared in unstimulated rings of intrapulmonary vein with and without endothelium. A23187 (0.1-10 microM) induced concentration-related contraction when endothelium was present. Destruction of endothelium markedly inhibited A23187-induced contraction. Methylene blue, hemoglobin or NG-methyl-L-arginine significantly enhanced A23187-induced contraction only in venous rings with endothelium consistent with attenuation of the contraction by the concomitant release of endothelium-derived relaxing factor (nitric oxide) [EDRF(NO)]. Histamine H1 receptor antagonists inhibited, and iproniazid enhanced, contraction elicited by A23187. A23187 induced release of greater amounts of histamine from venous rings with than without endothelium. A23187-induced contraction was not mimicked by the mast cell activator, compound 48/80, and was not inhibited by preexposure to compound 48/80 or in the presence of cromolyn or doxantrazole. A23187-induced contraction was not inhibited by pretreatment with indomethacin, phentolamine, lipoxygenase inhibitors or superoxide dismutase. The results indicate that A23187 induces endothelium-dependent contraction in bovine intrapulmonary vein and support histamine as one major mediator involved. The association of destruction of endothelium with an inhibition of both A23187-induced contraction and histamine release is consistent with the endothelium as a source for histamine which can exert a local vasoconstrictor effect in bovine intrapulmonary vein.
Assuntos
Calcimicina/farmacologia , Endotélio Vascular/fisiologia , Histamina/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Veias Pulmonares/efeitos dos fármacos , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Atropina/farmacologia , Bovinos , Cromolina Sódica/farmacologia , Endotelinas/farmacologia , Hemoglobinas/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Liberação de Histamina/efeitos dos fármacos , Técnicas In Vitro , Iproniazida/farmacologia , Azul de Metileno/farmacologia , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Tioxantenos/farmacologia , Xantonas , ômega-N-Metilarginina , p-Metoxi-N-metilfenetilamina/farmacologiaRESUMO
Estrogens have been postulated to play an important role in modulation of vascular responses to endogenous reactive substances. The effects of chronic in vivo treatment with 17 beta-estradiol on relaxant responses to acetylcholine were investigated in the rat aorta isolated from prepubertal female rats. The selectivity of effects of 17 beta-estradiol on acetylcholine-induced relaxation was evaluated using histamine, another endothelium-dependent relaxant in the rat aorta. 17 beta-Estradiol significantly enhanced endothelium-dependent relaxation induced by acetylcholine, but did not alter the vascular responses to acetylcholine in endothelium-denuded aortic rings isolated from prepubertal female rats. In contrast, 17 beta-estradiol did not change endothelium-dependent relaxation induced by histamine in endothelium-intact aortic rings. The results of the present study demonstrate that 17 beta-estradiol selectively enhances acetylcholine-induced endothelium-dependent relaxation in the rat aorta.
Assuntos
Acetilcolina/farmacologia , Aorta Torácica/fisiologia , Endotélio Vascular/fisiologia , Estradiol/farmacologia , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Animais , Aorta Torácica/efeitos dos fármacos , Betanecol , Compostos de Betanecol/farmacologia , Relação Dose-Resposta a Droga , Feminino , Histamina/farmacologia , Técnicas In Vitro , Músculo Liso Vascular/efeitos dos fármacos , Norepinefrina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
5-Hydroxytryptamine (5-HT) potentiated contractions of isolated rat bronchi evoked by electrical field stimulation (EFS). The degree of potentiation caused by 5-HT was dependent upon concentration of the amine present in the tissue bath. The effects of antagonists selective for different subtypes of the 5-HT receptor on potentiation of EFS-induced contractions by 5-HT were examined. Propranolol, a nonselective beta-adrenoceptor antagonist which can act as a 5-HT1 receptor antagonist, did not inhibit the effect of 5-HT on EFS-induced contractile responses. Similarly, 5-HT3 receptor antagonism with MDL 72222 or ICS 205-930, did not inhibit the facilitatory effects of 5-HT. However, ketanserin, mianserin and spiperone, 5-HT2 receptor antagonists, abolished the effects of 5-HT on EFS-induced responses. These latter results suggested that the potentiation was dependent upon activation of 5-HT2 receptors thus additional experiments were conducted using the 5-HT2 receptor agonist, alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT). alpha-Me-5-HT caused a concentration-dependent potentiation of EFS-induced contractile responses comparable to that observed with 5-HT. Concentrations of alpha-Me-5-HT that significantly potentiated EFS-induced contraction were essentially without effect on airway smooth muscle contraction elicited by exogenous acetylcholine. These results are consistent with a role for 5-HT2 receptor activation in mediating the facilitatory effects of 5-HT on cholinergic nerve-mediated responses in airways.
Assuntos
Broncoconstrição/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Serotonina/farmacologia , Animais , Sinergismo Farmacológico , Estimulação Elétrica , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
This study examined the effects of chlorpheniramine, citalopram and fluoxetine on 5-hydroxytryptamine (5-HT)-induced contraction and 5-HT uptake in rat thoracic aortic rings in vitro. Chlorpheniramine and citalopram markedly potentiated 5-HT-induced contraction. Potentiation by fluoxetine was less pronounced. Chlorpheniramine (0.01-1 microM) and citalopram (0.1-1 microM) induced concentration-dependent parallel shifts to the left of the 5-HT concentration-response curves. The potentiation by chlorpheniramine was selective as chlorpheniramine (1 microM) did not potentiate phenylephrine-induced contraction. The potentiation did not depend upon the presence of endothelium, and was not related to H1 receptor antagonism as diphenhydramine and pyrilamine (1 microM) did not similarly enhance 5-HT-induced contractions. Whereas cocaine (1-10 microM) similarly potentiated 5-HT-induced contraction, imipramine (1-10 microM) inhibited, rather than enhanced, contraction elicited by 5-HT. In the presence of 10 microM cocaine, maximally effective concentrations of chlorpheniramine (1 microM) or citalopram (100 nM) did not induce any additional potentiation of 5-HT-induced contraction. Cooling (4 degrees C) markedly inhibited uptake of [3H]5-HT in rings with and without endothelium. Although less marked, imipramine (10 microM), cocaine (1 microM), chlorpheniramine (1 microM) and citalopram (100 nM) inhibited [3H]5-HT uptake in endothelium-intact and endothelium-denuded rings. Fluoxetine also inhibited [3H]5-HT uptake, but the inhibition was only statistically significant in endothelium-intact rings. The monoamine oxidase (MAO) inhibitor, pargyline (10-100 microM), did not significantly affect 5-HT-induced contraction. The results demonstrate that chlorpheniramine, citalopram and to a lesser extent, fluoxetine potentiate 5-HT-induced contraction in rat aorta in which neuronal 5-HT uptake is negligible. The data are consistent with inhibition of non-neuronal 5-HT uptake as at least one mechanism responsible for potentiation of 5-HT-induced contraction in rat aorta by chlorpheniramine, citalopram and fluoxetine.
Assuntos
Clorfeniramina/farmacologia , Citalopram/farmacologia , Fluoxetina/farmacologia , Serotonina/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Cocaína/farmacologia , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos H1/farmacologia , Imipramina/farmacologia , Técnicas In Vitro , Masculino , Pargilina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The organic nitrates and related nitrovasodilators are relaxants of vascular and airway smooth muscle. Very little information is currently available regarding the influence of nitrates and related nitrovasodilators on pulmonary autacoid release. This study examined the influence of glyceryl trinitrate, isosorbide dinitrate and sodium nitroprusside on histamine release from bovine lung mince. Spontaneous histamine release from bovine lung mince was not altered by 0.1 nM to 1 microM glyceryl trinitrate, isosorbide dinitrate or sodium nitroprusside. Glyceryl trinitrate, isosorbide dinitrate and sodium nitroprusside produced a concentration-dependent decrease in A23187 (10 microM) stimulated histamine release. Glyceryl trinitrate also inhibited histamine liberation following the addition of compound 48/80. Further studies indicated that the inhibitory action of glyceryl trinitrate was reversed by coincubation with the guanylate cyclase inhibitor, methylene blue (10 microM). These findings indicate that glyceryl trinitrate, sodium nitroprusside and isosorbide dinitrate inhibit non-immunologically stimulated pulmonary histamine release and suggest that alterations in guanylate cyclase activity may influence pulmonary histamine release.
Assuntos
Liberação de Histamina/efeitos dos fármacos , Dinitrato de Isossorbida/farmacologia , Pulmão/efeitos dos fármacos , Nitroglicerina/farmacologia , Nitroprussiato/farmacologia , Vasodilatadores/farmacologia , Animais , Bovinos , Técnicas de Cultura , Histamina/análise , Pulmão/metabolismoRESUMO
Sex hormones have been postulated to play an important role in the modulation of vascular responsiveness to endogenous vasoactive substances. This study was designed to establish the effects of chronic treatment with estrogen in vivo on subsequent contractile responsiveness of aortic rings to angiotensin II or norepinephrine in vitro. Concentration-response curves for angiotensin II were compared in aortic rings with or without endothelium isolated from ovariectomized rats (275-299 g) pretreated with 17 beta-estradiol (approximately 1 mg/kg per day) or placebo for 14 days and from normal prepubertal female rats (125-149 g) pretreated with 17 beta-estradiol (approximately 5 mg/kg per day) or placebo for 14 days. Whether or not endothelium was present, angiotensin II-induced contraction was significantly depressed in rings from 17 beta-estradiol-treated ovariectomized or prepubertal rats when compared to controls, and the pattern of the effects of 17 beta-estradiol-treatment on the concentration-response curves for angiotensin II was similar in the two models. In contrast to angiotensin II-induced contraction, norepinephrine-induced contraction was significantly enhanced in aortic rings with or without endothelium from ovariectomized rats pretreated with 17 beta-estradiol (approximately 1 mg/kg per day, 14 days) and from normal prepubertal female rats pretreated with 17 beta-estradiol (approximately 5 mg/kg per day, 14 days) when compared to controls. The results demonstrate that chronic treatment with 17 beta-estradiol selectively reduced and enhanced contractile responsiveness of aortic rings to angiotensin II and norepinephrine, respectively. Further, the results indicate that the normal prepubertal female rat is an efficient model to investigate modulation by estrogen of aortic responsiveness to vasoactive agents in vitro.
Assuntos
Angiotensina II/antagonistas & inibidores , Estrogênios/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Norepinefrina/antagonistas & inibidores , Angiotensina II/farmacologia , Animais , Estradiol/farmacologia , Feminino , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Norepinefrina/farmacologia , Ovariectomia , Ratos , Ratos Sprague-Dawley , Vasoconstrição/efeitos dos fármacosRESUMO
We studied the morphological and contractile characteristics of rat thoracic aortic segments perfused for 3 or 6 days under pulsatile conditions. Light microscopic examination of the segments revealed the presence of an unchanged tunica media. However, the intimal surface was mostly devoid of endothelial cells. The perfused aortic segments showed a dramatic increase in spontaneous tone when compared to fresh and sham-treated aortic segments. Maximum responses to potassium and norepinephrine were reduced after 3 days of perfusion (20-40% reduction), while maximum responses to 5-hydroxytryptamine and angiotensin II were not significantly different. After 6 days of perfusion, maximum responses to all agonist were reduced (50-60%). Sensitivity to norepinephrine was not affected by the treatment, while sensitivity to 5-hydroxytryptamine was reduced. The perfused aortic segments relaxed well in response to isoproterenol. Our system provides a useful experimental model for short-term studies of hypertension- and atherosclerosis-related vascular changes. Further refinement and characterization could improve the performance of the system for longer-term studies.
Assuntos
Aorta Torácica/fisiologia , Contração Isométrica , Músculo Liso Vascular/fisiologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Aorta Torácica/citologia , Aorta Torácica/efeitos dos fármacos , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Isoproterenol/farmacologia , Cinética , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Nitroprussiato/farmacologia , Perfusão/instrumentação , Perfusão/métodos , Potássio/farmacologia , Ratos , Ratos Endogâmicos , Serotonina/farmacologia , Fatores de TempoRESUMO
Histamine has been reported to cause endothelium-dependent relaxation of vascular smooth muscle and vasodilation. This study was undertaken to examine the inhibitory effects of histamine on cylindrical segments of extrapulmonary arteries isolated from male Sprague Dawley rats. In arterial segments precontracted with phenylephrine (10 microM), histamine (0.1-100 microM) elicited concentration-dependent relaxation responses. Removal of the endothelium or pretreatment with methylene blue (10 microM) abolished relaxation responses to low concentrations of histamine and markedly inhibited those caused by histamine at concentrations greater than 1 microM. Incubation of endothelium-intact arterial segments with pyrilamine (1 microM) caused a significant rightward shift of the histamine concentration-response curves. Treatment of the segments with cimetidine (100 microM) or indomethacin (10 microM) only minimally antagonized histamine-induced relaxation in arteries with endothelium. Residual relaxation responses observed in arteries stripped of endothelium were unaffected by pretreatment with cimetidine, indomethacin, or pyrilamine. The results suggest that the inhibitory effect of histamine in rat pulmonary arteries is mediated predominantly by activation of H1-receptors on the endothelium and the subsequent release of endothelium-derived relaxing factor(s).
Assuntos
Endotélio Vascular/fisiologia , Histamina/farmacologia , Fenilefrina/farmacologia , Artéria Pulmonar/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Cimetidina/farmacologia , Indometacina/farmacologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Artéria Pulmonar/fisiologia , Pirilamina/farmacologia , Ratos , Ratos EndogâmicosRESUMO
Arterial contractile responses were studied in experimentally uremic rats. The ligation of 75% of the terminal branches of the left renal artery, followed by contralateral nephrectomy induced a chronic renal failure, as evidenced by significantly higher BUN concentrations and an elevation in blood pressure. Uremic rats exhibited elevations in total and HDL cholesterol, increased triglyceride levels, and significantly lowered HDL/total cholesterol ratios compared to control groups: 1) untreated control, 2) experimental control receiving renal infarction without contralateral nephrectomy, and 3) two kidney, one clip (2K1C) model of hypertension. Plasma total cholesterol levels in uremic rats increased by 50% in the first week following final surgery and plateaued at approximately 100% above control levels during postoperative weeks 3 through 10. Plasma transaminase levels were similar among all of the groups of rats studied indicating no effects of surgery on hepatic function. The contractile responses of aortic rings from uremic rats to submaximal concentrations of serotonin and clonidine were significantly increased and decreased, respectively, whereas the contractile response to norepinephrine was not altered. The enhanced sensitivity to serotonin of aortic rings from uremic rats was abolished following disruption of the endothelium. Neither the alteration of aortic contractile properties nor changes in plasma BUN and cholesterol concentrations were observed in hypertensive 2K1C rats. However, there was a tendency for decreased acetylcholine-induced relaxation in aortic rings of uremic and 2K1C rats. No significant histological evidence of atherosclerosis was found in aortic tissues of uremic rats during the interval of study. These results indicate that hypercholesterolemia, hypertriglyceridemia, and altered vascular sensitivity to serotonin and clonidine are likely to be primary changes in the uremic rat and are not secondary to the development of blood pressure elevation or overt evidence of structural change in the vessels of this model.
Assuntos
Hipercolesterolemia/complicações , Uremia/complicações , Animais , Pressão Sanguínea , Nitrogênio da Ureia Sanguínea , Clonidina/farmacologia , Hipercolesterolemia/fisiopatologia , Hipertensão Renovascular/complicações , Hipertensão Renovascular/fisiopatologia , Técnicas In Vitro , Lipídeos/sangue , Masculino , Ratos , Ratos Endogâmicos , Serotonina/farmacologia , Uremia/fisiopatologia , Vasoconstrição/efeitos dos fármacosRESUMO
Nitrates are generally regarded as bronchial smooth muscle relaxants. However, reports about the clinical efficacy of the nitrates in the treatment of asthma are conflicting. In the present study, the relaxant effects of glyceryl trinitrate, isosorbide dinitrate, sodium nitroprusside, and isoproterenol were measured and compared in vitro in airway preparations isolated from variously sized airways in bovine lung. Strips of trachealis from cervical and thoracic ends of the trachea and rings of intrapulmonary bronchi of various diameters (14 to 1 mm outer diameters) were mounted for recording of isometric tension. Submaximal tone was induced using 10(-6) M carbachol, and responses to cumulatively increasing concentrations of glyceryl trinitrate, isosorbide dinitrate, sodium nitroprusside, or isoproterenol were measured. Isoproterenol (10(-8) to 10(-4) M) was equiactive as a relaxant in all preparations. Glyceryl trinitrate (10(-7) to 10(-5) M) relaxed trachealis, but was progressively and significantly less effective as a relaxant as the diameters of the bronchial rings decreased. Although less potent than isoproterenol, sodium nitroprusside (10(-6) to 10(-4) M) was effective in relaxing all the airway preparations. Similar to glyceryl trinitrate, sodium nitroprusside was less effective in small than in large airways. However, the relationship between relaxant responses to sodium nitroprusside and airway size was not as marked as for glyceryl trinitrate. Isosorbide dinitrate at concentrations as great as 10(-5) M did not relax carbachol-induced tone in any of the bronchial rings and only induced a small amount of relaxation in trachealis at 10(-5) M.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Ferricianetos/farmacologia , Dinitrato de Isossorbida/farmacologia , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Nitroglicerina/farmacologia , Nitroprussiato/farmacologia , Animais , Carbacol/farmacologia , Bovinos , Relação Dose-Resposta a Droga , Técnicas In Vitro , Isoproterenol/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Tono Muscular/efeitos dos fármacos , Músculo Liso/fisiologia , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
The influence of endothelium on angiotensin II-induced contraction was investigated in rings of rat aorta, bovine coronary artery, bovine intrapulmonary artery and bovine intrapulmonary vein. Destruction of endothelium significantly enhanced angiotensin II-induced contraction in rat aorta and bovine coronary artery, but not in bovine intrapulmonary artery and bovine intrapulmonary vein. Indomethacin (10(-5) M) did not alter angiotensin II-induced contraction in rat aorta or bovine coronary artery. However, hemoglobin (10(-5) M) or methylene blue (10(-5) M) significantly enhanced angiotensin II-induced contraction in rat aorta and bovine coronary artery with, but not without, endothelium. Intimal rubbing did not affect stimulation of phosphoinositide hydrolysis by angiotensin II in rat aorta. The findings demonstrate that angiotensin II-induced contraction in vascular rings can be modulated by endothelium. However, the effect of endothelium apparently depends upon the species and vascular bed from which the vessel is isolated. Results obtained using inhibitors suggest that in rat aorta and bovine coronary artery release of endothelium-derived relaxant factor (EDRF), rather than cyclooxygenase products, is involved in mediating the inhibitory influence of endothelium. Further, similar stimulation of phosphoinositide hydrolysis in intimally rubbed and unrubbed rat aorta suggests that EDRF does not modulate angiotensin II-induced contraction in this vessel by inhibiting angiotensin II stimulation of phosphoinositide hydrolysis.
Assuntos
Angiotensina II/farmacologia , Endotélio Vascular/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Animais , Bovinos , Hemoglobinas/farmacologia , Hidrólise , Técnicas In Vitro , Indometacina/farmacologia , Contração Isométrica/efeitos dos fármacos , Azul de Metileno/farmacologia , Contração Muscular/efeitos dos fármacos , Fosfatidilinositóis/metabolismo , Ratos , Ratos EndogâmicosRESUMO
Development of tachyphylaxis to angiotensin-induced contraction was compared in rings of rat aorta with and without functional endothelium. Rat aorta with functional endothelium rapidly developed marked tachyphylaxis to contraction induced by angiotensin II or angiotensin III. Destruction of endothelium significantly depressed, but did not prevent, development of tachyphylaxis to contractile responses induced by repeated exposure to angiotensin II or angiotensin III. The findings suggest that two mechanisms are involved in the development of tachyphylaxis to angiotensin in rat aorta, an endothelium-dependent mechanism and an endothelium-independent mechanism.
Assuntos
Angiotensina III/farmacologia , Angiotensina II/análogos & derivados , Angiotensina II/farmacologia , Endotélio Vascular/fisiologia , Taquifilaxia , Animais , Aorta Torácica/efeitos dos fármacos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
The mechanism whereby nitroglycerin relaxes vascular smooth muscle remains uncertain. A current hypothesis suggests that nitroglycerin reacts with critical cellular sulfhydryl groups to form an intermediate, which activates guanylate cyclase, resulting in cGMP accumulation and relaxation. This study investigated further the potential involvement of sulfhydryls in nitroglycerin-induced vascular smooth muscle relaxation by evaluating effects of a variety of sulfhydryl alkylating and reducing agents on responses to nitroglycerin and other relaxants in bovine coronary arterial strips submaximally contracted using 30 mM K. Whereas 10(-4) M 5,5'-dithiobis-(2-nitrobenzoic acid), 10(-5) MN-ethylmaleimide, and 10(-4) MN-naphthylmaleimide did not affect nitroglycerin-induced relaxation, 10(-4) MN-ethylmaleimide and 10(-4) M ethacrynic acid significantly inhibited relaxation induced by nitroglycerin. Both ethacrynic acid and N-ethylmaleimide at 10(-4) M also inhibited relaxation induced by sodium nitroprusside. N-ethylmaleimide, but not ethacrynic acid, inhibited relaxation induced by isoproterenol and forskolin. Ethacrynic acid significantly reduced both relaxation and cGMP elevation induced by both 10(-7) M nitroglycerin and 10(-7) M sodium nitroprusside. Ethacrynic acid, but not N-ethylmaleimide, significantly reduced relaxation induced by 8-Br-cGMP. Pretreatment with the sulfhydryl-containing agents N-acetylcysteine, 2-mercaptoethanol, or dithiothreitol, at 10(-3) M did not affect nitroglycerin-induced relaxation in nontolerant arteries. Similarly, N-acetylcysteine and dithiothreitol did not alter the depressed responses to nitroglycerin in arteries in which tolerance to nitroglycerin was induced in vitro. A slight but statistically significant reversal of nitroglycerin-tolerance occurred after treatment of tolerant arteries with 2-mercaptoethanol.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Vasos Coronários/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Nitroglicerina/farmacologia , Reagentes de Sulfidrila/farmacologia , Animais , Bovinos , GMP Cíclico/metabolismo , Ácido Etacrínico/farmacologia , Etilmaleimida/farmacologia , Técnicas In Vitro , Relaxamento Muscular/efeitos dos fármacos , Compostos de Sulfidrila/farmacologiaRESUMO
This study was conducted to compare the influence of endothelium on mechanical responses of bovine intrapulmonary artery and vein to acetylcholine (ACh) and A23187 and to determine if a relationship exists between the responses and cyclic GMP (cGMP) accumulation. ACh and A23187 induced relaxation in artery and A23187 induced relaxation in vein. The relaxant responses in both vessels were abolished by rubbing the intimal surfaces, indicating that the relaxant responses depended upon the presence of a functionally intact endothelium. cGMP accumulation was temporally associated with both ACh- and A23187-induced endothelium-dependent relaxation. Both the relaxant responses and the accompanying cGMP accumulations were abolished or reduced markedly by intimal rubbing or pretreatment with methylene blue. Atropine abolished relaxation and cGMP accumulation induced by ACh in artery, but not relaxation and cGMP accumulation induced by A23187. Whereas indomethacin did not affect either ACh- or A23187-induced relaxation in artery, it slightly, but significantly, reduced A23187-induced relaxation in vein. In contrast to its effect in artery, ACh only induced contractile responses in vein and did not alter cGMP levels, whether or not functional venous endothelium was present. However, ACh did relax veins when arterial endothelium was present in crossover experiments using a modified sandwich technique. At concentrations which induced endothelium-dependent relaxation in artery, ACh similarly induced no, or only minimal, contraction in both artery and vein in which endothelium was functionally destroyed. These findings demonstrate that bovine intrapulmonary artery and vein exhibit endothelium-dependent relaxation in response to A23187, and similar to ACh-induced relaxation in the artery, A23187-induced relaxation is associated closely with accumulation of cGMP.(ABSTRACT TRUNCATED AT 250 WORDS)