RESUMO
With the draft sequence of the human genome available, there is a need to better define gene function in the context of systems biology. We studied 239 cardiovascular and renal phenotypes in 113 male rats derived from an F2 intercross and mapped 81 of these traits onto the genome. Aggregates of traits were identified on chromosomes 1, 2, 7, and 18. Systems biology was assessed by examining patterns of correlations ("physiological profiles") that can be used for gene hunting, mechanism-based physiological studies, and, with comparative genomics, translating these data to the human genome.
Assuntos
Fenômenos Fisiológicos Cardiovasculares , Mapeamento Cromossômico/métodos , Genômica/métodos , Animais , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/genética , Fenômenos Fisiológicos Cardiovasculares/efeitos dos fármacos , Cromossomos/genética , Cruzamentos Genéticos , Feminino , Humanos , Rim/fisiologia , Escore Lod , Masculino , Óxido Nítrico Sintase/genética , Norepinefrina/farmacologia , Fenótipo , Característica Quantitativa Herdável , Ratos , Vasodilatação/genéticaRESUMO
The role of leukocytes and platelets and of leukocyte- and platelet-derived eicosanoids in mediating acute changes in renal and glomerular hemodynamics was assessed in a model of antibody-induced mesangial cell injury in the rat. After a single intravenous injection (6 mg/kg) of the monoclonal antibody (ER4) against the mesangial cell membrane antigen Thy 1, significant decrements in glomerular filtration rate (GFR) and renal blood flow (RBF) were observed at 1 h, and were associated with increments in glomerular LC (+) leukocyte counts and in the synthesis of thromboxane (Tx)B2, leukotriene (LT)B4, and 12-hydroxyeicosatetraenoic acid (HETE). In rats with immune leukopenia, the rise in glomerular LC (+) leukocytes and in eicosanoid synthesis were abolished and the fall in GFR and RBF after administration of ER4 were completely ameliorated. Likewise, pretreatment of rats with both a thromboxane synthase and a 5-lipoxygenase inhibitor also blocked the fall in GFR and RBF and the rise in glomerular synthesis of TxB2 and LTB4 produced by ER4 without changing glomerular LC (+) leukocyte counts. Selective inhibition of thromboxane or 5-lipoxygenase alone only partially ameliorated the decrements in GFR and RBF produced by ER4. In animals with immune thrombocytopenia, the elevated glomerular synthesis of 12-HETE and fall in RBF but not GFR was ameliorated after administration of ER4. The ER4 antibody-induced fall in GFR was mainly caused by a marked decrement in the ultrafiltration coefficient, Kf, which was dependent on TxA2 and 5-lipoxygenase products, since pretreatment of animals with a thromboxane receptor antagonist or with a 5-lipoxygenase inhibitor partially ameliorated this decrement. Structural changes such as infiltration of glomerular capillaries by leukocytes and endothelial cell damage may also have accounted for the fall in Kf. These observations indicate that in antibody-mediated mesangial cell injury, infiltrating leukocytes and platelets mediate the changes in renal hemodynamics via synthesis of thromboxane and arachidonate 5-lipoxygenation products.
Assuntos
Eicosanoides/fisiologia , Mesângio Glomerular/imunologia , Hemodinâmica , Doenças do Complexo Imune/fisiopatologia , Animais , Antígenos de Superfície/imunologia , Plaquetas/fisiologia , Mesângio Glomerular/patologia , Mesângio Glomerular/fisiopatologia , Doenças do Complexo Imune/patologia , Leucócitos/fisiologia , Depleção Linfocítica , Masculino , Glicoproteínas de Membrana/imunologia , Microscopia Eletrônica , Ratos , Antígenos Thy-1RESUMO
To investigate whether a BP-regulatory locus exists in the vicinity of the renin locus on rat chromosome 13, we transferred this chromosome segment from the Dahl salt-sensitive (S) rat onto the genetic background of the Dahl salt-resistant (R) rat. In congenic Dahl R rats carrying the S renin gene and fed an 8% salt diet, systolic BP was significantly lower than in progenitor Dahl R rats: 127 +/- 1 mmHg versus 138 +/- 4 mmHg, respectively (P < 0.05). Moreover, the decreased BP in the congenic Dahl R strain was associated with decreased kidney renin mRNA and decreased plasma renin concentration. These findings demonstrate that the Dahl S strain carries alleles in or near the renin locus that confer lower plasma renin concentration and lower BP than the corresponding alleles in the Dahl R strain, at least when studied on the genetic background of the Dahl R rat and in the environment of a high salt diet. The occurrence of coincident reductions in kidney renin mRNA, plasma renin concentration, and BP after interstrain transfer of naturally occurring renin gene variants strongly suggests that genetically determined variation in renin gene expression can affect BP.
Assuntos
Hipertensão/genética , Renina/genética , Alelos , Animais , Mapeamento Cromossômico , Dieta , Feminino , Regulação Enzimológica da Expressão Gênica , Marcadores Genéticos , Rim/enzimologia , Masculino , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos , Ratos Mutantes , Renina/administração & dosagem , Cloreto de Sódio na DietaRESUMO
PURPOSE: Arachidonic acid is avidly metabolized to a potent vasoconstrictor, 20-hydroxyeicosatetraenoic acid (20-HETE), in the cerebral circulation. 20-HETE has been reported to contribute to the acute fall in cerebral blood flow following subarachnoid hemorrhage (SAH), but its role in the development of delayed vasospasm is unknown. The present study examined whether delayed vasospasm is associated with elevations in 20-HETE in CSF in the dual hemorrhage model of SAH in dogs and if blockade of the synthesis of 20-HETE with N-(3-chloro-4-morpholin-4-yl)phenyl-N'-hydroxyimido formamide (TS-011) can reverse delayed vasospasm in this model. MATERIALS AND METHODS: Delayed vasospasm was induced in 22 adult beagle dogs by dual injection of blood (0.5 mL/kg) into the cisterna magna on days 1 and 4. Sequential samples of CSF were collected before intracisternal injections of blood on days 1 and 4 and after the development of delayed vasospasm on day 7. Sequential angiograms were obtained before and after intracisternal injection of blood on days 1 and 4 and before and 1 hour after administration of TS-011 (1 mg/kg IV) on day 7. RESULTS: The dogs consistently developed delayed vasospasm, and the diameter of the basilar artery fell to 68 +/- 3% (n = 15), 3 days after the second intracisternal injection of blood. The levels of 20-HETE in CSF increased from 4 +/- 2 to 39 +/- 16 pg/mL. In 9 dogs with delayed vasospasm, acute blockade of the synthesis of 20-HETE with TS011 (1 mg/kg IV) significantly increased the diameter of the basilar artery by 39%. Chronic administration of TS-011 (1 mg/kg per day) attenuated the development of delayed vasospasm, and the diameter of the basilar artery fell by 17 +/- 1% versus the 33 +/- 3% decrease in diameter seen in control animals 3 days following the second injection of blood into the cisterna magna. CONCLUSIONS: These results indicate that the development of delayed vasospasm in dogs is associated with an increase in 20-HETE levels in CSF, and acute blockade of the synthesis of 20-HETE with TS-011 reverses delayed vasospasm in this model.
Assuntos
Formamidas/farmacologia , Ácidos Hidroxieicosatetraenoicos/fisiologia , Morfolinas/farmacologia , Hemorragia Subaracnóidea/complicações , Vasoespasmo Intracraniano/fisiopatologia , Animais , Artéria Basilar/diagnóstico por imagem , Artéria Basilar/fisiopatologia , Angiografia Cerebral , Cães , Ácidos Hidroxieicosatetraenoicos/antagonistas & inibidores , Ácidos Hidroxieicosatetraenoicos/líquido cefalorraquidiano , Hemorragia Subaracnóidea/diagnóstico por imagem , Vasoespasmo Intracraniano/diagnóstico por imagem , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologiaRESUMO
The blood vessel wall responds actively to an elevation in transmural pressure. This pressure-induced myogenic response is thought to set the basal level of vascular tone upon which metabolic and neural influences operate in concert to regulate organ blood flow. The cellular mechanisms that mediate the vascular muscle response to mechanical deformation via a changing transmural pressure include membrane depolarization, activation of phospholipase C, and a rise in intracellular [Ca(2+)](i), which appear to be nonadapting-remaining active as long as the pressure stimulus is applied. This brief review addresses some of the cellular events mediating transduction of transmural pressure by the vessel wall. Two possible mechanisms that are responsible for the nonadapting nature of pressure-induced myogenic tone are also explored, namely, formation of a P450 metabolite of arachidonic acid, which acts to buffer activation of K(+) channels as intracellular Ca(2+) rises, and direct activation of Ca(2+) channels by diacylglycerol. Evidence is provided suggesting that activation of phospholipase C is responsible for both the release of the arachidonic acid substrate for P450 enzymes and for the formation of diacylglycerol via its action on membrane-bound phospholipids.
RESUMO
A genetic segregation analysis was performed to identify genes that cosegregate with arterial blood pressure traits reflective of salt sensitivity. A population of 113 F2 male rats was derived from an intercross of inbred SS/JrHsd/Mcw (Dahl salt-sensitive) and BN/SsN/Mcw (Brown Norway) rats. Rats were maintained on an 8% salt diet from the age of 9 to 13 wk, and arterial pressure was measured for 3 h daily during the 4th wk of high salt intake in unanesthetized rats using implanted arterial catheters. At the end of the 3rd day of high-salt pressure recordings, the arterial pressure response to salt depletion was determined 1.5 days following treatment with Lasix and a low-sodium (0. 4%) diet. A genome-wide scan using 265 polymorphic simple sequence length polymorphism (SSLP) markers found that seven arterial pressure phenotypes determined at different times and circumstances, and representing two distinct indexes of salt sensitivity, mapped to the same region of rat chromosome 18. The trait of salt sensitivity was strongly influenced by the presence of SS alleles in this region of chromosome 18, and those rats which were homozygote SS/SS exhibited a significantly greater reduction of mean arterial pressure following sodium depletion (29 +/- 2 mmHg) than homozygote BN/BN (17 +/- 3 mmHg) or heterozygotic (22 +/- 2 mmHg) rats. This region of rat chromosome 18 corresponds to the long arm of human chromosome 5 and a region of human chromosome 18 that has been linked to hypertension in humans. Given the unlikely chance of these different blood pressure traits mapping to the same region, we believe these data provide evidence that this region of rat chromosome 18 plays an important role in salt-induced hypertension.
Assuntos
Pressão Sanguínea/genética , Cruzamentos Genéticos , Perfilação da Expressão Gênica , Predisposição Genética para Doença/genética , Hipertensão/genética , Alelos , Animais , Pressão Sanguínea/efeitos dos fármacos , Dieta Hipossódica , Furosemida/farmacologia , Ligação Genética , Marcadores Genéticos , Heterozigoto , Homozigoto , Hipertensão/metabolismo , Masculino , Mapeamento Físico do Cromossomo , Característica Quantitativa Herdável , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta/farmacologiaRESUMO
Perifusion of rat pancreatic islets with a physiologic, 6-mM amino acid mixture resulted in typical acute and second phase glucagon secretion over 30 min. At various intervals, islets were acutely fixed and processed for scanning electron microscopy, identification of alpha cells, and measurements of single alpha cell content of calcium (Ca), potassium (K) and sodium (Na) with energy-dispersive x-ray analysis. Biphasic glucagon secretion was attended by corresponding biphasic Ca accumulation and a reciprocal, biphasic suppression of K content and acute phase suppression of Na in alpha cells. All secretory and cellular events were preceded by an evanescent upward spike in alpha cell K at 1 min. These results indicate that alpha cell glucagon secretion in response to amino acid mixtures may be initiated by a K signal and is coupled subsequently to phasic changes in alpha cell Ca content. Fluctuations of alpha cell K and Na appear to relate inversely to Ca, suggesting that transmembrane fluxes of the three cations are interrelated.
Assuntos
Aminoácidos/farmacologia , Cálcio/metabolismo , Ilhotas Pancreáticas/metabolismo , Potássio/metabolismo , Sódio/metabolismo , Animais , Feminino , Glucagon/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Microscopia Eletrônica de Varredura , Ratos , Ratos EndogâmicosRESUMO
Micropuncture experiments were performed in volume-expanded rats to better define the nephron segments in which changes in renal perfusion pressure inhibit tubular reabsorption. Neural influences on the kidney were eliminated by renal denervation, and plasma levels of vasopressin, aldosterone, corticosterone, and norepinephrine were maintained at fixed levels by i.v. infusion. Fractional excretion of sodium, chloride, and water increased markedly after renal perfusion pressure was elevated from 110 to 150 mm Hg. Renal blood flow, glomerular filtration rate, and single nephron glomerular filtration rate measured from deep and superficial nephrons were unsaltered. Reabsorption of chloride and water in the proximal tubule of superficial nephrons decreased by 10% after renal perfusion pressure was elevated and contributed to the pressure-diuretic response. Changes in renal perfusion pressure also altered the reabsorption of water and chloride in juxtamedullary nephrons. The percentage of the filtered water load reaching the tip of the loop of Henle increased from 19.8 +/- 2.9 to 38.1 +/- 3.0% after renal perfusion pressure was elevated. Chloride delivery rose from 34.2 +/- 4.3 to 65.2 +/- 4.8% of the filtered load. These results support the view that alterations in medullary hemodynamics participate in the pressure-natriuretic response by inhibiting tubular reabsorption in the proximal tubule or the thin descending limb of the loop of Henle (or both) of juxtamedullary nephrons.
Assuntos
Diurese , Hipertensão/fisiopatologia , Túbulos Renais/fisiopatologia , Animais , Pressão Sanguínea , Taxa de Filtração Glomerular , Homeostase , Capacidade de Concentração Renal , Masculino , Néfrons/fisiopatologia , Pressão , Ratos , Ratos Endogâmicos , Circulação RenalRESUMO
In the present study, the pressure-natriuretic responses of 3- to 5- and 6- to 9-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were characterized to determine whether the relationship between sodium excretion and renal perfusion pressure is altered during the development of hypertension. Differences in the neural tone and renal hormone levels in SHR and WKY were minimized by denervating the kidney and fixing plasma concentrations of aldosterone, vasopressin, norepinephrine, and cortisol by intravenous infusion. Renal perfusion pressure was varied using adjustable occluders on the lower aorta. The slopes of the relationships between sodium excretion and renal perfusion pressure were not significantly different in 3- to 5-week-old SHR and WKY (0.31 +/- 0.05 vs 0.42 +/- 0.06 microEq/min/g kidney weight); however, the x-intercept of this relationship was significantly shifted to the right by 15 mm Hg in SHR compared to WKY. Blood pressure was moderately elevated even in the 3- to 5-week-old SHR in comparison to WKY (98 +/- 5 vs 81 +/- 6 mm Hg). As the degree of hypertension became more severe, the slope of the pressure-natriuresis relationship became significantly lower in 6- to 9-week-old SHR compared to the corresponding slope observed in age-matched WKY (0.16 +/- 0.02 vs 0.31 +/- 0.04 microEq/min/g kidney weight). These results indicate that the relationship between sodium excretion and renal perfusion pressure is altered even in very young SHR. Thus, the resetting of kidney function occurs very early and may be necessary for the development of hypertension in SHR.
Assuntos
Pressão Sanguínea , Hipertensão/fisiopatologia , Natriurese , Ratos Endogâmicos SHR/fisiologia , Ratos Endogâmicos/fisiologia , Envelhecimento/fisiologia , Animais , Diurese , Taxa de Filtração Glomerular , Hemodinâmica , Hipertensão/urina , Perfusão , Ratos , Ratos Endogâmicos WKY , Circulação RenalRESUMO
The present study examined whether renal prostaglandins influence the pressure-natriuretic response by altering medullary hemodynamics or renal interstitial pressure. The diuretic and natriuretic responses to changes in renal perfusion pressure were compared in control rats (n = 15) and in rats receiving either meclofenamate (2 mg/kg, n = 9) or indomethacin (2 mg/kg, n = 4). In control rats, urine flow and sodium excretion increased from 10 +/- 2 to 118 +/- 10 microliters/min/g kidney wt and from 1.8 +/- 0.3 to 21.0 +/- 1.5 mueq/min/g kidney wt, respectively, when renal perfusion pressure was increased from 109 to 167 mm Hg. Urinary excretion of prostaglandin E2 and thromboxane B2 increased significantly by 152% and 190%, respectively. Meclofenamate lowered thromboxane B2 and prostaglandin E2 excretion and prevented the increase in eicosanoid excretion produced by elevations in perfusion pressure. The pressure-diuretic and pressure-natriuretic responses of rats given meclofenamate or indomethacin were approximately half of those observed in the control rats. Papillary blood flow increased 21% and renal interstitial pressure rose from 5.0 +/- 0.7 to 8.2 +/- 0.7 mm Hg in control rats when pressure was elevated from 100 to 150 mm Hg. Meclofenamate and indomethacin lowered papillary blood flow and renal interstitial pressure and blunted the increases in these values produced by elevations in perfusion pressure. These results support the view that renal prostaglandins modulate the pressure-natriuresis relation by altering renal medullary hemodynamics and suggest that an intact renal prostaglandin system is necessary for the full expression of the medullary hemodynamic and natriuretic responses to increases in renal perfusion pressure.
Assuntos
Pressão Sanguínea/fisiologia , Medula Renal/irrigação sanguínea , Natriurese/fisiologia , Prostaglandinas/fisiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Dinoprostona/urina , Diurese/efeitos dos fármacos , Pressão Hidrostática , Indometacina/farmacologia , Córtex Renal/irrigação sanguínea , Medula Renal/fisiologia , Masculino , Ácido Meclofenâmico/farmacologia , Ratos , Ratos Endogâmicos , Fluxo Sanguíneo Regional , Sódio/urina , Tromboxano B2/urinaRESUMO
Blockade of nitric oxide reduces renal blood flow, but the site or sites at which nitric oxide alters renal vascular resistance are unknown. The effects of N omega-nitro-L-arginine (100 microM), an inhibitor of nitric oxide synthesis, on the pressure-diameter relation of renal arterioles was studied using a rat juxtamedullary microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. The basal diameters of the main arcuate and interlobular arteries and the proximal and distal afferent arterioles averaged 438 +/- 26, 64 +/- 4, 30 +/- 1, and 20 +/- 1 microns, respectively, at a perfusion pressure of 80 mm Hg. The diameters of the arcuate and interlobular arteries increased by 14 +/- 2% and 7 +/- 2%, whereas the proximal and distal afferent arterioles decreased by 3 +/- 1% and 7 +/- 2% when perfusion pressure was elevated to 160 mm Hg. Nitro-arginine had no effect on the basal diameters of arcuate and interlobular arteries. Nitro-arginine reduced the diameters of afferent arterioles by 7 +/- 2% at all perfusion pressures studied. Nitro-arginine increased active vascular tone in the interlobular artery and afferent arterioles and enhanced autoregulation of glomerular capillary pressure. L-Arginine (1 mM), the precursor to nitric oxide production, reversed the effects of nitro-arginine. These findings suggest that nitric oxide modulates vascular tone of the interlobular artery and afferent arterioles of deep nephrons and influences the ability of the preglomerular vasculature to autoregulate glomerular capillary pressure.
Assuntos
Glomérulos Renais/irrigação sanguínea , Óxido Nítrico/metabolismo , Circulação Renal/fisiologia , Sistema Vasomotor/fisiologia , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Arteríolas/fisiologia , Óxido Nítrico/antagonistas & inibidores , Nitroarginina , Perfusão , Pressão , Ratos , Ratos Endogâmicos , Circulação Renal/efeitos dos fármacos , Vasoconstrição , Sistema Vasomotor/efeitos dos fármacosRESUMO
The present study examined whether an alteration in renal medullary hemodynamics is associated with the development of hypertension in the spontaneously hypertensive rat (SHR). The relationships between whole kidney, cortical and papillary blood flows, and renal perfusion pressure were compared in 3- to 5-, 6- to 9-, and 12- to 16-week-old SHR and Wistar-Kyoto rats (WKY). Cortical and papillary blood flows were similar in the different age groups of SHR and WKY over most of the range of perfusion pressure studied. Control papillary blood flows, determined at a renal perfusion pressure equal to the mean arterial pressure of each animal, were not significantly different in the 3- to 5- and 12- to 16-week-old SHR in comparison to values observed in age-matched WKY. In contrast, the control papillary blood flow was 30% lower in 6- to 9-week-old SHR in comparison to the value observed in WKY. Papillary blood flows were significantly less in all age groups of SHR than the corresponding flows measured in WKY when they were compared at equivalent renal perfusion pressures. These findings indicate that medullary vascular resistance is elevated even in very young SHR and suggest that alterations in vasa recta hemodynamics may participate in the development of hypertension by shifting the pressure-natriuresis relationship toward higher pressures.
Assuntos
Hipertensão/fisiopatologia , Córtex Renal/irrigação sanguínea , Medula Renal/irrigação sanguínea , Ratos Endogâmicos SHR/fisiologia , Ratos Endogâmicos/fisiologia , Circulação Renal , Fatores Etários , Animais , Natriurese , Perfusão , Ratos , Ratos Endogâmicos WKY/fisiologia , Resistência VascularRESUMO
This study examines the nephron segments contributing to the blunted pressure-natriuretic response in Dahl salt-sensitive rats. Urine and late proximal and early distal tubular fluid samples were collected from 16-20-week-old, inbred Dahl salt-sensitive (DS/Jr) and salt-resistant (DR/Jr) rats, and Dahl salt-sensitive (DS) and salt-resistant (DR) rats from the Brookhaven colony, that were maintained from birth on a low (0.3%) sodium chloride diet. Urine flow and sodium and chloride excretions were 65% less in the DS/Jr than in the DR/Jr rats when their kidneys were perfused at an equal renal perfusion pressure of approximately 150 mm Hg. The percentages of the filtered load of water and chloride remaining at the end of the proximal tubule were significantly greater in DS/Jr rats than in DR/Jr rats; however, the percentages of the filtered load of water and chloride reaching the early distal tubule were significantly less, by 29% and 77%, respectively. Fractional reabsorption of water and chloride in the loop of Henle of DS/Jr rats was twice that observed in DR/Jr rats. Similar results were obtained in DS and DR rats of the Brookhaven strain. Urine flow and sodium and chloride excretions were 60% lower in DS than in DR rats at a renal perfusion pressure of 135 mm Hg. Proximal tubular reabsorption of water and chloride was similar in DS and DR rats; however, the percentages of the filtered load of water and chloride reabsorbed in the loop of Henle were greater in DS than in DR rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Cloretos/farmacocinética , Alça do Néfron/metabolismo , Cloreto de Sódio/farmacologia , Absorção , Animais , Pressão Sanguínea , Água Corporal/metabolismo , Dieta Hipossódica , Resistência a Medicamentos , Taxa de Filtração Glomerular , Túbulos Renais Proximais/metabolismo , Néfrons/metabolismo , Ratos , Ratos EndogâmicosRESUMO
The present study evaluated the effects of lovastatin on renal function and the development of hypertension in spontaneously hypertensive rats (SHR). Four-week-old SHR were given lovastatin (10 mg/kg) or vehicle twice daily by gavage. After 4 weeks of treatment, mean arterial pressure was significantly lower in lovastatin-treated SHR (131 +/- 4 mm Hg, n=5) than in control animals (160 +/- 4 mm Hg, n=12) (P<.05). The fall in arterial pressure in lovastatin-treated rats was accompanied by changes in renal function. The slope of the relationship between arterial pressure and sodium excretion was threefold greater in lovastatin-treated SHR (n=6) than in control rats (n=6), and this was associated with significant elevations in renal medullary blood flow and renal interstitial hydrostatic pressure. Glomerular filtration rate was 17% higher in lovastatin-treated SHR (n=6) than in control rats (n=6) (0.94 +/- 0.05 versus 0.81 +/- 0.07 mL/min per g of kidney weight, P<.05). The wall-to-lumen area ratio of renal arterioles was significantly reduced in lovastatin-treated SHR compared with vehicle-treated rats (0.86 +/- 0.05 versus 1.08 +/- 0.04 for vessels with inner diameters <50 microm and 0.62 +/- 0.02 versus 0.75 +/- 0.04 for vessels with inner diameters of 50 to 100 microm, P<.05). These results indicate that chronic treatment with lovastatin shifts the relations between renal medullary blood flow, renal interstitial pressure, sodium excretion, and renal perfusion pressure to lower levels of arterial pressure and attenuates the development of hypertension and renal vascular hypertrophy in SHR.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipertensão/prevenção & controle , Lovastatina/farmacologia , Ratos Endogâmicos SHR/fisiologia , Animais , Anti-Hipertensivos/farmacologia , Arteríolas/patologia , Pressão Sanguínea/efeitos dos fármacos , Espaço Extracelular/fisiologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Hidralazina/farmacologia , Pressão Hidrostática , Hipertensão/genética , Hipertensão/patologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Medula Renal/irrigação sanguínea , Natriurese/efeitos dos fármacos , Ratos , Circulação Renal/efeitos dos fármacosRESUMO
This study examined the role of endogenous 20 hydroxyeicosatetraenoic acid (20-HETE) in elevating Cl- transport in the medullary thick ascending loop of Henle (MTAL) of 9-week-old male Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats perfused in vitro. Basal transepithelial voltage (Vte; 14.9+/-0.9 versus 10.1+/-0.5 mV) and net lumen-to-bath Cl- flux (JCl) (155+/-6 versus 127+/-5 pEq. min-1. mm-1) were significantly greater in MTAL isolated from SS/Jr rats (n=16) than in those obtained from SR/Jr rats (n=16). Blockade of the synthesis of 20-HETE with 17-octadecynoic acid (17-ODYA; 10 micromol/L) increased Vte from 9. 9+/-0.8 to 13.1+/-1.0 mV and JCl from 127+/-7 to 152+/-8 pEq. min-1. mm-1 in the MTAL of SR/Jr rats (n=8), but it had no significant effect on Vte or JCl in the MTAL of SS/Jr rats (n=8). Exogenous 20-HETE (1 micromol/L) decreased Vte from 14.8+/-0.6 to 10.5+/-0.6 mV and JCl from 155+/-10 to 116+/-6 pEq. min-1. mm-1 in MTAL of SS/Jr rats (n=8), but it had no effect on Vte or JCl in the MTAL of SR/Jr rats (n=8). The expression of P4504A2 protein in the MTAL of SS/Jr rats was approximately half of that seen in the MTAL of SR/Jr rats. These results indicate that endogenously formed 20-HETE regulates transepithelial voltage and Cl- transport in the MTAL and that a diminished production of 20-HETE contributes to an elevation in Cl- transport in the MTAL of SS/Jr rats.
Assuntos
Cloretos/metabolismo , Ácidos Hidroxieicosatetraenoicos/fisiologia , Medula Renal/fisiologia , Alça do Néfron/fisiologia , Animais , Transporte Biológico/efeitos dos fármacos , Citocromo P-450 CYP4A , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Ácidos Graxos Insaturados/farmacologia , Ácidos Hidroxieicosatetraenoicos/farmacologia , Medula Renal/efeitos dos fármacos , Alça do Néfron/efeitos dos fármacos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Oxigenases de Função Mista/genética , Oxigenases de Função Mista/metabolismo , Ratos , Ratos Endogâmicos Dahl , Ratos Endogâmicos Lew , Ratos Sprague-DawleyRESUMO
Clofibrate has been reported to prevent the development of hypertension in Dahl S rats, but its mechanism of action remains to be determined. The present study examined the effects of clofibrate on renal P4504A activity and the pressure natriuresis relationship in Dahl S rats. Dahl S and R rats fed a low-salt diet (0.4% NaCl) were given either clofibrate (240 mg/kg/d) or vehicle (20 mmol/L Na2CO3) in their drinking water for 1 week and then switched to a high salt diet (8% NaCl) while continuing drug treatment. After 3 weeks, mean arterial pressure in ketamine-Inactin anesthetized rats averaged 121+/-2 (n=8) in Dahl R, 173+/-8 (n=6) in Dahl S, and 139+/-4 mm Hg (n=7) in clofibrate-treated Dahl S rats. Increasing renal perfusion pressure (RPP) from 100 to 150 mm Hg in Dahl R rats increased sodium excretion (U(Na)V) from 2.9+/-0.7 to 9.7+/-3.2 micromol/min/g kwt. In contrast, the pressure natriuresis relation was blunted in Dahl S rats and U(Na)V only increased from 2.7+/-0.9 to 6.1+/-1.3 micromol/min/g kwt. The pressure natriuresis relation was improved in clofibrate-treated Dahl S rats and U(Na)V increased from 5.1+/-1.3 to 16.7+/-2.6 micromol/min/g kwt. At similar levels of RPP, the fractional excretion of sodium tended to be higher in clofibrate-treated than in vehicle-treated Dahl S rats, but not significantly. Glomerular filtration rate (GFR) was 40% higher in clofibrate- compared to vehicle-treated Dahl S rats (0.9+/-0.2 versus 0.6+/-0.2 mL/min/g kwt), and was not significantly different from the values seen in Dahl R rats (0.9+/-0.1 mL/min/g kwt). Clofibrate induced the expression of P4504A protein in the renal cortex and outer medulla of Dahl S rats. These data suggest that induction of renal P4504A activity with clofibrate improves the pressure natriuresis relation in Dahl S rats by primarily increasing GFR.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Clofibrato/farmacologia , Sistema Enzimático do Citocromo P-450/biossíntese , Taxa de Filtração Glomerular/efeitos dos fármacos , Hipertensão/prevenção & controle , Hipolipemiantes/farmacologia , Rim/enzimologia , Oxigenases de Função Mista/biossíntese , Natriurese/efeitos dos fármacos , Animais , Citocromo P-450 CYP4A , Dieta Hipossódica , Indução Enzimática , Feminino , Hipertensão/genética , Isoenzimas/biossíntese , Rim/efeitos dos fármacos , Rim/fisiopatologia , Córtex Renal/enzimologia , Medula Renal/enzimologia , Ratos , Ratos Endogâmicos , Valores de Referência , Sódio na DietaRESUMO
The role of angiotensin II and kinins on the renal cortical and papillary hemodynamic and on the sodium and water excretory responses to converting enzyme inhibition with captopril was examined in euvolemic Munich-Wistar rats. Cortical and papillary blood flows were measured using a laser Doppler flowmeter. Cortical blood flow increased 28% after blockade of angiotensin II receptors with DuP 753 (2 mg/kg i.v., n = 6). Captopril (2 mg/kg i.v., n = 6) had no effect on cortical blood flow in rats pretreated with the angiotensin II antagonist. DuP 753 had no effect on papillary blood flow, nor did it prevent the rise in papillary blood flow produced by captopril (2 mg/kg, n = 6). Infusion of a kinin receptor antagonist, D-Arg, [Hyp3,Thi5,8,D-Phe7]-bradykinin (2.5 micrograms/min i.v.), reduced basal papillary blood flow by 15% and blocked the rise in papillary blood flow produced by captopril. Renal blood flow rose by 11% after DuP 753 (2 mg/kg, n = 6), and subsequent administration of captopril and the kinin antagonist had no effect on renal blood flow. Urine flow and sodium excretion increased after DuP 753, but captopril produced additional increases in urine flow and sodium excretion of 68% and 46% respectively. Fractional sodium excretion rose from 0.85 +/- 0.15% to 1.56 +/- 0.14% after captopril. Infusion of the kinin antagonist returned sodium and water excretion to control levels, but fractional sodium excretion was not significantly altered. Glomerular filtration rate was not altered by DuP 753 or captopril; however, it fell from 1.6 +/- 0.1 to 1.2 +/- 0.1 ml/min/g kidney wt during infusion of the kinin antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Angiotensina II/farmacologia , Captopril/farmacologia , Receptores de Neurotransmissores/antagonistas & inibidores , Circulação Renal/efeitos dos fármacos , Angiotensina II/antagonistas & inibidores , Animais , Bradicinina/análogos & derivados , Bradicinina/antagonistas & inibidores , Bradicinina/farmacologia , Hemodinâmica/efeitos dos fármacos , Imidazóis/farmacologia , Cininas/metabolismo , Lasers , Losartan , Punções , Ratos , Ratos Endogâmicos , Receptores da Bradicinina , Tetrazóis/farmacologia , UltrassonografiaRESUMO
Several experimental forms of hypertension require intact renal innervation for the development or maintenance (or both) of the elevated arterial pressure. We determined the relationships between urinary sodium and water excretion and arterial pressure in Dahl salt-sensitive rats (DS) with innervated (n = 6) and denervated (n = 7) kidneys after switching from a low to a high sodium diet. Arterial pressure significantly increased in both groups within 48 hours after they began to eat an 8% sodium chloride diet. This hypertension increased to 188 +/- 9 and 190 +/- 7 mm Hg, respectively, in rats with innervated and denervated kidneys after 12 days. Mean arterial pressures were not significantly different between groups on any day. The rise in arterial pressure of DS placed on a high sodium intake was associated with an elevation of urine flow rate and urinary sodium excretions in rats with either innervated or denervated kidneys. Urine flow rates and urinary sodium excretions were greater in denervated than in innervated rats on Days 4 through 7 after beginning the high sodium diet. This diuresis and natriuresis in rats with denervated kidneys were associated with greater water and sodium intakes on Days 4 to 7 of the high sodium diet when compared with rats with innervated kidneys. These results demonstrate that, following exposure to a high sodium intake, DS have increased arterial pressure within 24 hours. The development of this arterial hypertension is not dependent on intact renal innervation. In conscious DS, the renal innervation does participate in the regulation of urinary sodium excretion by promoting renal sodium and water reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/induzido quimicamente , Rim/inervação , Cloreto de Sódio/administração & dosagem , Animais , Peso Corporal/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Denervação , Diurese/efeitos dos fármacos , Ingestão de Líquidos , Espaço Extracelular/efeitos dos fármacos , Feminino , Natriurese/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Sódio/urina , Cloreto de Sódio/metabolismo , Sistema Nervoso Simpático/fisiologia , Fatores de Tempo , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
The renal microvascular responses of Wistar-Kyoto and spontaneously hypertensive rats to changes in perfusion pressure were compared using a juxtamedullary nephron microvascular preparation perfused in vitro with a physiological salt solution containing 5% albumin. In the spontaneously hypertensive rats, the internal diameters of arcuate and interlobular arteries and the proximal and distal afferent arterioles averaged 307 +/- 26, 52 +/- 2, 24 +/- 0.9, and 22 +/- 1.2 microns, respectively, at 80 mm Hg. They were 18-35% smaller (p less than 0.05) than the corresponding vessels measured in Wistar-Kyoto rats. In low calcium media, the arcuate and interlobular arteries and the proximal and distal afferent arterioles of spontaneously hypertensive rats exhibited a greater dilation than the vessels of Wistar-Kyoto rats. These observations suggest that the diameters of the preglomerular vasculature of the spontaneously hypertensive rats are reduced because of an elevated vascular tone rather than structural changes narrowing the lumen of these vessels. These results suggest that enhanced vascular tone in the preglomerular vasculature of juxtamedullary nephrons may contribute to the elevated renal medullary vascular resistance and resetting of the pressure-natriuretic relation previously observed in spontaneously hypertensive rats.
Assuntos
Tono Muscular , Músculo Liso Vascular/fisiologia , Animais , Indometacina/farmacologia , Microcirculação , Perfusão , Pressão , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Circulação Renal/efeitos dos fármacos , VasodilataçãoRESUMO
This study examined whether the calcium antagonist nisoldipine can shift the relations between sodium excretion, papillary blood flow, renal interstitial pressure, and renal perfusion pressure toward lower pressures in spontaneously hypertensive rats. Mean arterial pressure decreased similarly by 9% and 12% in Wistar-Kyoto and spontaneously hypertensive rats after nisoldipine (0.5 microgram/kg bolus + 0.017 microgram/kg/min). Urine flow and sodium excretion increased by 35% and 24% in Wistar-Kyoto rats after nisoldipine. In contrast, urine flow and sodium excretion rose by 121% and 132% in spontaneously hypertensive rats, and fractional sodium excretion rose from 1.9 +/- 0.3 to 4.2 +/- 0.4%. Control sodium excretion, papillary blood flow, and renal interstitial pressure were significantly lower in spontaneously hypertensive rats than in Wistar-Kyoto rats when compared at similar renal perfusion pressures. Sodium excretion, papillary blood flow, and renal interstitial pressure all increased in spontaneously hypertensive rats after nisoldipine, whereas it had no effect on papillary blood flow or renal interstitial pressure in Wistar-Kyoto rats. The relations among sodium excretion, papillary blood flow, renal interstitial pressure, and renal perfusion pressure were shifted toward lower pressures in spontaneously hypertensive rats given nisoldipine and became similar to those seen in Wistar-Kyoto rats. These results indicate that nisoldipine normalizes the relations among sodium excretion, renal interstitial pressure, papillary blood flow, and renal perfusion pressure in spontaneously hypertensive rats perhaps by correcting the defect in renal medullary perfusion associated with resetting of pressure natriuresis in this model of hypertension.