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The agonists of alpha(2)-adrenergic receptors such as clonidine, rilmenidine or monoxidine are known to lower blood pressure (BP) through a reduction of brain sympathetic outflow but their chronic antihypertensive effects in rats with low-renin or high-renin forms of experimental hypertension were not studied yet. Moreover, there is no comparison of mechanisms underlying BP reduction elicited by chronic peroral (po) or intracerebroventricular (icv) clonidine treatment. Male salt-sensitive Dahl rats fed 4% NaCl diet and Ren-2 transgenic rats were treated with clonidine administered either in the drinking fluid (0.5 mg/kg/day po) or as the infusion into lateral brain ventricle (0.1 mg/kg/day icv) for 4 weeks. Basal BP and the contributions of renin-angiotensin system (captopril 10 mg/kg iv) or sympathetic nervous system (pentolinium 5 mg/kg iv) to BP maintenance were determined in conscious cannulated rats at the end of the study. Both peroral and intracerebroventricular clonidine treatment lowered BP to the same extent in either rat model. However, in both models chronic clonidine treatment reduced sympathetic BP component only in rats treated intracerebroventricularly but not in perorally treated animals. In contrast, peroral clonidine treatment reduced angiotensin II-dependent vasoconstriction in Ren-2 transgenic rats, whereas it lowered residual blood pressure in Dahl rats. In conclusions, our results indicate different mechanisms of antihypertensive action of clonidine when administered centrally or systemically.
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Hipertensión , Hipotensión , Ratas , Masculino , Animales , Clonidina/farmacología , Angiotensina II/farmacología , Antihipertensivos/farmacología , Presión Sanguínea , Cloruro de Sodio , Ratas Transgénicas , Renina , Ratas Endogámicas Dahl , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Cloruro de Sodio Dietético , Sistema Nervioso SimpáticoRESUMEN
It is widely accepted that sympathetic nervous system plays a crucial role in the development of hypertension. On the other hand, the role of adrenal medulla (the adrenomedullary component of the sympathoadrenal system) in the development and maintenance of high blood pressure in man as well as in experimental models of hypertension is still controversial. Spontaneously hypertensive rats (SHR) are the most widely used animal model of human essential hypertension characterized by sympathetic hyperactivity. However, the persistence of moderately elevated blood pressure in SHR subjected to sympathectomy neonatally as well as the resistance of adult SHR to the treatment by sympatholytic drugs suggests that other factors (including enhanced activity of the adrenomedullary hormonal system) are involved in the pathogenesis of hypertension of SHR. This review describes abnormalities in adrenomedullary hormonal system of SHR rats starting with the hyperactivity of brain centers regulating sympathetic outflow, through the exaggerated activation of sympathoadrenal preganglionic neurons, to the local changes in chromaffin cells of adrenal medulla. All the above alterations might contribute to the enhanced release of epinephrine and/or norepinephrine from adrenal medulla. Special attention is paid to the alterations in the expression of genes involved in catecholamine biosynthesis, storage, release, reuptake, degradation and adrenergic receptors in chromaffin cells of SHR. The contribution of the adrenomedullary hormonal system to the development and maintenance of hypertension as well as its importance during stressful conditions is also discussed.
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Médula Suprarrenal/fisiopatología , Presión Sanguínea/genética , Hormonas/metabolismo , Hipertensión/genética , Hipertensión/metabolismo , Médula Suprarrenal/metabolismo , Animales , Humanos , Hipertensión/fisiopatología , Ratas Endogámicas SHR , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
Glucocorticoids (GCS) are known to modulate cardiovascular response during stress conditions. The present study was aimed to test the hypothesis that permissive and/or stimulating effect of GCs is essential for the maintenance of peripheral vascular resistance and for the adequate response of cardiovascular system to stressor exposure. The effects of acute pharmacological adrenalectomy (PhADX) on humoral and cardiovascular parameters were studied in adult Wistar rats under the basal conditions and during the acute restraint stress. Acute PhADX was performed by the administration of metyrapone and aminoglutethimide (100 mg/kg s.c. of each drug) resulting in a suppression of endogenous glucocorticoid synthesis. Blood pressure (BP), heart rate (HR) and core body temperature were measured using radiotelemetry. BP responses to administration of vasoactive agents were determined in pentobarbital-anesthetized animals. PhADX considerably attenuated stress-induced increase of BP, HR and core body temperature. PhADX did not abolish BP and HR lowering effects of ganglionic blocker pentolinium indicating preserved sympathetic function in PhADX rats. BP response to exogenous norepinephrine administration was attenuated in PhADX rats, suggesting reduced sensitivity of cardiovascular system. Suppression of corticosterone synthesis by PhADX increased basal plasma levels of ACTH, aldosterone and plasma renin activity in unstressed animals but there was no further increase of these hormones following stressor exposure. In conclusion, PhADX attenuated stress-induced rise of blood pressure, heart rate and core body temperature indicating an important permissive and/or stimulating role of glucocorticoids in the maintenance of the adequate response of cardiovascular system and thermoregulation to several stimuli including acute exposure to stressor.
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Aminoglutetimida/farmacología , Presión Sanguínea/efectos de los fármacos , Glucocorticoides/antagonistas & inhibidores , Frecuencia Cardíaca/efectos de los fármacos , Metirapona/farmacología , Restricción Física/fisiología , Adrenalectomía , Animales , Antimetabolitos/farmacología , Inhibidores de la Aromatasa/farmacología , Modelos Animales de Enfermedad , Glucocorticoides/biosíntesis , Masculino , Ratas , Ratas Wistar , Resistencia Vascular/efectos de los fármacosRESUMEN
Telmisartan is an angiotensin receptor blocker (ARB) and a selective peroxisome proliferator activated receptor gamma (PPARG) modulator. Recently, we tested metabolic effects of telmisartan (5 mg/kg body weight) in spontaneously hypertensive rats (SHR) fed a diet containing 60 % fructose, a widely used model of the metabolic syndrome. Surprisingly, we observed acute toxic effects of telmisartan. Rats lost body weight rapidly and died within 2 to 3 weeks due to bleeding into the upper gastrointestinal tract. SHR fed a high fructose diet and treated with telmisartan exhibited rapid decrease in blood pressure when compared to the SHR fed a high fructose diet and treated with valsartan. Concentrations of both unconjugated telmisartan and telmisartan glucuronide in the liver of SHR rats fed a high fructose diet were approximately 4 fold higher when compared to Brown Norway (BN) rats fed the same diet. Plasma concentrations of unconjugated telmisartan in the SHR were about 5 fold higher when compared to BN rats while plasma levels of telmisartan glucuronide were similar between the strains. Testing of other rat strains, diets, and the ARB valsartan showed that toxic effects of telmisartan in combination with high fructose diet are specific for the SHR. These results are consistent with the possibility that in some circumstances, SHR are predisposed to telmisartan toxicity possibly because of a genetically determined disturbance in telmisartan metabolism.
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Antihipertensivos/toxicidad , Azúcares de la Dieta/toxicidad , Fructosa/toxicidad , Hipertensión/patología , Telmisartán/toxicidad , Animales , Azúcares de la Dieta/administración & dosificación , Fructosa/administración & dosificación , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/patología , Hipertensión/genética , Masculino , Ratas , Ratas Endogámicas SHR , Ratas WistarRESUMEN
This study investigated the contribution of reactive oxygen species (ROS) to blood pressure regulation in conscious adult male Wistar rats exposed to acute stress. Role of ROS was investigated in rats with temporally impaired principal blood pressure regulation systems using ganglionic blocker pentolinium (P, 5 mg/kg), angiotensin converting enzyme inhibitor captopril (C, 10 mg/kg), nitric oxide synthase inhibitor L-NAME (L, 30 mg/kg) and superoxide dismutase mimeticum tempol (T, 25 mg/kg). Mean arterial pressure (MAP) was measured by the carotid artery catheter and inhibitors were administered intravenously. MAP was disturbed by a 3-s air jet, which increased MAP by 35.2+/-3.0 % vs. basal MAP after the first exposure. Air jet increased MAP in captopril- and tempol-treated rats similarly as observed in saline-treated rats. In pentolinium-treated rats stress significantly decreased MAP vs. pre-stress value. In L-NAME-treated rats stress failed to affect MAP significantly. Treatment of rats with P+L+C resulted in stress-induced MAP decrease by 17.3+/-1.3 % vs. pre-stress value and settling time (20.1+/-4.2 s). In P+L+C+T-treated rats stress led to maximal MAP decrease by 26.4+/-2.2 % (p<0.005 vs. P+L+C) and prolongation of settling time to 32.6+/-3.3 s (p<0.05 vs. P+L+C). Area under the MAP curve was significantly smaller in P+L+C-treated rats compared to P+L+C+T-treated ones (167+/-43 vs. 433+/-69 a.u., p<0.008). In conclusion, in rats with temporally impaired blood pressure regulation, the lack of ROS resulted in greater stress-induced MAP alterations and prolongation of time required to reach new post-stress steady state.
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Presión Sanguínea , Especies Reactivas de Oxígeno/metabolismo , Estrés Psicológico/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Animales , Masculino , Ratas , Ratas WistarRESUMEN
Vascular smooth muscle cells (VSMC) display considerable phenotype plasticity which can be studied in vivo on vascular remodeling which occurs during acute or chronic vascular injury. In differentiated cells, which represent contractile phenotype, there are characteristic rapid transient changes of intracellular Ca(2+) concentration ([Ca(2+)]i), while the resting cytosolic [Ca(2+)]i concentration is low. It is mainly caused by two components of the Ca(2+) signaling pathways: Ca(2+) entry via L-type voltage-dependent Ca(2+) channels and dynamic involvement of intracellular stores. Proliferative VSMC phenotype is characterized by long-lasting [Ca(2+)]i oscillations accompanied by sustained elevation of basal [Ca(2+)]i. During the switch from contractile to proliferative phenotype there is a general transition from voltage-dependent Ca(2+) entry to voltage-independent Ca(2+) entry into the cell. These changes are due to the altered gene expression which is dependent on specific transcription factors activated by various stimuli. It is an open question whether abnormal VSMC phenotype reported in rats with genetic hypertension (such as spontaneously hypertensive rats) might be partially caused by a shift from contractile to proliferative VSMC phenotype.
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Vasos Sanguíneos/metabolismo , Señalización del Calcio/fisiología , Acoplamiento Excitación-Contracción/fisiología , Hipertensión/metabolismo , Músculo Liso Vascular/metabolismo , Remodelación Vascular/fisiología , Animales , Vasos Sanguíneos/patología , Humanos , Hipertensión/patología , Músculo Liso Vascular/patología , Transducción de Señal/fisiología , Transcripción Genética/fisiologíaRESUMEN
Catecholaminergic system plays an important role in hypertension development. The available results on mRNA expression of catecholaminergic system genes in spontaneously hypertensive rats (SHR) are often contradictory. One of the possible causes might be the use of various reference genes as internal controls. In the present study, we searched for suitable reference genes in adrenal medulla or sympathetic ganglia of SHR and Wistar-Kyoto (WKY) rats, which would enable reliable comparison of mRNA expression between these two strains. The mRNA expression was measured by quantitative real-time PCR in adrenal medulla and superior cervical ganglia of 4-week-old or 24-week-old SHR and WKY rats. We evaluated 12 reference genes by three software tools (Normfinder, BestKeeper, geNorm) and compared them for the standardization of mRNA expression. Combination of reference genes Hprt1 and Ywhaz in adrenal medulla and Gapdh and 18S in sympathetic ganglia were chosen as the best ones. 18S was found as applicable reference gene in both tissues. We found many alterations in expression of catecholaminergic system genes in adrenal medulla and sympathetic ganglia of SHR. The usage of the most or the least stable reference gene as internal control changed results moderately in sympathetic ganglia but seriously in adrenal medulla. For example, tyrosine hydroxylase (Th) gene was underexpressed in adrenal medulla of adult SHR using the appropriate reference gene but unchanged after the standardization to the least stable reference gene. Our results indicate the importance of appropriate internal control. The suitability of reference genes should be checked again in the case of change in experimental conditions.
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Médula Suprarrenal/metabolismo , Ganglios Simpáticos/metabolismo , Perfilación de la Expresión Génica , Hipertensión/metabolismo , Animales , Masculino , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Estándares de ReferenciaRESUMEN
The incidence of metabolic syndrome increases in the developed countries, therefore biomedical research is focused on the understanding of its etiology. The study of exact mechanisms is very complicated because both genetic and environmental factors contribute to this complex disease. The ability of environmental factors to promote phenotype changes by epigenetic DNA modifications (i.e. DNA methylation, histone modifications) was demonstrated to play an important role in the development and predisposition to particular symptoms of metabolic syndrome. There is no doubt that the early life, such as the fetal and perinatal periods, is critical for metabolic syndrome development and therefore critical for prevention of this disease. Moreover, these changes are visible not only in individuals exposed to environmental factors but also in the subsequent progeny for multiple generations and this phenomenon is called transgenerational inheritance. The knowledge of molecular mechanisms, by which early minor environmental stimuli modify the expression of genetic information, might be the desired key for the understanding of mechanisms leading to the change of phenotype in adulthood. This review provides a short overview of metabolic syndrome epigenetics.
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Epigénesis Genética/genética , Patrón de Herencia/genética , Síndrome Metabólico/genética , Síndrome Metabólico/metabolismo , Animales , Susceptibilidad a Enfermedades/metabolismo , HumanosRESUMEN
Principal vasoactive systems - renin-angiotensin system (RAS), sympathetic nervous system (SNS), nitric oxide (NO) and prostanoids - exert their vascular effects through the changes in calcium levels and/or calcium sensitization. To estimate a possible modulation of calcium sensitization by the above vasoactive systems, we studied the influence of acute and chronic blockade of particular vasoactive systems on blood pressure (BP) changes elicited in conscious normotensive rats by acute dose-dependent administration of Rho-kinase inhibitor fasudil. Adult male chronically cannulated Wistar rats were used throughout this study. The acute inhibition of NO synthase (NOS) by L-NAME enhanced BP response to fasudil, the effect being considerably augmented in rats deprived of endogenous SNS. The acute inhibition of prostanoid synthesis by indomethacin modified BP response to fasudil less than the acute NOS inhibition. The chronic NOS inhibition caused moderate BP elevation and a more pronounced augmentation of fasudil-induced BP changes compared to the effect of acute NOS inhibition. This indicates both short-term and long-term NO-dependent attenuation of calcium sensitization. Long-term inhibition of RAS by captopril caused a significant attenuation of BP changes elicited by fasudil. In contrast, a long-term attenuation of SNS by chronic guanethidine treatment (in youth or adulthood) had no effect on BP response to fasudil, suggesting the absence of SNS does not affect calcium sensitization in vascular smooth muscle of normotensive rats. In conclusion, renin-angiotensin system contributes to the long-term increase of calcium sensitization and its effect is counterbalanced by nitric oxide which decreases calcium sensitization in Wistar rats.
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Presión Sanguínea/fisiología , Calcio/metabolismo , Ácido Nítrico/metabolismo , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/fisiología , Vasoconstricción/fisiología , Adaptación Fisiológica/fisiología , Animales , Masculino , Ratas , Ratas Wistar , Resistencia Vascular/fisiologíaRESUMEN
Increased systemic vascular resistance is responsible for blood pressure (BP) elevation in most forms of human or experimental hypertension. The enhanced contractility of structurally remodeled resistance arterioles is mediated by enhanced calcium entry (through L type voltage-dependent calcium channels - L-VDCC) and/or augmented calcium sensitization (mediated by RhoA/Rho kinase pathway). It is rather difficult to evaluate separately the role of these two pathways in BP control because BP response to the blockade of either pathway is always dependent on the concomitant activity of the complementary pathway. Moreover, vasoconstrictor systems enhance the activity of both pathways, while vasodilators attenuate them. The basal fasudil-sensitive calcium sensitization determined in rats deprived of endogenous renin-angiotensin system (RAS) and sympathetic nervous system (SNS) in which calcium entry was dose-dependently increased by L-VDCC opener BAY K8644, is smaller in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto (WKY) rats. In contrast, if endogenous RAS and SNS were present in intact rats, fasudil caused a greater BP fall in SHR than WKY rats. Our in vivo experiments indicated that the endogenous pressor systems (RAS and SNS) augment calcium sensitization mediated by RhoA/Rho kinase pathway, whereas the endogenous vasodilator systems (such as nitric oxide) attenuate this pathway. However, the modulation of calcium entry and calcium sensitization by nitric oxide is strain-dependent because NO deficiency significantly augments low calcium entry in WKY and low calcium sensitization in SHR. Further in vivo and in vitro experiments should clarify the interrelationships between endogenous vasoactive systems and the contribution of calcium entry and/or calcium sensitization to BP maintenance in various forms of experimental hypertension.
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Presión Sanguínea , Canales de Calcio/metabolismo , Señalización del Calcio , Calcio/metabolismo , Hipertensión/fisiopatología , Sistema Renina-Angiotensina , Vasoconstricción , Animales , Activación del Canal Iónico , Modelos Cardiovasculares , Ratas , Ratas Endogámicas SHR , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Spontaneously hypertensive rats (SHR) are characterized by enhanced sympathetic vasoconstriction, whereas their vasodilator mechanisms are relatively attenuated compared to their high BP. The objective of our in vivo study was to evaluate whether the impaired function of BKCa and/or KV channels is responsible for abnormal cAMP-induced vasodilatation in genetic hypertension. Using conscious SHR and normotensive WKY rats we have shown that under the basal conditions cAMP overproduction elicited by the infusion of beta-adrenoceptor agonist (isoprenaline) caused a more pronounced decrease of baseline blood pressure (BP) in SHR compared to WKY rats. Isoprenaline infusion prevented BP rises induced by acute NO synthase blockade in both strains and it also completely abolished the fully developed BP response to NO synthase blockade. These cAMP-induced vasodilator effects were diminished by the inhibition of either BKCa or KV channels in SHR but simultaneous blockade of both K(+) channel types was necessary in WKY rats. Under basal conditions, the vasodilator action of both K(+) channels was enhanced in SHR compared to WKY rats. However, the overall contribution of K(+) channels to cAMP-induced vasodilator mechanisms is insufficient in genetic hypertension since a concurrent activation of both K(+) channels by cAMP overproduction is necessary for the prevention of BP rise elicited by acute NO/cGMP deficiency in SHR. This might be caused by less effective activation of these K(+) channels by cAMP in SHR. In conclusion, K(+) channels seem to have higher activity in SHR, but their vasodilator action cannot match sufficiently the augmented vasoconstriction in this hypertensive strain.
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AMP Cíclico/metabolismo , Hipertensión/metabolismo , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Canales de Potasio con Entrada de Voltaje/metabolismo , Vasodilatación , Agonistas Adrenérgicos beta , Animales , Presión Sanguínea , Hipertensión/genética , Hipertensión/fisiopatología , Isoproterenol , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Resistencia VascularRESUMEN
High blood pressure (BP) of spontaneously hypertensive rats (SHR) is maintained by enhanced activity of sympathetic nervous system (SNS), whereas that of Ren-2 transgenic rats (Ren-2 TGR) by increased activity of renin-angiotensin system (RAS). However, both types of hypertension are effectively attenuated by chronic blockade of L-type voltage-dependent calcium channel (L-VDCC). The aim of our study was to evaluate whether the magnitude of BP response elicited by acute nifedipine administration is proportional to the alterations of particular vasoactive systems (SNS, RAS, NO) known to modulate L-VDCC activity. We therefore studied these relationships not only in SHR, in which mean arterial pressure was modified in a wide range of 100-210 mm Hg by chronic antihypertensive treatment (captopril or hydralazine) or its withdrawal, but also in rats with augmented RAS activity such as homozygous Ren-2 TGR, pertussis toxin-treated SHR or L-NAME-treated SHR. In all studied groups the magnitude of BP response to nifedipine was proportional to actual BP level and it closely correlated with BP changes induced by acute combined blockade of RAS and SNS. BP response to nifedipine is also closely related to the degree of relative NO deficiency. This was true for both SNS- and RAS-dependent forms of genetic hypertension, suggesting common mechanisms responsible for enhanced L-VDCC opening and/or their upregulation in hypertensive animals. In conclusions, BP response to nifedipine is proportional to the vasoconstrictor activity exerted by both SNS and RAS, indicating a key importance of these two pressor systems for actual L-VDCC opening necessary for BP maintenance.
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Presión Sanguínea/fisiología , Bloqueadores de los Canales de Calcio/uso terapéutico , Modelos Animales de Enfermedad , Hipertensión/tratamiento farmacológico , Nifedipino/uso terapéutico , Sistema Renina-Angiotensina/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Hipertensión/fisiopatología , Masculino , Nifedipino/farmacología , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Transgénicas , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiologíaRESUMEN
Most anesthetics induce characteristic hemodynamic changes leading to blood pressure (BP) reduction but the role of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and nitric oxide (NO) synthesis in this BP reduction is unknown. We therefore studied the influence of four widely used anesthetics - pentobarbital (P), isoflurane (ISO), ketamine-xylazine (KX) and chloralose-urethane (CU) - on the participation of these vasoactive systems in BP maintenance. BP effects elicited by the acute sequential blockade of RAS (captopril), SNS (pentolinium) and NO synthase (L-NAME) were compared in conscious and anesthetized Wistar or spontaneously hypertensive rats (SHR). Except for pentobarbital all studied anesthetics evidenced by diminished BP responses to pentolinium. The absolute pentolinium-induced BP changes were always greater in SHR than Wistar rats. KX anesthesia eliminated BP response to pentolinium and considerably enhanced BP response to NO synthase inhibition in SHR. In both rat strains the anesthesia with ISO or CU augmented BP response to captopril, decreased BP response to pentolinium and attenuated BP response to NO synthase inhibition. In conclusion, pentobarbital anesthesia had a modest influence on BP level and its maintenance by the above vasoactive systems. Isoflurane and chloralose-urethane anesthesia may be used in cardiovascular experiments if substantial BP decrease due to altered contribution of RAS, SNS and NO to BP regulation does not interfere with the respective research aim. Major BP reduction (namely in SHR) due to a complete SNS absence is a major drawback of ketamine-xylazine anesthesia.
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Anestésicos/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertensión/fisiopatología , Anestésicos Combinados/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Cloralosa/farmacología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Bloqueadores Ganglionares/farmacología , Hipertensión/metabolismo , Isoflurano/farmacología , Ketamina/farmacología , Masculino , Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Pentobarbital/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Uretano/farmacología , Xilazina/farmacologíaRESUMEN
Epidemiological studies have demonstrated that n-3 polyunsaturated fatty acid (PUFA) consumption is associated with a reduced risk of atherosclerosis and hyperlipidemia. It is well known that lipid metabolism is also influenced by thyroid hormones. The aim of our study was to test whether n-3 PUFA supplementation (200 mg/kg of body weight/day for 6 weeks given intragastrically) would affect lipid metabolism in Lewis male rats with altered thyroid status. Euthyroid, hypothyroid, and hyperthyroid status of experimental groups was well defined by plasma levels of triiodothyronine, the activity of liver mitochondrial glycerol-3-phosphate dehydrogenase, and by relative heart weight. Fasting blood glucose levels were significantly higher in the hyperthyroid compared to the euthyroid and hypothyroid rats (5.0±0.2 vs. 3.7±0.4 and 4.4±0.2 mmol/l, respectively). In hyperthyroid animals, the concentration of plasma postprandial triglycerides was also increased compared to euthyroid and hypothyroid rats (0.9±0.1 vs. 0.5±0.1 and 0.4±0.1 mmol/l, respectively). On the other hand, hypothyroidism compared to euthyroid and hyperthyroid status was associated with elevated plasma levels of total cholesterol (2.6±0.2 vs. 1.5±0.1 and 1.6±0.1 mmol/l, respectively), LDL cholesterol (0.9±0.1 vs. 0.4±0.1 and 0.2±0.1 mmol/l, respectively) as well as HDL cholesterol (1.6±0.1 vs. 1.0±0.1 and 1.3±0.1 mmol/l, respectively). Supplementation of n-3 PUFA in the present study did not significantly modify either relative heart weight or glucose and lipid levels in any thyroid status.
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Ácidos Grasos Omega-3/metabolismo , Hipertiroidismo/metabolismo , Hipotiroidismo/metabolismo , Metabolismo de los Lípidos , Animales , Colesterol/metabolismo , Suplementos Dietéticos/análisis , Ácidos Grasos Omega-3/administración & dosificación , Glicerolfosfato Deshidrogenasa/metabolismo , Humanos , Hipertiroidismo/enzimología , Hipotiroidismo/enzimología , Hígado/metabolismo , Masculino , Mitocondrias/enzimología , Mitocondrias/metabolismo , Ratas , Ratas Endogámicas Lew , Hormonas Tiroideas/metabolismoRESUMEN
Fifty years ago, Lewis K. Dahl has presented a new model of salt hypertension - salt-sensitive and salt-resistant Dahl rats. Twenty years later, John P. Rapp has published the first and so far the only comprehensive review on this rat model covering numerous aspects of pathophysiology and genetics of salt hypertension. When we summarized 25 years of our own research on Dahl/Rapp rats, we have realized the need to outline principal abnormalities of this model, to show their interactions at different levels of the organism and to highlight the ontogenetic aspects of salt hypertension development. Our attention was focused on some cellular aspects (cell membrane function, ion transport, cell calcium handling), intra- and extrarenal factors affecting renal function and/or renal injury, local and systemic effects of renin-angiotensin-aldosterone system, endothelial and smooth muscle changes responsible for abnormal vascular contraction or relaxation, altered balance between various vasoconstrictor and vasodilator systems in blood pressure maintenance as well as on the central nervous and peripheral mechanisms involved in the regulation of circulatory homeostasis. We also searched for the age-dependent impact of environmental and pharmacological interventions, which modify the development of high blood pressure and/or organ damage, if they influence the salt-sensitive organism in particular critical periods of development (developmental windows). Thus, severe self-sustaining salt hypertension in young Dahl rats is characterized by pronounced dysbalance between augmented sympathetic hyperactivity and relative nitric oxide deficiency, attenuated baroreflex as well as by a major increase of residual blood pressure indicating profound remodeling of resistance vessels. Salt hypertension development in young but not in adult Dahl rats can be attenuated by preventive increase of potassium or calcium intake. On the contrary, moderate salt hypertension in adult Dahl rats is attenuated by superoxide scavenging or endothelin-A receptor blockade which do not affect salt hypertension development in young animals.
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Hipertensión/metabolismo , Hipertensión/prevención & control , Cloruro de Sodio Dietético/efectos adversos , Factores de Edad , Animales , Presión Arterial/fisiología , Calcio/metabolismo , Hipertensión/etiología , Potasio/metabolismo , Ratas , Ratas Endogámicas Dahl , Sistema Renina-Angiotensina/fisiologíaRESUMEN
Several bacterial species have inherent ability to colonize solid tumors in vivo. However, their natural anti-tumor activity can be enhanced by genetic engineering that enables these bacteria express or transfer therapeutic molecules into target cells. In this review, we summarize latest research on cancer therapy using genetically modified bacteria with particular emphasis on blocking tumor angiogenesis. Despite recent progress, only a few recent studies on bacterial tumor therapy have focused on anti-angiogenesis. Bacteria-mediated anti-angiogenesis therapy for cancer, however, is an attractive approach given that solid tumors are often characterized by increased vascularization. Here, we discuss four different approaches for using modified bacteria as anti-cancer therapeutics--bactofection, DNA vaccination, alternative gene therapy and transkingdom RNA interference--with a specific focus on angiogenesis suppression. Critical areas and future directions for this field are also outlined.
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Bacterias/genética , Terapia Genética/métodos , Neoplasias/terapia , Animales , Técnicas de Transferencia de Gen , Vectores Genéticos , Humanos , Neovascularización Patológica/terapia , Organismos Modificados Genéticamente , Interferencia de ARN , Vacunas de ADNRESUMEN
AIM: Increased potassium intake attenuates the development of salt-dependent hypertension, but the detailed mechanisms of blood pressure (BP) reduction are still unclear. The aims of our study were (i) to elucidate these mechanisms, (ii) to compare preventive potassium effects in immature and adult animals and (iii) to evaluate the therapeutic effects of dietary potassium supplementation in rats with established salt hypertension. METHODS: Young (4-week-old) and adult (24-week-old) female salt-sensitive Dahl rats were fed a high-salt diet (5% NaCl) or a high-salt diet supplemented with 3% KCl for 5 weeks. The participation of vasoconstrictor (renin-angiotensin and sympathetic nervous systems) and vasodilator systems [prostanoids, Ca(2+) -activated K(+) channels, nitric oxide (NO)] was evaluated using a sequential blockade of these systems. RESULTS: Preventive potassium supplementation attenuated the development of severe salt hypertension in young rats, whereas it had no effects on BP in adult rats with moderate hypertension. Enhanced sympathetic vasoconstriction was responsible for salt hypertension in young rats and its attenuation for potassium-induced BP reduction. Conversely, neither salt hypertension nor its potassium-induced attenuation were associated with significant changes of the vasodilator systems studied. The relative deficiency of vasodilator action of NO and Ca(2+) -activated K(+) channels in salt hypertensive Dahl rats was not improved by potassium supplementation. CONCLUSIONS: The attenuation of enhanced sympathetic vasoconstriction is the principal mechanism of antihypertensive action exerted by preventive potassium supplementation in immature Dahl rats. Dietary potassium supplementation has no preventive effects on BP in adult salt-loaded animals or no therapeutic effects on established salt hypertension in young rats.
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Suplementos Dietéticos , Hipertensión/inducido químicamente , Potasio en la Dieta/farmacología , Cloruro de Sodio/efectos adversos , Sistema Nervioso Simpático/fisiología , Vasoconstricción/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Femenino , Hemodinámica , Nifedipino/farmacología , Ratas , Ratas Endogámicas Dahl , Vasodilatadores/farmacologíaRESUMEN
Consumption of cola beverages is very high worldwide. The health effects of cola intake are not clear, although epidemiological studies point toward associations with obesity, kidney diseases and osteoporosis. Experimental studies are surprisingly rare. In this study, we substituted drinking water of adult male Wistar rats with three different cola beverages for 3 months. Behavioural phenotyping, measurement of sex steroids in plasma and oxidative stress in testes were performed at the end of the study. A light-dark box showed increased locomotor activity and anxiety in all groups with cola intake. A subtle anti-depressive effect was seen in the forced swim test. Chronic cola intake increased both oestradiol and testosterone levels suggesting an additional mechanism of action beyond the known effects of caffeine on adenosine receptors.
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Conducta Animal , Bebidas Gaseosas , Hormonas Esteroides Gonadales/sangre , Estrés Oxidativo , Animales , Ansiedad , Bebidas Gaseosas/efectos adversos , Depresión/prevención & control , Estradiol/sangre , Preferencias Alimentarias , Masculino , Malondialdehído/metabolismo , Actividad Motora , Ratas , Ratas Wistar , Natación , Testículo/metabolismo , Testosterona/sangreRESUMEN
The effectiveness of bisphosphonate treatment for post-menopausal osteoporosis depends on patients adhering to the therapeutic regimen. We previously showed that patients prefer a once-monthly regimen and the present follow-up study aimed to analyse patients' motivation for this preference. Women with post-menopausal osteoporosis (n = 2035) completed a questionnaire targeting their bisphosphonate treatment preferences. The majority had chosen the once-monthly regimen due to the comfort (69%) and simplicity (59%) of the treatment and the need to take fewer pills (55%). Friends, relatives and print media were highlighted as important sources of information and many patients indicated a need for more information about osteoporosis and its management. Gastrointestinal and muscular side-effects were reported by about one-third of the patients, but these were well tolerated. It is concluded that once-monthly bisphosphonate treatment was preferred due to improved quality of life and should be offered to all patients with post-menopausal osteoporosis.