RESUMEN
BACKGROUND: Intramedullary rods and external fixators are reported to be more widely used than plating in osteosynthesis of femoral shaft fractures in children. In our institution plating is the routine, and we are reporting our experience in a retrospective study. METHODS: Two groups of patients were treated by AO plating for femoral shaft fractures. The first included 36 polytraumatized children and the second involved 10 cases of old malunited fractures. Average follow-up for the patients was 5 years. RESULTS: All children achieved union after one operation except one. There were no major complications except one case of mechanical failure. Insignificant limb length inequality occurred in only six children. CONCLUSION: We believed that plating of femoral shaft fractures is a reasonable option in treating children with fresh and neglected fractures.
Asunto(s)
Fracturas del Fémur/cirugía , Fijación de Fractura/métodos , Accidentes por Caídas , Accidentes de Tránsito , Adolescente , Placas Óseas , Niño , Preescolar , Femenino , Fracturas del Fémur/diagnóstico por imagen , Humanos , Masculino , Registros Médicos , Radiografía , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Somatic gene therapy of vascular diseases is a promising new field in modern medicine. Recent advancements in gene transfer technology have greatly evolved our understanding of the pathophysiologic role of candidate disease genes. With this knowledge, the expression of selective gene products provides the means to test the therapeutic use of gene therapy in a multitude of medical conditions. In addition, with the completion of genome sequencing programs, gene transfer can be used also to study the biologic function of novel genes in vivo. Novel genes are delivered to targeted tissue via several different vehicles. These vectors include adenoviruses, retroviruses, plasmids, plasmid/liposomes, and oligonucleotides. However, each one of these vectors has inherent limitations. Further investigations into developing delivery systems that not only allow for efficient, targeted gene transfer, but also are stable and nonimmunogenic, will optimize the clinical application of gene therapy in vascular diseases. This review further discusses the available mode of gene delivery and examines six major areas in vascular gene therapy, namely prevention of restenosis, thrombosis, hypertension, atherosclerosis, peripheral vascular disease in congestive heart failure, and ischemia. Although we highlight some of the recent advances in the use of gene therapy in treating vascular disease discovered primarily during the past two years, many excellent studies published during that period are not included in this review due to space limitations. The following is a selective review of practical uses of gene transfer therapy in vascular diseases. This review primarily covers work performed in the last 2 years. For earlier work, the reader may refer to several excellent review articles. For instance, Belalcazer et al. (6) reviewed general aspects of somatic gene therapy and the different vehicles used for the delivery of therapeutic genes. Gene therapy in restenosis and stimulation of angiogenesis in the cardiac muscle are discussed in reviews by several investigators (13,26,57,74,83). In another review, Meyerson et al. (43) discuss advances in gene therapy for vascular proliferative disorders and chronic peripheral and cardiac ischemia.
Asunto(s)
Terapia Genética , Enfermedades Vasculares/terapia , Animales , Vectores Genéticos , HumanosRESUMEN
Congestive heart failure (HF) is characterized by inadequate nitric oxide (NO) production in the vasculature. Because NO is degraded by oxygen radicals, we hypothesized that NO is degraded faster in HF from inadequate peripheral arterial antioxidant reserves. HF was induced in male Sprague-Dawley rats by left coronary artery ligation. Vascular endothelial function was evaluated by measuring the NO-mediated vasorelaxation response to acetylcholine (ACh; 10(-9)-10(-4) M) in excised aortas. This was repeated with the free radical generator pyrogallol (20 microM) and again with pyrogallol and superoxide dismutase (SOD; 60 U/ml). Aortic and myocardial SOD activity was also determined. ACh-induced vasorelaxation was reduced in HF (n = 9) compared with normal control rats (n = 11; P < 0.001). Pyrogallol further reduced vasorelaxation in HF: 74 +/- 11% at 10(-4) M ACh versus 58 +/- 10% in normal control rats (P < 0.004). There was a trend (P = 0.06) toward reduced SOD activity in HF aortas. In conclusion, altered NO-dependent vasorelaxation in HF is in part due to excessive degradation of NO and is likely related to reduced vascular SOD activity.
Asunto(s)
Endotelio Vascular/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Estrés Oxidativo , Animales , Aorta/enzimología , Aorta/fisiopatología , Técnicas In Vitro , Masculino , Miocardio/enzimología , Ratas , Ratas Sprague-Dawley , Superóxido Dismutasa/metabolismoRESUMEN
We identified abnormalities in the vascular beta-adrenergic receptor (beta-AR) signaling pathway in heart failure after myocardial infarction (MI). To examine these abnormalities, we measured beta-AR-mediated hemodynamics, vascular reactivity, and the vascular beta-AR molecular signaling components in rats with heart failure after MI. Six weeks after MI, these rats had an increased left ventricular (LV) end-diastolic pressure, decreased LV systolic pressure, and decreased rate of LV pressure change (dP/dt). LV dP/dt responses to isoproterenol were shifted downward, although the responses for systemic vascular resistance were shifted upward in heart failure rats (P < 0.05). Isoproterenol- and IBMX-induced vasorelaxations were blunted in heart failure rats (P < 0.05) with no change in the forskolin-mediated vasorelaxation. These changes were associated with the following alterations in beta-AR signaling (P < 0.05): decreases in beta-AR density (aorta: 58.7 +/- 6.0 vs. 35.7 +/- 1.9 fmol/mg membrane protein; carotid: 29.6 +/- 5.6 vs. 18.0 +/- 3.9 fmol/mg membrane protein, n = 5), increases in G protein-coupled receptor kinase activity levels (relative phosphorimage counts of 191 +/- 39 vs. 259 +/- 26 in the aorta and 115 +/- 30 vs. 202 +/- 7 in the carotid artery, n = 5), and decreases in cGMP and cAMP in the carotid artery (0.85 +/- 0.10 vs. 0.31 +/- 0.06 pmol/mg protein and 2.3 +/- 0.3 vs. 1.2 +/- 0.1 pmol/mg protein, n = 5) with no change in Galpha(s) or Galpha(i )in the aorta. Thus in heart failure there are abnormalities in the vascular beta-AR system that are similar to those seen in the myocardium. This suggests a common neurohormonal mechanism and raises the possibility that treatment in heart failure focused on the myocardium may also affect the vasculature.
Asunto(s)
Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatología , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Receptores Adrenérgicos beta/fisiología , 1-Metil-3-Isobutilxantina/farmacología , Agonistas Adrenérgicos beta/farmacología , Animales , Aorta/metabolismo , Aorta/fisiopatología , Aurora Quinasas , Presión Sanguínea , Arterias Carótidas/metabolismo , Arterias Carótidas/fisiopatología , Colforsina/farmacología , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Proteínas de Unión al GTP/metabolismo , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Técnicas In Vitro , Isoproterenol/farmacología , Ligadura , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiología , Presión VentricularRESUMEN
The objective of this study was to determine how maturation and aging affects beta (beta)-adrenergic receptor (AR) control of arterial vasorelaxation. Left ventricular (LV) hemodynamics and arterial vasorelaxation in thoracic artery segments were studied in Brown Norway, Fisher 344 cross rats at 6 weeks, 6 months, and 23 months of age. We defined changes in maturation as occurring between 6 weeks and 6 months of age and changes in aging as occurring between 6 months and 23 months of age. With maturation, isoproterenol resulted in a downward shift in heart rate and an upward shift in both LV dP/dt and peripheral vascular resistance responses. Similar changes were noted with aging except for the downward shift in LV dP/dt isoproterenol response. There was a dose-dependent increase in arterial vasorelaxation in response to isoproterenol in all age groups, but the 6-week-old animals had a 5-fold (P<0.01) increase in vasorelaxation compared to other age groups. The isoproterenol-induced arterial vasorelaxation response was not altered by removal of the endothelium. The vasodilatory responses to nitroglycerin, acetylcholine, and adenosine were diminished (P<0.05) with aging. The vasorelaxation responses to forskolin and IBMX were unchanged with maturation and diminished with aging. Incubation of arterial rings in cholera toxin resulted in a reduction in relaxation only in arteries from 6-week-old rats. Maturation resulted in no change in beta -AR density [20.2+/-0.7 v. 18.5+/-0.5 fmol/mg protein, P=n.s., 6 weeks (n=2, 18 aortas were combined v 6-month-old rats)]. With maturation, there was no change in G alpha(i)level. However, beta ARK1 levels were increased (55. 4+/-2.1 v. 40.8+/-0.4, arbitrary densitometry units) and G alpha(s)levels were decreased (29.5+/-0.8 v. 49.9+/-1.9, arbitrary densitometry units). Aging resulted in no change in beta -AR density (15.3+/-1.7 v. 18.5+/-0.5 fmol/mg membrane protein), but decreases in basal, isoproterenol-, naF-, and forskolin-stimulated AC activities. Compared to 6 week data, 23-month-old rats exhibited no change in either G alpha(i)or beta ARK1, however, G alpha(s) was decreased. In summary, beta -AR-stimulated arterial vasorelaxation is depressed during maturation and aging. Since there is no change in beta -AR density but a decrease in G alpha(s)and in basal/stimulated AC activities, the defect in beta -AR signaling during maturation and aging is probably a post receptor defect, i.e. possibly in the receptor-G protein coupling.
Asunto(s)
Adenilil Ciclasas/fisiología , Envejecimiento/fisiología , Vasos Sanguíneos/fisiología , Receptores Adrenérgicos beta/fisiología , Animales , Hemodinámica/fisiología , Ratas , Transducción de Señal/fisiologíaRESUMEN
The objective of this study was to design a methodology of gene transfer into a resistance vascular bed and to show if such a method can be used to examine the physiological function of a given gene product in vivo. We developed such a method and validated it by defining the role in vivo of endothelial nitric oxide synthase (eNOS). In a constant flow perfused rat hindlimb, gene transfer to the vascular endothelium was accomplished by incubating a "first-generation" serotype 5, replication-deficient, adenoviral vector (1.2 X 10(9) plaque-forming units/ml) containing cDNA encoding either the eNOS or the beta-galactosidase (beta-Gal) gene in the hindlimb vasculature for 30 min. Five days after infection, immunohistochemical staining for eNOS localized recombinant gene expression to vascular endothelial cells and eNOS protein levels were increased fourfold (11.9 +/- 6.6 vs. 2.9 +/- 1.3 intensity units/microg protein, n = 4, p < 0.05). Perfusion pressures were measured at different flow rates (10-50 ml/min). In addition, basal and acetylcholine (ACh)-stimulated vascular resistance (VR) in phenylephrine (PE)-precontracted (100 microM) hindlimb was measured at constant flow. There were flow-dependent increases (p < 0.05) in perfusion pressure. Overexpression of eNOS shifted the pressure-flow curve downward and administration of N(G)-nitro-L-arginine methyl ester (L-NAME) shifted the curve upward. Compared with beta-Gal-transfected rats, PE-induced VR decreased (p < 0.05) in eNOS-transfected rats (100 +/- 27 vs. 164 +/- 49 mmHg, n = 5). Addition of 100 microM L-NAME increased (p < 0.05) PE-induced VR in both eNOS-transfected and control rats (145 +/- 50 and 232 +/- 38 mmHg, n = 5, p < 0.05), respectively, which was partially abolished by L-arginine pretreatment. ACh-induced vasorelaxation was increased 45% (p < 0.05) in eNOS-transfected hindlimbs. L-NAME decreased (p < 0.05) ACh-induced vasorelaxation by 58% in eNOS-transfected hindlimbs versus 25% in beta-Gal-transfected hindlimbs (p < 0.05). We used this gene transfer method to examine the physiological function of a gene product in vivo and showed that (1) the flow-pressure relationship in the hindlimb vascular bed is NO dependent and (2) the eNOS enzyme modulates NO-mediated vasorelaxation in the rat hindlimb resistance arteries in vivo.
Asunto(s)
Adenoviridae/genética , Endotelio Vascular/enzimología , Técnicas de Transferencia de Gen , Óxido Nítrico Sintasa/genética , Óxido Nítrico/biosíntesis , Resistencia Vascular , Animales , Inhibidores Enzimáticos/farmacología , Miembro Posterior/anatomía & histología , Miembro Posterior/irrigación sanguínea , Miembro Posterior/metabolismo , Inmunohistoquímica , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Isoenzimas/metabolismo , NG-Nitroarginina Metil Éster/farmacología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nitroprusiato/farmacología , Ratas , Ratas Sprague-Dawley , Transfección , Vasodilatación , beta-Galactosidasa/genéticaRESUMEN
OBJECTIVES: To examine the relative roles of eNOS and iNOS (endothelial and inducible nitric oxide synthases) on basal and beta-adrenergic receptor (beta-AR)-stimulated arterial hemodynamic responses after myocardial infarction (MI). METHODS: Left ventricular (LV) pressures and steady-state and pulsatile arterial hemodynamics were measured at baseline, and after acute NOS inhibition with either NG-nitro-L-arginine methyl ester (L-NAME, 100 mg/kg) or iNOS inhibition with aminoguanidine (AG, 75 mg/kg) in sham-operated and MI Sprague-Dawley rats. RESULTS: In sham rats, L-NAME decreased (P < 0.05) peak positive LV dP/dt and aortic blood velocity by 19% and 53%, respectively, and increased (P < 0.05) mean arterial pressure (MAP); systemic vascular resistance, and LV end-diastolic pressure (EDP) by 20, 189 and 89%, respectively. The frequency-dependent components of hemodynamics including aortic input impedance modulus, characteristic impedance, and phase shift were increased (P < 0.05) with L-NAME, while pulsatile power was decreased (P < 0.05). AG increased (P < 0.05) aortic input impedance modulus and characteristic impedance but had no effect on any other hemodynamic variable. In MI rats, L-NAME decreased (P < 0.05) LV dP/dt and aortic blood velocity by 22 and 55%, respectively, and increased (P < 0.05) SVR by 108%. There was no effect of L-NAME on MAP or LV EDP in MI rats. After MI, AG increased (P < 0.05) heart rate and LV dP/dt but had no effect on other LV or pulsatile hemodynamic variables. Compared to sham rats, heart rate, LV dP/dt, and blood velocity-isoproterenol dose responses were shifted downward (P < 0.05), while SVR-isoproterenol dose response was shifted upward (P < 0.05) in MI rats. In sham rats, L-NAME potentiated (P < 0.05, at > 10(-2) micrograms/kg) the isoproterenol-induced increase in LV dP/dt and aortic blood velocity, and potentiated (P < 0.05) the isoproterenol-induced decline in SVR. As expected, AG had no effects on isoproterenol-stimulated hemodynamics in sham rats. After MI, there was no effect of L-NAME or AG on isoproterenol-stimulated hemodynamics. CONCLUSIONS: (1) Circulatory and cardiac responses to inhibition of NO by L-NAME suggest that eNOS, but not iNOS, is the principal regulator of integrated arterial hemodynamic function in rats. (2) Both basal and beta-AR-stimulated NO regulation of hemodynamic are attenuated after MI. (3) The attenuation of arterial hemodynamic effects after isoproterenol is mediated, in part, by alterations in the beta-AR-activation of eNOS system after MI.
Asunto(s)
Guanidinas/farmacología , Hemodinámica/efectos de los fármacos , Infarto del Miocardio/enzimología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Agonistas Adrenérgicos beta/farmacología , Análisis de Varianza , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Isoproterenol/farmacología , Infarto del Miocardio/fisiopatología , Óxido Nítrico Sintasa de Tipo II , Óxido Nítrico Sintasa de Tipo III , Ratas , Ratas Sprague-DawleyRESUMEN
After myocardial infarction (MI), nitric oxide (NO)-mediated vasorelaxation is attenuated in both conduit and resistance arteries. To determine if the attenuated vasorelaxation after MI is due to downregulation of eNOS protein, pharmacological, immunoblotting, and gene transfer of eNOS were performed in rats 3 weeks after MI. Gene transfer was accomplished using a "first-generation" serotype 5, replication-deficient, adenoviral vector (1.2 x 10(9) pfus) containing eNOS cDNA in the hindlimb vasculature for 30 min. Five days after infection, overexpression of eNOS protein was confirmed by immunohistochemical staining and immunoblotting. Recombinant gene expression was localized primarily to the vascular endothelial cells. After MI, eNOS protein level decreased (3.3 +/- 0.9 vs 2.1 +/- 0.8 intensity units/microg protein, n=6, P<0.05); after gene transfer it increased (P<0.05) two-fold to 4.3 +/- 1.2 intensity units/microg protein, n=5. There were no changes in hemodynamics in MI rats transfected with eNOS. Acetylcholine (ACh)-stimulated vasorelaxation was decreased (P<0.05) by 30% after MI and was restored to normal with eNOS transfection. Addition of 100 microm NG-nitro-L-arginine methyl ester (L-NAME) abolished the difference between sham, MI, and MI transfected rats. L-arginine (1 mm) restored the ACh-response in MI-transfected rats toward control, but it did not eliminate the difference between MI and sham rats. We conclude that the attenuated endothelial NO-mediated vasorelaxation in the hindlimb after MI is due to a downregulation of eNOS protein and overexpression of eNOS transgene restores normal endothelial NO-mediated vasorelaxation.
Asunto(s)
Endotelio Vascular/metabolismo , Insuficiencia Cardíaca/metabolismo , Isquemia Miocárdica/metabolismo , Óxido Nítrico Sintasa/metabolismo , Vasodilatación/fisiología , Acetilcolina/metabolismo , Acetilcolina/farmacología , Animales , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica , Hemodinámica , Miembro Posterior/irrigación sanguínea , Miembro Posterior/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/genética , Perfusión , Fenilefrina/farmacología , Ratas , Ratas Sprague-Dawley , Transfección , Transgenes , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Angiotensin II type 1 (AT1) receptor blockade attenuates myocardial fibrosis after myocardial infarction (MI). However, whether inhibition of fibrosis by AT1 receptor blockade influences myocardial stiffness and contractility is unknown. We measured left ventricular (LV) hemodynamics, papillary muscle function, and myocardial stiffness and fibrosis in rats randomized to losartan or placebo 1 day after MI and treated subsequently for 8 wk. Losartan decreased LV and right ventricular weights as well as mean aortic and LV systolic pressures in sham and MI rats. LV end-diastolic pressure increased after MI and was decreased with losartan. Maximal developed tension and peak rate of tension rise and decline were decreased in MI vs. sham rats. Interstitial fibrosis developed after MI and was prevented in losartan-treated MI rats. The development of abnormal myocardial stiffness after MI was prevented by losartan. After MI, AT1 receptor blockade prevents an abnormal increase in myocardial collagen content. This effect was associated with a normalization of passive myocardial stiffness.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Corazón/fisiopatología , Contracción Miocárdica/fisiología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocardio/patología , Animales , Aorta/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Elasticidad , Corazón/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Losartán/farmacología , Masculino , Contracción Miocárdica/efectos de los fármacos , Músculos Papilares/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
To examine arterial mechanical changes during aging, pressure-radius and axial force-radius curves were measured in vivo in carotid arteries from 6- and 23-month-old Brown Norway X Fischer 344 rats. Incremental passive circumferential stiffness (measured at 50, 100, and 200 mm Hg) was higher (P<0.01) in the 23- compared with the 6-month-old rats (14.02+/-1.23 versus 6.58+/-1.51; 2.68+/-0.56 versus 0.99+/-0.34; 1.10+/-0.24 versus 0.69+/-0.15 dyne/mm2x10(3), respectively). Incremental passive axial stiffness was increased (P<0.01) in the 23- compared with the 6-month-old rats (7.95+/-0.70 versus 4.24+/-0.81; 1.91+/-0.10 versus 0.61+/-0.16; 0.58+/-0.09 versus 0.36+/-0.06 dyne/mm2x10(3), respectively). Active incremental circumferential arterial stiffness at 100 and 200 mm Hg was increased (P<0.01) in the older rats. In 6-month-old rats, activation of vascular smooth muscle enhanced (P<0.01) the incremental circumferential and axial stiffness measured at 200 mm Hg. In 23-month-old rats, only active incremental stiffness was increased (P<0.01) at 200 mm Hg. Aging increased (P<0.05) media thickness, collagen content, and the collagen/elastin ratio by 12%, 21%, and 38%, respectively. Elastin density and the number of smooth muscle cell nuclei were decreased by 20% and 31%, respectively, with aging. Thus, structural alterations that occur with aging are associated with changes in both active and passive stiffness. Vascular smooth muscle tone modulates arterial wall anisotropy differently during aging.
Asunto(s)
Envejecimiento/fisiología , Arterias/fisiología , Músculo Liso Vascular/fisiología , Animales , Arterias Carótidas/fisiología , Hemodinámica , Norepinefrina/metabolismo , Ratas , Vasoconstricción , Vasoconstrictores/metabolismoRESUMEN
This study was designed to determine if adenoviral-mediated delivery of a transgene encoding the beta 2-adrenergic receptor (beta 2-AR) to the carotid arterial wall could result in alterations in in vivo vascular function. De-endothelialized rat carotid arteries were infused in vivo with 0.1 mg/ml elastase and adenovirus [6 x 10(9) plaque forming units (PFU)] containing either the marker gene beta-galactosidase (Adeno-beta-gal), DNA encoding the human beta 2-AR (Adeno-beta 2-AR), or no transgene. This low concentration of elastase increased the water permeability (5.2 +/- 0.6 v 1.9 +/- 0.4 x 10(-8) cm/s/mmHg, n = 4, P < 0.0001) without affecting either the vasomotor responsiveness or the morphology of the arterial wall. A transfection efficiency of 73% was achieved with Adeno-beta-gal (n = 3). beta-gal expression was associated with infrequent appearance of T and B lymphocytes, or neutrophil infiltration. Five days after infection with Adeno-beta 2-AR, the total beta-AR density increased six-fold (67.8 +/- 3.4 v 397.0 +/- 155.5 fmol/mg protein, n = 5, P < 0.01); isoproterenol-induced vasorelaxation at transmural pressures from 10-110/mmHg increased (P < 0.01) compared to arteries exposed to control virus (empty adenovirus), n = 4; and isoproterenol-stimulated cAMP production was increased by 65% (n = 5). Thus, adenoviral-mediated delivery of beta 2-ARs into large artery walls results in enhanced beta-AR-mediated vasorelaxation via augmentation in cAMP levels in vascular smooth muscle cells.
Asunto(s)
Arterias Carótidas/fisiología , Regulación de la Expresión Génica/fisiología , Músculo Liso Vascular/fisiología , Receptores Adrenérgicos beta 2/genética , Vasodilatación/fisiología , Adenoviridae/genética , Animales , Animales Modificados Genéticamente , Arterias Carótidas/metabolismo , ADN Viral/genética , Técnicas de Transferencia de Gen , Código Genético , Vectores Genéticos , Humanos , Inmunohistoquímica , Músculo Liso Vascular/metabolismo , Ratas , Ratas Sprague-Dawley , beta-Galactosidasa/genéticaRESUMEN
We wished to determine whether enhanced bioavailability of bradykinin (BK) and vasodilatory prostaglandins contribute to renovascular and sodium-handling effects of angiotensin-converting enzyme (ACE) inhibition after myocardial infarction (MI). We studied rats after coronary artery ligation treated for 3 weeks with captopril or losartan (2 g/L drinking water for each agent). Hemodynamic and renal function studies were performed in conscious rats before and after sequential infusion BK inhibitor (BKI, 0.02 ng/kg/min) and indomethacin (1 mg/kg). Myocardial infarction increased filtration fraction (FF) 20% (p < .004) but did not change glomerular filtration rate (GFR), urine flow (UF), renal blood flow (RBF), renal vascular resistance (RVR), urine sodium (UNa), or fractional excretion of sodium (FENa). Captopril decreased (p < 0.001) mean arterial pressure (MAP) 25%, UF 61%, RVR 65%, and FENa 75% and increased (p < 0.05) GFR 22%, and RBF 34%. Losartan decreased (p < 0.05) MAP 27%, UF 52%, RVR 21%, and FENa 44%. In captopril-treated MI rats, BKI decreased (p < 0.05) GFR 22% and RBF 25% and increased (p < 0.05) RVR 32%, UNa 43%, and FENa 28%, whereas indomethacin decreased (p < 0.05) GFR 24% and increased (p < 0.05) UNa 86% and FENa 112%. In losartan-treated MI rats, BKI increased (p < 0.05) UNa 42% and FENa 60%, whereas indomethacin increased (p < 0.05) UNa 79% and FENa 85%. Activation of the BK and prostaglandin systems may play an important role in regulating renal function during chronic ACE inhibition, primarily by enhancing the renal vasodilatory effects of angiotensin II (AII) blockade.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antagonistas de los Receptores de Bradiquinina , Bradiquinina/análogos & derivados , Inhibidores de la Ciclooxigenasa/farmacología , Indometacina/farmacología , Riñón/efectos de los fármacos , Infarto del Miocardio/tratamiento farmacológico , Animales , Compuestos de Bifenilo/uso terapéutico , Bradiquinina/farmacología , Captopril/uso terapéutico , Hemodinámica/efectos de los fármacos , Imidazoles/uso terapéutico , Riñón/fisiopatología , Pruebas de Función Renal , Losartán , Masculino , Infarto del Miocardio/fisiopatología , Ratas , Ratas Sprague-Dawley , Tetrazoles/uso terapéuticoRESUMEN
Rats with myocardial infarction (MI) after coronary artery ligation (n = 75) and sham operated rats (n = 40) were treated with captopril (2 g/l drinking water), hydralazine (80 mg/l drinking water), or untreated water for 3 wk. Arterial hemodynamics, carotid artery mechanical properties, and water permeability were measured. Arterial wall stress and interstitial fluid velocity were calculated. In infarcted rats, the characteristic impedance at matched pressure was increased by 135% (P < 0.02); captopril and hydralazine decreased characteristic impedance (P < 0.015). MI altered the material constants; captopril but not hydralazine normalized these constants. Water permeability was increased by 221% (P < 0.001) in infarcted rats; captopril but not hydralazine reversed water permeability (P < 0.05). MI resulted in a 59% increase (P < 0.05) in the arterial collagen area and a 22% decrease (P < 0.05) in the media thickness. Captopril but not hydralazine decreased (P < 0.03) collagen area. In conclusion, 1) arterial remodeling defined by alterations in the passive mechanical properties, water permeability, and structure occurs in rats after MI; and 2) captopril but not hydralazine reverses the arterial remodeling.
Asunto(s)
Arterias/fisiopatología , Infarto del Miocardio/fisiopatología , Animales , Aorta/fisiopatología , Arterias/patología , Presión Sanguínea , Agua Corporal/metabolismo , Espacio Extracelular/metabolismo , Hemodinámica , Masculino , Infarto del Miocardio/patología , Ratas , Ratas Sprague-Dawley , Estrés Mecánico , Resistencia Vascular , Vasoconstricción , Función VentricularRESUMEN
Activation of the renin-angiotensin and sympathetic nervous systems in heart failure may result in altered baroreflex control of heart rate. To determine the specific effects of treatment with captopril on baroreceptor dysfunction in heart failure, baroreflex control of heart rate was measured in conscious rats with heart failure 6 weeks after ligation of the left coronary artery. Plasma norepinephrine was measured as a reflection of sympathetic nervous system activity. After bolus injections of phenylephrine (2-50 micrograms/kg) and nitroprusside (2-50 micrograms/kg), the arterial baroreflex was analyzed by fitting percentage of mean arterial pressure changes and heart rate changes to a logistic regression function. There were no differences in baroreflex function between normal and sham-operated rats. Plasma norepinephrine was increased (P < .05) in the heart-failure rats and did not change with captopril treatment. In untreated rats, heart failure increased (P < .05) the centering point by 900%, threshold by 243% and saturation by 89%, whereas decreasing (P < .05) the operational point by 73%. There was a decrease (P < .05) in the nitroprusside-related gain and an increase (P < .05) in phenylephrine-related gain, but the overall baroreflex gain was not changed. In heart-failure rats, captopril increased (P < .05) threshold, saturation and centering point and decreased (P < .05) operational point and nitroprusside- and phenylephrine-related gain abnormalities. The increase in operational point and decreases in threshold, saturation, centering point and phenylephrine-related gain were the results of a specific interactive effect of captopril in heart failure (P = .0033, .0176, .0509, .0217 and .0567, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Captopril/farmacología , Insuficiencia Cardíaca/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Presorreceptores/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Masculino , Infarto del Miocardio/fisiopatología , Norepinefrina/sangre , Presorreceptores/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Reflejo/efectos de los fármacosRESUMEN
To characterize the interaction between mechanical and fluid transport properties in hypertension, we measured in vivo elastic material constants and hydraulic conductivity in intact segments of carotid arteries in normal and spontaneously hypertensive rats (SHR). With the use of a finite element model, the arterial wall was modeled as a large-deformation, two-phase (solid/fluid) medium, which accounts for the existence and motion of the tissue fluid. Measurements of internal diameter and transmural pressures were obtained during continuous increases in pressure from 0 to 200 mm Hg. Strain and stress components were calculated based on a pseudostrain exponential energy density function. To measure the hydraulic conductivity, segments of the carotid artery were isolated, filled with a 4% oxygenated albumin-Tyrode's solution, and connected to a capillary tube. The movement of the meniscus of the capillary tube represented the fluid filtration across the artery. To study the influence of transmural pressure on hydraulic conductivity, measurement of fluid filtration across the arterial wall was obtained at transmural pressures of 50 and 100 mm Hg. The material constants in the SHR (n = 9) were higher (p less than 0.05 for all variables) than in normal rats (n = 10): c = 1,343 +/- 96 versus 1,158 +/- 65 mm Hg, b1 = 1.84 +/- 0.24 versus 1.22 +/- 0.22, b2 = 0.769 +/- 0.114 versus 0.616 +/- 0.11, b3 = 0.017 +/- 0.005 versus 0.0065 +/- 0.002, b4 = 0.206 +/- 0.04 versus 0.083 +/- 0.03, b5 = 0.0594 +/- 0.007 versus 0.0217 +/- 0.006, and b6 = 0.22 +/- 0.09 versus 0.123 +/- 0.02, respectively. The hydraulic conductivity of the total wall, calculated from the filtration data, was lower (p less than 0.05) at both 50 and 100 mm Hg in the SHR (n = 6) compared with normal rats (n = 7): 1.12 +/- 0.31 x 10(-8) and 0.72 +/- 0.23 x 10(-8) versus 1.95 +/- 0.53 x 10(-8) and 1.35 +/- 0.47 x 10(-8) cm/(sec.mm Hg), respectively. The intergroup comparisons between 50 and 100 mm Hg in both SHR and normal rats were also different (p less than 0.05). The finite element model was used to predict tissue fluid pressure distribution, tissue fluid velocity distribution, and total Cauchy stress gradients developed in the arterial wall during fluid pressurization in both species.(ABSTRACT TRUNCATED AT 400 WORDS)
Asunto(s)
Arterias/fisiología , Presión Sanguínea , Hipertensión/fisiopatología , Modelos Cardiovasculares , Animales , Volumen Sanguíneo , Cardiomegalia/patología , Homeostasis , Ratas , Ratas Endogámicas SHR , Ratas EndogámicasRESUMEN
Our experience with 126 cases of bilharzial bladder cancer treated by radical cystectomy and followed up for at least 10 years is outlined. The operative mortality rate was 13.5%. The 5- and 10-year survival rates were 32.6 and 23% respectively. The difference between the two figures can be attributed to mortality from natural ageing rather than recurrence of cancer. Analysis of survival figures revealed that the tumour grade was the most important prognostic factor. Most treatment failures were due to local recurrence which developed soon after treatment.