RESUMEN
Maternal renal hemodynamic adaptation to human pregnancy is one of the most dramatic of all physiologic changes, but the factors that are responsible have remained elusive. In rat pregnancy, there are comparable renal hemodynamic changes, and in this species there is comprehensive evidence that the ovarian hormone relaxin (RLX) is responsible. This study investigated the renal effects of recombinant human RLX (rhRLX) in humans. Eleven volunteers (six male, five female) received intravenous infusions of rhRLX over 5 h at an infusion rate that was chosen to sustain serum concentrations that are comparable to early pregnancy. The renal clearances of inulin and para-aminohippurate were used to measure GFR and renal plasma flow, respectively. Irrespective of gender, renal plasma flow was increased by 47% compared with baseline levels (P < 0.0001), but no significant change was observed in GFR. There were no side effects or adverse reactions of rhRLX given as an intravenous infusion, and the data suggest that RLX indeed may be one of the elusive renal vasodilatory factors in human pregnancy. Further work is necessary to elucidate the complimentary factors that permit the concomitant increase in GFR during pregnancy.
Asunto(s)
Tasa de Filtración Glomerular/efectos de los fármacos , Proteínas Recombinantes/farmacología , Relaxina/farmacología , Circulación Renal/efectos de los fármacos , Adolescente , Adulto , Femenino , Humanos , MasculinoRESUMEN
Women with normal ovarian function (n = 9) and women who conceived with ovum donation (no circulating relaxin; n = 9) had serial measurements of renal function made during the first trimester of pregnancy by using 24-hour creatinine clearance (CrCl) and plasma osmolality (P(osm)). All pregnancies were associated with increasing CrCl and reduced P(osm), but the change from baseline was significantly greater in the women with normal ovarian function, indicating that in contrast to the rodent model, other factors in addition to circulating relaxin contribute to gestational renal adaptation to human pregnancy.
Asunto(s)
Creatinina/sangre , Pruebas de Función Renal , Riñón/metabolismo , Embarazo/sangre , Relaxina/sangre , Adulto , Retroalimentación/fisiología , Femenino , Humanos , Tasa de Depuración Metabólica , Equilibrio Hidroelectrolítico/fisiologíaRESUMEN
Administration of recombinant human relaxin (rhRLX) to conscious, chronically instrumented rats increases GFR and effective renal plasma flow (ERPF) and decreases effective renal vascular resistance (ERVR) with no significant change in mean arterial pressure. The Munich Wistar albino rat shows progressive chronic nephrosis with age and therefore was used to determine the functional and histologic consequences of rhRLX on matrix remodeling in the kidney of older rats. RLX-infused rats showed increased GFR and ERPF with decreased ERVR. Furthermore, in a double-blinded examination, the renal histology showed a significant decrease in glomerular and tubular collagen deposition in the rhRLX-infused aged rats. During short-term rhRLX administration (24 h), gelatinase activity was found to be essential for renal vasodilation and hyperfiltration. Surprisingly, after 20 d, improved renal function was insensitive to the inhibition of gelatinase activity, suggesting that collagen degradation in these rats had permanently altered the matrix of the renal vasculature. In conclusion, long-term administration of rhRLX improves renal function and ameliorates renal pathology in an aging rat model. The biphasic action of rhRLX on the kidney indicates that, acutely, the vessels dilate, causing increased filtration and renal blood flow with decreased vascular resistance as a result of upregulation of gelatinase activity. Subsequently, the renal vessels undergo alteration in supporting matrix, showing increased blood supply even in the face of acute matrix metalloproteinase inhibition, most likely as a result of the inhibitory properties of RLX on collagen production or increased collagen breakdown.
Asunto(s)
Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Riñón/patología , Riñón/fisiopatología , Nefrosis/patología , Nefrosis/fisiopatología , Relaxina/administración & dosificación , Circulación Renal/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Riñón/efectos de los fármacos , Masculino , Nefrosis/prevención & control , Ratas , Ratas WistarRESUMEN
Chronic administration of recombinant human relaxin (rhRLX) to conscious, normotensive rats (male and female) increases cardiac output (CO) and global arterial compliance (ACg) and reduces systemic vascular resistance (SVR) with no change in mean arterial pressure (MAP). Effects (magnitude and temporal pattern) of relaxin on systemic hemodynamics and arterial properties in hypertensive animal models are not known. Accordingly, the major goal of the present study was to determine the cardiovascular effects of rhRLX in hypertensive rats using 2 models: Long-Evans rats chronically administered angiotensin II (AII) and spontaneously hypertensive rats (SHR). CO and systemic arterial load, as quantified by SVR and ACg, were obtained using methods reported previously by us. In rats with AII-induced hypertension, acute rhRLX administration (up to 6 hours) significantly increased CO and ACg (24.9+/-3.9 and 34.3+/-12.6% above baseline, respectively) and significantly decreased SVR (17.2+/-3.5%) without changing MAP. In contrast, acute rhRLX administration to SHR and normotensive rats for up to 6 hours failed to produce any significant changes in CO, ACg, SVR, or MAP. However, chronic rhRLX administration (1 to 7 days) to SHR yielded significant changes (24.0+/-8.1 and 22.3+/-6.6% increases in CO and ACg, respectively, and a 13.3+/-5.3% decrease in SVR, with no change in MAP). In conclusion, rhRLX increases CO and reduces arterial load in hypertensive rats without reducing MAP. However, the time course of response to rhRLX treatment is dependent on the model of hypertension such that rats characterized by AII-mediated hypertension responded more rapidly to rhRLX administration than SHR.
Asunto(s)
Arterias/fisiopatología , Gasto Cardíaco/efectos de los fármacos , Hipertensión/fisiopatología , Relaxina/farmacología , Resistencia Vascular/efectos de los fármacos , Angiotensina II , Animales , Adaptabilidad/efectos de los fármacos , Esquema de Medicación , Femenino , Humanos , Hipertensión/inducido químicamente , Hipertensión/genética , Bombas de Infusión , Inyecciones Intravenosas , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Long-Evans , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Relaxina/administración & dosificación , VasoconstrictoresRESUMEN
Chronic administration of recombinant human relaxin (rhRLX) to conscious female nonpregnant rats that reaches serum concentrations of 10-30 ng/mL increases cardiac output and reduces systemic arterial load comparable to levels observed in midterm pregnancy. Chronic administration of the hormone to male rats increases cardiac output and reduces systemic arterial load to a similar extent. Short-term or chronic administration of rhRLX to conscious female rats that reaches serum concentrations of approximately 80 ng/mL results in minimal and insignificant changes. We conclude that: (1) rhRLX increases cardiac output and reduces arterial load irrespective of gender, and (2)the rhRLX dose response is biphasic.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Relaxina/farmacología , Animales , Presión Sanguínea , Femenino , Corazón/efectos de los fármacos , Corazón/fisiopatología , Humanos , Masculino , Ratas , Proteínas Recombinantes/farmacología , Caracteres SexualesRESUMEN
The endothelial endothelin B (ET(B)) receptor subtype is critical for renal vasodilation induced by relaxin in nonpregnant rats and during pregnancy (the latter via endogenous circulating relaxin). Here we tested whether expression of vascular ET(B) receptor protein is regulated by relaxin. Small renal arteries were harvested from virgin and midterm pregnant rats as well as nonpregnant rats that were administered recombinant human relaxin (rhRLX) at 4 mug/h or vehicle for 5 d or 4-6 h. Small renal arteries dissected from additional virgin rats were incubated in vitro with rhRLX or vehicle for 3 h at 37 C. ET(B) expression was also evaluated in cultured human endothelial cells: aortic, coronary, umbilical vein, and dermal microvascular endothelial cells. Cells were incubated for 4, 8, or 24 h with rhRLX (5, 1, or 0.1 ng/ml) or vehicle. ET(B) protein expression in arteries and cells was evaluated by Western analysis. No regulation of ET(B) expression was observed in small renal arteries in any of the experimental protocols, nor was there an increase in the vasorelaxation response to ET-3 in small renal arteries incubated in vitro with rhRLX. rhRLX only sporadically altered ET(B) expression in human coronary artery endothelial cells and human umbilical vein endothelial cells at certain time points or doses, and no regulation was observed in human aortic endothelial cells or human dermal microvascular endothelial cells. These results suggest that regulation of ET(B) receptor protein has little or no role in relaxin stimulation of the endothelial ET(B)/nitric oxide vasodilatory pathway.
Asunto(s)
Preñez/metabolismo , Receptor de Endotelina B/metabolismo , Relaxina/metabolismo , Vasodilatación/fisiología , Animales , Anticuerpos Monoclonales , Femenino , Masculino , Embarazo , Ratas , Ratas Long-Evans , Receptor de Endotelina B/inmunología , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Relaxina/farmacología , Arteria Renal/efectos de los fármacos , Arteria Renal/fisiología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiología , Vasodilatación/efectos de los fármacosRESUMEN
We previously showed that chronic administration of recombinant human relaxin (rhRLX; 4 microg/h) to conscious female, nonpregnant rats to reach serum levels corresponding to early to midgestation (approximately 20 ng/ml) increases cardiac output (CO) and global arterial compliance (AC) and decreases systemic vascular resistance (SVR), comparable to changes observed in midterm pregnancy. The goals of this study were to test whether chronic administration of rhRLX (4 microg/h) to conscious male rats will yield similar changes in CO and systemic arterial load and to determine whether higher infusion rates of rhRLX (50 microg/h) administered to nonpregnant female rats yielding serum concentrations corresponding to late pregnancy ( approximately 80 ng/ml) will further modify CO and SVR and global AC comparable to late gestation. CO and systemic arterial load, as quantified by SVR and AC, were obtained by using the same methods as in our previous studies. With respect to baseline, chronic rhRLX administration to male rats over 10 days at 4 mug/h increased both CO (20.5 +/- 4.2%) and AC (19.4 +/- 6.9%) and reduced SVR (12.7 +/- 3.9%). These results were comparable to those elicited by the hormone in nonpregnant female rats. In contrast, neither acute (over 4 h) nor chronic (over 6 days) infusion of the higher dose of rhRLX administered to conscious female rats resulted in significant changes in CO, AC, or SVR from baseline. We conclude that 1) rhRLX increases CO and AC and reduces SVR irrespective of sex, and 2) the rhRLX dose response is biphasic insofar as significant alterations in CO and systemic arterial load fail to occur at high serum concentrations.
Asunto(s)
Arterias/efectos de los fármacos , Arterias/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Gasto Cardíaco/fisiología , Estado de Conciencia/fisiología , Relaxina/administración & dosificación , Animales , Fenómenos Biomecánicos/métodos , Gasto Cardíaco/efectos de los fármacos , Estado de Conciencia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratas , Ratas Long-Evans , Factores Sexuales , Resistencia Vascular/efectos de los fármacos , Resistencia Vascular/fisiologíaRESUMEN
Relaxin emanates from the corpus luteum of the ovary and circulates during pregnancy. Because the hormone is a potent renal vasodilator and mediates the renal vasodilation and hyperfiltration of pregnancy in conscious rats, we reasoned that it might also contribute to the broader cardiovascular changes of pregnancy. We began investigating this concept by testing whether relaxin can modify systemic arterial hemodynamics and load when chronically administered to nonpregnant rats. The major objectives of the present work were to determine whether relaxin administration to nonpregnant rats 1) modifies cardiac output (CO), systemic vascular resistance, and global arterial compliance (AC), and 2) regulates the passive mechanics of isolated arteries. To accomplish the first objective, we developed a conscious rat model for assessment of global AC. Passive mechanics of small renal arteries were assessed using a pressure arteriograph. Chronic administration of recombinant human relaxin by sc osmotic minipump to conscious, female, nonpregnant rats reduced the steady arterial load by decreasing systemic vascular resistance, increased CO, and reduced the pulsatile arterial load by increasing global AC as quantified by two indices-AC estimated from the diastolic decay of aortic pressure and CO and AC estimated by the ratio of stroke volume-to-pulse pressure. In another group of rats, relaxin administration also regulated the passive mechanics of small renal arteries, indicating that, in addition to reduction in vascular smooth muscle tone, modification of the vascular structure (e.g. extracellular matrix) contributes to the increase in global AC. These findings suggest a role for relaxin in the systemic hemodynamic changes of pregnancy, as well as novel therapeutic potential for relaxin in modifying arterial stiffness and cardiac afterload.
Asunto(s)
Relaxina/farmacología , Relaxina/fisiología , Resistencia Vascular/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Adaptabilidad/efectos de los fármacos , Estado de Conciencia , Relación Dosis-Respuesta a Droga , Ciclo Estral , Femenino , Músculo Liso Vascular/efectos de los fármacos , Embarazo , Ratas , Ratas Long-Evans , Arteria Renal/efectos de los fármacosRESUMEN
During pregnancy, relaxin stimulates nitric oxide (NO)-dependent renal vasodilation, hyperfiltration and reduced myogenic reactivity of small renal arteries via the endothelial ETB receptor subtype. Our objective in this study was to elucidate the mechanisms by which relaxin stimulates the endothelial ETB receptor/NO vasodilatory pathway. Using chronically instrumented conscious rats, we demonstrated that a specific peptide inhibitor of the gelatinases MMP-2 and -9, cyclic CTTHWGFTLC (cyclic CTT), but not the control peptide, STTHWGFTLS (STT), completely reversed renal vasodilation and hyperfiltration in relaxin-treated rats. Comparable findings were observed with a structurally different and well-established, general antagonist of MMPs, GM6001. In contrast, phosphoramidon, an inhibitor of endothelin-converting enzyme, did not significantly change the renal vasodilatory response to relaxin administration. When small renal arteries were incubated with either of the general MMP inhibitors, GM6001 or TIMP-2 (tissue inhibitor of MMP), or with the specific gelatinase inhibitor, cyclic CTT, the reduced myogenic reactivity of these blood vessels from relaxin-treated nonpregnant and midterm pregnant rats was totally abolished. Moreover, a neutralizing antibody specific for MMP-2 completely abrogated the reduced myogenic reactivity of small renal arteries from relaxin-treated nonpregnant and midterm pregnant rats. In contrast, phosphoramidon did not significantly affect the reduction in myogenic reactivity. Using gelatin zymography, we showed increased pro and active MMP-2 activity in small renal arteries from relaxin-treated nonpregnant and midterm pregnant rats relative to the control animals. Thus, inhibitors of MMPs in general and of gelatinases in particular reverse the renal vascular changes induced by pregnancy or relaxin administration to nonpregnant rats. Finally, the typical reduction in myogenic reactivity of small renal arteries from relaxin-treated nonpregnant rats was absent in ETB receptor-deficient rats, despite an increase in vascular MMP-2 activity. These results indicate an essential role for vascular gelatinase, which is in series with, and upstream of, the endothelial ETB receptor/NO signaling pathway in the renal vasodilatory response to relaxin and pregnancy.
Asunto(s)
Gelatinasas/metabolismo , Riñón/efectos de los fármacos , Relaxina/farmacología , Arteria Renal/efectos de los fármacos , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Dipéptidos/farmacología , Enzimas Convertidoras de Endotelina , Femenino , Gelatinasas/antagonistas & inhibidores , Gelatinasas/fisiología , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Técnicas In Vitro , Riñón/fisiología , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 2 de la Matriz/fisiología , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/fisiología , Inhibidores de la Metaloproteinasa de la Matriz , Metaloendopeptidasas , Oligopéptidos/farmacología , Péptidos Cíclicos/farmacología , Embarazo , Inhibidores de Proteasas/farmacología , Ratas , Ratas Long-Evans , Proteínas Recombinantes/farmacología , Arteria Renal/fisiología , Vasodilatación/efectos de los fármacosRESUMEN
The pregnancy hormone relaxin elicits renal vasodilation, hyperfiltration, and osmoregulatory changes when chronically administered to conscious, nonpregnant rats. The objective in this study was to determine the dose response and time course of hormone action, as well as the time required for recovery on stopping its administration. The threshold dose of recombinant human relaxin (rhRLX) for renal vasodilation and reduction in plasma osmolality was 0.15 microg/h when given by subcutaneous osmotic minipump for 2 days (an infusion rate that achieved circulating levels of approximately 6 ng/ml). The peak response was observed during the 0.4 microg/h infusion rate (serum rhRLX of approximately 11 ng/ml), which was comparable to our previous work using a 4.0 microg/h (serum rhRLX of approximately 20 ng/ml). In contrast, a dose of 40 microg/h was ineffective (serum rhRLX of approximately 80 ng/ml). When 4.0 microg/h rhRLX was administered by osmotic minipump for shorter periods (=24 h), renal circulatory and osmoregulatory changes were observed by =6 h. After removal of the osmotic minipump, these changes persisted for at least 12 h, but they were fully restored by 24 h. Even briefer administration of 4.0 microg/h rhRLX by intravenous infusion showed an onset of action in the kidney by 1-2 h. In contrast, the 40 microg/h dose of rhRLX elicited minimal effects, and comparable to our earlier report, 4.0 microg/h purified porcine relaxin was also relatively ineffective during short-term intravenous administration. In conclusion, the effect of relaxin on the renal circulation and osmoregulation is biphasic, insofar as high doses are relatively inactive, and the onset of action is more rapid than previously believed. These findings may be important to consider when evaluating relaxin in the treatment of renal disease.