RESUMO
Application of information derived from a three-dimensional model of vasopressin bound to its antidiuretic receptor has resulted in the design and synthesis of a potent analog, [1-deamino, 2-phenylalanine, 7-(3,4-dehydroproline)]-arginine vasopressin; this analog has a specific antidiuretic activity of 13,000 +/- 1,250 units per milligram; noteworthy at these doses is the absence of any detectable pressor activity. Three modifications based on conformational considerations were introduced into the vasopressin molecule in preparing the analog: (i) to enhance binding, a double bond was introduced into the side chain of an amino acid residue occupying a corner position of a beta turn in the vasopressin conformation, (ii) the hydroxyl moiety was deleted from Tyr2, and (iii) to tighten the backbone structure and to enhance the enzymatic resistance of the analog, the NH2-terminal amino group was deleted.
Assuntos
Vasopressinas/análogos & derivados , Sequência de Aminoácidos , Desamino Arginina Vasopressina/análogos & derivados , Diurese/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Conformação Proteica , Relação Estrutura-Atividade , Vasopressinas/farmacologiaRESUMO
The distribution, blood transport, and metabolic clearance of physiological concentrations of antidiuretic hormone were studied in 10 hydrated normal subjects with radioiodinated arginine vasopressin (125I-AVP). At 37 degrees C no binding of 125I-AVP to plasma proteins could be demonstrated, but some metabolites were associated with plasma proteins. 125I-AVP was rapidly distributed into a space approximating the extracellular fluid volume. Metabolic breakdown products became demonstrable within minutes after injection. The mean metabolic clearance rate of 125I-AVP was 4.1 ml/min/kg and the mean plasma half-life 24.1 min. Renal clearance had a mean value of 80 ml/min and accounted for 27% of the total metabolic clearance. It is concluded that in man antidiuretic hormone circulates as a free (non-protein bound) peptide, diffuses readily into the extracellular fluid space, and is metabolized within minutes. A plasma half-life of 24 min is consistent with the duration of antidiuresis after hormone administration or release.
Assuntos
Arginina Vasopressina/metabolismo , Vasopressinas/análogos & derivados , Adulto , Arginina Vasopressina/sangue , Arginina Vasopressina/urina , Cromatografia em Papel , Feminino , Humanos , Iodoproteínas , MasculinoRESUMO
Prostaglandin E biosynthesis and its effect on water permeability were investigated in the toad urinary bladder. Arginine vasopressin (1 mU/ml) increased prostaglandin E (PGE) biosynthesis from 0.5+/-0.1 to 5.0+/-0.4 pmol/min per hemibladder (mean +/-SEM, n= 8, P less than 0.001). Maximal vasopressin-stimulated PGE biosynthesis, 6.4+/-0.2 pmol/min per hemibladder, occurred at vasopressin concentrations in excess of 3 mU/ml. Half-maximal stimulation of PGE biosynthesis occurred at a vasopressin concentration of approximately 0.7 mU/ml, whereas half-maximal stimulation of water flow occurred at a vasopressin concentration of approximately 5 mU/ml. Vasopressin-stimulated PGE biosynthesis did not depend on water flow along an osmotic gradient or upon sodium transport. Thin-layer chromatographic analysis of the lipids released from hemibladders labeled with tritium-arachidonic acid revealed that vasopressin stimulates the release of arachidonic acid from intracellular lipid stores without affecting the percentage of free arachidonic acid converted to PGE. Neither cyclic AMP nor theophylline stimulated PGE biosynthesis although they mimic arginine vasopressin (AVP) in stimulating water permeability. Biosynthesis of PGE was inhibited by mepacrine, a phospholipase inhibitor, and by agents that inhibit arachidonic acid oxygenase. The inhibition of PGE biosynthesis resulted in augmented vasopressin- and theophylline-stimulated water flow, but had no effect on cyclic AMP-stimulated water flow. We interpret these results to mean that endogenous PGE inhibits basal and vasopressin-stimulated adenylate cyclase activity. In contrast to the effects of AVP on permeability and transport, AVP stimulates PGE biosynthesis by a mechanism that does not depend on an increase in cellular cyclic AMP levels. The water permeability response of the toad urinary bladder to vasopressin is inhibited by PGE synthesized by the bladder in response to vasopressin.
Assuntos
Arginina Vasopressina/farmacologia , Prostaglandinas E/biossíntese , Bexiga Urinária/metabolismo , Vasopressinas/análogos & derivados , Água/metabolismo , Adenilil Ciclases/metabolismo , Animais , Anuros , Ácidos Araquidônicos/metabolismo , Cromatografia em Camada Fina , AMP Cíclico/farmacologia , Metabolismo dos Lipídeos , Permeabilidade , Quinacrina/farmacologia , Estimulação Química , Teofilina/farmacologiaRESUMO
Chlorpropamide is known to enhance the water permeability response of the toad urinary bladder to vasopressin and to theophylline. In other studies, we have shown that prostaglandin E synthesis by the toad bladder inhibits the water permeability response to arginine vasopressin and to theophylline. In this study, the effect of chlorpropamide on vasopressin-, theophylline-, and cyclic AMP-stimulated water flow and on prostaglandin E biosynthesis was investigated in the toad urinary bladder in vitro. Chlorpropamide inhibited prostaglandin E biosynthesis during vasopressin-, theophylline- and cyclic AMP-stimulated water flow. Tolbutamide and glyburide, two other sulfonylurea compounds, also enhanced vasopressin-stimulated water flow and inhibited vasopressin-stimulated prostaglandin E biosynthesis. We conclude that the mechanism of enhancement on vasopressin-stimulated water flow by the sulfonylureas is the inhibition of prostaglandin E biosynthesis.
Assuntos
Arginina Vasopressina/farmacologia , Clorpropamida/farmacologia , Prostaglandinas E/biossíntese , Bexiga Urinária/metabolismo , Vasopressinas/análogos & derivados , Água/metabolismo , Animais , Anuros , Cromatografia em Camada Fina , AMP Cíclico/farmacologia , Glibureto/farmacologia , Metabolismo dos Lipídeos , Permeabilidade , Estimulação Química , Relação Estrutura-Atividade , Teofilina/farmacologia , Tolbutamida/farmacologiaRESUMO
Rabbit renomedullary interstitial cells were isolated and grown in tissue culture. These cells synthesize 0.8 ng of prostaglandin E2 (PGE2) per microgram cellular protein per hour in monolayer tissue culture; prostaglandins A2 and F2alpha (PGA2 and PGF2alpha) biosynthesis was 10 and 5% of PGE2 biosynthesis, respectively. Arachidonic acid markedly stimulated the production of PGE2 and PGF2alpha, with conversion rates of 0.24 and 0.02%/h, respectively. Angiotensin II, hyperosmolality, bradykinin, and arginine vasopressin each stimulated PGE2 biosynthesis; maximum stimulation was 20, 3.7, 3.6, and 3.2 times basal production, respectively. PGE2 biosynthesis by the renomedullary interstitial cells was inhibited by isoproterenol, potassium, nonsteroidal anti-inflammatory agents (indomethacin, naproxen, ibuprofen, suprofen, meclofenamate, and acetylsalicylic acid), mepacrine (a phospholipase inhibitor), hydrocortisone, and cortisone. The rabbit renomedullary interstitial cell in tissue culture is a model system for the study of hormonal regulation of PGE2 biosynthesis.
Assuntos
Angiotensina II/farmacologia , Arginina Vasopressina/farmacologia , Bradicinina/farmacologia , Medula Renal/metabolismo , Rim/metabolismo , Prostaglandinas/biossíntese , Vasopressinas/análogos & derivados , Animais , Ácidos Araquidônicos/farmacologia , Divisão Celular , Células Cultivadas , Medula Renal/citologia , Medula Renal/efeitos dos fármacos , Concentração Osmolar , Potássio/farmacologia , Prostaglandinas A/biossíntese , Prostaglandinas E/biossíntese , Prostaglandinas F/biossíntese , Coelhos , Sódio/farmacologia , Relação Estrutura-AtividadeRESUMO
It has been shown by surface potential measurements that lysine vasopressin and oxytocin may be bound by ionic surfaces to very varied extents. To dodecyl sulphate and phosphatidylserine monolayers the binding is very strong and is comparable to that for biological receptors such as those in toad bladder. For dioleyl phosphate and the carboxyl group of the polypeptide alamethicin, the binding is rather weaker while, for the zwitterionic lipids phosphatidylcholine and phosphatidylethanolamine, and for the erythrocyte surface, which contains two varieties of carboxylic acid group, no interaction seems to take place. In no system does the lysyl amino group of the vasopressin appear necessary for adsorption and, in the dodecyl sulphate monolayers, the interaction is strong even when the ionization of the terminal alpha-amino group is suppressed.
Assuntos
Lipressina , Membranas Artificiais , Vasopressinas , Animais , Anuros , Sítios de Ligação , Cinética , Matemática , Potenciais da Membrana , Modelos Biológicos , Ocitocina , Fosfatidilserinas , Potenciometria , Dodecilsulfato de Sódio , Termodinâmica , Bexiga Urinária/fisiologia , Vasopressinas/análogos & derivadosRESUMO
The inactivation of the neurohypophyseal hormones arginine vasopressin and oxytocin, both 14C-labelled in the C-terminal glycine residue, by enzymes present in kidney homogenates of various species has been investigated, and some of the enzymes responsible have been partially purified and characterized. The Leu-Gly peptide bond of oxytocin is generally most effectively cleaved by kidney homogenates, although with certain species enzymic activity hydrolyzing the Pro-Leu bond is significant. Degradation of arginine vasopressin is slower than oxytocin in all species studied, and appears to occur by a different overall mechanism since cleavage of the Pro-Arg bond is more significant than hydrolysis of the Arg-Gly bond. The enzyme releasing glycinamide from oxytocin and the "Post-Proline Cleaving Enzyme", which releases C-terminal dipeptide from oxytocin and arginine vasopressin, were partially purified from lamb kidney by ammonium sulfate fractionation and column chromatography. The two enzymes are shown to be separate entities with different pH profiles. The prolyl peptidase activity released the C-terminal dipeptides from oxytocin and arginine vasopressin at similar rates and was inhibited by p-chloromercuriphenylsulfonic acid, 1,10-phenanthroline, L-1-tosylamido-2-phenylethylchloromethyl ketone, Co2+, Ca2+, and Zn2+, but significantly enhanced by dithiothreitol. The prolyl peptidase preparation cleaves proline-containing peptide substrates at the Pro-X bond. The rate of cleavage is dependent on the nature of residue X and with the conditions used there is no cleavage when X equals Pro; however, cleavage occurs when X is a D isomer: [Mpr1, D-Arg8] vasopressin is inactivated at a rate similar to [Mpr1, Arg8]- and [Mpr1, Lys8] vasopressin, suggesting that the known prolonged biological action of [Mpr1, D-Arg8] vasopressin is not due to resistance to the prolyl peptidase. In all characteristics tested the lamb kidney prolyl peptidase was identical to the post-proline cleaving enzyme isolated earlier from human uterus. In vivo experiments in the cat suggested that both the glycinamide-releasing enzyme and post-proline cleaving enzyme are present and effective in inactivating neurohypophyseal hormones in the intact animal.
Assuntos
Arginina Vasopressina/metabolismo , Rim/enzimologia , Lipressina/metabolismo , Ocitocina/metabolismo , Peptídeo Hidrolases/metabolismo , Vasopressinas/análogos & derivados , Animais , Cátions Bivalentes , Gatos , Cricetinae , Ditiotreitol/farmacologia , Cães , Ácido Edético/farmacologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Rim/efeitos dos fármacos , Cinética , Camundongos , Especificidade de Órgãos , Peptídeo Hidrolases/isolamento & purificação , Prolina , Coelhos , Ratos , Ovinos , Especificidade da Espécie , Suínos , Útero/enzimologiaRESUMO
Modification of the natural vasopressin molecule to form desmopressin acetate (DDAVP) resulted in a compound with prolonged antidiuretic activity and virtual elimination of vasopressor activity. Twenty-one patients with central diabetes insipidus who ranged in age from 3 to 68 years were treated with DDAVP, which was administered intranasally in a dosage ranging from 10 microgram every 12 hours to 20 microgram every eight hours. Effective control of symptoms was obtained in all cases. There were no consequential toxic effects. As previously reported, DDAVP appears to be the preferred drug for the management of central diabetes insipidus. Biochemical alteration of hormones may enhance desired therapeutic activity and eliminate toxic effects. The development of DDAVP is an example of the potential for development of useful therapeutic peptides.
Assuntos
Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido/tratamento farmacológico , Vasopressinas/análogos & derivados , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Desamino Arginina Vasopressina/administração & dosagem , Desamino Arginina Vasopressina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Indwelling, exteriorized, jugular vein catheters were placed in five thyroidectomized ewes at a time when myxedema was manifested clinically and chemically and three euthyroid sheep were used as controls. Post-operatively, tracer doses of [125I]-iodovasopressin were injected and serial blood specimens were obtained for determination of volume of distribution, plasma disappearance, and blood production rates. Serum vasopressin was measured by radioimmunoassay. The mean volumes of distribution for vasopressin in the hypothyroid and euthyroid sheep, respectively, were 8.15 and 5.90 liters, mean t1/2 of vasopressin 9.5 and 19.3 min, mean serum vasopressin concentrations 5.1 and 1.2 muU/ml, and mean blood production rates 2.84 and 0.23 mU/kg/h. Renal and organ biologic effectiveness of the elevated vasopressin levels was suggested by the lowered serum osmolalities in the hypothyroid sheep over controls (272 vs. 301 mosmol/kg). These results suggest an augmented secretion of vasopressin in the myxedematous state.
Assuntos
Arginina Vasopressina/metabolismo , Mixedema/fisiopatologia , Vasopressinas/análogos & derivados , Animais , Arginina Vasopressina/sangue , Feminino , Ovinos , TireoidectomiaRESUMO
Fourteen acutely hypophysectomized, anesthetized dogs were given a constant infusion of arginine vasopressin (AVP) and 131I-labeled arginine vasopressin ([131I]AVP). After 90 min, 3 blood samples were collected at 15 min intervals for determination of total body clearances of immunoreactive AVP and immunoreactive [131I]AVP. Seven dogs were then nephrectomized. Ninety minutes later, a second set of 3 blood samples was collected at 15 min intervals for clearance measurements in these and the 7 time-control dogs. Prenephrectomy AVP clearance averaged 5.1+/-1.0 ml/min-kg (mean +/- SE, n=7), and the 210-240 min postnephrectomy AVP clearance average 4.9+/-0.8. The 90-120 min average clearance in the time-control dogs was 6.1+/-0.9 ml/min-kg (n=7) and AVP clearance in these dogs increased (P less than 0.01) with time to 7.3+/-0.9 ml/min-kg during the 210-240 min period of constant infusion. Although the postnephrectomy AVP clearance was not significantly changed from prenephrectomy levels, it was significantly lower (P less than 0.05) than the 210-240 min average clearance in the time-controls. Clearance of [131I]AVP was 3.3+/-0.2 ml/min-kg (n=7) before nephrectomy and 2.9+/-0.2 ml/min-kg after nephrectomy. This was a significant 12% reduction (P less than 0.01). [131I]AVP clearance in the time control dogs was 3.9+/-0.3 during 90-120 min of infusion and 3.9+/-0.4 during 210-240 min of infusion. [131I]AVP clearance before nephrectomy was 79+/-12% of AVP clearance (P less than 0.005) and afther nephrectomy was 74+/-16% of AVP clearance (P less than 0.05). Although these results might suggest that [131I]AVP clearance is at least a qualitative indicator of AVP clearance, there was no significant correlation (P less than 0.20) between AVP clearance and [131I]AVP clearance.
Assuntos
Arginina Vasopressina/metabolismo , Rim/metabolismo , Vasopressinas/análogos & derivados , Animais , Arginina Vasopressina/sangue , Arginina Vasopressina/imunologia , Cães , Hipofisectomia , Radioisótopos do Iodo , Taxa de Depuração MetabólicaRESUMO
Using a new antiserum, an enzymatic radioiodination of arginine vasopressin (AVP), and the methodology of Robertson et al. (1,2), we have developed a sensitive and specific radioimmunoassay for plasma AVP in the monkey. The sensitivity of the assay is 0.5 muU/ml, the cross reaction with oxytocin (OT), minimal. We used this assay to study the effects that variations in blood osmolality have in regulating AVP secretion in unanesthetized, chair-restrained, chamber-isolated, adult female rhesus monkeys. Under water ad lib conditions, plasma AVP and osmolality were relatively constant, averaging 1.7 +/- 0.6 (SD) muU/ml and 298 +/- 3 mosmol/kg, respectively. Water loading decreased plasma AVP and osmolality to 0.6 +/- 0.2 muU/ml and 282 +/- 6 mosmol/kg, respectively. When fluid restriction increased osmolality, plasma AVP rose progressively to twice the baseline after 1 day, and to 6 times the baseline after 3 days. The rise in plasma AVP was linearly correlated with the rise in osmolality (r = 0.93; P less than 0.001). Intravenous infusions of hypertonic saline produced significant rises in plasma osmolality and plasma AVP. There was a dose-related rise in plasma AVP that declined later at the expected rate with the infusion of physiological amounts of synthetic AVP.
Assuntos
Arginina Vasopressina/sangue , Macaca mulatta/sangue , Macaca/sangue , Vasopressinas/análogos & derivados , Animais , Anticorpos , Arginina Vasopressina/imunologia , Haplorrinos , Radioimunoensaio/métodosRESUMO
The development of a sensitive radioimmunoassay for plasma arginine vasopressin (pAVP) is described. Using this assay, the levels of vasopressin were determined in the plasma of nondehydrated and dehydrated rats after exposure to ether or acceleration stress. Plasma AVP was also determined in rats following nicotine administration. Nondehydrated rats showed no significant changes in pAVP 1, 2, 5, or 15 min after exposure to ether for 1 min. Dehydrated rats, on the other hand, had significantly reduced pAVP after exposure to ether. One group (180-220 g) showed a decline in pAVP of 27% at 2 min (P less than 0.05) and and 47% at 5 min (P less than 0.001) after stress. In a group of larger animals (350-400 g), pAVP levels were reduced by 55% at 1 min (P less than 0.05) and 72% at 2 min (P less than 0.01) after ether stress. A third group (250-300 g) also had significantly reduced pAVP values of 57% (P less than 0.01) 5 min after ether stress but not at 15 min. Nondehydrated rats which were centriguated at -4.1 Gx for 5, 15 or 120 min showed no significant alterations in pAVP. No decrease in pAVP was observed in dehydrated rats centrifugated for 5 min; after 120 min of centrifugation, mean pAVP was reduced by 40% (P less than 0.02) when compared to be noncentrifugated controls. In contrast to either ether or acceleration stress, nicotine provoked a marked rise (P less than 0.005) in pAVP 10 min after injection. From these results it was concluded that ether or acceleration stress does not evoke an increase in the pAVP levels of rats, and furthermore, in dehydrated rats, these stressors will produce a significant decline in pAVP.
Assuntos
Arginina Vasopressina/sangue , Desidratação/sangue , Estresse Fisiológico/sangue , Vasopressinas/análogos & derivados , Animais , Arginina Vasopressina/análise , Éter , Feminino , Masculino , Nicotina/farmacologia , Radioimunoensaio , Ratos , RotaçãoRESUMO
The effect of beta-endorphin upon plasma arg8-vasopressin release was studied in vivo in rabbits and in vitro in rat neural lobes. Following intravenous administration of 200 mug/kg synthetic beta-endorphin plasma AVP rose significantly by five minutes after injection and remained elevated for twenty-five minutes compared to controls. In contrast beta-endorphin had no significant effect on AVP release from isolated rat neural lobes in vitro. beta-Endorphin stimulates AVP secretion in vivo, but this is not due to a direct action upon the neural lobe.
Assuntos
Arginina Vasopressina/metabolismo , Endorfinas/farmacologia , Neuro-Hipófise/metabolismo , Vasopressinas/análogos & derivados , Animais , Arginina Vasopressina/sangue , Técnicas In Vitro , Neuro-Hipófise/efeitos dos fármacos , Coelhos , RatosRESUMO
The effect of blood volume on the osmotic control of the antidiuretic hormone, arginine vasopressin (AVP), has been studied in 18 healthy young adults. Changes in blood osmolality and/or volume were produced by each of 3 procedures--fluid deprivation, orthostasis, and hypertonic saline infusion--and the resultant changes in plasma AVP were measured by radioimmunoassay and expressed as a function of the simultaneous level of plasma osmolality. When the subjects were hydropenic and recumbent, a highly significant correlation between plasma AVP and osmolality was observed that was described by the regression equation y = 0.35 (x -281.0) where y represents the plasma AVP concentration in pg/ml and x the plasma osmolality in mosmol/kg. When these same hydropenic subjects were studied in the upright position, a maneuver that reduces intrathoracic blood volume, plasma AVP and osmolality still showed a significant correlation, but the regression equation describing this relation, y = 0.31 (x -277.8), occupied a position significantly to the left of that found during recumbency. Conversely, when the same subjects were studied during infusion of hypertonic saline, a procedure that increases blood volume, plasma AVP and osmolality again correlated significantly but the regression equation describing this relation, y = 0.32 (x -282), now occupied a position significantly to the right of that obtained during recumbent and hydropenic conditions. These results indicate that moderate increases or decreases in blood volume do influence the osmoregulation of AVP in man, but the effects are relatively small and limited to adjustments in the set of the receptor toward higher or lower levels of osmolality.
Assuntos
Arginina Vasopressina/sangue , Volume Sanguíneo , Vasopressinas/análogos & derivados , Adulto , Sangue , Desidratação , Feminino , Hematócrito , Humanos , Masculino , Concentração Osmolar , Postura , Solução Salina HipertônicaRESUMO
Plasma arginine vasopressin (PAV) concentration was determined by radioimmunoassay during the diurnal cycle in 8 recombent healthy male subjects. Two subjects were studied again 3 weeks later while receiving 1 mycles. In 8 out of 10 cycles, a nocturnal increase in PAV was found; there was a progressive rise during the night in 5 subjects and a peak occurred at 2400 or 3400 h. In 1 subject no variation was detected and in another, the pattern was compleetly different. The mean PAV in the 10 cycles was significantly (P less than 0.001) higher during the night than during the day. Dexamethasone did not modify the pattern of variation, but induced a significant (P less than 0.001) decrease in PAV. Hematocrit remained stable throughout the study as did osmolality, except at 2000 h, when a significant (P less than 0.001) increase (5 mOsm) on average occurred in every subject. Blood sugar, sodium or chloride did not account for the observed rise in osmolality and no simultaneous change in PAV occurred. A rise in PAV explains, to some extent, the known nocturnal decrease in urine output. Diurnal variations in PAV must be taken into account in clinical investigations involving vasopressin.
Assuntos
Arginina Vasopressina/sangue , Ritmo Circadiano , Vasopressinas/análogos & derivados , Adulto , Dexametasona/farmacologia , Estudos de Avaliação como Assunto , Hematócrito , Humanos , Masculino , Métodos , Concentração Osmolar , Radioimunoensaio , Fatores de TempoRESUMO
A patient with the syndrome of chronic hypernatremia (serum Na+: mean = 154, range 139-184 mEq/l, n = 30) and hypodipsia due to a hypothalamic injury was studied to evaluate osmolar and baroreceptor control of arginine vasopressin (AVP) secretion. Resting plasma AVP levels measured by radioimmunoassay were inappropriately low for the degree of plasma hyperosmolality: range = less than 0.5-2.1 pg/ml, n = 10, with corresponding levels of plasma osmolality (P osM) greater than 300 m osmol/kg, suggesting either direct damage to the AVP synthesis and storage area or impaired afferent osmoreceptor function. Direct pituitary damage seemed unlikely, since anterior pituitary function was normal by standard testing. The existence of adequate neurohypophyseal stores of AVP was demonstrated by baroreceptor stimulation with the hypotensive agent trimethaphan (Arfonad): plasma AVP rising to 50.0 pg/ml during transient hypotension (BP = 70/0). Osmoreceptor function was evaluated during acute water loading followed by hypertonic saline infusion. During hypertonic saline infusion plasma AVP levels correlated with P osM (R = .87, P less than .01, n = 8), suggesting some residual osmotic regulation of AVP release. The osmotic threshold for AVP release (the x-axis intercept of the plasma AVP-P osM regression line) was not higher than normal. However, the AVP levels throughout this study remained markedly subnormal for the degree of plasma hyperosmolality (maximum plasma AVP = 1.9 PG/ML when P os M = 327 M OSMOL/KG). Since a substantial amount of AVP was released with baroreceptor stimulation, the inadequate rise in plasma AVP level with hyperosmolality indicates that afferent input from the osmoreceptor/thirst area of the hypothalamus is selectively impaired in this patient. These findings directly demonstrate a dissociation of osmoreceptor function from the AVP secretory apparatus in man.
Assuntos
Arginina Vasopressina/sangue , Hipernatremia/metabolismo , Pressorreceptores/metabolismo , Vasopressinas/análogos & derivados , Equilíbrio Hidroeletrolítico , Humanos , Soluções Hipertônicas , Hipotálamo/lesões , Doença Iatrogênica , Masculino , Pessoa de Meia-Idade , Cloreto de Sódio/farmacologia , Trimetafano/farmacologiaRESUMO
The effect of metergoline, a specific antiserotoninergic drug, on ACTH secretion was investigated in 29 normal volunteers and in 4 patients with increased ACTH production (3 with Addison's disease, 1 with Cushing's disease). In 15 normal subjects, a 4-day treatment with 10 mg daily of metergoline significantly blunted the ACTH response to insulin hypoglycemia. Mean peak ACTH values before and after treatment were, respectively, 333 +/- 39.2 (SE) and 235 +/- 38.8 pg/ml (P less than 0.05). The corresponding values of plasma cortisol were 29.6 +/- 2.96 and 20.5 +/- 2.67 mug/100 ml (P less than 0.05). In contrast, metergoline failed to affect the ACTH response to lysine-vasopressin (LVP) administered iv (8 subjects studied) and im (6 subjects studied). In 3 patients suffering from Addison's disease, an appreciable although not statistically significant lowering of the plasma ACTH levels was noted during metergoline administration. The mean pre- and post-treatment values of plasma ACTH in these patients were, respectively, 1116 +/- 192.2 and 666 +/- 100.8 pg/ml, 4240 +/- 50.0 and 3398 +/- 368.0 pg/ml, and 431 +/- 44.0 and 352 +/- 23.9 pg/ml. In one patient with Cushing's disease caused by a pituitary adenoma, metergoline did not appreciably modify plasma ACTH levels. Taken together, these results lend support to the concept of a physiological stimulating effect of serotonin on ACTH secretion. Moreover, they are compatible with the view that serotonin exerts its action chiefly at the hypothalamic level while LVP promotes ACTH release by a primary action on the pituitary.
Assuntos
Hormônio Adrenocorticotrópico/metabolismo , Ergolinas , Hidrocortisona/metabolismo , Hipoglicemia/induzido quimicamente , Insulina , Lipressina , Metergolina , Antagonistas da Serotonina , Vasopressinas/análogos & derivados , Doença de Addison/fisiopatologia , Adulto , Síndrome de Cushing/fisiopatologia , Feminino , Humanos , Hipoglicemia/fisiopatologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Pessoa de Meia-Idade , Serotonina/fisiologiaRESUMO
A study of plasma arginine vasopressin in 17 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) associated with bronchogenic carcinoma, revealed that the arginine vasopressin levels were distinctly elevated in most. In 14 patients with bronchogenic carcinoma, but without overt SIADH, plasma levels of arginine vasopressin were significantly higher than in normal subjects (p less than 0.001). This, together with the finding of a lower than normal plasma osmolality in this group, suggests that inappropriate ADH excess might be much more common in patients with bronchogenic carcinoma than previously thought. The normal positive correlation between plasma osmolality and plasma arginine vasopressin was found to be reversed in SIADH. Seven of nine patients with overt SIADH, studied after fluid deprivation, showed an increase in plasma arginine vasopressin coincident with an increase in plasma osmolality (r = +0.8, p less than 0.01); in one patient, plasma arginine vasopressin returned to the original level following rehydration. The possibility that this might imply a degree of physiologic control to what is generally considered an autonomous secretion is discussed. It is, however, considered more likely that other factors, including changes in plasma volume and glomerular filtration, might explain the increase in plasma levels of arginine vasopressin.
Assuntos
Arginina Vasopressina/sangue , Carcinoma Broncogênico/sangue , Neoplasias Pulmonares/sangue , Vasopressinas/análogos & derivados , Vasopressinas/sangue , Adulto , Idoso , Carcinoma Broncogênico/complicações , Feminino , Humanos , Hiponatremia/complicações , Neoplasias Pulmonares/complicações , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Síndrome , Privação de ÁguaRESUMO
[1-(L-2-Hdroxy-3-mercaptopropanic acid)]arginine-vasopressin (hydroxy-AVP), [1-(L-2-hydroxy-3-mercaptopropanoic acid),8-D-arginine]vasopressin (hydroxy-DAVP), and [1-(L-2-hydroxy-3-mercaptopropanoic acid),4-valine,8-D-arginine]vasopressin (hydroxy-VDAVP) were synthesized by a combination of the solid-phase and solution methods of peptide synthesis. Protected octapeptides synthesized by the solid-phase method were further acylated by 1 + 8 couplings in solution to furnish the key intermediates. Hydroxy-AVP has antidiuretic potency of 470 units/mg and activity in the rat vasopressor assay of 550 units/mg, representing a small enhancement of activity over that of arginine-vasopressin (AVP) in each case. Hydroxy-DAVP and hydroxy-VDAVP have essentially the same high antidiuretic activity (900 units/mg) and very low vasopressor potencies (0.9 and less than 0.02 units/mg, respectively). Hydroxy-AVP, hydroxy-DAVP, and hydroxy-VDAVP thus have antidiuretic-pressor selectivity (A/P) of 1, 1000, and greater than 45 000, respectively. These data are compared with those of other vasopressin analogues. Hydroxy-VDAVP is a highly specific antidiuretic peptids and may be useful in pharmacological studies of antidiuresis.
Assuntos
Arginina Vasopressina/análogos & derivados , Vasopressinas/análogos & derivados , Arginina Vasopressina/síntese química , Arginina Vasopressina/farmacologia , Diurese/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
In attempting to design an antagonist of the antidiuretic response to arginine-vasopressin (AVP) [1-deaminopenicillamine,4-valine,8-D-arginine]vasopressin (dPVDAVP) was synthesized by the solid-phase method and assayed for antidiuretic, vasopressor, and oxytocic activities. dPVDAVP has an antidiuretic potency of 123 +/- 22 units/mg, one-tenth that of its parent [deamino,4-valine,8-D-arginine]vasopressin (dVDAVP). Like dVDAVP its antidiuretic effect in conscious diabetes insipidus rats is greatly prolonged when compared to AVP. dPVDAVP causes a prolonged inhibition of vasopressor responses to AVP but not to norepinephrine or angiotensin II. It has an antivasopressor pA2 value of 7.82 +/- 0.05 when tested against AVP. Thus the penicillamine substitution at position 1 in dVDAVP increased its antivasopressor activity sixfold (dVDAVP has a pA2 value of 7.03 +/- 0.11). dPVDAVP is thus the most potent vasopressor antagonist yet reported. dPVDAVP was also found to be a potent inhibitor of the in vitro oxytocic response to oxytocin (pA2 value = 7.23 +/- 0.04). dPVDAVP with its potent and specific ability to antagonize the vasopressor effects of AVP should be a useful pharmacological tool with which to explore the possible participation of AVP's potent vasoconstrictor properties in cardiovascular regulation in physiological and pathological states.