RESUMEN
AIMS/HYPOTHESIS: This study aimed to identify the expression of angiotensin II receptors in isolated human islets and beta cells and to examine the functional consequences of their activation. MATERIALS AND METHODS: Single-cell RT-PCR was used to identify whether human islet cells express mRNA for type 1 angiotensin II receptors (AT(1)), and western blotting was used to determine AT(1) protein expression by human islets and MIN6 beta cells. We measured changes in intracellular calcium by microfluorimetry using Fura 2-loaded MIN6 cells and human islet cells. Dynamic insulin secretory responses were determined by RIA following perifusion of human islets and MIN6 cells. RESULTS: Human islets expressed mRNAs for both the angiotensin precursor, angiotensinogen, and for angiotensin-converting enzyme. In addition, human and mouse beta cells expressed AT(1). These were functionally coupled to increases in intracellular calcium, which occurred at least in part through phospholipase-C-sensitive mechanisms and calcium influx through voltage-operated calcium channels. Short-term exposure of human islets and MIN6 cells to angiotensin II caused a rapid, short-lived initiation of insulin secretion at 2 mmol/l glucose and potentiation of insulin secretion induced by glucose (at 8 and 16.7 mmol/l). CONCLUSIONS/INTERPRETATION: These data demonstrate that the AT(1) is expressed by beta cells and that angiotensin II effects a short-lived and direct stimulation of human and mouse beta cells to promote insulin secretion, most probably through elevations in intracellular calcium. Locally produced angiotensin II may be important in regulating a coordinated insulin secretory response from beta cells.
Asunto(s)
Angiotensina II/farmacología , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Receptores de Angiotensina/fisiología , Angiotensina Amida/farmacología , Angiotensina II/fisiología , Angiotensinógeno/genética , Angiotensinógeno/fisiología , Animales , Western Blotting , Calcio/análisis , Línea Celular , Células Cultivadas , Fluorometría , Regulación de la Expresión Génica , Glucosa/farmacología , Humanos , Imidazoles/farmacología , Secreción de Insulina , Células Secretoras de Insulina/química , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Islotes Pancreáticos/citología , Ratones , Nifedipino/farmacología , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/fisiología , Piridinas/farmacología , ARN Mensajero/análisis , ARN Mensajero/genética , Receptores de Angiotensina/análisis , Receptores de Angiotensina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Saralasina/farmacologíaRESUMEN
Angiotensin II interacts with specific cell surface angiotensin AT1 and AT2 receptors and, in some vertebrates, with an atypical angiotensin AT receptor. This study was designed to characterize the angiotensin receptor in the heart of Bothrops jararaca snake. A specific and saturable angiotensin II binding site was detected in cardiac membranes and yielded Kd=7.34+/-1.41 nM and B(max)=72.49+/-18 fmol/mg protein. Competition-binding studies showed an angiotensin receptor with low affinity to both angiotensin receptor antagonists, losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole) and PD123319 ((s)-1-(4-[dimethylamino]-3-methylphenyl)methyl-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate). Studies on the intracellular signaling pathways showed that phospholipase C/inositol phosphate breakdown and adenylylcyclase/cyclic AMP generation were not coupled with this angiotensin receptor. An adenylylcyclase enzyme sensitive to forskolin was detected. The results indicate the presence of an angiotensin receptor in the heart of B. jararaca snake pharmacologically distinct from angiotensin AT1 and AT2 receptors. It seems to belong to a new class of angiotensin receptors, like some other atypical angiotensin AT receptors that have already been described.
Asunto(s)
Bothrops/metabolismo , Miocardio/metabolismo , Receptores de Angiotensina/metabolismo , 1-Sarcosina-8-Isoleucina Angiotensina II/farmacología , Angiotensina Amida/farmacología , Angiotensina II/análogos & derivados , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Colforsina/farmacología , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Imidazoles/farmacología , Fosfatos de Inositol/metabolismo , Losartán/farmacología , Masculino , Membranas/efectos de los fármacos , Membranas/metabolismo , Piridinas/farmacología , Receptores de Angiotensina/efectos de los fármacos , Saralasina/farmacología , TritioRESUMEN
To determine the contribution of plasma catecholamines to the cardiovascular effects of elevated levels of angiotensin II (Ang II) in trout, this study investigated (1) the stimulatory effects of [Asn1-Val5]-Ang II on plasma catecholamine levels, (2) the cardiovascular effects of Ang II with and without alpha-adrenoceptor blockade and (3) the relationship between plasma adrenaline concentrations and their cardiovascular effects. Bolus intravascular injections of Ang II (25-1200 pmol kg-1) elicited dose-dependent (between 75 and 1200 pmol kg-1) increases in plasma adrenaline levels; mean plasma noradrenaline levels only increased in response to a dose of 1200 pmol kg-1. Ang-II-elicited increases in plasma adrenaline levels ranged from 3.3+/-0.3 nmol l-1 for 75 pmol kg-1 Ang II to 125.1+/-40.0 nmol l-1 for 1200 pmol kg-1 Ang II. Injections of Ang II (25-1200 pmol kg-1) also elicited dose-dependent increases in dorsal aortic pressure (PDA), systemic resistance (RS), cardiac output (Q) and stroke volume (Vs). In fish first treated with the alpha -adrenoceptor blocker phenoxybenzamine, Ang II injections elicited a decrease in q_dot and Vs, and the increases in PDA and RS following administration of the 600 and 1200 pmol kg-1 Ang II doses were significantly reduced. Bolus injections of adrenaline (1.8x10(-10) to 1.4x10(-8) mol kg-1) elicited dose-dependent increases in PDA at a plasma adrenaline concentration of 16.5 nmol l-1 and in RS at a plasma adrenaline concentration of 50.5 nmol l-1. Adrenaline injections also elicited increases in Q and Vs at plasma adrenaline concentrations of 50.5 nmol l-1; however, higher plasma adrenaline concentrations were not associated with further increases in either Q or Vs. These results demonstrate that, in vivo, Ang II can act as a potent non-cholinergic secretagogue of humoral adrenaline in trout and that some of the cardiovascular effects of exogenous Ang II can be attributed to increased levels of plasma adrenaline. Our data also indicate that the cardiovascular effects of Ang-II-mediated humoral catecholamines are recruited in a dose-dependent manner and, as such, may require an acute stimulation of the renin-angiotensin system to contribute significantly to the pressor activity of endogenous angiotensins.
Asunto(s)
Angiotensina II/fisiología , Fenómenos Fisiológicos Cardiovasculares , Epinefrina/metabolismo , Oncorhynchus mykiss/fisiología , Antagonistas Adrenérgicos alfa/farmacología , Angiotensina Amida/farmacología , Animales , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Epinefrina/sangre , Epinefrina/farmacología , Femenino , Masculino , Norepinefrina/sangre , Fenoxibenzamina/farmacología , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiologíaRESUMEN
In the paper was described the influence of angiotensin-2, captopril, bestatin, and angiotensin-2-(3-7) fragment on drinking, feeding and alcohol directed behaviour. It was found that dipsogenic doses of angiotensin-2 could inhibit food and alcohol intake mostly by a suppression of food and alcohol motivations. Specific antagonist of "classical" angiotensin-2 receptors saralasin could not block angiotensin-2 effects. A significant decrease of food and ethanol intake was revealed after intraventricular injections of enzyme blockers captopril and bestatin, which increase endogenic levels of angiotensin-1 and angiotensin-3, and also angiotensin-2-(3-7). So was shown the ability of angiotensins to suppress the dominant food or alcohol motivations by the activation of some other but not the "classical" angiotensin-2 receptors. Was suggested the involvement of angiotensins in the coordination of the different kinds of functional systems to create the optimal conditions for realization of drinking behaviour.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Angiotensina II/fisiología , Conducta de Ingestión de Líquido/fisiología , Conducta Alimentaria/fisiología , Motivación , Aminopeptidasas/antagonistas & inhibidores , Angiotensina Amida/farmacología , Animales , Captopril/farmacología , Conducta de Ingestión de Líquido/efectos de los fármacos , Interacciones Farmacológicas , Conducta Alimentaria/efectos de los fármacos , Leucina/análogos & derivados , Leucina/farmacología , Masculino , Fragmentos de Péptidos , Ratas , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Saralasina/farmacología , Factores de TiempoRESUMEN
A decline in the function of the renin angiotensin aldosterone system may induce adaptive changes in response to angiotensin II (ANG II) with age. We have examined platelet ANG II receptor density, blood pressure and aldosterone responses to ANG II [Asn1, Val5-ANG II] (Hypertensin, Ciba Geigy, Horsham, Sussex, England) infusion in 8 young, 24 to 30 years, and 8 older, 54 to 65 years, healthy volunteers. To measure circulating ANG II, we established a new method for specific and simultaneous measurement of exogenous [Asn1, Val5] (Hypertensin) and endogenous [Asp1,Ile5] ANG II in plasma by using isocratic HPLC and radioimmunoassays with cross-reacting antibodies and compared results with immunoreactive ANG II which was measured conventionally using monoclonal antibodies. Baseline endogenous ANG II (Asp1,Ile5-ANG II) levels in venous plasma were marginally, but not significantly, lower in the old [mean (95% confidence limits): 3.4 (< 0.1 to 7.7) v 3.7 (1.2 to 6.2), fmol/mL] and during suppression by the Hypertensin infusion appeared consistently, but not significantly, lower in the old [0.9 (0 to 3.1) v 2.1 (0.6 to 3.7), after 3 ng/kg/min], while the same infusion rate in young and old resulted in similar plasma Hypertensin levels. Baseline systolic blood pressure (SBP) was similar in both groups but the percentage increases in SBP at infusion rates of 1, 3.0, and 10 ng/kg/min were greater in the old than in the young (9.1 v 2.8, P < .05; 16.3 v 8.0, P < .01; 30.4 v 14.0%, P < .001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Envejecimiento/fisiología , Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Hormonas/sangre , Adulto , Anciano , Aldosterona/sangre , Angiotensina Amida/sangre , Angiotensina Amida/farmacología , Angiotensina II/administración & dosificación , Angiotensina II/sangre , Plaquetas/metabolismo , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Radioinmunoensayo , Receptores de Angiotensina/efectos de los fármacos , Receptores de Angiotensina/metabolismoAsunto(s)
Presión Sanguínea/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatadores/farmacología , Acetilcolina/farmacología , Angiotensina Amida/farmacología , Animales , Presión Sanguínea/fisiología , Gatos , Interacciones Farmacológicas , Femenino , Histamina/farmacología , Isoproterenol/farmacología , Masculino , Nitroprusiato/farmacología , Norepinefrina/farmacologíaRESUMEN
It is shown in acute experiments in cats that byphasic arterial pressure changes occurred due to action of two heterodirectional and equivalent humoral stimuli. Magnitudes of both initial depressor and following pressor phases were authentically less than the ones due to separate action of those stimuli. It is noticed that the character of sum reaction depends neither on action mechanisms of vasoactive agents in the blood circulation system nor differences in the latent period of the effect of those drugs, but connected with intensiveness of stimuli. Predominance of depressor phase magnitude was shown to observe due to a rise of stimuli intensiveness down to complete disappearance of pressor reaction.
Asunto(s)
Acetilcolina/farmacología , Angiotensina Amida/farmacología , Angiotensina II/análogos & derivados , Presión Sanguínea/efectos de los fármacos , Histamina/farmacología , Norepinefrina/farmacología , Acetilcolina/administración & dosificación , Angiotensina Amida/administración & dosificación , Animales , Gatos , Combinación de Medicamentos , Femenino , Histamina/administración & dosificación , Inyecciones Intravenosas , Masculino , Norepinefrina/administración & dosificaciónRESUMEN
The responses of human adrenocortical cells to stimulation by ACTH(1-24), desacetyl-alpha-MSH, alpha-MSH and angiotensin II amide have been compared. Both desacetyl-alpha-MSH, thought to be the major form of the peptide in the human pituitary and in circulating plasma, and alpha-MSH caused a significant stimulation of aldosterone, corticosterone and cortisol secretion. Significant stimulation of the production of these steroids was obtained with desacetyl-alpha-MSH at a concentration of 1 nmol/l, while the response to alpha-MSH was considerably less sensitive, with a minimum effective concentration of 0.1 mumol/l. These values compared with minimum effective concentrations of 1 pmol/l for ACTH and 0.1 mumol/l for angiotensin II amide. Although cell types were not separated, it is possible to conclude that none of the peptides showed any specificity for the zona glomerulosa, and in each case the same minimum effective concentration of peptide was required for both aldosterone and cortisol secretion. Yields of steroid obtained under conditions of maximal stimulation by ACTH(1-24), alpha-MSH and desacetyl-alpha-MSH were at least three to five times the basal output of aldosterone, four to eight times that for corticosterone and more than seven to sixteen times that for cortisol. Angiotensin II amide was a relatively poor stimulant with maximal stimulation only 1.5 x basal. In these experiments the minimum effective concentration for desacetyl-alpha-MSH (1 nmol/l) was close to the circulating concentration of desacetyl-alpha-MSH (0.3 nmol/l) in man, and it is thus possible that this peptide may have a physiological role in the control of adrenocortical function.
Asunto(s)
Corteza Suprarrenal/efectos de los fármacos , Fragmentos de Péptidos/farmacología , alfa-MSH/análogos & derivados , Corteza Suprarrenal/citología , Corteza Suprarrenal/metabolismo , Aldosterona/metabolismo , Angiotensina Amida/farmacología , Células Cultivadas , Corticosterona/metabolismo , Cosintropina/farmacología , Humanos , Hidrocortisona/metabolismo , alfa-MSH/farmacologíaRESUMEN
The effects of verapamil and benzyl-aza-15-crown-5 on pressor reactions of blood pressure and perfusion pressure in the femoral artery after administration of noradrenaline, tyramine, angiotensin amide and stimulation of the femoral nerve were studied in acute experiments on anesthetized cats (pentobarbital sodium, 50 mg/kg). Verapamil (0.5 mg/kg) and benzyl-aza-15-crown-5 (9 mg/kg) suppressed pressor reactions to the nerve stimulation and produced no changes at administration of noradrenaline, tyramine and angiotensin amide. One can suggest that the mechanism of the vasodilating action of verapamil and benzyl-aza-15-crown-5 is due to their inhibitory effect on calcium-dependent release of noradrenaline from terminals of the sympathetic nerves. The search of vasodilating agents in the series of crown-ether derivatives is promising.
Asunto(s)
Vasos Sanguíneos/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Éteres Corona , Éteres Cíclicos/farmacología , Verapamilo/farmacología , Angiotensina Amida/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Vasos Sanguíneos/fisiología , Bloqueadores de los Canales de Calcio/toxicidad , Gatos , Interacciones Farmacológicas , Éteres Cíclicos/toxicidad , Ratones , Norepinefrina/farmacología , Succinilcolina/farmacología , Factores de Tiempo , Tiramina/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
The effects of prior sodium depletion on the steroidogenic responses of the rat adrenal gland have been investigated using a method of perfusing the isolated adrenal gland of the rat in situ. Secretion rates of aldosterone in response to the known adrenocortical stimulants ACTH, angiotensin II amide and alpha-MSH were measured. In each case, the adrenals from sodium-deplete animals responded to a lower dose of the stimulant than the normal animals. This resulted in a 10-fold increase in sensitivity to ACTH, a 100-fold increase in sensitivity to angiotensin II amide, and a 1000-fold increased sensitivity to alpha-MSH, bringing the threshold concentration required for aldosterone secretion into the physiological range of alpha-MSH concentrations. The perfused adrenal gland is particularly sensitive to angiotensin II amide; a bolus administration of 1 amol gave a significant increase in aldosterone secretion in the sodium-deplete group. These data confirm previous reports of increased adrenal sensitivity to alpha-MSH and angiotensin II in sodium depletion, and also suggest the existence of intraglandular mechanisms for signal amplification which may be involved in mediating the adrenal response to very small concentrations of stimulant.
Asunto(s)
Glándulas Suprarrenales/efectos de los fármacos , Aldosterona/metabolismo , Angiotensina Amida/farmacología , Angiotensina II/análogos & derivados , Dieta Hiposódica , Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/farmacología , Animales , Masculino , Ratas , Ratas Endogámicas , alfa-MSH/farmacologíaRESUMEN
The interplay of juxtaglomerular (jg) calcium fluxes and exposure to AII in the regulation of jg renin secretion, was examined in vivo. An inhibitor of angiotensin I converting enzyme (captopril), a blocker of calcium channels (verapamil) and AII amide were infused, singly or in combination, into the ear vein of conscious rabbits. The effects on arterial pressure, and on levels of active and inactive plasma renin were monitored. Captopril (50 micrograms X min-1 X kg-1) produced a greater percentage increase in renin secretion than did verapamil (20 micrograms X min-1 X kg-1), whilst the percentage fall in arterial pressure was similar. AII amide counteracted more effectively the actions of captopril than those of verapamil. When captopril was infused first, addition of verapamil did not enhance renin secretion (P greater than 0.2). When verapamil was infused first, addition of captopril greatly enhance renin secretion (P less than 0.01). However, when captopril was infused first, and its actions then suppressed by AII amide, addition of verapamil led to extremely high rates of renin secretion. The findings suggest the following: the short loop negative feedback plays in vivo an important role in the rapid modulation of jg renin secretion and the action of AII may involve up- and down-regulation at the receptor and/or post-receptor level; infused agents have rapid access to the critical sites of jg cells; exposure to raised concentrations to AII not only reduces the effectiveness of AII, but also enhances jg secretory responses to lack of AII, as well as to calcium channel blockade. Thus, at least some of the jg calcium channels appear to respond both to AII and to blockers; extreme changes in the levels of active renin are possible without changes of inactive renin levels. Secretion of the latter may be under separate control, or its secretion rate parallelled by the rate of its activation.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Bloqueadores de los Canales de Calcio/farmacología , Canales Iónicos/fisiología , Renina/sangre , Angiotensina Amida/farmacología , Angiotensina II/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Calcio/metabolismo , Captopril/antagonistas & inhibidores , Captopril/farmacología , Estado de Conciencia , Retroalimentación , Canales Iónicos/efectos de los fármacos , Aparato Yuxtaglomerular/efectos de los fármacos , Aparato Yuxtaglomerular/metabolismo , Conejos , Tasa de Secreción/efectos de los fármacos , Verapamilo/farmacologíaRESUMEN
In anesthetized dogs with cannulae implanted in the lateral cerebral ventricle, the water transfer from the CSF to the blood was studied using determination of drainage of tritiated water injected into the ventricle. Vasopressin and aldosterone accelerated the transfer of tritiated water into veins whereas angiotensin decelerated it. The data obtained suggest that the above hormones regulate volume and osmolality of the CSF.
Asunto(s)
Aldosterona/farmacología , Angiotensina Amida/farmacología , Angiotensina II/análogos & derivados , Arginina Vasopresina/farmacología , Plexo Coroideo/metabolismo , Agua/metabolismo , Animales , Líquido Cefalorraquídeo/fisiología , Plexo Coroideo/efectos de los fármacos , Perros , TritioRESUMEN
The secretion of aldosterone and its responses to stimulation have been studied in rat adrenal zona glomerulosa tissue incubated as intact capsules or as collagenase-dispersed cell suspensions, and in intact perfused rat adrenal glands. Several differences are apparent in the functions of the various preparations. Aldosterone secretion rates are similar in incubated intact capsules and in the perfused gland. Relative to corticosterone, lower yields of aldosterone are obtained in dispersed glomerulosa cell in vitro. This may be related to the loss in the dispersed cells of a pool of tissue steroid (aldosterone or a precursor) which is revealed only in intact tissue incubations by trypsin stimulation of aldosterone secretion. Trypsin-released aldosterone is increased by prior dietary sodium restriction. In addition, differences occur in the responses of dispersed cells and perfused glands to stimulation. Perfused glands from animals on a normal diet are less sensitive to stimulation by ACTH or alpha-MSH, but more sensitive than dispersed cells to angiotensin II amide. In the perfused gland, sensitivity of response (lowest effective concentration) to all three stimulants is increased by prior dietary sodium restriction, in contrast to dispersed cells in which increased sensitivity has been reported only to alpha-MSH. The perfused gland is particularly sensitive to angiotensin II amide, and a bolus administration of 1 amol gives significant stimulation in glands from animals on low sodium intake. Electrical (field) stimulation or dopamine administration at 10(-6) mol/l (which is ineffective in dispersed cells) both depress aldosterone secretion by the perfused gland. The data suggest that the sequestered pool of steroid is utilized in the perfused gland for aldosterone secretion. They furthermore suggest that in the intact gland there are mechanisms, which involve neural components, for intraglandular regulation of aldosterone secretion, which are lost in dispersed cells in vitro. Such mechanisms may be involved in sensitivity increases in sodium depletion.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Aldosterona/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Hormona Adrenocorticotrópica/farmacología , Angiotensina Amida/farmacología , Animales , Dopamina/farmacología , Estimulación Eléctrica , Femenino , Técnicas In Vitro , Masculino , Hormonas Estimuladoras de los Melanocitos/farmacología , Perfusión , Ratas , Ratas Endogámicas , Tripsina/farmacologíaRESUMEN
Eicosapentaenoic acid (EPA), the precursor fatty acid of three series of prostaglandins, has been reported to have an antiatherothrombotic potential. We gave highly purified EPA in a soft capsule (90% ethylester form of EPA; EPA-E) to 6 healthy male volunteers for 4 weeks. After the administration of 900 mg/day of EPA-E for two weeks or longer, a significant reduction in plasma beta thromboglobulin level was observed, and after 4 weeks' administration, significantly blunted pressor responsiveness to infused angiotensin II was observed. These changes were not observed 4 weeks after EPA-E had been discontinued. After 4 weeks' ingestion of EPA-E, the platelet count, mean platelet volume, platelet aggregation with adenosine diphosphate or collagen, plasma recalcification time, prothrombin time, plasma antithrombin III, fibrinogen or plasmin concentrations, serum concentrations of total cholesterol, triglycerides, total phospholipid, nonesterified fatty acid or high-density lipoprotein cholesterol were unchanged. From the data presented it can be said that EPA-E causes a mild depression of vascular contractility and of platelet aggregability in vivo and exerts a beneficial influence on several cardiovascular factors.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Vasos Sanguíneos/efectos de los fármacos , Ácido Eicosapentaenoico/análogos & derivados , beta-Tromboglobulina/metabolismo , Administración Oral , Adulto , Angiotensina Amida/farmacología , Coagulación Sanguínea/efectos de los fármacos , HDL-Colesterol/sangre , Ácido Eicosapentaenoico/farmacología , Ácidos Grasos no Esterificados/sangre , Humanos , Masculino , Agregación Plaquetaria/efectos de los fármacos , Recuento de Plaquetas/efectos de los fármacosRESUMEN
Acute hypertensive damage to small arteries and arterioles in rats was induced by intravenous injections of Hypertensin. The in vitro immunological method of the agarose migration technique was used to demonstrate delayed-type autoimmunity against arterial vessel-wall antigens. By this technique the autoimmunity could be demonstrated for about 16 weeks after the acute hypertensive damage to the arterial vessels. The results of the autoimmunity were given as migration indices. These were lowest during the first 4-5 weeks after the damage to the vessels whereupon they showed higher and higher values, and finally the migration indices were identical with those of the control rats after about 16 weeks.
Asunto(s)
Arterias/inmunología , Autoanticuerpos/inmunología , Hipersensibilidad Tardía/inmunología , Hipertensión/inmunología , Angiotensina Amida/administración & dosificación , Angiotensina Amida/farmacología , Animales , Arterias/citología , Arterias/efectos de los fármacos , Arteriolas/efectos de los fármacos , Arteriolas/inmunología , Movimiento Celular , Femenino , Hipersensibilidad Tardía/sangre , Hipertensión/sangre , Inyecciones Intravenosas , Leucocitos/inmunología , Masculino , Ratas , Ratas EndogámicasRESUMEN
Using the in-situ, isolated, perfused rat adrenal system, the actions of adrenal stimulants on steroidogenesis and perfusion medium flow rates (under constant perfusion pump conditions) have been studied. In a series of 100 experiments, initial rates of corticosterone output and flow rates were found to be positively correlated, although there was no such relationship between initial rates of aldosterone output and flow rates. Furthermore, in stable perfusion conditions, bolus injections of ACTH increased both flow rate and steroid output in a dose-related manner. In individual experiments there was a clear correlation between corticosterone and flow, but the association between aldosterone secretion rate and flow was less evident. It is possible that this discrepancy arises because of temporal differences in the responses of these two steroids. Flow was also stimulated by dibutyryl cyclic AMP (dbcAMP), with correlations with steroid output similar to ACTH, but the specific zona glomerulosa stimulants angiotensin II amide and potassium ions had, if anything, inhibitory effects on flow, but only at high concentrations. The data suggest that ACTH and dbcAMP evoke specific responses in the adrenal vasculature, resulting in relatively decreased intraglandular vascular resistance. They furthermore suggest that the secretory functions of the inner adrenocortical zones are subject to the additional control of vascular elements in the intact gland.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Hormona Adrenocorticotrópica/farmacología , Corticosterona/metabolismo , Glándulas Suprarrenales/irrigación sanguínea , Glándulas Suprarrenales/efectos de los fármacos , Aldosterona/metabolismo , Angiotensina Amida/farmacología , Animales , Bucladesina/farmacología , Perfusión , Potasio/farmacología , Ratas , Estimulación QuímicaRESUMEN
Biological activities of asn1-,val5-angiotensin II (Hypertensin, Ciba, Asn1-,Val5-ANG II), ile5-angiotensin II (human angiotensin II, Ile5-ANG II) and sar1-angiotensin II (Sar1-ANG II) were compared in man. In 7 normal men 5 pmol/kg X min each of Asn1-,Val5-ANG II, Ile5-ANG II and Sar1-ANG II was infused iv from 0900 h to 0930 h at 1-week intervals. Average increments of blood pressure at the end of the infusions were 11/12, 23/20 and 36/30 mmHg, respectively (significant differences among the 3: P less than 0.001), average decrements of plasma renin activity were 0.30, 0.32 and 0.27 ng/ml X H, respectively (no significant difference among the 3), average increments of plasma aldosterone were 1.1, 2.3 and 4.4 ng/100 ml, respectively (significant difference between the former 2: P les than 0.001, between the latter 2: P less than 0.02), and durations of blood pressure rise after the cessation of these infusions (T) were 2-5 (average 5) min, 10-25 (average 20) min and 35-60 (average 40) min, respectively (significant difference between the former 2:less than P 0.01, between the latter 2: P less than 0.001). From these results it is evident that the pressor and steroidogenic actions of Ile5-ANG II are significantly stronger than those of Asn1-,Val5-ANG II and that the duration of pressor action of the former is much longer than that of the latter. Therefore, when the activities of angiotensin II (ANG II) derivatives are compared with those of ANG II in man, Ile5-ANG II--natural human ANG II--should always be used instead of Asn1-,Val5-ANG II. The pressor and steroidogenic actions and T of Sar1-ANG II are significantly stronger or longer than those of Ile5-ANG II. The reason for this is thought to be that Sar1-ANG II is bound tightly to the vascular and adrenal ANG II receptors and is not readily metabolized.
Asunto(s)
Angiotensina Amida/farmacología , Angiotensina II/análogos & derivados , Adulto , Aldosterona/sangre , Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Humanos , Masculino , Renina/sangreRESUMEN
The extent to which results obtained using in-vitro techniques can be taken to reflect in-vivo physiological responses in the study of adrenocortical function has not been subjected to systematic study. Some evidence suggests that in-vitro preparative methods may affect the secreted steroid profile. For this reason it seemed desirable to study adrenal function using an isolated perfused whole gland technique, and this study reports results obtained with known aldosterone stimulants. Angiotensin II, ACTH and potassium ions all stimulated aldosterone secretion in a dose-dependent manner. The stimulation thresholds of these substances were compatible with their normal circulating concentrations. For angiotensin II stimulation this preparation was two orders of magnitude more sensitive than any in-vitro preparation. Most importantly, the specific glomerulosa effectors, angiotensin II and potassium, selectively stimulated aldosterone output, and had no consistent effect on corticosterone secretion at any dose used. On the other hand, ACTH stimulated both corticosterone and aldosterone output at all effective concentrations. The actions of alpha-MSH were also studied using this preparation. Low doses of alpha-MSH selectively stimulated aldosterone secretion, while higher doses were needed to stimulate corticosterone. The onset of response to all stimulants was invariably seen within the first 10 min after administration of stimulants. Maximal aldosterone output was achieved within the first 10 min whereas corticosterone secretion usually peaked 10-20 min later. The amount of aldosterone produced by this preparation was much higher than the amount produced by dispersed cell preparations, and closely approximated to the levels of aldosterone obtained in adrenal vein blood.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Glándulas Suprarrenales/metabolismo , Aldosterona/metabolismo , Glándulas Suprarrenales/efectos de los fármacos , Hormona Adrenocorticotrópica/farmacología , Angiotensina Amida/farmacología , Animales , Corticosterona/metabolismo , Masculino , Hormonas Estimuladoras de los Melanocitos/farmacología , Perfusión , Potasio/farmacología , Ratas , Ratas Endogámicas , Tasa de Secreción/efectos de los fármacosRESUMEN
Pulsatile changes in the volume of an arm segment were recorded with an air-filled plethysmograph and related to intra-arterial blood pressure. Alterations in transmural arterial pressure were obtained by changing the pressure in a large chamber surrounding the entire arm. Arterial compliance values were calculated in late diastole when pressure and volume changes were slow. Compliance varied with transmural arterial pressure in a hyperbolic manner, rising steeply at low pressure. Noradrenaline and hypertensin did not change the arterial compliance values, while dihydroergotamine reduced them. Nitroglycerine caused a pronounced increase in compliance values in doses that did not change cardiac output and arterial pressure.
Asunto(s)
Músculo Liso Vascular/efectos de los fármacos , Nitroglicerina/farmacología , Vasoconstrictores/farmacología , Adulto , Angiotensina Amida/farmacología , Brazo/irrigación sanguínea , Arterias/efectos de los fármacos , Arterias/fisiología , Presión Sanguínea , Dihidroergotamina/farmacología , Elasticidad , Humanos , Masculino , Músculo Liso Vascular/fisiología , Contracción Miocárdica , Norepinefrina/farmacología , PletismografíaRESUMEN
Anionic groups on cerebral arteriolar endothelium were localized using cationized ferritin (CF), and alterations in the distribution of these groups were documented in arterioles with increased permeability to horseradish peroxidase (HRP) in angiotensin-induced acute hypertension. Normotensive animals showed a uniform distribution of anionic groups on the endothelial luminal plasma membrane when fixed or live vessels were reacted with CF. Anionic groups were localized at the mouth of pinocytotic vesicles in both preparations; however, only live cells demonstrated CF particles within vesicles, and the possibility that these represent pinocytosed CF particles cannot be ruled out. Cationized ferritin particles were not observed on the plasma membranes within interendothelial spaces in either of the preparations. Sixty percent of hypertensive animals with pressures over 200 mmHg showed increased arteriolar permeability to HRP. At 2.5 min, permeable arteriolar segments with active vesicular transport of HRP showed marked reduction or loss of CF binding. Capillaries and venules in the adjacent cortex and nonpermeable arterioles demonstrated linear endothelial CF binding similar to controls. Most permeable vessels of animals killed 6-20 min after onset of acute hypertension when the blood-brain barrier is usually closed showed CF binding on endothelium indicating that there is rapid restoration of the net negative charge. These studies demonstrate that increased arteriolar permeability in acute hypertension is associated with a transient alteration of surface charge. The mechanism by which charge is altered remains to be determined.