RESUMEN
Anti-Vel is an uncommon antibody to a high-prevalence antigen. Its clinical significance and management in the prenatal setting are not well characterized. We present a case that demonstrates the utility of serial prenatal anti-Vel quantitative serologic monitoring with 2-ME serum treatment during pregnancy. The patient is a 23-year-old Hispanic woman with history of prior pregnancy and prior transfusion who was discovered to have an antibody to the high-prevalence Vel antigen in the first trimester (week 7) of her second pregnancy. Interval measurements of the serologic antibody titers were performed during the next 26 weeks. The untreated serum (IgM and IgG) titer increased from a baseline of 4 to 16 during that interval, while the 2-ME (presumed IgG component) titer remained stable at 4. Responding to ultrasound findings suspicious for fetal anemia, the child was delivered without complications at 34 weeks' gestation. At birth, the DAT was negative and there was no evidence of HDN. Placed in the context of other similar reports, this case demonstrates the importance of separately reporting the IgG fraction (after either DTT treatment or 2-ME treatment) from the untreated (IgM and IgG) fraction and the importance of correlating the treated serum titer with potential clinical significance.
Asunto(s)
Antígenos de Grupos Sanguíneos/inmunología , Eritroblastosis Fetal/prevención & control , Isoanticuerpos/sangre , Atención Prenatal , Anemia/sangre , Anemia/diagnóstico por imagen , Anemia/genética , Especificidad de Anticuerpos , Cesárea , Ditiotreitol/farmacología , Procedimientos Quirúrgicos Electivos , Eritroblastosis Fetal/sangre , Femenino , Sangre Fetal/inmunología , Enfermedades Fetales/sangre , Enfermedades Fetales/diagnóstico por imagen , Enfermedades Fetales/genética , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Recién Nacido , Masculino , Mercaptoetanol/farmacología , Embarazo , Suero/efectos de los fármacos , Suero/inmunología , Ultrasonografía Prenatal , Adulto JovenRESUMEN
This case study on a 54-year-old woman shows the exact progression of one abdominal lipolysis treatment with a phosphatidylcholine compound mixture. The mixture consists of phosphatidylcholine 50 mg/mL, NaCl 0.9% as diluent (50%), buflomedil (in a concentration of 5%), and vitamin B complexes (B2, B3, B6; 1%). The patient's weight, blood values, ultrasound findings, measurement, and histologic findings before the treatment, shortly after treatment, and 3 days, 10 days, 4 weeks, and 8 weeks after treatment are documented.
RESUMEN
Endothelial dysfunction, as observed in hypertension and atherosclerosis, is associated with a reduction in the bioavailability of endothelium-derived nitric oxide (NO). We tested the hypothesis that alterations in the soluble guanylyl cyclase (sGC) pathway may also contribute to the pathogenesis of hypertension. Therefore, we investigated the expression and activity of sGC in young (6 weeks) and aging (17 months) spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto rats (WKY). Endothelium-independent relaxation of aortic rings in response to the sGC activator YC-1 was attenuated in SHR, and expression of both alpha(1) and beta(1) subunits of heterodimeric sGC and the basal contents of cGMP were reduced specifically in SHR aorta. Moreover, mRNA expression of the cGMP receptor and effector protein cGMP-dependent protein kinase type Ialpha (cGKIalpha) was also reduced. Interestingly, downregulation of both sGC and cGKIalpha expression was observed in young, ie, normotensive SHR, whereas impairment of the endothelium-independent relaxation was found only in aging SHR. Accordingly, similar cGMP levels were reached in response to YC-1 in young SHR and young WKY, suggesting a compensatory increased sensitivity or effectiveness of the sGC pathway in young SHR. In aging SHR, however, increased sensitivity to YC-1 no longer compensated for the impairment of endothelium-independent relaxation, suggesting that other mechanisms were involved. In fact, endothelium-independent relaxations were partially restored by superoxide dismutase, suggesting a pathophysiological role of superoxide production, particularly at later disease stages. Thus, tissue-specific downregulation of components of the sGC/cGMP pathway is an early event in the pathogenesis of hypertension.
Asunto(s)
Envejecimiento/metabolismo , Animales Recién Nacidos/metabolismo , Guanilato Ciclasa/metabolismo , Hipertensión/metabolismo , Ratas Endogámicas SHR/metabolismo , Animales , Animales Recién Nacidos/crecimiento & desarrollo , Animales Recién Nacidos/fisiología , Aorta/fisiología , Aorta Torácica/enzimología , GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/genética , Endotelio Vascular/fisiopatología , Hipertensión/fisiopatología , Técnicas In Vitro , Isoenzimas/metabolismo , Masculino , Miocardio/enzimología , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas SHR/fisiología , Ratas Endogámicas WKY , Solubilidad , Distribución Tisular , VasodilataciónRESUMEN
In ischemia, the heart generates and releases kinins as mediators that seem to have cardioprotective actions. Kinin-generating pathways are present in the heart. Kininogen, kininogenases, kinins, and B2 kinin receptors can be measured in cardiac tissue. Kinins are released under conditions of ischemia. In anesthetized rats and dogs with coronary artery ligation and in human patients with myocardial infarction, kinin plasma levels are increased. In isolated rat hearts, the outflow of kinins is enhanced during ischemia but markedly attenuated after deendothelialization, pointing to the coronary vascular endothelium as the main possible source. Kinins administered locally exert beneficial cardiac effects. In isolated rat hearts with ischemia-reperfusion injuries, perfusion with bradykinin (BK) reduces the duration and incidence of ventricular fibrillation, improves cardiodynamics, reduces release of cytosolic enzymes, and preserves energy-rich phosphates and glycogen stores. In anesthetized animals, intracoronary BK is followed by comparable beneficial changes and limits infarct size. Inhibition of breakdown of BK and related peptides induces beneficial cardiac effects. Treatment with ACE inhibitors such as ramipril increases cardiac kinin levels and reduces post-ischemic reperfusion injuries in isolated rat hearts and infarct size in anesthetized animals. The importance of an intact endothelium that continuously generates kinins is supported by observations that basal and ramipril-induced release of kinins and PGI2 is markedly reduced after deendothelialization of isolated hearts. Blockade of B2 kinin receptors increases ischemia-induced effects. Endothelial formation of NO and PGI2 by ACE inhibition is prevented by the specific B2 kinin receptor antagonist icatibant. In isolated hearts, ischemia-reperfusion injuries deteriorate with icatibant, which also abolishes the cardioprotective effects of ACE inhibitors and of exogenous BK. Infarct size reduction by ACE inhibitors and by BK in anesthetized animals is reversed by icatibant. Kinins contribute to the cardioprotective effects associated with ischemic preconditioning because preconditioning or BK-induced antiarrhythmic and infarct size-limiting effects are attenuated by icatibant. In conclusion, kinins may act as mediators of endogenous cardioprotective mechanisms. Kinins are generated and released during ischemia, with subsequent formation of PGI2 and NO probably derived mainly from the coronary vascular endothelium. Their cardioprotective profile resembles that of ACE inhibitors.
Asunto(s)
Bradiquinina/fisiología , Isquemia Miocárdica/fisiopatología , Miocardio/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas de los Receptores de Bradiquinina , Circulación Coronaria , Perros , Humanos , Conejos , RatasRESUMEN
Congestive heart failure (CHF) is one of the most common causes of death in western countries. The aim of this study was to establish and validate the working heart model in rat hearts with CHF. In the rat model the animals show parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure. The focus of attention was the evaluation of cardiodynamics (e.g.contractility) in the isolated 'working heart' model. The geometric properties of the left ventricle were measured by planimetry (stereology). Formulae available in the past for determining certain parameters in the working heart model (e.g.external heart work) have to be fitted to the circumstances of the infarcted rat hearts with its different organ properties.CHF was induced in Wistar Kyoto (WKY/NHsd) and spontaneously hypertensive rats (SHR/NHsd) by creating a permanent (8 week) occlusion of the left coronary artery, 2 mm distal to the origin from the aorta, by a modified technique (Itter et al. 2004). This resulted in a large infarction of the free left ventricular wall. We were able to establish and adapt a new and predictive working heart model in spontaneously hypertensive rat hearts with myocardial infarction (MI) 8-12 weeks after coronary artery ligation. At this stage the WKY rat did not show any symptoms of CHF. The SHR rat represented characteristic parameters and symptoms that could be extrapolated to the clinical situation of patients with end-stage heart failure (NYHA III-IV). Upon inspection, severe clinical symptoms of CHF such as dyspnoea, subcutaneous oedema, palebluish limbs and impaired motion were prominent. On necropsy the SHR showed lung oedema, hydrothorax, large dilated left and right ventricular chambers and hypertrophy of the septum. In the working heart model the infarcted animals showed reduced heart power, diminished contractility and enhanced heart work, much more so in the SHR/NHsd than in the Wistar Kyoto rat (WKY/NHsd). The aim for the future is to find a causal therapy of heart failure treatment. At present, only palliative therapy is possible for patients with heart failure. For this reason the working heart model in CHF rat hearts should provide a valuable method for early testing of new therapeutic approaches for patients with CHF.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca/fisiopatología , Contracción Miocárdica/fisiología , Infarto del Miocardio/fisiopatología , Función Ventricular , Animales , Presión Sanguínea , Gasto Cardíaco , Vasos Coronarios/patología , Frecuencia Cardíaca , Ligadura/métodos , Masculino , Ratas , Ratas Endogámicas SHR , Ratas WistarRESUMEN
OBJECTIVE: The aim was to characterise the new compound HOE642 as a selective and cardioprotective Na+/H+ exchange inhibitor in various models. METHODS: The effect of HOE642 was tested in the osmotically activated Na+/H+ exchange of rabbit erythrocytes and in propionate induced swelling of human thrombocytes. Recovery of pH after an NH4Cl prepulse and effects on other ion transport systems by patch clamp technique were investigated in rat cardiomyocytes. NHE subtype specifity of the compound was determined by 22Na+ uptake inhibition in a fibroblast cell line separately expressing subtype isoforms 1-3. Protective effects of HOE642 in cardiac ischaemia and reperfusion by ligation of coronary artery were investigated in isolated working rat hearts and in anaesthetised rats. RESULTS: HOE642 concentration dependently inhibited the amiloride sensitive sodium influx in rabbit erythrocytes, reduced the swelling of human platelets induced by intracellular acidification, and delayed pH recovery in rat cardiomyocytes. In the isolated working rat heart subjected to ischaemia and reperfusion HOE642 dose dependently reduced the incidence and the duration of reperfusion arrhythmias. It also reduced the the release of lactate dehydrogenase and creatine kinase, and preserved the tissue content of glycogen, ATP, and creatine phosphate. In anaesthetised rats undergoing coronary artery ligation intravenous and oral pretreatment with HOE642 caused a dose dependent reduction or a complete prevention of ventricular premature beats, ventricular tachycardia, and ventricular fibrillation. The compound was well tolerated and neutral to circulatory variables. Other cardiovascular agents tested in this model were not, or were only partly, effective at doses showing marked cardiodepressive effects. CONCLUSIONS: HOE642 is a very selective NHE subtype 1 inhibitor showing cardioprotective and antiarrhythmic effects in ischaemic and reperfused hearts. Further development of well tolerated compounds like HOE642 could lead to a new therapeutic approach in clinical indications related to cardiac ischaemia and reperfusion.
Asunto(s)
Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Eritrocitos/citología , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Guanidinas/farmacología , Concentración de Iones de Hidrógeno , Masculino , Miocardio/citología , Miocardio/metabolismo , Perfusión , Conejos , Ratas , Ratas Sprague-Dawley , Intercambiadores de Sodio-Hidrógeno/metabolismo , Sulfonas/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: The cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary hypertension and ischaemia reperfusion-induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents. EXPERIMENTAL APPROACH: A library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca(2+) levels. The lead compound SAR7334 was further characterized by whole-cell patch-clamp techniques. The effects of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic BP were investigated. KEY RESULTS: SAR7334 inhibited TRPC6, TRPC3 and TRPC7-mediated Ca(2+) influx into cells with IC50 s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC5-mediated Ca(2+) entry was not affected. Patch-clamp experiments confirmed that the compound blocked TRPC6 currents with an IC50 of 7.9 nM. Furthermore, SAR7334 suppressed TRPC6-dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short-term study, SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR). CONCLUSIONS AND IMPLICATIONS: Our results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR. SAR7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo.
Asunto(s)
Diglicéridos/farmacología , Descubrimiento de Drogas , Indanos/farmacología , Canales Catiónicos TRPC/antagonistas & inhibidores , Células Cultivadas , Diglicéridos/síntesis química , Diglicéridos/química , Relación Dosis-Respuesta a Droga , Humanos , Indanos/síntesis química , Indanos/química , Datos de Secuencia Molecular , Estructura Molecular , Relación Estructura-Actividad , Canales Catiónicos TRPC/metabolismoRESUMEN
Young (approximately 1 month old) male normotensive Wistar-Kyoto rats (n=26) and spontaneously hypertensive rats (n=38) were randomized into three groups treated via drinking water for approximately 2 years with, respectively, placebo, low doses, or high doses of an angiotensin-converting enzyme inhibitor, ramipril (10 microg x kg[-1] x d[-1], non-blood pressure-lowering dose, or 1 mg x kg[-1] x d[-1], blood pressure-lowering dose). Relative to placebo treatment in each respective rat strain, both ramipril dosages increased endothelial constitutive nitric oxide synthase expression (Western blot) and resultant synthesis of nitric oxide (porphyrinic sensor) in freshly excised carotids and thoracic aortas, respectively. Paradoxically, this activity was associated with an increased/decreased superoxide accumulation (chemiluminescence) in freshly excised aortas from 24-/22-month-old normotensive/hypertensive rats. In normotensive rats, relative to placebo treatment, the threefold increase in superoxide accumulation with antihypertensive ramipril treatment is most likely from the >300% increase in endothelial constitutive nitric oxide synthase expression (some of which may be disarranged by local insufficiencies in L-arginine or tetrahydrobiopterin). In hypertensive rats, relative to placebo treatment, the 35% increase in nitric oxide availability by long-term antihypertensive ramipril treatment may contribute to the preservation of the endothelium and prevent its dysfunction by inhibiting superoxide production. Increased nitric oxide production with concomitant decreased superoxide accumulation (approximately one third of placebo levels) correlates positively with the previously reported +40% life span extension for rats with genetic hypertension that were treated with antihypertensive doses of ramipril.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Hipertensión/metabolismo , Óxido Nítrico/metabolismo , Superóxidos/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Calcimicina/farmacología , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Óxido Nítrico Sintasa/metabolismo , Ramipril/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Valores de ReferenciaRESUMEN
In this study, we investigated the outcome of lifelong treatment with the angiotensin II type 1 receptor (AT(1)) blocker fonsartan (HR 720) in young stroke-prone spontaneously hypertensive rats (SHR-SP). In addition to the primary end point, lifespan, and to determine the mechanisms involved in the treatment-induced effects, parameters such as left ventricular hypertrophy, cardiac function/metabolism, endothelial function, and the expression/activity of endothelial nitric oxide synthase and of angiotensin-converting enzyme (ACE) were also investigated. Ninety 1-month-old SHR-SP were allotted to 2 groups and treated via drinking water with an antihypertensive dose of fonsartan (10 mg. kg(-1). d(-1)) or placebo. Fonsartan doubled the lifespan to 30 months in SHR-SP, which was comparable to the lifespan of normotensive Wistar-Kyoto rats. After 15 months, a time when approximately 80% of the placebo group had died, left ventricular hypertrophy was completely prevented in fonsartan-treated animals. Furthermore, cardiac function and metabolism as well as endothelial function were significantly improved. These effects were correlated with increased endothelial nitric oxide synthase expression in the heart and carotid artery and with markedly decreased tissue ACE expression/activities. Lifespan extension and cardiovascular protection by long-term AT(1) blockade with fonsartan led to similar beneficial effects, as observed with long-term ACE inhibition.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Imidazoles/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Compuestos de Bifenilo/uso terapéutico , Hipertensión/metabolismo , Imidazoles/uso terapéutico , Longevidad/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores de Angiotensina/metabolismoRESUMEN
In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B2) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT1) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dtmax) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT1 receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT1 receptors are discussed to explain the cardiac and vascular actions of losartan.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/farmacología , Vasos Sanguíneos/efectos de los fármacos , Corazón/efectos de los fármacos , Imidazoles/farmacología , Ratas Endogámicas SHR/fisiología , Tetrazoles/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Agua Corporal/metabolismo , Peso Corporal/efectos de los fármacos , Trastornos Cerebrovasculares/genética , Ingestión de Líquidos/efectos de los fármacos , Predisposición Genética a la Enfermedad , Corazón/fisiopatología , Losartán , Masculino , Miocardio/metabolismo , Miocardio/patología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas SHR/genética , Ratas Wistar , Factores de TiempoRESUMEN
We have previously established the existence of atrial natriuretic factor (ANF) gene expression within the renal parenchyma. Neither the role nor the regulation of this extracardiac source of ANF is clearly defined. To determine whether renal ANF gene expression, similar to cardiac expression, is linked to the activity of the renin-angiotensin system (RAS), we compared renal ANF gene expression in rats after suprarenal aortic banding, a hypertension model associated with activation of RAS, and in the deoxycorticosterone acetate (DOCA)-salt model, which is characterized by depression of RAS. Renal ANF mRNA was measured with a quantitative competitive reverse transcription polymerase chain reaction method. DOCA-salt hypertension significantly reduced the expression of renal ANF. In contrast, aortic banding significantly increased renal ANF expression. In both cases, ANF gene expression in the heart increased. Ramipril treatment at 10 micrograms/kg of aortic-banded rats, a treatment that specifically affects local RAS but maintains hypertension, normalized renal ANF mRNA levels. Altogether, these results suggest that renal ANF gene expression is modulated by local RAS and is independent of circulating RAS and hypertension per se. The marked decrease of renal ANF mRNA in DOCA-salt hypertension suggests a pathogenic role for renal ANF gene downregulation by decreasing the sodium excretory mechanism mediated by the local expression of ANF acting on receptors found in the inner medullary collecting ducts. In aortic banding, renal ANF gene expression upregulation suggests a local compensatory function consistent with the consensus role of natriuretic peptides in the modulation of RAS, thus ameliorating the sodium-retaining effects of renal underperfusion.
Asunto(s)
Factor Natriurético Atrial/genética , Regulación de la Expresión Génica , Hipertensión/genética , Riñón/metabolismo , Animales , Aorta Abdominal , Presión Sanguínea , Peso Corporal , Desoxicorticosterona , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Tamaño de los Órganos , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Renina/sangre , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sodio en la Dieta , Transcripción GenéticaRESUMEN
Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in beta-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to beta-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G(s alpha) protein and beta-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G(i alpha) was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G(i alpha) and the extent of post-MI remodeling in WKY. A similar correlation between G(i alpha) and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G(i alpha) could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gi-Go/fisiología , Hipertensión/complicaciones , Hipertrofia Ventricular Izquierda/fisiopatología , Infarto del Miocardio/fisiopatología , Animales , Factor Natriurético Atrial/biosíntesis , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/análisis , Subunidades alfa de la Proteína de Unión al GTP Gs/análisis , Técnicas In Vitro , Masculino , Contracción Miocárdica , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores Adrenérgicos beta/análisisRESUMEN
A stimulated brain renin-angiotensin system has been implicated in genetic hypertension. We compared the effects of an intracerebroventricular injection of angiotensin II (100 ng) on the expression of inducible transcription factors c-Fos, c-Jun, and Krox-24 in the brain of spontaneously hypertensive rats (SHR). in Wistar rats with nephrogenic hypertension induced by aortic banding, and in normotensive Wistar-Kyoto and Wistar rats immunohistochemically. Generally, the angiotensin II-induced transcription factor expression was strictly confined to four distinct forebrain areas: the subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus. In SHR, the angiotensin II-induced c-Fos and c-Jun expressions were significantly enhanced compared with those in normotensive control strains as well as in secondary hypertensive Wistar rats. Krox-24 expression in the subfornical organ, median preoptic area, and paraventricular nucleus of SHR was also significantly increased compared with that in all control strains. In the supraoptic nucleus, significant differences could be discriminated between SHR and secondary hypertensive Wistar rats. Injection of isotonic saline or arginine vasopressin (100 ng) as controls did not induce any expression of c-Fos, c-Jun, or Krox-24. Our findings demonstrate an enhanced sensitivity of SHR to angiotensin II-induced transcription factor expression in distinct brain areas involved in central blood pressure and osmotic control that is independent of blood pressure.
Asunto(s)
Angiotensina II/farmacología , Proteínas de Unión al ADN/metabolismo , Hipertensión/metabolismo , Proteínas Inmediatas-Precoces , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , Factores de Transcripción/metabolismo , Antagonistas de Receptores de Angiotensina , Animales , Arginina Vasopresina/farmacología , Compuestos de Bifenilo/farmacología , Presión Sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas de Unión al ADN/efectos de los fármacos , Proteína 1 de la Respuesta de Crecimiento Precoz , Imidazoles/farmacología , Inmunohistoquímica , Inyecciones Intraventriculares , Losartán , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Wistar , Tetrazoles/farmacología , Factores de Transcripción/efectos de los fármacosRESUMEN
The effect of chronic low- and high-dose treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril (0.01 and 1 mg/kg per day) on the development of hypertension and left ventricular hypertrophy as well as on functional and biochemical alterations of the heart was studied in stroke-prone spontaneously hypertensive rats treated prenatally and subsequently up to the age of 20 weeks. The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment of rats with the bradykinin B2-receptor antagonist Hoe 140 (500 micrograms/kg per day SC) from 6 to 20 weeks of age. High- but not low-dose ACE inhibitor treatment prevented the development of hypertension and left ventricular hypertrophy. Chronic bradykinin receptor blockade did not attenuate the antihypertensive and antihypertrophic actions of ramipril. High-dose ramipril treatment improved cardiac function, as demonstrated by an increase in left ventricular pressure (29.9%), dP/dtmax (34.9%), and coronary flow (22.1%), without a change in heart rate. The activities of lactate dehydrogenase and creatine kinase and lactate concentration in the coronary effluent were reduced by 39.3%, 55.5%, and 66.7%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 31.3%, 39.9%, and 73.7%, respectively, whereas lactate was decreased by 20.8%. Chronic low-dose ACE inhibitor treatment led to a pattern of changes in cardiodynamics and cardiac metabolism similar to that observed with the high dose. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by chronic bradykinin receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Bradiquinina/fisiología , Corazón/efectos de los fármacos , Hipertensión/prevención & control , Hipertrofia Ventricular Izquierda/prevención & control , Ramipril/uso terapéutico , Adenosina Trifosfato/metabolismo , Administración Oral , Animales , Bradiquinina/análogos & derivados , Bradiquinina/antagonistas & inhibidores , Bradiquinina/farmacología , Bradiquinina/uso terapéutico , Trastornos Cerebrovasculares/etiología , Circulación Coronaria/efectos de los fármacos , Creatina Quinasa/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Glucógeno/metabolismo , Corazón/fisiopatología , Hipertensión/metabolismo , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/fisiopatología , L-Lactato Deshidrogenasa/metabolismo , Lactatos/metabolismo , Masculino , Miocardio/enzimología , Miocardio/metabolismo , Fosfocreatina/metabolismo , Embarazo , Ramipril/administración & dosificación , Ramipril/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Presión Ventricular/efectos de los fármacosRESUMEN
We investigated the effects of aortic banding-induced hypertension on the endothelium-dependent vasodilator responses in the aorta and coronary circulation of Sprague-Dawley rats. We studied the influence of hypertension on the endothelial nitric oxide synthase (NOS III) expression, assessed by Western blot and reverse transcription-polymerase chain reactions experiments, and on the superoxide anion (O2-) production. Two weeks after aortic banding, the endothelium-dependent relaxations were not altered. At this time, the expression of NOS III in the aorta and in confluent coronary microvascular endothelial cells (RCMECs) exhibited no marked changes, whereas O2- production was enhanced 1.9-fold in aortas from aortic-banded rats. Six weeks after aortic banding, the endothelium-dependent dilations were markedly impaired in the heart (50% decrease) and aorta (35% decrease). Analysis of NOS III protein and mRNA levels revealed marked increases in both aortas and confluent RCMECs (2.6- to 4-fold) from aortic-banded compared with sham-operated rats. There was no further increase in O2production in both the aorta and confluent RCMECs from aortic-banded rats. An enhanced nitrotyrosine protein level was also detected in the aorta from 6-week aortic-banded rats. These findings indicate that in hypertension induced by aortic banding, an enhanced O2- production alone is not sufficient to produce endothelial dysfunction. Endothelial vasodilator hyporesponsiveness was observed only when NOS III expression and O2- production were increased and was associated with the appearance of enhanced nitrotyrosine residues. This would suggest that the development of endothelial dysfunction is linked to an overproduction of not one, but two, endothelium-derived radicals that might lead to the formation of peroxynitrite.
Asunto(s)
Aniones/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Óxido Nítrico Sintasa/metabolismo , Superóxidos/metabolismo , Animales , Aorta/fisiopatología , Presión Sanguínea , Constricción Patológica , Endotelio Vascular/citología , Corazón/anatomía & histología , Técnicas In Vitro , Isoenzimas/metabolismo , Masculino , Miocardio/metabolismo , Nitratos/metabolismo , Tamaño de los Órganos , Perfusión , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , VasodilataciónRESUMEN
Spontaneously hypertensive rats (SHR) begin to die from cardiovascular complications at approximately 15 months of age. We tested whether chronic ACE-inhibitor treatment would extend the lifespan of such old animals. We also studied cardiac hypertrophy and function, endothelial function and expression, and activity of NO synthase (eNOS). One hundred 15-month-old SHR were randomized into 3 groups, control (n=10), placebo-treated (n=45), and ramipril-treated with an antihypertensive dose of 1 mg. kg(-1). d(-1) in drinking water (n=45). Ex vivo experiments were performed after 15 months (control) and 21 months, when approximately 80% of the placebo group had died. Late treatment with ramipril significantly extended lifespan of the animals from 21 to 30 months. Fully established cardiac hypertrophy, observed in placebo-treated animals and in controls, was significantly reversed by ramipril treatment. In isolated working hearts, a significantly improved function associated with increased cardiac eNOS expression was seen versus placebo and control hearts. Endothelial dysfunction in isolated aortic rings from control and placebo-treated SHR was significantly improved by ACE inhibition and associated with enhanced NO release. Late treatment of SHR with the ACE inhibitor ramipril extended lifespan from 21 to 30 months, which is comparable to the lifespan of untreated normotensive Wistar-Kyoto rats. This lifespan extension, probably due to blood pressure reduction, correlated with increased eNOS expression and activity followed by a regression of left ventricular hypertrophy and cardiac and vascular dysfunction.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/mortalidad , Ramipril/uso terapéutico , Factores de Edad , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Presión Sanguínea/efectos de los fármacos , Western Blotting , Peso Corporal , Cardiomegalia/complicaciones , Interpretación Estadística de Datos , Endotelio Vascular/citología , Endotelio Vascular/enzimología , Endotelio Vascular/metabolismo , Corazón/efectos de los fármacos , Corazón/fisiología , Ventrículos Cardíacos/metabolismo , Hipertensión/complicaciones , Técnicas In Vitro , Mediciones Luminiscentes , Masculino , Miocardio/metabolismo , Óxido Nítrico/análisis , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/metabolismo , Placebos , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Superóxidos/análisis , Factores de TiempoRESUMEN
We investigated functional changes in aortic preparations of spontaneously hypertensive rats treated in utero and subsequently up to 20 weeks of age with the angiotensin converting enzyme (ACE) inhibitors ramipril (0.01 and 1 mg/kg per day) and perindopril (0.01 mg/kg per day). Early-onset treatment with the high dose of ramipril inhibited aortic ACE activity, prevented the development of hypertension, increased aortic vasodilator responses to acetylcholine (10(-8) to 10(-6) mol/L), decreased vasoconstrictor responses to norepinephrine (10(-8) mol/L), and increased aortic cyclic GMP content by 160%. Low-dose ramipril inhibited aortic ACE activity and attenuated the aortic vasoconstrictor response to norepinephrine but had no effect on blood pressure. Low-dose treatment with ramipril and perindopril resulted in a significant increase in aortic cyclic GMP content by 98% and 77%, respectively. Long-term coadministration of the bradykinin B2-receptor antagonist Hoe 140 abolished the ACE inhibitor-induced increase in aortic cyclic GMP. Our data demonstrate that long-term treatment with ACE inhibitors can alter vascular function of compliance vessels independently of the antihypertensive action. The increase in aortic cyclic GMP was due to bradykinin potentiating the action of the ACE inhibitors.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/metabolismo , Hipertensión/prevención & control , Indoles/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Peptidil-Dipeptidasa A/metabolismo , Ramipril/farmacología , Ratas Endogámicas SHR/fisiología , Envejecimiento/fisiología , Análisis de Varianza , Angiotensina I/farmacología , Angiotensina II/farmacología , Animales , Aorta/metabolismo , Aorta/fisiopatología , Bradiquinina/análogos & derivados , Bradiquinina/antagonistas & inhibidores , Bradiquinina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Hipertensión/genética , Técnicas In Vitro , Intercambio Materno-Fetal , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatología , Perindopril , Embarazo , Ratas , Valores de Referencia , Sístole/efectos de los fármacosRESUMEN
We investigated the preventive effects of long-term treatment with the angiotensin converting enzyme inhibitor ramipril on myocardial left ventricular hypertrophy and capillary length density in spontaneously hypertensive rats. Rats were treated in utero and subsequently up to 20 weeks of age with a high dose (1 mg/kg per day) or with a low dose (0.01 mg/kg per day) of ramipril. Animals given a high dose of ramipril remained normotensive, whereas those given a low dose developed hypertension in parallel to vehicle-treated controls. At the end of the treatment period, converting enzyme activity in heart tissue was inhibited dose-dependently in the treated groups. Both groups revealed an increase in myocardial capillary length density together with increased myocardial glycogen and reduced citric acid concentrations. Left ventricular mass was reduced only in high dose- but not in low dose-treated animals. Our results demonstrate that early onset treatment with a converting enzyme inhibitor can induce myocardial capillary proliferation, even at doses too low to antagonize the development of hypertension or left ventricular hypertrophy. We hypothesize that potentiation of kinins is responsible for this effect, probably by augmenting myocardial blood flow, which is a well-known trigger mechanism of angiogenesis in the heart.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Cardiomiopatía Hipertrófica/prevención & control , Vasos Coronarios/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Ramipril/farmacología , Administración Oral , Factores de Edad , Análisis de Varianza , Animales , Animales Recién Nacidos , Citratos/metabolismo , Ácido Cítrico , Vasos Coronarios/ultraestructura , Relación Dosis-Respuesta a Droga , Femenino , Glucógeno/metabolismo , Hipertrofia , Intercambio Materno-Fetal , Microscopía Electrónica , Miocardio/metabolismo , Peptidil-Dipeptidasa A/análisis , Embarazo , Ratas , Ratas Endogámicas SHRRESUMEN
Incorporation of a C-terminal pentahydroxy functionality led to potent, low molecular weight hydrophilic renin inhibitors lacking the P1' side chain. As these compounds are easy to synthesize and have sufficient water solubility, they were chosen for further study. Compound 33 was transported across rabbit intestinal brush border membrane vesicles and yielded a hypotensive effect in sodium-depleted rhesus monkeys which lasted for 90 min when dosed at 2 mg/kg id.
Asunto(s)
Amino Azúcares/síntesis química , Renina/antagonistas & inhibidores , Alcoholes del Azúcar/síntesis química , Amino Azúcares/farmacocinética , Amino Azúcares/farmacología , Animales , Antibacterianos/farmacocinética , Disponibilidad Biológica , Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Femenino , Humanos , Intestino Delgado/metabolismo , Lactamas , Macaca mulatta , Masculino , Conejos , Solubilidad , Relación Estructura-Actividad , Alcoholes del Azúcar/farmacocinética , Alcoholes del Azúcar/farmacologíaRESUMEN
Based on the concept of transition-state analogs, a series of nonpeptide renin inhibitors with the new (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane moiety at the C-terminal functionality were synthesized and evaluated for inhibition of renin both in vitro and in vivo. All compounds exhibited potencies in the nanomolar or even subnanomolar range when tested versus human renin in vitro. Selected inhibitors were evaluated in anesthetized, sodium-depleted rhesus monkeys and produced a marked reduction in mean arterial blood pressure (MAP) upon intraduodenal administration of a dose of 2 mg/kg. Compound 38 (S 2864) containing an amino piperidyl succinic acid derived N-terminal is the most promising member in this series. 38 inhibited human renin with an IC50 of 0.38 nM, did not affect other human aspartic proteinases, and decreased mean arterial blood pressure significantly by 27% with a duration of action of 90 min after administration of 2 mg/kg id in anesthetized, sodium-depleted rhesus monkeys.