RESUMO
Intestinal salt and fluid secretion is stimulated by Escherichia coli heat-stable enterotoxins (ST) through activation of a membrane guanylate cyclase found in the intestine. Guanylin is an endogenous intestinal peptide that has structural similarity to the bacterial peptides. Synthetic preparations of guanylin or E. coli ST 5-17 stimulated Cl- secretion in T84 cells cultured on semipermeable membranes as measured by increases in short circuit current (Isc). The guanylin/ST receptors appeared to be on the apical surface of T84 cells, since addition of guanylin to the apical, but not basolateral, reservoir stimulated Isc. Bumetanide added to the basolateral side effectively inhibited the Isc responses of T84 cells to either guanylin or ST 5-17. Guanylin appeared to be about one-tenth as potent as ST in stimulating transepithelial Cl- secretion. Guanylin and E. coli ST 5-17 both caused massive (> 1,000-fold) increases in cGMP levels in T84 cells, but guanylin was less potent than ST. Both peptides fully inhibited the binding of 125I-ST to receptor sites on intact T84 cells. The radioligand binding data obtained with guanylin or ST 5-17 best fit a model predicting two receptors with different affinity for these ligands. The Ki values for guanylin were 19 +/- 5 nM and 1.3 +/- 0.5 microM, whereas the Ki values for ST 5-17 were 78 +/- 38 pM and 4.9 +/- 1.4 nM. We conclude that guanylin stimulated Cl- secretion via the second messenger, cGMP, in T84 human colon cells. At least two guanylin receptors with different affinities for these ligands may exist in the cultured T84 cells. It may be postulated that guanylin is an endogenous hormone that controls intestinal Cl- secretion by a paracrine mechanism via cGMP and that E. coli ST stimulates Cl- secretion by virtue of an opportunistic mechanism through activation of guanylin receptors.
Assuntos
Toxinas Bacterianas/farmacologia , Cloretos/metabolismo , GMP Cíclico/metabolismo , Enterotoxinas/farmacologia , Hormônios Gastrointestinais , Guanilato Ciclase , Mucosa Intestinal/efeitos dos fármacos , Peptídeos/farmacologia , Receptores de Peptídeos , Toxinas Bacterianas/metabolismo , Ligação Competitiva , Transporte Biológico Ativo/efeitos dos fármacos , Bumetanida/farmacologia , Polaridade Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Enterotoxinas/metabolismo , Proteínas de Escherichia coli , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Peptídeos Natriuréticos , Receptores de Superfície Celular/metabolismo , Receptores de Enterotoxina , Receptores Acoplados a Guanilato CiclaseRESUMO
Guanylin and uroguanylin are peptides that stimulate membrane guanylate cyclases (GC) and regulate intestinal and renal function via cGMP. Complementary DNAs were isolated encoding opossum preproguanylin and a 279-amino acid portion of a receptor-guanylate cyclase expressed in opossum kidney (OK) cells (GC-OK). The tissue expression of messenger RNA transcripts for these signaling molecules were then compared. Northern and/or reverse transcription-PCR assays revealed that guanylin, uroguanylin, and GC-OK messenger RNAs are expressed in tissues within the digestive, renal, central nervous, reproductive, and lymphoid organ systems. Receptor autoradiography localized the receptors for uroguanylin and guanylin to renal proximal tubules and seminiferous tubules of testis. Synthetic guanylin and uroguanylin peptides activated the receptor-GCs in opossum kidney cortex and in cultured OK cells eliciting increased intracellular cGMP. Expression of agonist and receptor-GC signaling molecules provides a pathway for paracrine and/or autocrine regulation of cellular functions via cGMP in the digestive, renal, central nervous, reproductive, and lymphoid/immune organ systems. Uroguanylin also links the intestine and kidney in a potential endocrine axis that activates tubular receptor-GCs and influences renal function.
Assuntos
Hormônios Gastrointestinais , Peptídeos/metabolismo , Transdução de Sinais , Sequência de Aminoácidos , Animais , Sequência de Bases , Sistema Nervoso Central/metabolismo , DNA Complementar/genética , Sistema Digestório/metabolismo , Genitália/metabolismo , Rim/metabolismo , Sistema Linfático/metabolismo , Dados de Sequência Molecular , Peptídeos Natriuréticos , Gambás , Peptídeos/genética , Precursores de Proteínas/genética , RNA Mensageiro/metabolismoRESUMO
Uroguanylin and guanylin are peptides isolated from urine and intestinal mucosa, which regulate cyclic GMP production in enterocytes by activating an apical membrane, receptor-guanylate cyclase. This study extended our previous findings, which showed that colonic mucosa of opossums contained uroguanylin and guanylin peptides, by purifying prouroguanylin and proguanylin from this tissue. Prouroguanylin and proguanylin coeluted from Sephadex G-75 gelfiltration columns with a similar molecular size between 6 and 12 kDa. Mass spectrometry indicated that proguanylin (approximately 8.7 kDa) had a 10% lower molecular mass than prouroguanylin (approximately 9.7 kDa). Isoelectric focusing separated prouroguanylin (pI approximately 4.5) from proguanylin (pI approximately 7.5). N-terminal sequence analysis of reverse phrase-HPLC purified prohormones revealed 13 amino acids in opossum proguanylin that shared 77-85% identity with human and rat proguanylin, but only 23% identity with opossum prouroguanylin. The N-terminal 19 residues obtained for opossum prouroguanylin shared 32-42% identity with rat and human proguanylin. Prouroguanylin and proguanylin were both inactive and required pretreatment with proteases to elicit cyclic GMP responses in T84 cells. V8 protease treatment of proguanylin liberated a bioactive, 16-amino acid form of guanylin. Chymotrypsin treatment activated prouroguanylin, but inactivated the bioactive peptide domain within proguanylin. In summary, colonic mucosa contains the bioactive peptide and inactive prohormone forms of uroguanylin and guanylin. Thus, after proteolytic processing of prouroguanylin and proguanylin, bioactive uroguanylin and guanylin could both function to regulate guanylate cyclase activity by autocrine and/or paracrine actions on enterocytes. Also, these peptide hormones are implicated in an intestinal-renal axis for the endocrine regulation of salt and water homeostasis.
Assuntos
Colo/química , Endopeptidases/fisiologia , Hormônios Gastrointestinais , Precursores de Proteínas/isolamento & purificação , Precursores de Proteínas/metabolismo , Sequência de Aminoácidos , Animais , Células Cultivadas , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Quimotripsina/farmacologia , Colo/citologia , Humanos , Mucosa Intestinal/química , Mucosa Intestinal/citologia , Espectrometria de Massas , Dados de Sequência Molecular , Gambás , Precursores de Proteínas/química , RatosRESUMO
Guanylin and uroguanylin are small peptides containing two disulfide bonds that activate membrane guanylate cyclase-receptors in the intestine, kidney and other epithelia. Hybridization assays with a uroguanylin complementary DNA (cDNA) detected uroguanylin-like messenger RNAs (mRNAs) in the opossum spleen and testis, but these transcripts are larger than uroguanylin mRNAs. RT of RNA from spleen to produce cDNAs for amplification in the PCR followed by cloning and sequencing revealed a novel lymphoid-derived cDNA containing an open reading frame encoding a 109-amino acid polypeptide. This protein shares 84% and 40% of its residues with preprouroguanylin and preproguanylin, respectively. A 15-amino acid, uroguanylin-like peptide occurs at the COOH-terminus of the precursor polypeptide. However, this peptide is unique in having only three cysteine residues. We named the gene and its peptide product lymphoguanylin because the source of the first cDNA isolated was spleen and its mRNA is expressed in all of the lymphoid tissues tested. A 15-amino acid form of lymphoguanylin containing a single disulfide bond was synthesized that activates the guanylate cyclase receptors of human T84 intestinal and opossum kidney (OK) cells, although with less potency than uroguanylin and guanylin. Northern and/or RT-PCR assays detected lymphoguanylin mRNA transcripts in many tissues and organs of opossums, including those within the lymphoid/immune, cardiovascular/renal, reproductive, and central nervous organ systems. Lymphoguanylin joins guanylin and uroguanylin in a growing family of peptide agonists that activate transmembrane guanylate cyclase receptors, thus influencing target cell function via the intracellular second messenger, cGMP.
Assuntos
Clonagem Molecular , Hormônios Gastrointestinais , Gambás/genética , Peptídeos/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , GMP Cíclico/metabolismo , DNA Complementar/química , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Tecido Linfoide/química , Masculino , Dados de Sequência Molecular , Peptídeos Natriuréticos , Especificidade de Órgãos , Peptídeos/química , Peptídeos/farmacologia , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência , Baço/química , Testículo/químicaRESUMO
The natriuretic response was studied in anesthetized rats during the intravenous infusion of L-arginine analogues to inhibit the production of endothelium-derived nitric oxide. In an initial experimental series, rats were administered saline vehicle or vehicle containing 300 mumol/kg body wt N omega-monomethyl-L-arginine, N omega-nitro-L-arginine methyl ester, N omega-monomethyl-D-arginine, or L-arginine. Infusion of the competitive inhibitors N omega-monomethyl-L-arginine and N omega-nitro-L-arginine methyl ester significantly increased mean arterial pressure to 155 +/- 3 and 145 +/- 5 mm Hg, respectively, compared with a mean arterial pressure of 118 +/- 3 mm Hg determined in the vehicle control group. Sodium excretion averaged 3.27 +/- 1.08 and 2.52 +/- 0.78 mu eq/min in the N omega-monomethyl-L-arginine- and N omega-nitro-L-arginine methyl ester-treated rats, respectively, and each was significantly higher than the basal sodium excretion of 0.20 +/- 0.05 mu eq/min in the vehicle-treated control animals. Plasma renin activity was significantly lower in the N omega-monomethyl-L-arginine- and N omega-nitro-L-arginine methyl ester-treated groups than in the vehicle-treated group. Neither L-arginine nor N omega-monomethyl-D-arginine administration significantly altered any of the measured variables compared with vehicle alone. In a second experimental series, an adjustable snare was placed around the suprarenal aorta for the purpose of controlling renal perfusion pressure independently of increases in the systemic mean arterial pressure initiated by infusion of N omega-nitro-L-arginine methyl ester (75 mumol/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Arginina/análogos & derivados , Arginina/farmacologia , Pressão Sanguínea/fisiologia , Natriurese/fisiologia , Óxido Nítrico/metabolismo , Sódio/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , GMP Cíclico/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Masculino , NG-Nitroarginina Metil Éster , Ratos , Ratos Endogâmicos , Renina/sangue , ômega-N-MetilargininaRESUMO
We evaluated pressure-dependent stimulation of renin release in rats with sustained hypertension induced by chronic blockade of nitric oxide synthase with N omega-nitro-L-arginine methyl ester (L-NAME) for 5 to 7 days. Rats were anesthetized and catheters were inserted into the carotid artery and abdominal aorta for measurement of arterial pressures. An adjustable snare was placed around the suprarenal aorta, and this snare was tightened to reduce renal perfusion pressure. Pressure-dependent renin release was evaluated in hypertensive rats by reducing renal perfusion pressure to 125, 85, and 65 mm Hg. Renin release was also evaluated in normotensive control rats at these same pressures. Basal systemic arterial pressures averaged 159 +/- 3 and 124 +/- 4 mm Hg (P < .001), respectively, in the L-NAME-treated (n = 22) and normotensive control (n = 18) rats. Basal plasma renin activity was lower in L-NAME than control rats (5.0 +/- 0.3 versus 9.5 +/- 1.3 U, P < .01), and plasma renin activity was markedly attenuated at all comparable levels of renal perfusion pressure. Maximal plasma renin activity levels were achieved at perfusion pressures reduced to 65 mm Hg, and plasma renin activity averaged 14 +/- 2 and 34 +/- 7 U (P < .01) in L-NAME hypertensive and control rats, respectively. However, infusion of the nitric oxide donor sodium nitroprusside similarly stimulated plasma renin activity levels to 39 +/- 3 and 45 +/- 3 U (P > .05), in the hypertensive and normal control groups, respectively. Overall, these findings are consistent with the hypothesis that prolonged L-NAME administration attenuates pressure-dependent renin release by inhibiting nitric oxide formation, which may function as a paracrine mechanism inversely linking renal perfusion pressure with the stimulation of renin release.
Assuntos
Inibidores Enzimáticos/farmacologia , Hipertensão/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Renina/metabolismo , Animais , Anti-Hipertensivos/farmacologia , Hipertensão/induzido quimicamente , Masculino , Nitroprussiato/farmacologia , Pressão , Ratos , Ratos Sprague-Dawley , Renina/sangueRESUMO
The present study examined the role of the renal nerves in the development of hypertension produced by chronic infusion of angiotensin II in the conscious rat. The animals were divided into four groups, and a unilateral nephrectomy was performed. The remaining kidney was denervated in two groups, whereas in the other two groups of animals the nerves were left intact. Four days later either angiotensin II (83 ng/min) or saline infusions were begun through subcutaneously implanted osmotic minipumps. The rats were subsequently studied for 14 days. The results indicate that renal denervation significantly attenuated the pressor response to angiotensin II for approximately 6 days. Following this period, there was no difference in blood pressure between the innervated and denervated rats infused with angiotensin II, as both groups attained a hypertensive level of 170 to 180 mm Hg, which was 60 to 70 mm Hg above the blood pressure of the control rats infused with saline. Kidney norepinephrine content was reduced 95% by the denervation procedure and by 40% following infusion of angiotensin II into rats with intact renal nerves. These data demonstrate that, while the renal nerves appear to play a modulatory role in the development of the hypertension, they are not essential for the pathogenesis to occur nor do they determine the final level of hypertension achieved following chronic infusion of angiotensin II in the rat.
Assuntos
Angiotensina II/toxicidade , Hipertensão Renovascular/induzido quimicamente , Rim/inervação , Animais , Pressão Sanguínea/efeitos dos fármacos , Denervação , Hipertensão Renovascular/fisiopatologia , Masculino , Nefrectomia , Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos , Sistema Renina-AngiotensinaRESUMO
The acute response to ganglionic blockade (hexamethonium bromide, 30 mg/kg, i.v.) was used to evaluate the neurogenic contributions to mean arterial pressure maintenance in the conscious one-kidney, one clip hypertensive dog. Approximately 2 hours (112 minutes) after ganglionic blockade, captopril (10 mg/kg, i.v.) was given to block the renin-angiotensin system. Hypertensive animals were studied 3 days after clipping (group 2) or 2 to 4 weeks after clipping (groups 3 and 4). Groups 2 and 3 were fed a regular sodium diet, but group 4 animals were sodium and volume depleted. Normotensive control animals (group 1) were fed a regular sodium diet. On the day of the acute experiment the baseline blood pressures measured in group 2 (151 +/- 10 mm Hg, n = 5), group 3 (154 +/- 5 mm Hg, n = 7), and group 4 (160 +/- 8 mm Hg, n = 7) were not different (p greater than 0.05) from each other, but all were elevated (p less than 0.05) compared with the group 1 animals (106 +/- 3 mm Hg, n = 8). Also, there were no significant differences (p greater than 0.05) in the baseline plasma catecholamine levels among the three hypertensive groups. Ganglionic blockade produced a greater fall in blood pressure (p less than 0.05) in the sodium/volume-depleted dogs of group 4 (-35 mm Hg) than in group 1 (-10 mm Hg), group 2 (-3 mm Hg), or group 3 (-12 mm Hg) animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hipertensão Renovascular/fisiopatologia , Sódio/metabolismo , Animais , Captopril/farmacologia , Catecolaminas/fisiologia , Cães , Feminino , Hemodinâmica/efeitos dos fármacos , Hexametônio , Compostos de Hexametônio/farmacologia , Renina/sangue , Sistema Renina-AngiotensinaRESUMO
The effects of synthetic atrial natriuretic factor on renin secretion were examined in anesthetized dogs with either a single filtering kidney or a single denervated nonfiltering kidney. In dogs with a single filtering kidney (Series 1, n = 6), a priming dose of atrial natriuretic factor (2 micrograms/kg, i.v.) followed by sustained intravenous infusions at doses of 200 and 400 ng/kg/min for 20 minutes each produced striking decrements (p less than 0.05) in renin secretion, from 1083 +/- 322 to 205 +/- 120 and 286 +/- 168 ng of angiotensin I per minute. This fall in renin secretion was associated with significant increases (p less than 0.05) in creatinine clearance, urine flow, sodium excretion, and the filtered load of sodium. Renal blood flow increased only transiently. In dogs with a single denervated nonfiltering kidney (Series 2, n = 6), infusion of atrial natriuretic factor at these doses also produced marked inhibition (p less than 0.05) of renin secretion, from 311 +/- 98 to 72 +/- 22 and 91 +/- 37 ng of angiotensin I per minute. Renal blood flow remained significantly elevated (p less than 0.05) throughout the infusion, in contrast to renal blood flow in Series I. Similar results were obtained in a third series of dogs (n = 6) with a single denervated nonfiltering kidney, during sustained intrarenal arterial infusions of atrial natriuretic factor. These results suggest that an increase in the sodium load delivered to the macula suppression of renin secretion by atrial natriuretic factor is mediated through its interactions with the two intrarenal receptor mechanisms, the renal vascular receptor and the macula densa.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Fator Natriurético Atrial/farmacologia , Rim/efeitos dos fármacos , Renina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Creatinina/metabolismo , Denervação , Cães , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/inervação , Rim/fisiologia , Taxa de Depuração Metabólica , Potássio/sangue , Circulação Renal/efeitos dos fármacos , Sódio/sangueRESUMO
Renal function and renin release were studied in anesthetized, uninephrectomized dogs during intrarenal infusions of the calcium influx blockers, verapamil and nifedipine. Verapamil increased renal blood flow by 20% (p less than 0.05) but did not alter glomerular filtration rate. Verapamil produced five-to-seven fold increases in urine flow and the rates of excretion of sodium and chloride (p less than 0.01). Significant increases in the rates of excretion of potassium, calcium and magnesium were also observed. Despite its striking effects on renal function, verapamil, in nonhypotensive doses, failed to alter renin secretion. Intrarenal infusion of nifedipine had no consistent effect on renal blood flow or the rate of glomerular filtration but increased urine flow and the rates of excretion of sodium and chloride by more than three fold (p less than 0.01). Nonhypotensive doses of nifedipine had no significant effect on renin release. In dogs with a denervated nonfiltering kidney, an intrarenal verapamil or nifedipine infusion did not produce a significant change in renin release. This study demonstrates a striking effect of calcium entry blockers on the reabsorption of sodium, chloride, and water by the renal tubules in intact dogs but renin release did not increase unless hypotension occurred.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Rim/efeitos dos fármacos , Nifedipino/farmacologia , Piridinas/farmacologia , Renina/metabolismo , Verapamil/farmacologia , Animais , Água Corporal/metabolismo , Denervação , Cães , Eletrólitos/metabolismo , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Infusões Intra-Arteriais , Rim/inervação , Rim/metabolismo , Circulação Renal/efeitos dos fármacosRESUMO
Circadian changes in plasma renin activity (PRA) and plasma aldosterone concentration (PAC) in normal and hypertensive rats were determined by measurements at 8 a.m., 4 p.m. and 12 midnight (MN). For the normals, PRA and PAC were highest at 4 p.m. Animals made hypertensive by constriction one renal artery with the other kidney intact were studied after 4, 5, 7 and 10 weeks; the clear-cut circadian rhythm for PRA in normals had disappeared but for PAC the circadian rhythm was present in the 4-, 5- and 10-week groups. Both PRA and PAC were elevated in all four hypertensive groups compared with the normal controls and there was a highly significant correlation between PRA and PAC. The 4 p.m. peak value for PAC was much higher in relation to the 8 a.m. and 12 MN values values in the hypertensive animals than in the normals. Sodium balance studies failed to demonstrate any appreciable differences among the groups. When the hypertensive animals were divided into two groups on the basis of the level of hypertension, the rats with moderate hypertension showed an average elevation in PRA which was significant in only the 4- and 7-week groups whereas PRA was elevated in all four groups with severe hypertension. Thus, the present data help to define the activity of the renin-angiotensin-aldosterone system in two-kidney, one clip hypertension in the rat.
Assuntos
Aldosterona/sangue , Ritmo Circadiano , Hipertensão/sangue , Renina/sangue , Animais , Pressão Sanguínea , Ratos , Sódio/metabolismoRESUMO
Unilateral nephrectomy of sodium-restricted male Sprague-Dawley rats produced a sustained elevation in systolic blood pressure (SBP) that was reversed by sodium repletion. A chronic intraperitoneal infuson of SQ14,225 prevented the development of hypertension in sodium-deplete unilaterally nephrectomized rats. Sodium depletion of two-kidney rats increased SBP to a lesser extent, while unilateral nephrectomy of sodium replete animals had no effect. These results provide evidence for a new model of experimental hypertension in the rat and emphasize the importance of a renal component, as demonstrated by unilateral nephrectomy, in the maintenance of normal pressure-volume relationships.
Assuntos
Modelos Animais de Doenças , Hipertensão/etiologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Masculino , Nefrectomia , Ratos , Sódio/deficiênciaRESUMO
This study examines the hypothesis that the renal prostaglandins function as essential mediators in stimulus-secretion coupling for one or more of the basic receptor mechanisms in the control of renin release. Changes in plasma renin activity (PRA) were evaluated in response to suprarenal aortic constriction before and after indomethacin administration in conscious dogs with either a single denervated nonfiltering kidney or with intact filtering kidneys. Suprarenal aortic constriction was adjusted to reduce renal perfusion pressure below the autoregulatory range in both groups of dogs. Inhibition of cyclooxygenase with indomethacin significantly decreased urinary prostaglandin E2 (PGE2) excretion, but indomethacin failed to block or attenuate the increase in PRA in response to a decrease in renal perfusion pressure in either group of dogs. These results fail to support the hypothesis that the renal prostaglandins function as essential mediators of the intrarenal receptor mechanisms for renin release which are activated by a decrease in renal perfusion pressure below the autoregulatory range.
Assuntos
Rim/fisiologia , Prostaglandinas/fisiologia , Renina/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Denervação , Dinoprostona , Cães , Feminino , Indometacina/farmacologia , Rim/efeitos dos fármacos , Rim/inervação , Pressorreceptores/fisiologia , Prostaglandinas E/urina , Circulação Renal/efeitos dos fármacosRESUMO
Advances leading to recognition of the relation of the renin-angiotensin system to aldosterone include: (1) development of analytic techniques for measuring aldosterone, (2) discovery of an aldosterone-stimulating factor in circulating plasma, (3) the finding that a potent aldosterone-stimulating factor is secreted by the kidney, (4) evidence that synthetic angiotensin II increases aldosterone secretion, (5) fractionation of crude kidney extracts and the finding that aldosterone-stimulating factor is renin, (6) the observation that high plasma renin activity occurs in secondary aldosteronism, and (7) recognition that the renin-angiotensin-aldosterone system occurs in congestive heart failure and in renovascular and malignant hypertension. The early use of blocking agents for the renin-angiotensin system is described along with the landmarks of progress. These include the observations that: (1) arterial pressure decreases in experimental renovascular hypertension in response to angiotensin blockade, (2) angiotensin provides important support for arterial pressure in low cardiac output states including congestive heart failure, (3) the kidney participates in this important compensatory mechanism, and (4) cellular receptors for angiotensin are present in the two inner zones of the adrenal cortex.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Sistema Renina-Angiotensina , Animais , Captopril/história , História do Século XX , Humanos , Fisiologia/história , Sistema Renina-Angiotensina/efeitos dos fármacos , Estados UnidosRESUMO
In response to a meat meal containing 125 mEq of sodium, conscious dogs (n = 5) with an arteriovenous (AV) fistula and chronic compensated heart failure exhibited temporally related increases in postprandial plasma immunoreactive atrial natriuretic factor (iANF), right atrial pressure, and sodium excretion. In separate experiments, two weeks of dietary sodium restriction produced similar marked stimulation of renin and aldosterone both in normal dogs (n = 5), and in AV fistula dogs (n = 5) with chronic high circulating levels of ANF. Plasma iANF did not change (P greater than .05) in either group. These results suggest that the ANF system is involved in the postprandial regulation of sodium excretion in the AV fistula dogs with compensated heart failure. In the postabsorptive state, however, the activity of the renin-aldosterone axis is closely related to dietary sodium intake and appears to function independently of the ANF system for the prevention of sodium loss.
Assuntos
Fator Natriurético Atrial/fisiologia , Baixo Débito Cardíaco/urina , Sódio/urina , Aldosterona/sangue , Animais , Fístula Arteriovenosa/sangue , Fístula Arteriovenosa/fisiopatologia , Fístula Arteriovenosa/urina , Fator Natriurético Atrial/sangue , Débito Cardíaco/fisiologia , Baixo Débito Cardíaco/sangue , Cães , Feminino , Renina/sangue , Sistema Renina-Angiotensina/fisiologia , Sódio/administração & dosagem , Sódio/farmacologia , Sódio na Dieta/efeitos adversosRESUMO
It is well established that acute systemic blockage of L-arginine conversion to nitric oxide by NW-nitro-L-arginine methyl ester (L-NAME) and other substituted analogs of L-arginine produces vasoconstriction and elevates the blood pressure. The present study in rats reports that chronic L-NAME injections (185 mumol/L/kg body weight, intraperitoneally; every 12 h) for 4 days produces sustained arterial hypertension which is fully and rapidly reversed by acute administration of excess L-arginine. The magnitude of the hypertension is not different between L-NAME treated rats fed normal or high sodium diets. The results from this simple experimental model suggest that chronic blockade of nitric oxide synthesis results in sustained arterial hypertension that is not enhanced by sodium loading.
Assuntos
Hipertensão/metabolismo , Óxido Nítrico/metabolismo , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Pressão Sanguínea/fisiologia , Peso Corporal , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Renina/sangue , Sódio/urina , Fatores de TempoRESUMO
Atrial natriuretic factor 95-126 [ANF (95-126)] is a novel 32 amino acid peptide which is thought to originate from the kidney. The systemic hemodynamic and renal effects of equimolar doses of intravenous synthetic ANF (95-126) and synthetic alpha ANF (99-126) were examined in normal dogs (n = 6) and in dogs with an arteriovenous (AV) fistula and chronic compensated high-output heart failure (n = 5). ANF (95-126) and alpha ANF (99-126) were infused at 5 and 10 pmol/kg/min for 75-min periods each. In the normal and AV fistula dogs the two peptides similarly decreased mean arterial pressures and right atrial pressures (P less than .05). Creatinine clearance and urinary volume excretion increased (P less than .05) in the normal dogs with both peptides, but only ANF (95-126) produced significant elevations (P less than .05) of these two parameters in the AV fistula animals. With the highest infusion dose, ANF (95-126) increased urinary sodium excretion to at least twice the levels observed with alpha ANF (99-126) in both groups of dogs (P less than .05). The decreases in plasma renin and aldosterone were comparable for the two peptides in both groups of animals. These results indicate that ANF (95-126) is more potent than alpha ANF (99-126) for the promotion of a natriuresis, particularly in AV fistula dogs with compensated high-output heart failure, in which the sodium excretory actions of alpha ANF (99-126) were attenuated markedly.
Assuntos
Fator Natriurético Atrial/farmacologia , Baixo Débito Cardíaco/fisiopatologia , Diuréticos/farmacologia , Rim/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Animais , Baixo Débito Cardíaco/urina , Creatina/urina , Cães , Relação Dose-Resposta a Droga , Feminino , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Rim/fisiologiaRESUMO
The renal hemodynamic and excretory effects of intrarenal infusions of synthetic beta-human calcitonin gene-related peptide (beta-hCGRP) were examined in normal sodium replete dogs (Group 1, n = 6), in sodium replete dogs pretreated with indomethacin (Group 2, n = 6), and in sodium deplete dogs (Group 3, n = 5). In all groups of anesthetized dogs beta-hCGRP was infused at 5 and 10 ng.kg-1.min-1 for 50 min periods each. In the sodium replete group, beta-hCGRP infusions strikingly increased renal blood flow, but this response was markedly attenuated in the other 2 groups. During beta-hCGRP infusions, the clearance of creatinine also increased significantly in the sodium replete and deplete groups, but not in the indomethacin pretreated animals. No consistent changes in urinary sodium excretion or plasma renin activity were observed with beta-hCGRP infusions in any of the 3 groups of dogs. These results indicate that beta-hCGRP is a potent renal vasodilator and can increase renal blood flow and glomerular filtration. The data also suggest that the renal hemodynamic actions of beta-hCGRP are partially mediated by renal prostaglandins, and that the vasodilatory effects of beta-hCGRP may be antagonized by high circulating levels of endogenous angiotensin II in sodium-volume depletion. Finally, beta-hCGRP does not appear to have significant actions on urinary sodium excretion or plasma renin activity under the experimental conditions of the present study.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Calcitonina/farmacologia , Rim/fisiologia , Neuropeptídeos/farmacologia , Circulação Renal/efeitos dos fármacos , Animais , Peptídeo Relacionado com Gene de Calcitonina , Creatinina/metabolismo , Diurese/efeitos dos fármacos , Cães , Eletrólitos/sangue , Eletrólitos/urina , Feminino , Indometacina/farmacologia , Infusões Parenterais , Rim/efeitos dos fármacos , Neuropeptídeos/administração & dosagem , Valores de ReferênciaRESUMO
The systemic cardiovascular and renal effects of synthetic beta-human calcitonin gene-related peptide (beta-hCGRP) were examined in conscious normotensive and one-kidney one-clip (1K-1C) hypertensive dogs. beta-hCGRP was infused intravenously at 10 and 50 ng/kg/min for 75-min periods each. Mean arterial pressure did not change significantly (p greater than 0.05) in either group during low dose infusion of beta-hCGRP, but infusion of beta-hCGRP at 50 ng/kg/min produced a fall in mean arterial pressure from 140 +/- 4 to 116 +/- 6 mmHg (p less than 0.05) in the hypertensive dogs (n = 4) and from 100 +/- 4 to 78 +/- 3 mmHg (p less than 0.05) in the normotensive dogs (n = 4). Heart rates increased significantly during infusion of beta-hCGRP in both groups. Also, renal sodium and potassium excretion decreased (p less than 0.05) in the two groups at both the low and high doses of beta-hCGRP. Creatinine clearance was unchanged in normal dogs and decreased (p less than 0.05) in 1K-1C hypertensive dogs at the high rate of beta-hCGRP infusion. The clearance of p-aminohippurate increased approximately 20% (p less than 0.05) in both groups with the low dose infusion of beta-hCGRP but further increases were elicited only in the normotensive dogs in response to the elevation in the beta-hCGRP infusion rate. Plasma renin and aldosterone levels increased (p less than 0.05) above control levels during the maximum hypotensive response to beta-hCGRP infusion in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Calcitonina/farmacologia , Hipertensão Renovascular/fisiopatologia , Rim/fisiopatologia , Neuropeptídeos/farmacologia , Circulação Renal/efeitos dos fármacos , Aldosterona/sangue , Animais , Peptídeo Relacionado com Gene de Calcitonina , Modelos Animais de Doenças , Cães , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Infusões Intravenosas , Rim/efeitos dos fármacos , Rim/fisiologia , Neuropeptídeos/administração & dosagem , Potássio/sangue , Potássio/urina , Renina/sangue , Sódio/sangue , Sódio/urina , Resistência Vascular/efeitos dos fármacosRESUMO
Reduced expression of the low-affinity p75 neurotrophin receptor (p75(NTR)) occurs in prostate epithelial cells during malignant transformation. Recent studies indicating that the p75(NTR) can transduce signals that induce apoptosis suggest that diminished p75(NTR) in transformed prostate cells may contribute to immortalization. Mutations in the transmembrane domain of the p75(NTR) gene have been associated with decreased p75(NTR) protein expression and may block the ability of the p75(NTR) to induce apoptosis. Therefore, we used Western blot to analyze prostate cancer (PC) cell lines for p75(NTR) protein expression and gene single strand conformation polymorphism (SSCP) analysis and direct DNA sequencing to analyze mutations in the transmembrane domain of the p75(NTR). p75(NTR) Protein was present in all cell lines, and mutations in the p75(NTR) gene were not detected in cDNA derived from any cell line. To define the expression pattern of p75(NTR) in PCs in vivo, we used immunohistochemical techniques to examine tissue specimens from 20 benign, 19 malignant primary, and 14 metastatic prostate specimens. In benign prostate tissues, expression of p75(NTR) was universally detected in basal cells but not in secretory epithelial or stromal cells. In both primary and metastatic PC tissues, p75(NTR) immunoreactivity could not be detected in malignant prostate epithelial cells. However, in contrast to the benign prostate, p75(NTR) protein was expressed in stromal cells surrounding malignant epithelial cells. Stromal p75(NTR) expression was present in 84% (16 of 19) primary and in 86% (12 of 14) metastatic specimens. These data show that in the benign prostate p75(NTR) protein is expressed by basal cells and not stromal cells whereas in malignant prostate p75(NTR) protein is expressed by stromal cells but not prostatic carcinoma cells. Reversal of the p75(NTR) stromal-epithelial pattern of expression between benign and malignant prostate suggests that p75(NTR) may contribute to the development and maintenance of prostate cancer.