RESUMEN
AIM: The aim of this study was to investigate the renal structural properties in diabetic nephropathy. METHODS: Flow-pressure and pressure-glomerular filtration rate (GFR) relationships were determined for maximally vasodilated kidneys at 10 (pre-diabetic stage) and 42 weeks of age (diabetic stage) in Otsuka Long-Evans Tokushima Fatty rats (OLETF), an animal model of type 2 diabetes mellitus, using age-matched Long-Evans Tokushima Otsuka rats (LETO) as non-diabetic controls (n = 9 of each age for each strain). Kidneys were then perfusion-fixed for histological analysis. RESULTS: At 10 weeks of age, the slope of flow-pressure relationship (minimal renal vascular resistance, reflecting overall luminal dimensions of preglomerular and postglomerular vasculature) was steeper in OLETF than in LETO. In contrast, the threshold pressure for beginning filtration (preglomerular-to-postglomerular vascular resistance ratio) at pressure-GFR relationship did not differ between the two strains; however, the slope of the relationship (glomerular filtration capacity) was lower in OLETF than in LETO. Thus, in the kidneys of 10-week-old OLETF rats, vascular narrowing and impaired glomerular filtration capacity already existed with no abnormalities in preglomerular-to-postglomerular vascular resistance ratio. From the age of 10-42 weeks, the following results were obtained: (1) Minimal renal vascular resistance decreased in both strains, but it diminished markedly in OLETF. (2) The pressure for beginning filtration increased in LETO, but remained unchanged in OLETF. (3) Glomerular filtration capacity decreased to the similar extent in both strains. (4) Histologically, the vascular lumen and wall thickness increased in the interlobular arteries of both strains. However, vascular luminal widening was more pronounced in OLETF, resulting in the reduction in wall to lumen ratio. (5) Glomerular injuries and increased blood pressure occurred only in OLETF. CONCLUSION: In conclusion, during progression from the prediabetic to diabetic stage of OLETF, the pre-existing vascular narrowing was markedly attenuated without the concomitant increase in preglomerular-to-postglomerular vascular resistance ratio. Combined with increased blood pressure, these renal structural alterations could lead to the elevation of intraglomerular pressure in OLETF.
Asunto(s)
Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/patología , Riñón/irrigación sanguínea , Animales , Glucemia/análisis , Presión Sanguínea/fisiología , Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/fisiopatología , Tasa de Filtración Glomerular/fisiología , Riñón/patología , Riñón/fisiopatología , Masculino , Tamaño de los Órganos/fisiología , Proteinuria/complicaciones , Ratas , Ratas Endogámicas OLETF , Resistencia Vascular/fisiología , Vasodilatación/fisiologíaRESUMEN
In 10- to 12-week-old Dahl salt-sensitive (DS) and salt-resistant (DR) rats fed a 0.3% salt diet (n=10 in each group), flow-pressure and pressure-glomerular filtration rate (F-P and P-GFR, respectively) relationships were established for maximally vasodilated perfused kidneys. From these relationships, 3 indices of vascular structural properties were estimated: slope of F-P (minimal renal vascular resistance reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of P-GFR (glomerular filtration capability against pressure), and threshold pressure for beginning filtration at P-GFR (preglomerular-to-postglomerular vascular resistance ratio). Thereafter, maximal renal vascular resistance was determined to assess wall-to-lumen ratios of the resistance vessels in half of each group. In the remainder, the kidneys were perfusion-fixed for histological analysis. Mean arterial pressure did not differ between the DS and DR rats. There were no significant differences in the slopes of F-P between the 2 groups. In contrast, the slope of P-GFR was significantly lower (33%) in DS rats than in DR rats, although the DS kidneys began filtering at a threshold pressure similar to that of the DR kidneys. Thus, in DS rats, there were no abnormalities in luminal dimensions at preglomerular and postglomerular vascular segments, but the kidney filtration capacity decreased at any given increase in pressure. Maximal vascular resistance was greater in DS than in DR rats, a finding compatible with the histological appearance, which showed vascular hypertrophy with little, if any, vascular narrowing in the interlobular arteries of DS rats. In conclusion, hypertrophic remodeling without vascular narrowing at preglomerular resistance vessels and structural defects in filtering at the glomeruli could occur in prehypertensive DS rats.
Asunto(s)
Hipertensión/patología , Riñón/irrigación sanguínea , Cloruro de Sodio Dietético/farmacología , Animales , Hemodinámica , Hipertensión/fisiopatología , Riñón/fisiopatología , Masculino , Ratas , Arteria Renal/patología , Arteria Renal/fisiopatologíaRESUMEN
Background: A hepatic artery-portal vein reciprocal response and hepatic hemodynamics have well been investigated under normal condition, but not under pathologic condition with decreased vascular bed. This study was designed to determine the hemodynamic changes in the hepatic blood flow, tissue perfusion and interrelationship between portal venous flow (PVF) and hepatic arterial flow (HAF) after inflow interruption in the various size of hepatic vascular bed. Methods: Anesthetized dogs were used to measure PVF and HAF using a transit time flow meter and hepatic tissue flow (HTF) using a laser Doppler flow meter before and after portal venous (PVO) or hepatic arterial occlusion (HAO) under various range of portal triad occlusion (PTO). Results: The ratio of HAF/TLF (total liver flow) was 38+/-14% under the basal condition. This ratio did not change under the 30% PTO where there was a similar decrease in PVF and HAF, but reduced to 25+/-12% under the 70% PTO where there was more selective reduction in HAF than PVF. Although a reciprocal HAF increase was observed under any conditions after PVO, the TLF and HTF decreases after PVO were largest under the 70% PTO with the highest PVF/TLF ratio. On the other hand, there was no reciprocal PVF increase in any conditions after HAO, and the TLF and HTF decreases after HAO were minimal under the 70% PTO with the lowest HAF/TLF ratio. Conclusions: With decreasing hepatic vascular bed, dependency of the remnant hepatic hemodynamics and tissue perfusion on the portal blood flow increased. These findings suggest that an integrity of portal venous flow becomes crucial in the remnant hepatic tissue perfusion after extensive hepatic resection.
RESUMEN
To determine whether platelet response to mental stress is altered in essential hypertension, platelet aggregability and plasma beta-thromboglobulin were determined in 24 patients with essential hypertension (11 patients with World Health Organization (WHO) stage I and 13 patients with stage II) and 14 normotensive controls before and after a 10-min arithmetic stress (serial subtraction of 7 from 1000). In normotensive subjects, arithmetic stress did not affect primary aggregations to 1.0 micromol/L adenosine diphosphate (ADP) and to 2.5 micromol/L 5-hydroxytryptamine (5-HT), ADP threshold for biphasic aggregation and plasma beta-thromboglobulin level. In hypertensive patients with WHO stage I, these parameters were similar to those in normotensives before arithmetic stress, but the arithmetic stress test significantly increased primary aggregation to reagents and beta-thromboglobulin level, and decreased threshold of ADP for biphasic aggregation. In WHO stage II patients, platelet aggregability to reagents and beta-thromboglobulin level were already enhanced as compared with WHO stage I patients and normotensive subjects before arithmetic stress. However, the stress-induced changes in platelet function were less pronounced in WHO stage II patients compared with stage I patients. In conclusion, platelet aggregability and proaggregatory effect of mental stress differed depending on the severity of hypertension in patients with essential hypertension; the transient activation of platelet function during stress with no enhancement under the resting condition in the early phase of hypertension and the continuous activation of platelet function in the advanced phase with hypertensive organ damage.
Asunto(s)
Plaquetas/fisiología , Hipertensión/fisiopatología , Agregación Plaquetaria , Estrés Psicológico/fisiopatología , Adenosina Difosfato , Adulto , Anciano , Aldosterona/sangre , Sitios de Unión , Biomarcadores/sangre , Catecolaminas/sangre , Femenino , Humanos , Hipertensión/sangre , Masculino , Persona de Mediana Edad , Recuento de Plaquetas , Renina/sangre , Serotonina , Índice de Severidad de la Enfermedad , Estrés Psicológico/sangre , beta-Tromboglobulina/metabolismoRESUMEN
We investigated whether plasma brain and atrial natriuretic peptide (BNP and ANP, respectively) levels could reflect left ventricular (LV) geometry and function in patients with mild to moderate essential hypertension. A positive correlation was found between LV mass index (LVMI) and plasma ANP levels in 84 untreated, hypertensive patients, but not between LVMI and plasma BNP levels. As compared with other geometric patterns, plasma BNP levels were increased in concentric hypertrophy, in which LVMI was increased and LV diastolic function was decreased. These data suggest that production of BNP was increased in hypertensive patients with concentric hypertrophy via LV overload or depression of diastolic function.
Asunto(s)
Factor Natriurético Atrial/sangre , Ventrículos Cardíacos/diagnóstico por imagen , Hipertensión/sangre , Péptido Natriurético Encefálico/sangre , Remodelación Ventricular , Adulto , Anciano , Biomarcadores/sangre , Ecocardiografía , Epinefrina/sangre , Femenino , Humanos , Hipertensión/diagnóstico por imagen , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Radioinmunoensayo , Renina/sangreRESUMEN
The effects of a novel calcium antagonist, benidipine hydrochloride, on responses of platelets to mental stress were evaluated in nine patients with essential hypertension. Before and 12 weeks after the monotherapy with benidipine (2-4 mg/day), platelet aggregability and plasma beta-thromboglobulin were determined during rest and after a 10-min arithmetic stress. Before the treatment, arithmetic stress significantly increased platelet aggregability in response to adenosine diphosphate (ADP) and plasma beta-thromboglobulin level. Blood pressure, pulse rate, and plasma catecholamines also increased during arithmetic stress. The treatment with benidipine did not affect resting values of platelet functions, but attenuated significantly stress-induced alterations in primary aggregation to 1.0 microM ADP (34 +/- 4% to 40 +/- 3% before treatment vs. 32 +/- 2% to 34 +/- 3% after benidipine), ADP threshold for biphasic aggregation (2.2 +/- 0.4 to 1.8 +/- 0.3 microM before treatment vs. 2.2 +/- 0.3 to 2.2 +/- 0.4 microM after benidipine) and plasma beta-thromboglobulin level (74 +/- 16 to 104 +/- 15 ng/ml before treatment vs. 60 +/- 10 to 52 +/- 8 ng/ml after benidipine; p < 0.05 for Stress x Treatment interactions in all values). The pretreatment elevations in blood pressure and sympathetic activity with stress were not modified by benidipine treatment. In conclusion, the monotherapy with benidipine did not affect platelet function during the resting condition, but significantly suppressed the platelet activation induced by arithmetic stress in patients with essential hypertension.
Asunto(s)
Plaquetas/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Hipertensión/sangre , Inhibidores de Agregación Plaquetaria/farmacología , Adulto , Anciano , Plaquetas/fisiología , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Agregación Plaquetaria/efectos de los fármacos , Estrés Psicológico/sangre , beta-Tromboglobulina/análisisRESUMEN
To assess whether electrocardiographic variables are useful to detect the regression of left ventricular (LV) mass after long-term antihypertensive treatment, we related electrocardiographic voltages to echocardiographic variables before and after treatment with an ACE inhibitor, temocapril (TEM), or direct vasodilator, cadralazine (CAD). Twenty-one patients with essential hypertension were treated with either TEM (n = 11) or CAD (n = 10) for one year. LV mass index (LVMI) by echocardiography and Sokolow-Lyon voltage (SV1 + RV5), Cornell voltage (RaVL + SV3) and RV5 + RV6 by standard 12-lead electrocardiographic voltages were determined before and after treatment. Both drugs decreased blood pressure to the same extent. Both Sokolow-Lyon voltage and RV5 + RV6 tended to decrease in the ACE group (40.0 +/- 9.4 to 37.2 +/- 9.4 mm and 44.7 +/- 13.5 to 41.7 +/- 11.7 mm, respectively, N.S.), but not in the CAD group (38.4 +/- 6.8 to 39.7 +/- 7.7 mm and 42.9 +/- 10.4 to 46.8 +/- 11.2 mm, respectively, N.S.). LVMI decreased in the ACE group (-24 +/- 22 g/m2), whereas it increased in the CAD group (37 +/- 27 g/m2, p < 0.01). Change in LVMI was correlated with the changes in RV5 + RV6 and Sokolow-Lyon voltage (r = 0.73, p < 0.01 and r = 0.70, p < 0.01, respectively), but not with that in Cornell voltage. These results indicated that the changes in voltage criteria of RV5 + RV6 and Sokolow-Lyon are useful to assess the change in LVM after antihypertensive treatment in patients with essential hypertension although voltage variables in electrocardiogram were not sensitive to detect changes in LVMI.
Asunto(s)
Antihipertensivos/uso terapéutico , Electrocardiografía , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/tratamiento farmacológico , Tiazepinas/uso terapéutico , Anciano , Ecocardiografía , Femenino , Humanos , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Persona de Mediana Edad , Piridazinas/uso terapéutico , Vasodilatadores/uso terapéuticoRESUMEN
A 55-year-old man was admitted to our hospital because of bilateral leg lymphedema. He also showed subcutaneous nodules and CT scan disclosed multiple enlarged lymph nodes at thoracic, abdominal, and inguinal areas. Biopsy of the inguinal lymph node and the subcutaneous nodule revealed noncaseating epithelioid cell granuloma, a finding consistent with sarcoidosis. Lymphedema was attributed to the blockade of lymph flow by the systemic lymph node involvement of the disease. Within 1 week after the initiation of steroid therapy, his leg edema disappeared. Lymphedema could be the initial symptom of systemic sarcoidosis.
Asunto(s)
Linfedema/etiología , Sarcoidosis/complicaciones , Sarcoidosis/diagnóstico , Diagnóstico Diferencial , Humanos , Pierna , Ganglios Linfáticos/patología , Linfedema/patología , Masculino , Persona de Mediana Edad , Sarcoidosis/patología , Piel/patologíaRESUMEN
To assess whether we could predict left ventricular (LV) geometric patterns on echocardiography from voltages in standard electrocardiograms (ECG) in patients with essential hypertension, standard 12-lead ECG and echocardiograms were recorded in 106 consecutive, untreated patients (50+/-11 yr old) with essential hypertension. Subjects were assigned to the following four groups based on relative wall thickness (RWT) and LV mass index (LVMI) as determined by echocardiography: a normal geometry group (n = 44), a concentric remodeling group (increased RWT and normal LVMI, n = 10), an eccentric hypertrophy group (increased LVMI and normal RWT, n = 23), and a concentric hypertrophy group (increased RWT and LVMI, n = 29). The following ECG variables were determined: Sokolow-Lyon voltage (SV1 = RV5: SL), Cornell voltage (RaVL + SV3: CN), sum of 12-lead QRS voltage (12-lead sum), and RV6/RV5 ratio (RV6/V5). LVMI correlated with SL, CN, and 12-lead sum, but not with RV6/V5 in the study group as a whole. The concentric hypertrophy group showed increased voltages for all ECG variables except RV6/V5. The concentric remodeling group showed increased voltages for SL and 12-lead sum, but a decreased RV6/V5 ratio. In contrast, the eccentric hypertrophy group had increased voltage only for the 12-lead sum. The combination of SL, RV6/V5, and CN showed modest sensitivity and specificity in the diagnosis of concentric remodeling, concentric hypertrophy, and normal geometry, but not in the diagnosis of eccentric hypertrophy. Conventional ECG criteria can predict LVMI, but not LV geometry in the patients with essential hypertension. The combination of SL, CN, and RV6/V5 is useful in differentiating the four LV geometric patterns seen in essential hypertension.
Asunto(s)
Ecocardiografía , Electrocardiografía/métodos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/etiología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: To study the effects of denervation of the kidney on renal vascular resistance at maximal dilatation and renal function during the development of hypertension in the spontaneously hypertensive rat (SHR). METHODS: SHR aged 6 weeks were subjected to left renal denervation or a sham-operation (n = 18 denervated, n = 13 sham). When they were aged 10 weeks, pairs of denervated and sham-operated left kidneys were perfused with 2% dextran in Tyrode's solution and pressure-flow and pressure-glomerular filtration rate (GFR) relationships at maximal vasodilation were established. The awake mean arterial blood pressure, in-vivo renal function and renal noradrenaline content were also measured. RESULTS: There were no significant differences between the pressure-flow relationships for denervated and sham-operated kidneys. However, there was a marked, parallel, shift leftwards in the pressure-GFR relationship (P < 0.001). Thus, the denervated kidneys commenced filtering at a lower threshold perfusion pressure than did the sham-operated ones. In-vivo renal plasma flow and GFR were significantly greater in the denervated left kidneys of SHR than they were in the contralateral kidneys. The noradrenaline content in denervated kidneys was 5 +/- 3% of that in innervated kidneys. The awake mean arterial pressure was 135 +/- 1 and 138 +/- 2 mmHg in the denervated and sham-operated groups respectively. CONCLUSION: Denervation of the kidney of SHR aged 6 weeks of age altered the pressure-GFR but not the pressure-flow relationship for these rats 4 weeks later. The results are compatible with there having been an increase in average preglomerular and a decrease in post-glomerular vessel lumen diameters. These changes suggest that the renal nerves affect the structural development of the renal vasculature in SHR.
Asunto(s)
Desnervación , Hipertensión/fisiopatología , Riñón/fisiología , Arteria Renal/inervación , Resistencia Vascular/fisiología , Animales , Presión Sanguínea , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Tasa de Filtración Glomerular , Hipertensión/etiología , Hipertensión/terapia , Riñón/irrigación sanguínea , Riñón/metabolismo , Masculino , Norepinefrina/metabolismo , Ratas , Ratas Endogámicas SHR , Flujo Plasmático RenalRESUMEN
To test the validity of transit-time ultrasound flowmetry for chronic measurement of renal blood flow in dogs, we compared this method with the renal clearance of para-aminohippuric acid (CPAH) (corrected for hematocrit), and with direct volumetric measurements. When flow-probes were implanted without silastic sheeting to stabilize the implant, there was significant disparity between the (within-dog) mean levels of renal blood flow estimated by flow-probe and CPAH. In contrast, when the flow-probe implants were stabilized with silicone sheeting, there was close agreement in each dog between the flow rates measured by the two methods. When flow-probes were calibrated volumetrically in situ, there was a close linear relationship between flow derived from the flow-probe and that measured volumetrically (r = 0.98 +/- 0.02). We conclude that valid, chronic measurement of renal blood flow in dogs can be achieved using transit-time ultrasound flowmetry, provided the implant is stabilized with silicone sheeting.
Asunto(s)
Riñón/irrigación sanguínea , Circulación Renal/fisiología , Ultrasonografía/métodos , Animales , Velocidad del Flujo Sanguíneo , Perros , Pruebas de Función Renal/métodos , Masculino , Prótesis e Implantes , Reproducibilidad de los Resultados , Reología/métodos , Elastómeros de Silicona , Ácido p-Aminohipúrico/farmacocinéticaRESUMEN
1. We tested the effects on systemic haemodynamics and renal function, of inhibition of endopeptidase (EP) 24.15 (E.C. 3.4.24.15), in conscious uninephrectomized rabbits in which the activities of angiotensin converting enzyme (ACE, E.C. 3.4.15.1) and neutral endopeptidase (EP 24.11, E.C. 3.4.24.11) were already inhibited. To test the role of bradykinin B2-receptors in mediating the effects following inhibition of these enzymes, the antagonist Hoe 140 was used. 2. Hoe 140 (0.1 mg kg-1, i.v.) did not affect resting mean arterial pressure or heart rate, but antagonized the depressor effect of right atrial administration of bradykinin. The dose-response curve for bradykinin was shifted more than 1000 fold to the right for more than 4 h. Hoe 140 approximately doubled resting urine flow and increased fractional Na+ excretion from 4.2 to 6.0%; consistent with the hypothesis that it exerts a partial agonist effect on the kidney. 3. Combined inhibition of ACE (captopril; 0.25 mg kg-1 plus 0.2 mg kg-1h-1) and EP 24.11 (SCH 39370; 3 mg kg-1 plus 3 mg kg-1h-1) was followed by a sustained reduction in arterial pressure (-6 +/- 2 mmHg) and increase in heart rate (35 +/- 7 beats min-1). There was a small increase in renal blood flow (by 6.5 +/- 3.2% relative to vehicle-treatment) without a change in glomerular filtration rate, and about a 150% increase in Na+ excretion. Hoe 140 (0.1 mg kg-1, i.v.) pretreatment did not influence the renal effects of captopril and SCH 39370, although it did appear to blunt their hypotensive and tachycardic effects. 4. When EP 24.15 was inhibited with N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB; 5 mg kg-1 plus 3 mg kg-1h-1, i.v.) in rabbits pretreated with captopril and SCH 39370, no changes in systemic haemodynamics or renal function were observed. 5. We concluded that in conscious uninephrectomized rabbits, EP 24.15 does not play a major role in modulating renal function, at least under conditions where ACE and EP 24.11 are already inhibited. In contrast, ACE and/or EP 24.11 do modulate renal function in this model, but their influences are mediated chiefly through metabolism of peptides other than bradykinin.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores Enzimáticos/farmacología , Riñón/ultraestructura , Metaloendopeptidasas/antagonistas & inhibidores , Neprilisina/antagonistas & inhibidores , Receptores de Bradiquinina/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Captopril/farmacología , Estado de Conciencia , Dipéptidos/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/enzimología , Metaloendopeptidasas/metabolismo , Neprilisina/metabolismo , Oligopéptidos/farmacología , Peptidil-Dipeptidasa A/metabolismo , Inhibidores de Proteasas/farmacología , ConejosRESUMEN
1. The role of the metalloendopeptidase EC 3.4.24.15 (EP 24.15) in peptide metabolism in vivo is unknown, in part reflecting the lack of a stable enzyme inhibitor. The most commonly used inhibitor, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB, Ki = 16 nM), although selective in vitro, is rapidly degraded in the circulation to cFP-Ala-Ala, an angiotensin converting enzyme (ACE) inhibitor. This metabolite is thought to be generated by neutral endopeptidase (NEP; EC 3.4.24.11), as the Ala-Tyr bond of cFP-AAY-pAB is cleaved by NEP in vitro. In the present study, we have examined the role of NEP in the metabolism of cFP-AAY-pAB in vivo, and have tested a series of inhibitor analogues, substituted at the second alanine, for both potency and stability relative to the parent compound. 2. Analogues were screened for inhibition of fluorescent substrate cleavage by recombinant rat testes EP 24.15. D-Ala or Asp substitution abolished inhibitory activity, while Val-, Ser- and Leu-substituted analogues retained activity, albeit at a reduced potency. A relative potency order of Ala (1) > Val (0.3) > Ser (0.16) > Leu (0.06) was observed. Resistance to cleavage by NEP was assessed by incubation of the analogues with rabbit kidney membranes. The parent compound was readily degraded, but the analogues were twice (Ser) and greater than 10 fold (Leu and Val) more resistant to cleavage. 3. Metabolism of cFP-AAY-pAB and the Val-substituted analogue was also examined in conscious rabbits. A bolus injection of cFP-AAY-pAB (5 mg kg-1, i.v.) significantly reduced the blood pressure response to angiotensin I, indicating ACE inhibition. Pretreatment with NEP inhibitors, SCH 39370 or phosphoramidon, slowed the loss of cFP-AAY-pAB from the plasma, but did not prevent inhibition of ACE. Injection of 1 mg kg-1 inhibitor resulted in plasma concentrations at 10 s of 23.5 microM (cFP-AAY-pAB) and 18.0 microM (cFP-AVY-pAB), which fell 100 fold over 5 min. Co-injection of 125I-labelled inhibitor revealed that 80-85% of the radioactivity had disappeared from the circulation within 5 min, and h.p.l.c. analysis demonstrated that only 25-30% of the radiolabel remained as intact inhibitor at this time. Both analogues were cleared from the circulation at the same rate, and both inhibitors blunted the pressor response to angiotensin I, indicative of ACE inhibition. 4. These results suggest that both NEP and other clearance/degradation mechanisms severely limit the usefulness of peptide-based inhibitors such as cFP-AAY-pAB. To examine further EP 24.15 function in vivo, more stable inhibitors, preferably non-peptide, must be developed, for which these peptide-based inhibitors may serve as useful molecular templates.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Dipéptidos/farmacología , Glicopéptidos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/farmacología , Análisis de Varianza , Angiotensina II/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Bradiquinina/farmacología , Relación Dosis-Respuesta a Droga , Hormona Liberadora de Gonadotropina , Técnicas In Vitro , Riñón/citología , Riñón/enzimología , Metaloendopeptidasas/sangre , Metaloendopeptidasas/metabolismo , Conejos , Ratas , Estereoisomerismo , Vasoconstrictores/farmacologíaRESUMEN
The objective of this study was to assess the regression of vascular structural changes seen in essential hypertension after long-term monotherapy with a calcium antagonist and to clarify the relations to cytosolic free calcium and neurohumoral factors. Blood pressure, minimal vascular resistance (MVR) by strain-gauge plethysmography, cytosolic free calcium in platelets ([Ca2+]i) by Quin 2 method, plasma renin activity (PRA) and plasma aldosterone concentration (PAC), plasma noradrenaline (PNA) and parathyroid hormone (PTH) were measured in 14 essential hypertensives during a placebo period and 2 and 6 months after anti-hypertensive treatment with nilvadipine. Blood pressure decreased from 174 +/- 10/104 +/- 8 mm Hg during the placebo period to 154 +/- 13/93 +/- 14 mm Hg 2 weeks after nilvadipine, and the hypotensive effects were found throughout the 6-month period. Although increased MVR seen in hypertensives did not change after 2 months (from 2.1 +/- 0.7 to 1.9 +/- 0.6 mm Hg/ml/min per 100 ml tissue (PRU), NS), MVR decreased significantly at 6 months (1.6 +/- 0.4, PRU, P < 0.05). Elevated [Ca2+]i seen in hypertensives during the placebo period decreased significantly 2 months after nilvadipine treatment (156 +/- 26 and 140 +/- 27 nM, P < 0.01). The changes in MVR were associated with those in [Ca2+]i 6 months after nilvadipine (r = 0.56, P < 0.05). However, the changes in MVR did not correlate with those in PRA, PAC, PNA or PTH.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Calcio/metabolismo , Hipertensión/tratamiento farmacológico , Nifedipino/análogos & derivados , Resistencia Vascular/efectos de los fármacos , Adulto , Anciano , Análisis de Varianza , Bloqueadores de los Canales de Calcio/farmacología , Citosol/efectos de los fármacos , Citosol/metabolismo , Femenino , Humanos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Masculino , Persona de Mediana Edad , Nifedipino/farmacología , Nifedipino/uso terapéutico , Hormona Paratiroidea/metabolismo , Pletismografía , Probabilidad , Factores de TiempoRESUMEN
This study was designed to investigate the changes in plasma and tissue endothelin-1/endothelin-2 (ET) after liver ischemia and to assess the protective effect of anti-ET 1/ET 2 monoclonal antibody (ET antibody) against ischemia-reperfusion injury. The ET levels in the liver tissue, hepatic venous blood of the ischemic and non-ischemic sides, and in the portal venous blood were measured before and after partial liver ischemia for 1 hour in the adult dog. The ET levels in the liver tissue and hepatic venous blood on the ischemic side increased slightly during ischemia and markedly after reperfusion, whereas those on the nonischemic side showed no significant increases. The ET levels in the portal venous blood peaked at 1 to 3 hours after ischemia, which was significantly higher than the levels in the hepatic venous blood on the ischemic side and which correlated with the portal venous pressure elevated because of the partial liver clamping. The administration of antibody (2 mg/kg, intravenous) before reperfusion resulted in a significant inhibition of the postreperfusion elevations of serum-glutamic-oxaloacetic transaminase (GOT), S-glutamic pyruvic transaminase (GPT), and the indocyanine green (ICG) dye retention rate. In conclusion, ET was produced both in the liver tissue exposed to ischemia and in the vascular endothelium of the portal bed exposed to portal congestion. The ET released from the vascular endothelium, including the liver and the portal bed, was found to be a possible factor of ischemia-reperfusion injury.
Asunto(s)
Endotelinas/metabolismo , Isquemia/metabolismo , Hígado/irrigación sanguínea , Daño por Reperfusión/etiología , Animales , Perros , Hígado/metabolismo , Vena Porta/fisiología , Presión VenosaRESUMEN
OBJECTIVE: This study reports further refinement of a prediction scoring system, which was established in 1980 as a guide to determine a safe limit for hepatectomy, based on 10 years of use. SUMMARY BACKGROUND DATA: In the past, whether major resection was safe was judged empirically from the net resection volume or the residual hepatic volume combined with the patient's liver function. However, such judgment was not based on objectively defined criteria. METHODS: Patients with hepatocellular carcinoma (HCC; n = 376) and metastatic cancer (n = 58) who had hepatectomy at some time from 1981 through 1990 were entered into this study. A prediction score (PS) was computed using a multiple regression equation that consists of computed tomographic scan-estimated resection rate, indocyanine green retention rate, and the patient's age. A PS greater than 55 was classified as a risky zone, a PS of 45 to 55 was considered borderline and a PS less than 45 was a safe zone. RESULTS: With HCC and chronic liver disease, all patients in the risky zone died, whereas 33% in the borderline zone died and 7.3% died who were in the safe zone. With metastatic cancer with normal liver, all patients in the risky zone died, whereas no patient in either the borderline or safe zones died. The major cause of death in the risky zone was liver failure due to excessive resection. In the borderline and safe zones, liver failure developed primarily after abdominal sepsis or pulmonary infection, particularly for those with adverse prognostic factors such as disturbed glucose tolerance, lower platelet count, and higher indocyanine green retention rate. CONCLUSION: Prediction scores can eliminate deaths related to excessive resection for patients with normal or injured livers. When patients have adverse prognostic factors, careful surgery and postoperative management is mandatory to avoid liver failure triggered by intra- or extra-abdominal sepsis, even if the score remains in a borderline or safe zone.
Asunto(s)
Carcinoma Hepatocelular/cirugía , Hepatectomía , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Anciano , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/secundario , Humanos , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/complicaciones , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
To examine the utility of the single-dose captopril test in detecting renovascular hypertension (RVHT), the authors measured peripheral plasma renin activity (PRA), before and thirty and sixty minutes after an oral dose of captopril (25 mg), in 28 patients with RVHT and 22 patients with high-renin essential hypertension (EHT) without renal artery stenosis who were consuming 8 grams of sodium chloride per day. There was considerable overlap of individual values in basal PRA between the two groups. Sixty minutes after captopril, PRA was higher in RVHT than in EHT patients (74.8 +/- 63.9 versus 15.1 +/- 11.9 ng/mL/hr, P < 0.01). With the cutoff point set at 16 ng/mL/hr, RVHT was detected with a sensitivity of 96% and a specificity of 77%. The discriminating power was also superior to that based on blood pressure response to angiotensin II analogue under sodium depletion, rapid-sequence intravenous pyelography, or renography. These results show that captopril-stimulated peripheral PRA is an adequate screening tool for detecting RVHT in a population with high-renin hypertension.
Asunto(s)
Captopril , Hipertensión Renovascular/diagnóstico , Hipertensión/diagnóstico , Obstrucción de la Arteria Renal/complicaciones , Adulto , Angiografía , Angiotensina II/análogos & derivados , Angiotensina II/antagonistas & inhibidores , Presión Sanguínea/efectos de los fármacos , Captopril/farmacología , Diagnóstico Diferencial , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión Renovascular/etiología , Riñón/irrigación sanguínea , Riñón/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Renografía por Radioisótopo , Arteria Renal/diagnóstico por imagen , Obstrucción de la Arteria Renal/diagnóstico por imagen , Renina/sangre , Sensibilidad y Especificidad , Cloruro de Sodio Dietético/administración & dosificación , UrografíaRESUMEN
The thyroid function was evaluated before and after 6 months of recombinant human erythropoietin (rhEPO) treatment (1,500-9,000 U/week) in 22 hemodialysis patients with hematocrit levels < 25%. Based upon the changes in hematocrit following rhEPO treatment, the patients were divided into two groups: 11 patients with an increase of the hematocrit level > 5% (group I) and 11 patients with an increase < 5% (group II). Before rhEPO administration, the levels of thyroid hormones, especially free thyroxine (T4) and free triiodothyronine (T3), were below the normal range despite normal thyrotropin values in most of the patients (low T4:7 cases in group I and 9 in group II; low T3:10 cases in group I and 10 in group II). RhEPO treatment significantly increased both total amount and free fractions of thyroid hormones in group I, whereas it did not affect these values in group II. Consequently, the pretreatment low T4 or low T3 status was resolved in a substantial number of the patients in group I (low T4:5 cases, low T3:4 cases). In addition, there was a significant correlation between the increases in hematocrit and free T3 in all studied subjects (r = 0.603; p < 0.05). These results suggest that anemia may participate to some extent in the pathogenesis of thyroid dysfunction in hemodialysis patients with renal anemia.