RESUMO
Previous studies propose 20-hydroxyeicosatetraenoic acid (20-HETE), a major arachidonic acid metabolite of cytochrome P-450 (CYP), as a possible mediator of Na(+)-K(+)-ATPase inhibition by dopamine (DA). The aim of this study was to investigate the intracellular mechanisms involved in this effect and to elucidate the DA receptor associated with the 20-HETE pathway in the rat kidney. DA (10(-5) M) inhibited Na(+)-K(+)-ATPase activity in microdissected tubular segments to 59.4 +/- 3.8% of control activity. This response was suppressed by the CYP4A inhibitor 17-octadecynoic acid (10(-6) M), which had no effect per se, thus confirming the participation of CYP arachidonic acid metabolites in DA-induced Na(+)-K(+)-ATPase inhibition. We next examined whether 20-HETE is involved in the signaling pathways triggered by either D(1) or D(2) receptors. Neither fenoldopam nor quinpirole (D(1) and D(2) agonists, respectively, both 10(-5) M) modified Na(+)-K(+)-ATPase activity when tried alone. However, coincubation of a threshold concentration of 20-HETE (10(-9) M) with fenoldopam resulted in a synergistic inhibition of Na(+)-K(+)-ATPase activity (66 +/- 2% of control activity), while 20-HETE plus quinpirole had no effect. Furthermore, 20-HETE (10(-9) M) synergized with forskolin (10(-5) M) and with the diacylglycerol analog 1-oleoyl-2-acetoyl-sn-glycerol (OAG; 10(-11) M; 62.0 +/- 5.3 and 69.9 +/- 2.0% of control activity, respectively), indicating a cooperative role of 20-HETE with the D(1)-triggered pathways. In line with these results, no additive effect was observed when OAG and 20-HETE were combined at concentrations which per se produced maximal inhibition (10(-6) M). These results demonstrate that the inhibition of Na(+)-K(+)-ATPase activity by DA in the proximal tubule may be the result of the synergism between 20-HETE and the D(1) signaling pathway.
Assuntos
Ácidos Hidroxieicosatetraenoicos/fisiologia , Túbulos Renais Proximais/metabolismo , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Animais , Colforsina/farmacologia , Diglicerídeos/farmacologia , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Sinergismo Farmacológico , Ácidos Graxos Insaturados/farmacologia , Fenoldopam/farmacologia , Ácidos Hidroxieicosatetraenoicos/farmacologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/enzimologia , Masculino , Proteína Quinase C-alfa/metabolismo , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Transdução de Sinais/fisiologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Frações Subcelulares/enzimologia , Distribuição TecidualRESUMO
OBJECTIVE: The effects of the co-administration of fenoldopam (FD) or levodopa (LD) with dopamine (DA) on arterial blood pressure were studied in rats to assess the possibility of synergic effects that might be of some clinical importance. METHODS AND RESULTS: Mean arterial blood pressure (MBP) in the carotid artery of anaesthetized rats was registered. All agents induced dose-dependent reductions in mean arterial blood pressure when administered in a non-cumulative schedule to rats pretreated with phentolamine. For each drug, the doses that induced a 50% of reduction in basal mean arterial blood pressure, (ED50) calculated by standard linear regression analysis of the log dose-response curve and were 5.49 mg/kg, (n=10), 2.86 mg/kg, (n=11) and 0.445 mg/kg, (n=12), for FD, LD and DA, respectively. The interactions were evaluated by simultaneous administration of different fixed ratios of DA with FD (1:12.3) or DA with LD (1:6) and obtaining dose-response curves and ED50's for each mixture. An isobolographic analysis was then performed, which demonstrated that the co-administration had synergistic effects as illustrated by statistically higher reductions of blood pressure under each combination as compared to theoretical calculated additive effects. CONCLUSIONS: The present results show that in the rat, after alpha-adrenergic blockade, the association of DA and FD could inappropriately potentiate the hypotension induced by both drugs.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Dopamina/farmacologia , Fenoldopam/farmacologia , Levodopa/farmacologia , Vasodilatadores/farmacologia , Animais , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Ratos , Ratos Sprague-DawleyRESUMO
La insuficiencia renal aguda (IRA) es uno de los trastornos fisiopatológicos frecuentes en el paciente crítico y a menudo se presenta formando parte del síndrome de disfunción múltiple de órganos. La presencia de IRA aumenta la mortalidad, aunque la causa de muerte no dependa directamente de la insuficiencia renal. Por estas razones, se han hecho múltiples intentos por evitar la aparición de este trastorno, a fin de mejorar la evolución de los pacientes críticos. El patrón patogénico inicial de la IRA en cualquiera de sus formas se caracteriza por un intenso y sostenido aumento de las resistencias vasculares renales, ya sea como consecuencia de cambios en la hemodinamia sistémica o intrarrenal. La modificación de este perfil constituye la base teórica de cualquier estrategia de prevención de la IRA causada por necrosis tubular aguda. En tal sentido, se han ensayado diversos fármacos que han demostrado, a nivel experimental o en sujetos sanos, efectos positivos sobre el flujo sanguíneo renal, la tasa de filtrado glomerular o la eliminación de sodio y agua. Los diuréticos de asa y la dopamina son los fármacos que han generado mayor entusiasmo y un uso muy extendido, sobre todo en las unidades de cuidado intensivo. Lamentablemente, revisiones cuidadosas de los estudios realizados en pacientes en riesgo de IRA o en las etapas tempranas de la misma, no han mostrado evidencia suficiente que sustente el uso de estos fármacos en este contexto y por el contrario, se han demostrado posibles efectos secundarios perjudiciales que los hacen potencialmente riesgosos. El restablecimiento de una adecuada perfusión renal con expansión de volumen y eventualmente noradrenalina en los pacientes sépticos, junto con la restricción de fármacos nefrotóxicos, son las únicas medidas con efectividad demostrada hasta el momento
Assuntos
Humanos , Injúria Renal Aguda , Diuréticos/uso terapêutico , Dopamina , Isquemia , Necrose Tubular Aguda , Rim/irrigação sanguínea , Injúria Renal Aguda , Fenoldopam , Necrose Tubular Aguda , Manitol , NorepinefrinaRESUMO
La insuficiencia renal aguda (IRA) es uno de los trastornos fisiopatológicos frecuentes en el paciente crítico y a menudo se presenta formando parte del síndrome de disfunción múltiple de órganos. La presencia de IRA aumenta la mortalidad, aunque la causa de muerte no dependa directamente de la insuficiencia renal. Por estas razones, se han hecho múltiples intentos por evitar la aparición de este trastorno, a fin de mejorar la evolución de los pacientes críticos. El patrón patogénico inicial de la IRA en cualquiera de sus formas se caracteriza por un intenso y sostenido aumento de las resistencias vasculares renales, ya sea como consecuencia de cambios en la hemodinamia sistémica o intrarrenal. La modificación de este perfil constituye la base teórica de cualquier estrategia de prevención de la IRA causada por necrosis tubular aguda. En tal sentido, se han ensayado diversos fármacos que han demostrado, a nivel experimental o en sujetos sanos, efectos positivos sobre el flujo sanguíneo renal, la tasa de filtrado glomerular o la eliminación de sodio y agua. Los diuréticos de asa y la dopamina son los fármacos que han generado mayor entusiasmo y un uso muy extendido, sobre todo en las unidades de cuidado intensivo. Lamentablemente, revisiones cuidadosas de los estudios realizados en pacientes en riesgo de IRA o en las etapas tempranas de la misma, no han mostrado evidencia suficiente que sustente el uso de estos fármacos en este contexto y por el contrario, se han demostrado posibles efectos secundarios perjudiciales que los hacen potencialmente riesgosos. El restablecimiento de una adecuada perfusión renal con expansión de volumen y eventualmente noradrenalina en los pacientes sépticos, junto con la restricción de fármacos nefrotóxicos, son las únicas medidas con efectividad demostrada hasta el momento (AU)
Assuntos
Humanos , Rim/irrigação sanguínea , Isquemia , Injúria Renal Aguda/prevenção & controle , Injúria Renal Aguda/tratamento farmacológico , Necrose Tubular Aguda/fisiopatologia , Necrose Tubular Aguda/prevenção & controle , Diuréticos/uso terapêutico , Dopamina/uso terapêutico , Manitol/uso terapêutico , Fenoldopam/uso terapêutico , Norepinefrina/uso terapêutico , Injúria Renal Aguda/etiologia , Necrose Tubular Aguda/complicaçõesRESUMO
Justificativa e Objetivos - O fenoldopam é um agonista dopaminérgico seletivo para os receptores dopaminérgicos tipo 1 (DAð1) que causa vasodilatação periférica e o objetivo deste artigo é reunir as informações clínicas sobre este fármaco. Conteúdo - Neste artigo foram revisadas as experiências em urgências e emergências hipertensivas, mostrando que o fenoldopam apresenta vantagens sobre o nitroprussiato de sódio (NPS) no tratamento das mesmas. Ao contrário do NPS, o fenoldopam causa vasodilatação periférica, ao mesmo tempo que induz diurese e natriurese em pacientes com hipertensão grave sem causar os efeitos deletérios pelo tiocianato. Conclusões - O fenoldopam parenteral, pelos seus efeitos renais e menor impacto de efeitos colaterais, pode ser considerado uma boa alternativa ao nitroprussiato de sódio no tratamento de emergências hipertensivas
Assuntos
Fenoldopam , Hipertensão/tratamento farmacológico , Infusões Parenterais , Nitroprussiato , Pressão Arterial , DopaminérgicosRESUMO
A new class of vasodilators exhibiting selective dopamine-1 receptor agonist activity is being introduced into clinical practice. Inasmuch as various vasodilators either augment or decrease myocardial blood flow ("coronary steal") depending on their pharmacologic action, the goal of this study was to assess the effects of fenoldopam (selective dopamine-1 receptor agonist) and dopamine (nonselective dopamine-1 receptor agonist) on regional myocardial blood flow in the presence of coronary occlusion. Accordingly, in 16 dogs anesthetized with pentobarbital, the left anterior descending coronary artery was occluded. Cardiovascular and renal hemodynamic effects were measured before and after intravenous infusion of renal equipotent doses of either fenoldopam (n = 9, 0.1 micrograms/kg/min) or dopamine (n = 7, 1 micrograms/kg/min). Both fenoldopam and dopamine caused a significant and comparable increase in renal blood flow. Fenoldopam but not dopamine significantly decreased the calculated peripheral vascular resistance and subsequently increased cardiac output. Dopamine had no effect on regional myocardial blood flow. In contrast, fenoldopam augmented transmural myocardial blood flow in normal (from 114 +/- 10 to 188 +/- 27 ml/100 gm/min, p less than 0.02) and ischemic border myocardium (from 45 +/- 5 to 68 +/- 11 ml/100 gm/min, p less than 0.03 and p less than 0.02 vs dopamine). There was a significant increase in blood flow to both the endocardial and epicardial layers of normal and ischemic border myocardium. These changes were accompanied by a significant reduction in coronary vascular resistance in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Circulação Coronária/efeitos dos fármacos , Dopaminérgicos/farmacologia , Dopamina/farmacologia , Hemodinâmica/efeitos dos fármacos , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Constrição , Doença das Coronárias/fisiopatologia , Cães , Fenoldopam , Circulação Renal/efeitos dos fármacos , Estimulação QuímicaRESUMO
Fenoldopam administration orally or i.v. resulted in significant increases in paraaminohippuric acid (PAH) clearance in both four control dogs and four dogs with chronic renal failure. Oral fenoldopam resulted in significant plasma levels of fenoldopam sulfate metabolites. One metabolite, fenoldopam-8-sulfate, a potential inhibitor of organic anion transport, did not depress renal cortical slice accumulation of PAH. The data therefore indicate that in dogs with chronic renal failure, PAH clearance after fenoldopam administration is a reliable measure of renal plasma flow, and fenoldopam can result in an increase in renal plasma flow.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Falência Renal Crônica/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Administração Oral , Animais , Creatinina/sangue , Cães , Dopaminérgicos/farmacologia , Feminino , Fenoldopam , Humanos , Técnicas In Vitro , Injeções Intravenosas , Córtex Renal/efeitos dos fármacos , Córtex Renal/metabolismo , Masculino , Ácido p-Aminoipúrico/sangueRESUMO
The pharmacology of SK&F R-105058 and SK&F R-106114, N-ethyl carbamate ester prodrugs of fenoldopam, was evaluated in pentobarbital-anesthetized dogs. The selective dopamine 1 (DA1) antagonist, SCH 23390, significantly attenuated the renal vasodilator effects of SK&F R-82526, the active enantiomer of fenoldopam. This dose of SCH 23390 also significantly attenuated the increase in renal blood flow and decrease in renal vascular resistance induced by the administration of either SK&F R-106114 or SK&F R-105058. The cholinesterase inhibitor, physostigmine, at a dose that significantly enhanced the renal effects of acetylcholine, did not alter the in vivo renal vasodilator effects of SK&F R-105058 or prevent conversion of SK&F R-105058 to fenoldopam. Thus, these data indicate that the renal vasodilator activity of fenoldopam prodrugs involves activation of DA1 receptors and that, unlike other carbamate ester prodrugs, conversion to the parent compound is unlikely to involve cholinesterase.
Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/análogos & derivados , Benzazepinas/farmacologia , Carbamatos/farmacologia , Pró-Fármacos/farmacologia , Vasodilatadores/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacocinética , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Anestesia , Animais , Benzazepinas/farmacocinética , Biotransformação , Pressão Sanguínea/efeitos dos fármacos , Carbamatos/farmacocinética , Cães , Feminino , Fenoldopam , Pentobarbital , Fisostigmina/farmacologia , Pró-Fármacos/farmacocinética , Circulação Renal/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/farmacocinéticaRESUMO
In vitro incubation of Listeria monocytogenes-immune spleen cells in the presence of dopamine or fenoldopam, a dopamine-1 (D1) agonist, inhibited alpha/beta-interferon (IFN) synthesis induced by the mitogen lipopolysaccharide (LPS), in a manner that appeared to be concentration dependent. In addition, the inhibitory effect of dopamine and fenoldopam on the synthesis of IFN was prevented by incubating immune spleen cells in the presence of haloperidol, a D1 antagonist.
Assuntos
Benzazepinas/farmacologia , Dopamina/farmacologia , Interferon Tipo I/antagonistas & inibidores , Lipopolissacarídeos/antagonistas & inibidores , Animais , Benzazepinas/antagonistas & inibidores , Dopamina/fisiologia , Antagonistas de Dopamina , Feminino , Fenoldopam , Haloperidol/farmacologia , Interferon Tipo I/biossíntese , Interferon Tipo I/fisiologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos , Baço/citologia , Baço/imunologia , Baço/metabolismo , Timidina/metabolismoRESUMO
The renal and pulmonary hemodynamic effects of fenoldopam, dobutamine, dopamine and norepinephrine were compared in the pentobarbital-anesthetized dog. Animals were pretreated with propranolol (1 mg/kg, i.v.) to eliminate beta-adrenoceptor-mediated effects in the renal and pulmonary circulations. Heparinized blood was withdrawn from the right femoral artery and transferred, via a peristaltic pump, to the pulmonary arterial branch supplying the left diaphragmatic lobe of the lung. The flow rate of the pump was set so that the perfusion pressure in the lobe was equal to resting diastolic pulmonary artery blood pressure. Under these conditions of constant flow, changes in perfusion pressure reflect changes in pulmonary vascular resistance. Renal blood flow was measured in the same experiments via an electromagnetic flow probe which was placed directly on the left renal artery. Intraarterial administration of fenoldopam resulted in a marked reduction in renal vascular resistance at doses that had virtually no effect on pulmonary vascular resistance. Conversely, dobutamine increased pulmonary vascular resistance slightly, and had no effect on the renal circulation. Dopamine increased pulmonary vascular resistance at all doses, and exhibited a biphasic effect on renal vascular resistance. At low doses, dopamine produced a modest reduction in renal vascular resistance, and at higher doses, dopamine significantly increased renal vascular resistance. Norepinephrine increased both pulmonary and renal vascular resistance at all doses, as expected. These results indicate that fenoldopam may be hemodynamically favorable over dobutamine and dopamine in the management of patients with low output cardiac failure since fenoldopam improves renal hemodynamics at doses that have little or no effect on the pulmonary circulation.