RESUMO
No information is available about sex-related differences in unloading-induced cardiac atrophy. We aimed to compare the course of unloading-induced cardiac atrophy in intact (without gonadectomy) male and female rats, and in animals after gonadectomy, to obtain insight into the influence of sex hormones on this process. Heterotopic heart transplantation (HT((x)) was used as a model for heart unloading. Cardiac atrophy was assessed as the weight ratio of heterotopically transplanted heart weight (HW) to the native HW on days 7 and 14 after HTx in intact male and female rats. In separate experimental groups, gonadectomy was performed in male and female recipient animals 28 days before HT(x) and the course of cardiac atrophy was again evaluated on days 7 and 14 after HT(x). In intact male rats, HT(x) resulted in significantly greater decreases in whole HW when compared to intact female rats. The dynamics of the left ventricle (LV) and right ventricle (RV) atrophy after HT(x) was quite similar to that of whole hearts. Gonadectomy did not have any significant effect on the decreases in whole HW, LV, and RV weights, with similar results in male and female rats. Our results show that the development of unloading-induced cardiac atrophy is substantially reduced in female rats when compared to male rats. Since gonadectomy did not alter the course of cardiac atrophy after HTx, similarly in both male and female rats, we conclude that sex-linked differences in the development of unloading-induced cardiac atrophy are not caused by the activity of sex hormones.
Assuntos
Transplante de Coração , Coração , Feminino , Masculino , Animais , Ratos , Transplante de Coração/efeitos adversos , Transplante de Coração/métodos , Ventrículos do Coração/patologia , Atrofia/patologia , Hormônios Esteroides Gonadais , Miocárdio/patologiaRESUMO
Spontaneously hypertensive rats (SHR) display deficiency of epoxyeicosatrienoic acids (EETs). Their possible interaction with renal sympathetic nerves remains unexplored; synthesis of EET-A [disodium (S)-2-(13-(3-pentyl)ureido)-tridec-8(Z)-enamido)succinate], a stable 14,15-EET analog, helps clarify the issue. In anesthetized SHR, untreated or pretreated with EET-A, we assessed early responses of blood pressure (MAP), renal hemodynamics and excretion, and indices of nitric oxide (NO) activity, to bilateral noninvasive renal denervation (DNX). DNX significantly decreased MAP, with or without EET-A pretreatment. Renal perfusion decreased in EET-A treated but not in control rats. After EET-A pretreatment DNX decreased renal excretion of sodium and total solutes, compared to increasing tendency in untreated rats. In EET-A treated but not in untreated SHR denervation reduced the excretion of NO metabolites. Antihypertensive action of EET-A in anesthetized SHR was not clearly dependent on renal nerve activity. On the other hand, DNX unmasked the unexpected effect of EET-A to lower renal perfusion. The mechanism of this novel finding is unclear, as is also the simultaneous post-denervation decrease in renal excretion, again, observed only under EET-A treatment. Possibly, the decrease was secondary to falling MAP and renal perfusion. Increased renal excretion of nitric oxide metabolites under EETs elevation strongly suggests facilitation of NO release; the effect that was observed only with intact renal nerve activity.
Assuntos
Anti-Hipertensivos , Hipertensão , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea , Eicosanoides , Hemodinâmica , Hipertensão/metabolismo , Rim/metabolismo , Óxido Nítrico/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Sódio , Succinatos/farmacologiaRESUMO
An important complication of the prolonged left ventricle assist device support in patients with heart failure is unloading-induced cardiac atrophy which proved resistant to various treatments. Heterotopic heart transplantation (HTx) is the usual experimental model to study this process. We showed previously that implantation of the newly designed intraventricular spring expander can attenuate the atrophy when examined after HTx in the failing heart (derived from animals with established heart failure). The present study aimed to examine if enhanced isovolumic loading achieved by implantation of the expander would attenuate cardiac post-HTx atrophy also in the healthy heart. Cardiac atrophy was assessed as the ratio of the transplanted-to-native heart weight (HW) and its degree was determined on days 7, 14, 21 and 28 after HTx. The transplantation resulted in 32±3, 46±2, 48±3 and 46±3 % HW loss when measured at the four time points; implantation of the expander had no significant effect on these decreases. We conclude that enhanced isovolumic loading achieved by intraventricular implantation of the expander does not attenuate the development of cardiac atrophy after HTx in the healthy heart. This indicates that such an approach does not represent a useful therapeutic measure to attenuate the development of unloading-induced cardiac atrophy.
Assuntos
Transplante de Coração/instrumentação , Transplante de Coração/métodos , Coração Auxiliar , Miocárdio/patologia , Transplante Heterotópico/instrumentação , Transplante Heterotópico/métodos , Animais , Atrofia/patologia , Atrofia/cirurgia , Coração/diagnóstico por imagem , Masculino , Ratos , Ratos Endogâmicos LewRESUMO
We found recently that in Ren-2 transgenic hypertensive rats (TGR) addition of soluble epoxide hydrolase inhibitor (sEHi) to treatment with angiotensin-converting enzyme inhibitor (ACEi), surprisingly, increased the mortality due to heart failure (HF) induced by creation of the aorto-caval fistula (ACF). Since TGR exhibit sex-related differences in mortality, we examined here if such differentiation exists also in the response to the treatment with ACEi (trandolapril), alone or combined with sEHi [cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid, (c-AUCB)]. ACEi improved survival in males to 74 % (vs. 0 %) and in females to 65 % (vs. 32 %). ACEi and sEHi combined also improved the survival in male ACF TGR, however, it was significantly less (38 %) than after ACEi alone. In contrast, in females the combined treatment significantly improved the final survival rate (84 %). There were no significant sex-linked differences in survival rate in untreated or treated normotensive Hannover Sprague-Dawley rats. In conclusion, in HF patients with co-existing hypertension and RAS hyperactivity, the sex may co-determine the rate of HF progression, and can influence the effectiveness of the therapeutic measures applied. Therefore, in the relevant pre-clinical studies the sex-linked differences should be seriously considered. Our data indicate that TGR might be an optimal model for such studies.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Epóxido Hidrolases/antagonistas & inibidores , Hipertensão/mortalidade , Renina , Caracteres Sexuais , Fístula Vascular/mortalidade , Animais , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Epóxido Hidrolases/metabolismo , Feminino , Hipertensão/tratamento farmacológico , Hipertensão/genética , Masculino , Mortalidade/tendências , Peptidil Dipeptidase A/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Renina/genética , Resultado do Tratamento , Fístula Vascular/tratamento farmacológico , Fístula Vascular/genéticaRESUMO
The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study we used another model, i.e. Cyp1a1-Ren-2 transgenic rats (iTGR) in which hypertension can be induced by natural xenobiotic indole-3 carbinol (I3C) added to the diet. We investigated whether the development of high blood pressure (BP) in 5-month-old iTGR animals fed I3C diet for 10 days is solely due to enhanced Ang II-dependent vasoconstriction or whether enhanced sympathetic vasoconstriction also participates in BP maintenance in this form of hypertension. Using acute sequential blockade of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and NO synthase (NOS) we have demonstrated that the observed gradual increase of BP in iTGR fed I3C diet was entirely due to the augmentation of Ang II-dependent BP component without significant changes of sympathetic BP component. Thus, the hypertension in iTGR resembles to that of homozygous TGR in which high BP was entirely dependent on Ang II-dependent vasoconstriction. Moreover, our measurements of acute BP response to Rho kinase inhibitor fasudil in animals subjected to a combined blockade of RAS, SNS and NOS indicated the attenuation of basal calcium sensitization in both iTGR and homozygous TGR.
Assuntos
Citocromo P-450 CYP1A1/metabolismo , Hipertensão/fisiopatologia , Renina/metabolismo , Sistema Nervoso Simpático/fisiologia , Angiotensina II/genética , Angiotensina II/metabolismo , Animais , Pressão Sanguínea/fisiologia , Citocromo P-450 CYP1A1/genética , Hipertensão/genética , Masculino , Ratos , Ratos Transgênicos , Renina/genética , Sistema Renina-Angiotensina/fisiologia , Vasoconstrição/fisiologiaRESUMO
Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ET(A)) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ET(A) receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ET(A) blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ET(A) antagonists, at least under certain pathological conditions.
Assuntos
Diuréticos/uso terapêutico , Antagonistas do Receptor de Endotelina A/uso terapêutico , Receptor de Endotelina A/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/prevenção & controle , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Diuréticos/farmacologia , Antagonistas do Receptor de Endotelina A/farmacologia , Endotelina-1/antagonistas & inibidores , Endotelina-1/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologiaRESUMO
We showed recently that increasing kidney epoxyeicosatrienoic acids (EETs) by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, retarded the development of renal dysfunction and progression of aorto-caval fistula(ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). In that study the final survival rate of untreated ACF TGR was only 14 % but increased to 41 % after sEH blockade. Here we examined if sEH inhibition added to renin-angiotensin system (RAS) blockade would further enhance protection against ACF-induced CHF in TGR. The treatment regimens were started one week after ACF creation and the follow-up period was 50 weeks. RAS was blocked using angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 6 mg/l) and sEH with an sEH inhibitor (sEHi, c-AUCB, 3 mg/l). Renal hemodynamics and excretory function were determined two weeks post-ACF, just before the onset of decompensated phase of CHF. 29 weeks post-ACF no untreated animal survived. ACEi treatment greatly improved the survival rate, to 84 % at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53 %). Untreated ACF TGR exhibited marked impairment of renal function and the treatment with ACEi alone or combined with sEH inhibition did not prevent it. In conclusion, addition of sEHi to ACEi treatment does not provide better protection against CHF progression and does not increase the survival rate in ACF TGR: indeed, the rate decreases significantly. Thus, combined treatment with sEHi and ACEi is not a promising approach to further attenuate renal dysfunction and retard progression of CHF.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Benzoatos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Indóis/uso terapêutico , Insuficiência Renal/prevenção & controle , Ureia/análogos & derivados , Animais , Fístula Arteriovenosa , Benzoatos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Epóxido Hidrolases/antagonistas & inibidores , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/mortalidade , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Insuficiência Renal/etiologia , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
The present experiments were performed to evaluate if increased heart tissue concentration of fatty acids, specifically myristic, palmitic and palmitoleic acids that are believed to promote physiological heart growth, can attenuate the progression of unloading-induced cardiac atrophy in rats with healthy and failing hearts. Heterotopic abdominal heart transplantation (HT(x)) was used as a model for heart unloading. Cardiac atrophy was assessed from the ratio of the native- to-transplanted heart weight (HW). The degree of cardiac atrophy after HT(x) was determined on days 7, 14, 21 and 28 after HT(x) in recipients of either healthy or failing hearts. HT(x) of healthy hearts resulted in 23+/-3, 46+/-3, 48+/-4 and 46+/-4 % HW loss at the four time-points. HT(x) of the failing heart resulted in even greater HW losses, of 46+/-4, 58+/-3, 66+/-2 and 68+/-4 %, respectively (P<0.05). Activation of "fetal gene cardiac program" (e.g. beta myosin heavy chain gene expression) and "genes reflecting cardiac remodeling" (e.g. atrial natriuretic peptide gene expression) after HT(x) was greater in failing than in healthy hearts (P<0.05 each time). Exposure to isocaloric high sugar diet caused significant increases in fatty acid concentrations in healthy and in failing hearts. However, these increases were not associated with any change in the course of cardiac atrophy, similarly in healthy and post-HT(x) failing hearts. We conclude that increasing heart tissue concentrations of the fatty acids allegedly involved in heart growth does not attenuate the unloading-induced cardiac atrophy.
Assuntos
Ácidos Graxos Monoinsaturados/metabolismo , Insuficiência Cardíaca/metabolismo , Transplante de Coração/métodos , Ácido Mirístico/metabolismo , Ácido Palmítico/metabolismo , Transplante Heterotópico/métodos , Animais , Insuficiência Cardíaca/cirurgia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ratos , Ratos Endogâmicos LewRESUMO
Drugs interfering with the renin-angiotensin-aldosterone system (RAAS) improved the prognosis in patients with hypertension, heart failure, diabetes and chronic kidney disease. However, combining different drugs brought no further benefit while increasing the risk of hyperkalemia, hypotension and acute renal failure. This was so with combining angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptors type 1 antagonists (ARB). Dissimilarly, in animal disease models this dual therapy proved clearly superior to single drug treatment and became the optimal standard regime for comparison with other treatments. This review analyzes the causes of the discrepancy of effects of the dual therapy between animal experiments versus clinical studies, and is focused on the outcomes in chronic kidney disease. Discussed is the role of species differences in RAAS, of the variability of the disease features in humans versus relative stability in animals, of the genetic uniformity in the animals but not in humans, and of the biased publication habits of experimental versus clinical studies. We attempt to understand the causes and reconcile the discordant findings and suggest to what extent dual RAAS inhibition should be continued in animal experiments and why its application in the clinics should be limited to strictly selected groups of patients.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Modelos Animais de Doenças , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/imunologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/imunologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/prevenção & controle , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Animais , Medicina Baseada em Evidências , Humanos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/imunologia , Hiperpotassemia/prevenção & controle , Hipertensão/induzido quimicamente , Hipertensão/imunologia , Hipertensão/prevenção & controle , Especificidade da Espécie , Resultado do TratamentoRESUMO
Pathophysiological mechanisms underlying the development of renal dysfunction and progression of congestive heart failure (CHF) remain poorly understood. Recent studies have revealed striking differences in the role of epoxyeicosatrienoic acids (EETs), active products of cytochrome P-450-dependent epoxygenase pathway of arachidonic acid, in the progression of aorto-caval fistula (ACF)-induced CHF between hypertensive Ren-2 renin transgenic rats (TGR) and transgene-negative normotensive Hannover Sprague-Dawley (HanSD) controls. Both ACF TGR and ACF HanSD strains exhibited marked intrarenal EETs deficiency and impairment of renal function, and in both strains chronic pharmacologic inhibition of soluble epoxide hydrolase (sEH) (which normally degrades EETs) normalized EETs levels. However, the treatment improved the survival rate and attenuated renal function impairment in ACF TGR only. Here we aimed to establish if the reported improved renal function and attenuation of progression of CHF in ACF TGR observed after she blockade depends on increased vasodilatory responsiveness of renal resistance arteries to EETs. Therefore, we examined the responses of interlobar arteries from kidneys of ACF TGR and ACF HanSD rats to EET-A, a new stable 14,15-EET analog. We found that the arteries from ACF HanSD kidneys rats exhibited greater vasodilator responses when compared to the ACF TGR arteries. Hence, reduced renal vasodilatory responsiveness cannot be responsible for the lack of beneficial effects of chronic sEH inhibition on the development of renal dysfunction and progression of CHF in ACF HanSD rats.
Assuntos
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Insuficiência Cardíaca/fisiopatologia , Hipertensão/fisiopatologia , Rim/irrigação sanguínea , Renina/fisiologia , Vasodilatação/fisiologia , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacologia , Acetilcolina/farmacologia , Animais , Progressão da Doença , Relação Dose-Resposta a Droga , Insuficiência Cardíaca/genética , Hipertensão/genética , Rim/efeitos dos fármacos , Rim/fisiologia , Masculino , Norepinefrina/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Circulação Renal/efeitos dos fármacos , Circulação Renal/fisiologia , Vasodilatação/efeitos dos fármacosRESUMO
The subclass of triglyceride-rich lipoproteins - remnant-like particles (RLP) seems to be strong and independent risk factor for cardiovascular disease. We evaluated the role of RLP and other risk factors (RF) with sonographically measured intima-media thickness of carotid arteries (IMT CCA) in a cohort of Czech population including women defined according to the time after menopause. We investigated relation of IMT CCA to age, weight, central obesity, plasma lipids including remnant-like particles cholesterol (RLP-C) and triglycerides (RLP-TG) in 136 men and 160 women. Using multiple linear regression analysis, significant association between IMT CCA and RLP-C was found in women 1-7 years after menopause. In the whole group of women, only age and fasting blood glucose were independently associated with IMT CCA. In men only age significantly correlated with IMT CCA. Significant decrease of all plasma lipids between 1988 and 1996 in men was detected, while in women significant increase in triglycerides and no change in non-HDL cholesterol was observed. RLP-C was the strongest independent RF for atherosclerosis in postmenopausal women but its association with IMT CCA was limited to several years after menopause. In conclusion, women changing reproductive status could be more sensitive to atherogenic impact of remnant lipoproteins.
Assuntos
Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Espessura Intima-Media Carotídea , Lipoproteínas/sangue , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment with cis-4-[4-(3-adamantan-1-yl-ureido) cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/l in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs to levels observed in sham-operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/l in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue.
Assuntos
Benzoatos/uso terapêutico , Epóxido Hidrolases/antagonistas & inibidores , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Renal/prevenção & controle , Ureia/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/sangue , Ácido 8,11,14-Eicosatrienoico/metabolismo , Angiotensina I/sangue , Angiotensina II/sangue , Inibidores da Enzima Conversora de Angiotensina , Animais , Benzoatos/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Compostos de Epóxi/metabolismo , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico por imagem , Rim/metabolismo , Masculino , Miocárdio/metabolismo , Fragmentos de Peptídeos/sangue , Distribuição Aleatória , Ratos , Insuficiência Renal/sangue , Insuficiência Renal/etiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Ultrassonografia , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
UNLABELLED: Background/Aims . High salt (HS) intake may elevate blood pressure (BP), also in animals without genetic salt sensitivity. The development of salt-dependent hypertension could be mediated by endogenous vasoactive agents; here we examined the role of vasodilator epoxyeicosatrienoic acids (EETs) and vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE). METHODS: In conscious Wistar rats on HS diet systolic BP (SBP) was examined after chronic elevation of EETs using 4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (c-AUCB), a blocker of soluble epoxide hydrolase, or after inhibition of 20-HETE with 1-aminobenzotriazole (ABT). Thereafter, in acute experiments the responses of renal artery blood flow (Transonic probe) and renal regional perfusion (laser-Doppler) to intrarenal acetylcholine (ACh) or norepinephrine were determined. RESULTS: HS diet increased urinary 20-HETE excretion. The SBP increase was not reduced by c-AUCB but prevented by ABT until day 5 of HS exposure. Renal vasomotor responses to ACh or norepinephrine were similar on standard and HS diet. ABT but not c-AUCB abolished the responses to ACh. Conclusions . 20-HETE seems to mediate the early-phase HS diet-induced BP increase while EETs are not engaged in the process. Since HS exposure did not alter renal vasodilator responses to Ach, endothelial dysfunction is not a critical factor in the mechanism of salt-induced blood pressure elevation.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Ácidos Hidroxieicosatetraenoicos/metabolismo , Circulação Renal/efeitos dos fármacos , Sódio na Dieta/efeitos adversos , Acetilcolina/metabolismo , Animais , Pressão Arterial , Epóxido Hidrolases/sangue , Ácidos Hidroxieicosatetraenoicos/antagonistas & inibidores , Masculino , Óxido Nítrico/fisiologia , Norepinefrina/metabolismo , Concentração Osmolar , Ratos , Ratos Wistar , Triazóis/farmacologiaRESUMO
Acute liver failure (ALF) is a clinical syndrome resulting from widespread damage of hepatocytes, with extremely high mortality rate. Urgent orthotopic liver transplantation was shown to be the most effective therapy for ALF but this treatment option is limited by scarcity of donor organs. Therefore, hepatocyte transplantation (Tx) has emerged as a new therapeutical measure for ALF, however, the first clinical applications proved unsatisfactory. Apparently, extensive preclinical studies are needed. Our aim was to examine if hepatocytes isolated from transgenic "firefly luciferase" Lewis rats into the recipient liver would attenuate the course of thioacetamide (TAA)-induced ALF in Lewis rats. Untreated Lewis rats after TAA administration showed a profound decrease in survival rate; no animal survived 54 h. The rats showed marked increases in plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, in plasma level of bilirubin and ammonia (NH(3)), and in a significant decrease in plasma albumin. Hepatocyte Tx attenuated the course of TAA-induced ALF Lewis rats which was reflected by improved survival rate and reduced degree of liver injury showing as lowering of elevated plasma ALT, AST, NH(3) and bilirubin levels and increasing plasma albumin. In addition, bioluminescence imaging analyses have shown that in the TAA-damaged livers the transplanted hepatocyte were fully viable throughout the experiment. In conclusion, the results show that hepatocyte Tx into the liver can attenuate the course of TAA-induced ALF in Lewis rats. This information should be considered in attempts to develop new therapeutic approaches to the treatment of ALF.
Assuntos
Transplante de Células/métodos , Hepatócitos/transplante , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/terapia , Tioacetamida/toxicidade , Animais , Falência Hepática Aguda/mortalidade , Masculino , Ratos , Ratos Endogâmicos Lew , Taxa de Sobrevida/tendênciasRESUMO
The aim of the present study was to test the hypothesis that chronic hypoxia would aggravate hypertension in Ren-2 transgenic rats (TGR), a well-defined monogenetic model of hypertension with increased activity of endogenous renin-angiotensin system (RAS). Systolic blood pressure (SBP) in conscious rats and mean arterial pressure (MAP) in anesthetized TGR and normotensive Hannover Sprague-Dawley (HanSD) rats were determined under normoxia that was either continuous or interrupted by two weeks´ hypoxia. Expression, activities and concentrations of individual components of RAS were studied in plasma and kidney of TGR and HanSD rats under normoxic conditions and after exposure to chronic hypoxia. In HanSD rats two weeks´ exposure to chronic hypoxia did not alter SBP and MAP. Surprisingly, in TGR it decreased markedly SBP and MAP; this was associated with substantial reduction in plasma and kidney renin activities and also of angiotensin II (ANG II) levels, without altering angiotensin-converting enzyme (ACE) activities. Simultaneously, in TGR the exposure to hypoxia increased kidney ACE type 2 (ACE2) activity and angiotensin 1-7 (ANG 1-7) concentrations as compared with TGR under continuous normoxia. Based on these results, we propose that suppression of the hypertensiogenic ACE-ANG II axis in the circulation and kidney tissue, combined with augmentation of the intrarenal vasodilator ACE2-ANG 1-7 axis, is the main mechanism responsible for the blood pressure-lowering effects of chronic hypoxia in TGR.
Assuntos
Angiotensina II/sangue , Angiotensina I/sangue , Hipertensão/prevenção & controle , Hipóxia/complicações , Rim/enzimologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/sangue , Proteínas Proto-Oncogênicas/sangue , Receptores Acoplados a Proteínas G/sangue , Sistema Renina-Angiotensina , Renina/sangue , Vasoconstrição , Vasodilatação , Fatores Etários , Enzima de Conversão de Angiotensina 2 , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Hipertensão/sangue , Hipertensão/genética , Hipertensão/fisiopatologia , Hipóxia/enzimologia , Hipóxia/fisiopatologia , Proto-Oncogene Mas , Ratos Sprague-Dawley , Ratos Transgênicos , Renina/genética , Transdução de SinaisRESUMO
The present study was performed to evaluate the role of intrapulmonary activity of the two axes of the renin-angiotensin system (RAS): vasoconstrictor angiotensin-converting enzyme (ACE)/angiotensin II (ANG II)/ANG II type 1 receptor (AT1) axis, and vasodilator ACE type 2 (ACE2)/angiotensin 1-7 (ANG 1-7)/Mas receptor axis, in the development of hypoxic pulmonary hypertension in Ren-2 transgenic rats (TGR). Transgene-negative Hannover Sprague-Dawley (HanSD) rats served as controls. Both TGR and HanSD rats responded to two weeks´ exposure to hypoxia with a significant increase in mean pulmonary arterial pressure (MPAP), however, the increase was much less pronounced in the former. The attenuation of hypoxic pulmonary hypertension in TGR as compared to HanSD rats was associated with inhibition of ACE gene expression and activity, inhibition of AT1receptor gene expression and suppression of ANG II levels in lung tissue. Simultaneously, there was an increase in lung ACE2 gene expression and activity and, in particular, ANG 1-7 concentrations and Mas receptor gene expression. We propose that a combination of suppression of ACE/ANG II/AT1receptor axis and activation of ACE2/ANG 1-7/Mas receptor axis of the RAS in the lung tissue is the main mechanism explaining attenuation of hypoxic pulmonary hypertension in TGR as compared with HanSD rats.
Assuntos
Angiotensina I/metabolismo , Hipertensão Pulmonar/prevenção & controle , Hipóxia/complicações , Pulmão/enzimologia , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina , Renina/metabolismo , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Animais , Pressão Arterial , Modelos Animais de Doenças , Hipertensão Pulmonar/enzimologia , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/enzimologia , Hipóxia/fisiopatologia , Proto-Oncogene Mas , Ratos Sprague-Dawley , Ratos Transgênicos , Receptor Tipo 1 de Angiotensina/metabolismo , Renina/genética , Transdução de Sinais , Vasoconstrição , VasodilataçãoRESUMO
Ventricular assist devices (VAD) have recently established themselves as an irreplaceable therapeutic modality of terminal heart failure. Because of the worldwide shortage of donors, ventricular assist devices play a key role in modern heart failure therapy. Some clinical data have revealed the possibility of cardiac recovery during VAD application. On the other hand, both clinical and experimental studies indicate the risk of the cardiac atrophy development, especially after prolonged mechanical unloading. Little is known about the specific mechanisms governing the unloading-induced cardiac atrophy and about the exact ultrastructural changes in cardiomyocytes, and even less is known about the ways in which possible therapeutical interventions may affect heart atrophy. One aim of this review was to present important aspects of the development of VAD-related cardiac atrophy in humans and we also review the most significant observations linking clinical data and those derived from studies using experimental models. The focus of this article was to review current methods applied to alleviate cardiac atrophy which follows mechanical unloading of the heart. Out of many pharmacological agents studied, only the selective beta2 agonist clenbuterol has been proved to have a significantly beneficial effect on unloading-induced atrophy. Mechanical means of atrophy alleviation also seem to be effective and promising.
Assuntos
Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Agonistas Adrenérgicos beta/uso terapêutico , Animais , Atrofia/etiologia , Atrofia/patologia , Atrofia/terapia , Clembuterol/uso terapêutico , Insuficiência Cardíaca/patologia , HumanosRESUMO
Sorption isotherms of elecampe (Inula helenium L.) and burdock (Arctium lappa L.) root samples were obtained at 25 °C. Elecampe exhibited hysteresis loop in the range of 0.35-0.90 a(w) , whereas burdock roots showed significant differences between adsorption and desorption isotherms from 0.65 to 0.80 a(w) . Blahovec-Yanniotis was considered to give the best fit over the whole range of a(w) tested. Various parameters describing the properties of sorbed water derived from GAB, Henderson and Blahovec-Yanniotis models have been discussed. Differential scanning calorimetric method was used to measure the glass transition temperature (T (g)) of root samples in relation to water activity. The safe moisture content was determined in 12.01 and 14.96 g/100 g d. b. for burdock and elecampe root samples at 25 °C, respectively. Combining the T (g) line with sorption isotherm in one plot, it was found that the glass transition temperature concept overestimated the temperature stability for both root samples.
Assuntos
Arctium/química , Inula/química , Raízes de Plantas/química , Temperatura de Transição , Adsorção , Varredura Diferencial de Calorimetria/métodos , Fenômenos Químicos , Armazenamento de Alimentos/métodos , Modelos Teóricos , Água/químicaRESUMO
The relationship between angiotensin II (ANG II) and endothelin-1 (ET-1) is known to be complex; both peptides can initiate and potentiate the gene expression of each other. This pilot study investigated the effects of the AT(1) receptor blocker losartan or the direct renin inhibitor aliskiren on mean arterial pressure (MAP) and albuminuria and the renal ANG II and ET-1 levels. 3-month-old male Ren-2 transgenic rats (TGR) were treated either with losartan (5 mg kg(-1) day(-1)) or aliskiren (10 mg kg(-1) day(-1)) for 10 weeks. At the end of the experiment, rats were decapitated and cortical and papillary parts of kidneys were separated. Plasma and tissue ANG II levels were measured by RIA and tissue ET-1 concentrations by ELISA. In all four groups of animals ET-1 levels were lowest in renal cortex and more than 100-fold higher in the papilla. Cortical and papillary ET-1 concentrations in untreated TGR significantly exceeded those of control HanSD rats and were significantly depressed by both drugs. In both strains, papillary ANG II concentrations were moderately but significantly higher than cortical ANG II, TGR exhibited higher ANG II levels both in cortex and papilla as compared to control HanSD rats. Aliskiren and losartan at the doses used depressed similarly the levels of ANG II in cortex and papilla and reduced ET-1 significantly in the renal cortex and papilla below control levels in HanSD rats. Albuminuria, which was more than twice as high in TGR as in HanSD rats, was normalized with aliskiren and reduced by 28% with losartan, although MAP was reduced to a similar degree by both drugs. Despite similar reductions of MAP and renal ET-1 and ANG II levels aliskiren appears to be more effective than losartan, at the doses used, in reducing albuminuria in heterozygous hypertensive Ren-2 rats.
Assuntos
Albuminúria/tratamento farmacológico , Amidas/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina II/metabolismo , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Endotelina-1/metabolismo , Fumaratos/farmacologia , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Losartan/farmacologia , Renina/genética , Albuminúria/genética , Albuminúria/metabolismo , Albuminúria/fisiopatologia , Angiotensina II/sangue , Animais , Modelos Animais de Doenças , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Projetos Piloto , Radioimunoensaio , Ratos , Ratos Transgênicos , Fatores de TempoRESUMO
Renin-angiotensin system (RAS) plays a key role in the regulation of renal function, volume of extracellular fluid and blood pressure. The activation of RAS also induces oxidative stress, particularly superoxide anion (O(2)(-)) formation. Although the involvement of O(2)(-) production in the pathology of many diseases is known for long, recent studies also strongly suggest its physiological regulatory function of many organs including the kidney. However, a marked accumulation of O(2)(-) in the kidney alters normal regulation of renal function and thus may contribute to the development of salt-sensitivity and hypertension. In the kidney, O(2)(-) acts as vasoconstrictor and enhances tubular sodium reabsorption. Nitric oxide (NO), another important radical that exhibits opposite effects than O(2)(-), is also involved in the regulation of kidney function. O(2)(-) rapidly interacts with NO and thus, when O(2)(-) production increases, it diminishes the bioavailability of NO leading to the impairment of organ function. As the activation of RAS, particularly the enhanced production of angiotensin II, can induce both O(2)(-) and NO generation, it has been suggested that physiological interactions of RAS, NO and O(2)(-) provide a coordinated regulation of kidney function. The imbalance of these interactions is critically linked to the pathophysiology of salt-sensitivity and hypertension.