RESUMEN
Salt hypertensive Dahl rats are characterized by sympathoexcitation and relative NO deficiency. We tested the hypothesis that the increased blood pressure (BP) response to fasudil in salt hypertensive Dahl rats is due to augmented calcium sensitization in the salt-sensitive strain and/or due to their decreased baroreflex efficiency. BP reduction after acute administration of nifedipine (an L-type voltage-dependent calcium channel blocker) or fasudil (a Rho kinase inhibitor) was studied in conscious intact rats and in rats subjected to acute NO synthase inhibition or combined blockade of the renin-angiotensin system (captopril), sympathetic nervous system (pentolinium), and NO synthase (L-NAME). Intact salt-sensitive (SS) Dahl rats fed a low-salt diet had greater BP responses to nifedipine (-31 ± 6 mmHg) or fasudil (-34 ± 7 mmHg) than salt-resistant (SR) Dahl rats (-16 ± 4 and -17 ± 2 mmHg, respectively), and a high-salt intake augmented the BP response only in SS rats. These BP responses were doubled after acute NO synthase inhibition, indicating that endogenous NO attenuates both calcium entry and calcium sensitization. Additional pentolinium administration, which minimized sympathetic compensation for the drug-induced BP reduction, magnified the BP responses to nifedipine or fasudil in all groups except for salt hypertensive SS rats due to their lower baroreflex efficiency. The BP response to the calcium channel blocker nifedipine can distinguish SS and SR rats even after calcium sensitization inhibition by fasudil, which was not seen when fasudil was administered to nifedipine-pretreated rats. Thus, enhanced calcium entry (potentiated by sympathoexcitation) in salt hypertensive Dahl rats is the abnormality that is essential for their BP increase, which was further augmented by increased calcium sensitization in salt-sensitive Dahl rats.
Asunto(s)
Hipertensión , Cloruro de Sodio Dietético , Animales , Presión Sanguínea , Calcio , Hipertensión/tratamiento farmacológico , Ratas , Ratas Endogámicas Dahl , VasoconstricciónRESUMEN
Activation of nuclear factor-κB (NF-κB) by increased production of reactive oxygen species (ROS) might induce transcription and expression of different antioxidant enzymes and also of nitric oxide synthase (NOS) isoforms. Thus, we aimed at studying the effect of NF-κB inhibition, caused by JSH-23 (4-methyl-N (1)-(3-phenyl-propyl)-benzene-1,2-diamine) injection, on ROS and NO generation in hereditary hypertriglyceridemic (HTG) rats. 12-week-old, male Wistar and HTG rats were treated with JSH-23 (bolus, 10 µmol, i.v.). After one week, blood pressure (BP), superoxide dismutase (SOD) activity, SOD1, endothelial NOS (eNOS), and NF-κB (p65) protein expressions were higher in the heart of HTG rats compared to control rats. On the other hand, NOS activity was decreased. In HTG rats, JSH-23 treatment increased BP and heart conjugated dienes (CD) concentration (measured as the marker of tissue oxidative damage). Concomitantly, SOD activity together with SOD1 expression was decreased, while NOS activity and eNOS protein expression were increased significantly. In conclusion, NF-κB inhibition in HTG rats led to decreased ROS degradation by SOD followed by increased oxidative damage in the heart and BP elevation. In these conditions, increased NO generation may represent rather a counterregulatory mechanism activated by ROS. Nevertheless, this mechanism was not sufficient enough to compensate BP increase in HTG rats.
Asunto(s)
Miocardio/metabolismo , Factor de Transcripción ReIA/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Glutatión/análisis , Ventrículos Cardíacos/metabolismo , Hiperlipoproteinemia Tipo IV/patología , Hiperlipoproteinemia Tipo IV/veterinaria , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fenilendiaminas/farmacología , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Factor de Transcripción ReIA/genéticaRESUMEN
BACKGROUND: Our previous experiments demonstrated that selective endothelin A (ETA) receptor blockade had antihypertensive effects in Ren-2 transgenic rats (TGRs), but the mechanisms responsible for this change of blood pressure (BP) have not been explored yet. METHOD: Four-week-old male heterozygous TGRs and their normotensive controls--Hannover Sprague-Dawley (HanSD) rats--were fed high-salt diet (2% NaCl) and were treated with selective ETA receptor blocker atrasentan (5âmg/kg per day) for 8 weeks. At the end of the study, the contribution of principle vasoactive systems was evaluated by the sequential blockade of the renin-angiotensin system (captopril), sympathetic nervous system (pentolinium) and nitric oxide synthase [N-nitro-L-arginine methyl ester (L-NAME)]. The role of calcium influx through L-type voltage-dependent calcium channels in BP maintenance was evaluated using nifedipine. In a separate group of animals, the efficiency of distinct vasodilator systems--prostanoids (blocked by nonselective cyclooxygenase inhibitor indomethacin) and Ca-activated K channels (inhibited by tetraethylammonium)--was also analyzed. RESULTS: Atrasentan attenuated the development of hypertension in heterozygous TGRs, but had no effects in Hannover Sprague-Dawley rats. Moreover, atrasentan moderately attenuated renin-angiotensin system-dependent vasoconstriction, whereas it had no effect on sympathetic vasoconstriction. The nifedipine-sensitive BP component was markedly decreased by atrasentan treatment. In contrast, vasodilatation mediated by nitric oxide, endogenous prostanoids or Ca-activated K channels was reduced in atrasentan-treated TGRs, indicating the absence of compensatory augmentation of endothelin B receptor-mediated vasodilation in these animals. CONCLUSION: BP-lowering effect of chronic atrasentan treatment in TGRs was mainly caused by reduced Ca influx through L-type voltage-dependent calcium channels due to missing ETA receptor-dependent vasoconstriction and attenuated angiotensin II-dependent vasoconstriction.
Asunto(s)
Calcio/metabolismo , Antagonistas de los Receptores de la Endotelina A/química , Hipertensión/fisiopatología , Nifedipino/química , Pirrolidinas/uso terapéutico , Alimentación Animal , Animales , Antihipertensivos/química , Atrasentán , Presión Sanguínea/fisiología , Calcio/química , Canales de Calcio Tipo L/metabolismo , Captopril/química , Masculino , NG-Nitroarginina Metil Éster/química , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Tartrato de Pentolinio/química , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Renina/genética , Sistema Renina-Angiotensina/efectos de los fármacos , Cloruro de Sodio Dietético/farmacología , Sistema Nervioso Simpático/fisiopatología , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
Although Ren-2 transgenic rat (TGR) is defined as a model of angiotensin II-dependent hypertension, we studied whether the renin-angiotensin system (RAS) is really the main contributor to blood pressure (BP) elevation in hetero- and homozygous TGRs. Moreover, we examined whether repeated antisense (AS) therapy against AT(1) receptors would have a similar effect on the BP and the contribution of the principle vasoconstrictor/vasodilator systems to BP regulation in young and adult TGRs. From the age of 30 (young) and 100 (adult) days, rats were injected with AS for 40 days in 10-day intervals. After 10 and 40 days of AS therapy, the basal BP and acute BP responses to the sequential blockade of the RAS, sympathetic nervous (SNS) and nitric oxide systems were determined in conscious rats. The RAS system was the major system maintaining elevated BP in young homozygous animals, whereas there was an increasing contribution of the SNS in heterozygous TGR with age. The AS therapy in the young TGR had a transient BP-lowering effect that was associated with reduced cardiac hypertrophy; the AS therapy was most effective in young homozygous TGR, causing a substantial reduction of angiotensin-dependent vasoconstriction. In heterozygous rats, AS therapy at earlier stages was related to an inhibition of sympathetic vasoconstriction, whereas to RAS inhibition in established hypertension. In conclusion, repeated AS therapy had transient antihypertensive effects exclusively in young TGR. The contribution of the RAS to BP maintenance is highly important only in homozygous TGRs, whereas it is surpassed by SNS in heterozygous TGR.
Asunto(s)
Hipertensión/terapia , Oligonucleótidos Antisentido/uso terapéutico , Receptor de Angiotensina Tipo 1/metabolismo , Factores de Edad , Envejecimiento/genética , Envejecimiento/fisiología , Animales , Antihipertensivos/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Heterocigoto , Homocigoto , Masculino , Óxido Nítrico/fisiología , Ratas , Ratas Transgénicas , Receptor de Angiotensina Tipo 1/genética , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
Recombinant inbred (RI) strains (Prague HXB/BXH set) represent a unique model that allows for permanent summation of genetic and physiological information as well as the study of age-dependent changes in phenotypes and/or gene regulation. This study compared blood pressure (BP) measured in adult animals of RI strains by radiotelemetry with BP values obtained in conscious rats of comparable age subjected to short-term carotid catheterization or with those obtained by direct carotid puncture under ether anesthesia (almost 20 years ago). After radiotelemetry recording, the contribution of major vasoactive systems to BP maintenance was studied by consecutive inhibition of the renin-angiotensin system (RAS), sympathetic nervous system (SNS), and nitric oxide synthase. We found highly significant interrelationships among baseline BP values obtained by radiotelemetry, carotid catheterization, or carotid puncture. This indicates considerable stability of RI strains over the course of their long existence, and confirms the reliability of BP values used for genetic studies performed in the past. Subsequent analysis of vasoactive system participation revealed the importance of SNS for the maintenance of BP, as determined by either radiotelemetry or catheterization. The BP of catheterized rats also correlated closely with acute captopril-induced BP changes, but this was not the case for rats measured by radiotelemetry. NO-dependent vasodilatation matched the BP effects of SNS and RAS in both measuring conditions. Residual BP (recorded at sodium nitroprusside-induced dilatation of resistance vessels) was also responsible for a significant portion of the BP variation in RI strains. Our study confirms the validity of RI strains for the further genetic and physiological research of hypertension.
Asunto(s)
Presión Sanguínea/genética , Modelos Animales de Enfermedad , Hipertensión/genética , Ratas Endogámicas SHR/genética , Ratas Endogámicas/genética , Animales , Antihipertensivos/farmacología , Cateterismo , Frecuencia Cardíaca/genética , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Monitoreo Fisiológico , Óxido Nítrico Sintasa/metabolismo , Tamaño de los Órganos/genética , Ratas , Proteínas Recombinantes/genética , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/fisiología , TelemetríaRESUMEN
Prague hypertriglyceridemic (HTG) rats represent a suitable model of metabolic syndrome. We have established the set of F(2) hybrids derived from HTG and Lewis progenitors to investigate the relationship between respective polymorphism(s) of Igf2 gene and blood pressure (BP) or other cardiovascular phenotypes. HTG rats had elevated systolic BP and plasma triglycerides but lower plasma cholesterol compared to Lewis rats of both genders. In males, there was higher mean arterial pressure, diastolic BP and relative heart weight in HTG than in Lewis rats. The results obtained in the total population of F(2) hybrids indicated strong segregation of Igf2 genotype with plasma triglycerides. There was no segregation of Igf2 genotype with any BP component except BP changes occurring after the blockade of either renin-angiotensin system (RAS) or NO synthase. When F(2) population was analyzed according to gender, male F(2) progeny homozygous for HTG Igf2 allele had significantly higher plasma triglycerides and greater BP changes after NO synthase blockade than those homozygous for Lewis allele. On the contrary, male F(2) progeny homozygous for HTG Igf2 allele had significantly lower plasma cholesterol and smaller BP changes after RAS blockade. PCR analysis of Igf2 gene by using of microsatelite D1Mgh22 has shown polymorphism between HTG and Lewis rats. Sequence analysis of cDNA revealed insertion of 14 nucleotides in HTG gene. In conclusion, polymorphism in Igf2 gene may be responsible for differences in lipid metabolism between HTG and Lewis rats. It remains to determine how these abnormalities could be involved in BP regulation by particular vasoactive systems.
Asunto(s)
Presión Sanguínea/fisiología , Hipertrigliceridemia/sangre , Hipertrigliceridemia/genética , Hipertrigliceridemia/fisiopatología , Factor II del Crecimiento Similar a la Insulina/genética , Lípidos/sangre , Animales , Peso Corporal/genética , Cruzamientos Genéticos , Análisis Mutacional de ADN , Femenino , Ligamiento Genético , Genotipo , Corazón/anatomía & histología , Hipertrigliceridemia/patología , Riñón/anatomía & histología , Masculino , Repeticiones de Microsatélite , Tamaño de los Órganos/genética , Ratas , Ratas Endogámicas Lew , Ratas EndogámicasRESUMEN
Several non-aromatic substituted oxime derivatives (formamidoxime, acetaldoxime, acetone oxime, acetohydroxamic acid, formaldoxime) function as vasorelaxant NO donors when added to precontracted aortic rings in vitro. This study was aimed to evaluate whether these substances posses vasodilator properties under in vivo conditions. We studied blood pressure changes elicited by administration of these compounds to conscious chronically catheterized Wistar rats in which endogenous NO synthesis was acutely inhibited by N(omega)-nitro-L-arginine methyl ester (L-NAME) pretreatment (30 mg/kg i.v.). Three of the tested substances (formaldoxime, acetohydroxamic acid and formamidoxime) induced pronounced dose-dependent blood pressure reduction which was further augmented when baroreflex operation was interrupted by ganglionic blockade (5 mg/kg pentolinium). Pretreatment of rats with methylene blue (soluble guanylate cyclase inhibitor) was used to estimate the contribution of NO to observed blood pressure lowering effects of the above compounds. Nitric oxide seems to be responsible for the entire formaldoxime-induced blood pressure decrease and for a considerable part of blood pressure changes elicited by formamidoxime. On the contrary, we did not find a significant NO contribution to blood pressure reduction caused by acetohydroxamic acid. In conclusion, our study confirmed in vivo vasodilator effects of three above mentioned compounds which were earlier demonstrated to induce in vitro vasorelaxation. It indicated a variable contribution of nitric oxide to blood pressure changes elicited by particular compounds. Substances with hydrophilic character (formamidoxime, acetohydroxamic acid, formaldoxime) were effective, whereas less hydrophilic substance (acetaldoxime) or slightly hydrophobic one (acetone oxime) were ineffective.
Asunto(s)
Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Óxido Nítrico/fisiología , Oximas/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Animales , Aorta/fisiología , Presión Sanguínea/fisiología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Ácidos Hidroxámicos/farmacología , Masculino , NG-Nitroarginina Metil Éster/farmacología , Tartrato de Pentolinio/farmacología , Ratas , Ratas Wistar , Vasodilatación/fisiologíaRESUMEN
The attenuated nitric oxide (NO) formation and/or elevated production of reactive oxygen species are often found in experimental and human hypertension. We aimed to determine possible effects of N-acetylcysteine (1.5 g/kg/day) and N-acetyl-5-methoxytryptamine (melatonin, 10 mg/kg/day) in adult spontaneously hypertensive rats (SHR) with established hypertension. After a six-week-treatment, blood pressure was measured and NO synthase (NOS) activity, concentration of conjugated dienes, protein expression of endothelial NOS, inducible NOS and nuclear factor-kappaB (NF-kappaB) in the left ventricle were determined. Both treatments improved the NO pathway by means of enhanced NOS activity and reduced reactive oxygen species level as indicated by decreased conjugated diene concentrations and lowered NF-kappaB expression. N-acetylcysteine (but not melatonin) also increased the endothelial NOS protein expression. However, only melatonin was able to reduce blood pressure significantly. Subsequent in vitro study revealed that both N-acetylcysteine and melatonin lowered the tone of phenylephrine-precontracted femoral artery via NO-dependent relaxation. Nevertheless, melatonin-induced relaxation also involved NO-independent component which was preserved even after the blockade of soluble guanylate cyclase by oxadiazolo[4,3-a]quinoxalin-1-one. In conclusion, both N-acetylcysteine and melatonin were able to improve the NO/reactive oxygen species balance in adult SHR, but blood pressure was significantly lowered by melatonin only. This implies that a partial restoration of NO/reactive oxygen species balance achieved by the antioxidants such as N-acetylcysteine has no therapeutic effect in adult rats with established hypertension. The observed antihypertensive effect of melatonin is thus mediated by additional mechanisms independent of NO pathway.
Asunto(s)
Acetilcisteína/farmacología , Antioxidantes/farmacología , Depuradores de Radicales Libres/farmacología , Hipertensión/tratamiento farmacológico , Melatonina/farmacología , Acetilcisteína/uso terapéutico , Alcadienos , Animales , Antioxidantes/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Western Blotting , Depuradores de Radicales Libres/uso terapéutico , Masculino , Melatonina/uso terapéutico , Miografía , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa/efectos de los fármacos , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismo , Vasoconstricción/efectos de los fármacosRESUMEN
Increased blood pressure (BP) in genetic hypertension is usually caused by high activity of sympathetic nervous system (SNS) which is enhanced by central angiotensin II but lowered by central nitric oxide (NO). We have therefore evaluated NO synthase (NOS) activity as well as neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) protein expression in brainstem and midbrain of adult spontaneously hypertensive rats (SHR) characterized by enhanced sympathetic vasoconstriction. We also studied possible participation of brain NO in antihypertensive effects of chronic captopril treatment of adult SHR. NOS activity was increased in midbrain of SHR compared to Wistar-Kyoto (WKY) rats. This could be ascribed to enhanced iNOS expression, whereas nNOS expression was unchanged and eNOS expression was reduced in this brain region. In contrast, no significant changes of NOS activity were found in brainstem of SHR in which nNOS and iNOS expression was unchanged, but eNOS expression was increased. Chronic captopril administration lowered BP of adult SHR mainly by attenuation of sympathetic tone, whereas the reduction of angiotensin II-dependent vasoconstriction and the decrease of residual BP (amelioration of structural remodeling of resistance vessels) were less important. This treatment did not affect significantly either NOS activity or expression of any NOS isoform in the two brain regions. Our data do not support the hypothesis that altered brain NO formation contributes to sympathetic hyperactivity and high BP of adult SHR with established hypertension.
Asunto(s)
Presión Sanguínea/fisiología , Encéfalo/enzimología , Óxido Nítrico Sintasa/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Captopril/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Tamaño de los Órganos/efectos de los fármacos , Tartrato de Pentolinio/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
The imbalance between NO (nitric oxide) and ROS (reactive oxygen species) is an important factor in the development of hypertension. The aim of the present study was to determine the preventive and therapeutic effects of NAC (N-acetylcysteine) in SHRs (spontaneously hypertensive rats). Young and adult SHRs and WKY (Wistar-Kyoto) rats were treated with NAC (20 g/l in the drinking water). After 8 weeks of treatment, BP (blood pressure) and NOS (NO synthase) activity, conjugated dienes and GSH (reduced glutathione) in the kidney and left ventricle were determined. Protein expression of eNOS (endothelial NOS), inducible NOS and NF-kappaB (nuclear factor kappaB) were also determined in the left ventricle and kidney. Chronic NAC treatment partially attenuated the rise in BP in young SHRs (179+/-6 compared with 210+/-8 mmHg in untreated animals), but it had no significant effect on BP in adult SHRs. The antioxidant action of NAC, measured as a decrease of the concentration of conjugated dienes or inhibition of NF-kappaB expression, was greater in young than in adult SHRs. Similarly, eNOS protein expression was attenuated more in young than in adult SHRs, although NAC treatment increased NOS activity to a similar extent in both young and adult rats. In conclusion, both decreased ROS production and increased NOS activity appear to participate in the BP changes after NAC treatment in young SHRs. In adult SHRs with established hypertension, however, the secondary alterations (such as pronounced structural remodelling of resistance vessels) might attenuate the therapeutic effect of NAC.
Asunto(s)
Acetilcisteína/uso terapéutico , Antioxidantes/uso terapéutico , Hipertensión/tratamiento farmacológico , Envejecimiento , Animales , Glutatión/metabolismo , Ventrículos Cardíacos/metabolismo , Hipertensión/metabolismo , Riñón/metabolismo , Masculino , FN-kappa B/análisis , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II/análisis , Óxido Nítrico Sintasa de Tipo III/análisis , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Hypertension due to chronic inhibition of NO synthase (NOS) by Nomega-nitro-L-arginine methyl ester (L-NAME) administration is characterized by both impaired NO-dependent vasodilation and enhanced sympathetic vasoconstriction. The aim of our study was to evaluate changes in the participation of major vasoactive systems in L-NAME-treated rats which were subjected to simultaneous antihypertensive (captopril) or antioxidant (N-acetylcysteine, NAC) treatment. Three-month-old Wistar males treated with L-NAME (60 mg/kg/day) for 5 weeks were compared to rats in which L-NAME treatment was combined with simultaneous chronic administration of captopril or NAC. Basal blood pressure (BP) and its acute responses to consecutive i.v. injections of captopril (10 mg/kg), pentolinium (5 mg/kg), L-NAME (30 mg/kg), tetraethylammonium (TEA, 16 mg/kg) and nitroprusside (NP, 20 microg/kg) were determined in conscious rats at the end of the study. The development of L-NAME hypertension was prevented by captopril treatment, whereas NAC treatment caused only a moderate BP reduction. Captopril treatment normalized the sympathetic BP component and significantly reduced residual BP (measured at full NP-induced vasodilation). In contrast, chronic NAC treatment did not modify the sympathetic BP component or residual BP, but significantly enhanced NO-dependent vasodilation. Neither captopril nor NAC treatment influenced the compensatory increase of TEA-sensitive vasodilation mediated by endothelium-derived hyperpolarizing factor in L-NAME-treated rats. Chronic captopril treatment prevented L-NAME hypertension by lowering of sympathetic tone, whereas chronic NAC treatment attenuated L-NAME hypertension by reduction in the vasodilator deficit due to enhanced NO-dependent vasodilation.
Asunto(s)
Acetilcisteína/uso terapéutico , Antihipertensivos/uso terapéutico , Captopril/uso terapéutico , Hipertensión/prevención & control , Acetilcisteína/farmacología , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Captopril/farmacología , Hipertensión/inducido químicamente , Masculino , NG-Nitroarginina Metil Éster/antagonistas & inhibidores , NG-Nitroarginina Metil Éster/farmacología , Nitroprusiato/farmacología , Nitroprusiato/uso terapéutico , Tartrato de Pentolinio/farmacología , Tartrato de Pentolinio/uso terapéutico , Ratas , Ratas Wistar , Tetraetilamonio/farmacología , Tetraetilamonio/uso terapéuticoRESUMEN
The aim of this study was to evaluate the production of superoxide anions as well as their role in the induction and/or maintenance of high blood pressure in rats with N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. In the preventive study, we compared adult Wistar rats treated with L-NAME for 4 weeks with L-NAME-treated rats that were simultaneously given N-acetylcysteine (NAC) in their drinking water. Basal blood pressure, superoxide production, conjugated dienes concentration and NO synthase (NOS) activity were measured at the end of the experiment. Chronic NOS inhibition by L-NAME treatment increased blood pressure, enhanced superoxide production in the aorta and elevated the concentration of conjugated dienes in the heart and kidney. All these changes were prevented by simultaneous NAC administration, which augmented NOS activity in L-NAME-treated rats. In the therapeutic study, the effects of chronic NAC treatment were studied in rats with established hypertension which developed during 4 weeks of L-NAME administration. The blood pressure effects of chronic NAC treatment in established L-NAME hypertension were only moderate, although this treatment also restored NOS activity and lowered conjugated dienes in the heart and kidney. Since chronic NAC treatment had better preventive than therapeutic effects, it seems that reactive oxygen species play a more important role in the induction than in the maintenance of L-NAME hypertension.
Asunto(s)
Acetilcisteína/farmacología , Inhibidores Enzimáticos/farmacología , Hipertensión/metabolismo , Hipertensión/prevención & control , NG-Nitroarginina Metil Éster/farmacología , Especies Reactivas de Oxígeno/metabolismo , Animales , Antioxidantes/farmacología , Aorta/efectos de los fármacos , Aorta/metabolismo , Óxidos N-Cíclicos/farmacología , Interacciones Farmacológicas , Hipertensión/inducido químicamente , Masculino , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas Wistar , Marcadores de SpinRESUMEN
Distinct changes of membrane lipid content could contribute to the abnormalities of ion transport that take part in the development of salt hypertension in Dahl rats. The relationships between lipid content and particular ion transport systems were studied in red blood cells (RBC) of Dahl rats kept on low- and high-salt diets for 5 weeks since weaning. Dahl salt-sensitive (SS/Jr) rats on high-salt diet had increased blood pressure, levels of plasma triacylglycerols and total plasma cholesterol compared to salt-resistant (SR/Jr) rats. Furthermore, RBC of SS/Jr rats differed from SR/Jr ones by increased content of total membrane phospholipids, but membrane cholesterol was not changed significantly. SS/Jr rats had higher RBC intracellular Na+ (Na(i)+) content and enhanced bumetanide-sensitive Rb+ uptake. RBC membrane content of cholesterol and phospholipids correlated positively with RBC Na(i)+ content, with the activity of Na+-K+ pump and Na+-K+-2Cl- cotransport and also with Rb+ leak. The content of phosphatidylserines plus phosphatidylinositols was positively associated with RBC Na(i)+ content, with the activity of Na+-K+ pump and Na+-K+-2Cl- cotransport and with Rb+ leak. The content of sphingomyelins was positively related to Na+-K+-2Cl- cotransport activity and negatively to ouabain-sensitive Rb+-K+ exchange. We can conclude that observed relationships between ion transport and the membrane content of cholesterol and/or sphingomyelins, which are known to regulate membrane fluidity, might participate in the pathogenesis of salt hypertension in Dahl rats.
Asunto(s)
Membrana Eritrocítica/química , Eritrocitos/metabolismo , Hipertensión/metabolismo , Lípidos de la Membrana/análisis , Cloruro de Sodio Dietético/administración & dosificación , Animales , Colesterol/sangre , Eritrocitos/química , Hipertensión/etiología , Transporte Iónico , Masculino , Ratas , Ratas Endogámicas Dahl , Simportadores de Cloruro de Sodio-Potasio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
OBJECTIVES: The contribution of the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS) to blood pressure (BP) maintenance was evaluated in rats with N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension. Furthermore, we studied the extent of nitric oxide (NO) synthesis inhibition and the participation of remaining NO in the counterbalance of pressor systems, with a special reference to inducible nitric oxide synthase (iNOS). METHODS: Wistar rats subjected to chronic L-NAME treatment (40 mg/kg per day for 4 weeks) were used. A consecutive blockade of RAS (captopril) and SNS (pentolinium) was followed by acute L-NAME injection. Dimethylguanidine or aminoguanidine were used to affect NO synthesis by iNOS. RESULTS: L-NAME hypertensive rats had borderline augmentation of depressor response to captopril injection, but their BP fall after pentolinium was considerably enhanced compared with controls. Residual BP (recorded after simultaneous blockade of the RAS and the SNS) was elevated by 20-40% in hypertensive rats. Pronounced inhibition of NO synthase activity (50% reduction in the aorta and myocardium) was detected in L-NAME hypertensive rats in which the BP rise elicited by acute L-NAME injection was considerably attenuated (by 60-80%). In contrast, acute administration of dimethylguanidine [mixed endothelial NO synthase (eNOS)/iNOS inhibitor] to hypertensive rats induced a major BP rise similar to that caused by L-NAME injection in controls. Aminoguanidine (a selective iNOS inhibitor) caused a substantial BP rise in L-NAME hypertensive rats only. CONCLUSION: The contribution of SNS to BP maintenance in L-NAME hypertension is more important than that of RAS. In L-NAME hypertensive rats the iNOS becomes a major source of hemodynamically important NO production, which is still insufficient to compensate prevailing vasoconstriction.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Hipertensión/fisiopatología , NG-Nitroarginina Metil Éster/administración & dosificación , NG-Nitroarginina Metil Éster/antagonistas & inhibidores , Vasodilatadores/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/fisiopatología , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Guanidinas/administración & dosificación , Guanidinas/antagonistas & inhibidores , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Hipertensión/enzimología , Inyecciones Intravenosas , Masculino , Modelos Cardiovasculares , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/efectos de los fármacos , Óxido Nítrico Sintasa/fisiología , Óxido Nítrico Sintasa de Tipo II , Ratas , Ratas Wistar , Sistema Renina-Angiotensina/efectos de los fármacos , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , Vasodilatadores/administración & dosificaciónRESUMEN
Total genome scan was carried out in 266 F2 intercrosses from the Prague hypertriglyceridemic (HTG) rat that shares several clinical characteristics with human metabolic syndrome. Two loci for plasma triglycerides (TG) were localized on chromosome 2 (Chr 2) (LOD 4.4, 3.2). The first locus overlapped with the rat syntenic region of the human locus for the metabolic syndrome and for small, dense LDL, while the second overlapped with the syntenic region of another locus for small, dense LDL in humans by the comparative mapping approach. Loci for TG on rat Chr 13 (LOD 3.3) and Chr 1 (LOD 2.7) overlapped with the syntenic region of loci for human familial combined hyperlipidemia (FCHL) in Finnish and Dutch populations, respectively. The concordances of loci for TG localized in this study with previously reported loci for FCHL and its related phenotypes are underlying the generalized importance of these loci in dyslipidemia. These data suggest the close relationship between dyslipidemia in HTG rats and human FCHL, establishing a novel animal model for exploration of pathophysiology and therapy based on genomic determinants.
Asunto(s)
Mapeo Cromosómico/métodos , Modelos Animales de Enfermedad , Hiperlipidemia Familiar Combinada/genética , Animales , Colesterol/sangre , Femenino , Ligamiento Genético/genética , Marcadores Genéticos/genética , Pruebas Genéticas/métodos , Genoma , Humanos , Hiperlipidemia Familiar Combinada/sangre , Hiperlipidemia Familiar Combinada/patología , Masculino , Fenotipo , Sitios de Carácter Cuantitativo/genética , Ratas , Ratas Endogámicas Lew , Ratas Wistar , Caracteres Sexuales , Triglicéridos/sangreRESUMEN
Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/genética , Hipertensión/genética , Hipertensión/metabolismo , Carácter Cuantitativo Heredable , Animales , Antihipertensivos/farmacología , Inhibidores Enzimáticos/farmacología , Escala de Lod , Losartán/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/metabolismo , Tartrato de Pentolinio/farmacología , Sitios de Carácter Cuantitativo , Ratas , Ratas Wistar , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
The precise role of nitric oxide (NO) in hypertension is still not fully understood, although this vasodilator system represents the main counterbalance of major pressor systems. The aim of our study was to determine the contributions of superoxide anions, the renin-angiotensin system (RAS), the sympathetic nervous system (SNS) and NO to the maintenance of blood pressure (BP) in Prague hereditary hypertriglyceridaemic (HTG) rats with genetic hypertension. Conscious chronically cannulated rats were subjected to the consecutive blockade of the RAS (losartan, 10 mg/kg), the SNS (pentolinium, 5 mg/kg) and NO synthase [N(omega)-nitro-L-arginine (L-NAME), 30 mg/kg]. Some additional rats were pretreated with tempol (a membrane-permeable mimetic of superoxide dismutase). A subsequent genetic study in HTG x Lewis F(2) hybrid rats (n=284) was designed to reveal potential associations of particular BP components with baseline BP. The progenitor study indicated that BP elevation was more pronounced in male than female HTG rats (as compared with normotensive Lewis controls). Higher BP in HTG rats was due to the increased residual BP (measured after combined RAS and SNS blockade) and the augmentation of BP responses to tempol or losartan. In contrast, BP responses to pentolinium or l-NAME were similar in all experimental groups. It should, however, be noted that the baseline BP of progenitor animals was correlated positively with both residual BP and the magnitude of the BP response to pentolinium, but not with BP response to L-NAME. Similarly, the baseline BP of F(2) hybrid rats was positively associated with residual BP, the BP response to pentolinium and the relative SNS contribution to BP maintenance [expressed as a percentage of baseline mean arterial pressure (MAP) values], as well as with the ratio of BP changes elicited by ganglion blockade and NO synthase inhibition (Delta MAP(pentolinium)/Delta MAP(L-NAME) ratio), reflecting the balance of main vasopressor and vasodepressor systems. Thus our studies, performed in progenitor and F(2) hybrid rats, revealed that changes in BP induced by L-NAME do not keep pace with the progressive augmentation of pentolinium-induced changes in BP occurring over a wide range of increasing BP. The altered balance between enhanced SNS-dependent vasoconstriction and unchanged NO-dependent vasodilation ('relative NO deficiency' in rats with high BP) might result in BP elevation in this form of genetic hypertension.