RESUMEN
BACKGROUND: Blockade of brain renin-angiotensin system (RAS) overactivity by firibastat, the first centrally acting aminopeptidase A (APA) inhibitor prodrug, has already demonstrated its effectiveness in improving cardiac function after myocardial infarction (MI). We developed QGC606, a more potent and more selective APA inhibitor prodrug and studied its effects after long-term oral administration in mice post-MI. METHODS: Two days after MI induced by the left anterior descending artery ligation, adult male mice were randomized into 4 groups to receive oral treatment during 4 weeks with vehicle; QGC606; firibastat; or the angiotensin-I converting enzyme inhibitor ramipril, used as positive control. RESULTS: Four weeks post-MI, brain APA was overactivated in vehicle-treated MI mice. QGC606 treatment normalized brain APA hyperactivity to control values measured in sham-operated mice. Four weeks post-MI, QGC606-treated mice had higher left ventricular (LV) ejection fractions, significantly smaller LV end-systolic diameter and volume, significantly lower HF biomarkers mRNA expression (Myh7 and Anf) and plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) and noradrenaline levels than saline-treated mice. QGC606 treatment significantly improved the dP/dt max and min, LV end-diastolic pressure without affecting blood pressure (BP), whereas we observed a decrease in BP in ramipril-treated mice. We observed also a reduction of cardiac fibrosis, highlighted by lower connective tissue growth factor mRNA levels and a reduction of both the fibrotic area and MI size in QGC606-treated mice. CONCLUSIONS: Chronic oral QGC606 administration in post-MI mice showed beneficial effects in improving cardiac function and reducing cardiac remodeling and fibrosis but, unlike ramipril, without lowering BP.
Asunto(s)
Insuficiencia Cardíaca , Infarto del Miocardio , Profármacos , Animales , Fibrosis , Glutamil Aminopeptidasa , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Ratones , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Miocardio/patología , Profármacos/uso terapéutico , ARN Mensajero , Ramipril/farmacología , Ramipril/uso terapéutico , Remodelación VentricularRESUMEN
In the brain, aminopeptidase A (APA) generates angiotensin III, one of the effector peptides of the brain renin-angiotensin system (RAS), exerting tonic stimulatory control over blood pressure (BP) in hypertensive rats. Oral administration of firibastat, an APA inhibitor prodrug, in hypertensive rats, inhibits brain APA activity, blocks brain angiotensin III formation and decreases BP. In this study, we evaluated the efficacy of firibastat in combination with enalapril, an angiotensin I-converting enzyme inhibitor, and hydrochlorothiazide (HCTZ), in conscious hypertensive deoxycorticosterone acetate (DOCA)-salt rats, which display high plasma arginine-vasopressin levels, low circulating renin levels and resistance to treatment by systemic RAS blockers. We determined mean arterial BP, heart rate, plasma arginine-vasopressin levels and renin activity in DOCA-salt rats orally treated with firibastat, enalapril or HCTZ administered alone or in combination. Acute oral firibastat administration (30 mg/kg) induced a significant decrease in BP, whereas enalapril (10 mg/kg) or HCTZ (10 mg/kg) administered alone induced no significant change in BP in conscious DOCA-salt rats. The BP decrease induced by acute and nine-day chronic tritherapy [Firibastat+Enalapril+HCTZ] was significantly greater than that observed after bitherapy [Enalapril+HCTZ]. Interestingly, the chronic administration of a combination of firibastat with [Enalapril+HCTZ] reduced plasma arginine-vasopressin levels by 62% relative to those measured in DOCA-salt rats receiving bitherapy. Our data show that tritherapy with firibastat, enalapril and HCTZ improves BP control and arginine-vasopressin release in an experimental salt-dependent model of hypertension, paving the way for the development of new treatments for patients with currently difficult-to-treat or resistant hypertension.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Acetato de Desoxicorticosterona/farmacología , Disulfuros/farmacología , Enalapril/farmacología , Hidroclorotiazida/farmacología , Hipertensión/tratamiento farmacológico , Ácidos Sulfónicos/farmacología , Vasopresinas/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Modelos Animales de Enfermedad , Glutamil Aminopeptidasa/metabolismo , Hipertensión/metabolismo , Masculino , Ratas , Ratas Endogámicas WKY , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
In the brain, aminopeptidase A (APA), a membrane-bound zinc metalloprotease, generates angiotensin III from angiotensin II. Brain angiotensin III exerts a tonic stimulatory effect on the control of blood pressure (BP) in hypertensive rats and increases vasopressin release. Blocking brain angiotensin III formation by the APA inhibitor prodrug RB150/firibastat normalizes arterial BP in hypertensive deoxycorticosterone acetate (DOCA)-salt rats without inducing angiotensin II accumulation. We therefore hypothesized that another metabolic pathway of brain angiotensin II, such as the conversion of angiotensin II into angiotensin 1-7 (Ang 1-7) by angiotensin-converting enzyme 2 (ACE2) might be activated following brain APA inhibition. We found that the intracerebroventricular (icv) administration of RB150/firibastat in conscious DOCA-salt rats both inhibited brain APA activity and induced an increase in brain ACE2 activity. Then, we showed that the decreases in BP and vasopressin release resulting from brain APA inhibition with RB150/firibastat were reduced if ACE2 was concomitantly inhibited by MLN4760, a potent ACE2 inhibitor, or if the Mas receptor (MasR) was blocked by A779, a MasR antagonist. Our findings suggest that in the brain, the increase in ACE2 activity resulting from APA inhibition by RB150/firibastat treatment, subsequently increasing Ang 1-7 and activating the MasR while blocking angiotensin III formation, contributes to the antihypertensive effect and the decrease in vasopressin release induced by RB150/firibastat. RB150/firibastat treatment constitutes an interesting therapeutic approach to improve BP control in hypertensive patients by inducing in the brain renin-angiotensin system, hyperactivity of the beneficial ACE2/Ang 1-7/MasR axis while decreasing that of the deleterious APA/Ang II/Ang III/ATI receptor axis.
Asunto(s)
Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Antihipertensivos/farmacología , Disulfuros/farmacología , Glutamil Aminopeptidasa/antagonistas & inhibidores , Hipertensión/fisiopatología , Ácidos Sulfónicos/farmacología , Angiotensina III/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Acetato de Desoxicorticosterona/administración & dosificación , Modelos Animales de Enfermedad , Glutamil Aminopeptidasa/metabolismo , Hipertensión/inducido químicamente , Masculino , Ratones , Ratas Wistar , Cloruro de Sodio DietéticoRESUMEN
The pathophysiology of heart failure (HF) and hypertension are thought to involve brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector peptide in the brain RAS, provides tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme responsible for generating brain angiotensin III, constitutes a potential therapeutic target for hypertension treatment. We focus here on studies of RB150/firibastat, the first prodrug of the specific and selective APA inhibitor EC33 able to cross the blood-brain barrier. We consider its development from therapeutic target discovery to clinical trials of the prodrug. After oral administration, firibastat crosses the gastrointestinal and blood-brain barriers. On arrival in the brain, it is cleaved to generate EC33, which inhibits brain APA activity, lowering BP in various experimental models of hypertension. Firibastat was clinically and biologically well tolerated, even at high doses, in phase I trials conducted in healthy human subjects. It was then shown to decrease BP effectively in patients of various ethnic origins with hypertension in phase II trials. Brain RAS hyperactivity leads to excessive sympathetic activity, which can contribute to HF after myocardial infarction (MI). Chronic treatment with oral firibastat (4 or 8 weeks after MI) has been shown to normalize brain APA activity in mice. This effect is accompanied by a normalization of brain RAS and sympathetic activities, reducing cardiac fibrosis and hypertrophy and preventing cardiac dysfunction. Firibastat may therefore represent a novel therapeutic advance in the clinical management of patients with hypertension and potentially with HF after MI.
Asunto(s)
Encéfalo/metabolismo , Glutamil Aminopeptidasa/antagonistas & inhibidores , Insuficiencia Cardíaca/prevención & control , Hipertensión/tratamiento farmacológico , Angiotensina II/metabolismo , Angiotensina III/metabolismo , Animales , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Ensayos Clínicos como Asunto , Disulfuros/farmacología , Disulfuros/uso terapéutico , Glutamil Aminopeptidasa/metabolismo , Insuficiencia Cardíaca/etiología , Humanos , Hipertensión/metabolismo , Infarto del Miocardio/complicaciones , Sistema Renina-Angiotensina , Ácidos Sulfónicos/farmacología , Ácidos Sulfónicos/uso terapéuticoRESUMEN
Brain renin-angiotensin system (RAS) hyperactivity has been implicated in sympathetic hyperactivity and progressive left ventricular (LV) dysfunction after myocardial infarction (MI). Angiotensin III, generated by aminopeptidase A (APA), is one of the main effector peptides of the brain RAS in the control of cardiac function. We hypothesized that orally administered firibastat (previously named RB150), an APA inhibitor prodrug, would attenuate heart failure (HF) development after MI in mice, by blocking brain RAS hyperactivity. Two days after MI, adult male CD1 mice were randomized to three groups, for four to eight weeks of oral treatment with vehicle (MIâ¯+â¯vehicle), firibastat (150â¯mg/kg; MIâ¯+â¯firibastat) or the angiotensin I converting enzyme inhibitor enalapril (1â¯mg/kg; MIâ¯+â¯enalapril) as a positive control. From one to four weeks post-MI, brain APA hyperactivity occurred, contributing to brain RAS hyperactivity. Firibastat treatment normalized brain APA hyperactivity, with a return to the control values measured in sham group two weeks after MI. Four and six weeks after MI, MIâ¯+â¯firibastat mice had a significant lower LV end-diastolic pressure, LV end-systolic diameter and volume, and a higher LV ejection fraction than MIâ¯+â¯vehicle mice. Moreover, the mRNA levels of biomarkers of HF (Myh7, Bnp and Anf) were significantly lower following firibastat treatment. For a similar infarct size, the peri-infarct area of MIâ¯+â¯firibastat mice displayed lower levels of mRNA for Ctgf and collagen types I and III (markers of fibrosis) than MIâ¯+â¯vehicle mice. Thus, chronic oral firibastat administration after MI in mice prevents cardiac dysfunction by normalizing brain APA hyperactivity, and attenuates cardiac hypertrophy and fibrosis.
Asunto(s)
Encéfalo/metabolismo , Inhibidores Enzimáticos/farmacología , Glutamil Aminopeptidasa/antagonistas & inhibidores , Corazón/fisiopatología , Infarto del Miocardio/fisiopatología , Sistema Renina-Angiotensina , Administración Oral , Animales , Biomarcadores/metabolismo , Cardiomegalia/complicaciones , Cardiomegalia/diagnóstico por imagen , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Enalapril/farmacología , Fibrosis , Glutamil Aminopeptidasa/metabolismo , Corazón/efectos de los fármacos , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/fisiopatología , Mediadores de Inflamación/metabolismo , Masculino , Ratones , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico por imagen , Sistema Renina-Angiotensina/efectos de los fármacos , Volumen Sistólico/efectos de los fármacosRESUMEN
AIMS: Inhibition of brain angiotensin III by central infusion of aminopeptidase A (APA) inhibitor firibastat (RB150) inhibits sympathetic hyperactivity and heart failure in rats after myocardial infarction (MI). This study evaluated effectiveness of systemic treatment with firibastat compared with AT1R blocker, losartan. METHODS AND RESULTS: MI was induced by ligation of left coronary artery in male Wistar rats. Rats were treated from 1 to 5 weeks after MI in protocol 1 with vehicle, or firibastat at 50 mg/kg/d subcutaneously (s.c.) or 150 mg/kg/d oral, once daily, and in protocol 2, with vehicle, firibastat 150 mg/kg or losartan 50 mg/kg oral twice daily. At 5 weeks, left ventricle function was evaluated by echocardiography and Millar catheter. After MI, rats developed moderate severe heart failure. Both s.c. and oral firibastat inhibited brain APA and attenuated left ventricle dysfunction. Oral firibastat and losartan similarly improved left ventricular end diastolic pressure. However, whereas firibastat improved dP/dtmax, losartan lowered dP/dtmax and left ventricular peak systolic pressure, and increased plasma creatinine by ~50%. On the other hand, losartan more effectively inhibited cardiac fibrosis. CONCLUSION: Inhibition of the brain renin-angiotensin system by oral APA inhibitor is at least as effective as oral AT1R blocker to inhibit cardiac dysfunction after MI but without hypotension or renal dysfunction.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Angiotensina III/metabolismo , Encéfalo/efectos de los fármacos , Disulfuros/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Glutamil Aminopeptidasa/antagonistas & inhibidores , Insuficiencia Cardíaca/prevención & control , Losartán/administración & dosificación , Infarto del Miocardio/tratamiento farmacológico , Ácidos Sulfónicos/administración & dosificación , Administración Oral , Animales , Encéfalo/enzimología , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Fibrosis , Glutamil Aminopeptidasa/metabolismo , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Inyecciones Subcutáneas , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/enzimología , Infarto del Miocardio/fisiopatología , Ratas Wistar , Transducción de Señal , Función Ventricular Izquierda/efectos de los fármacos , Presión Ventricular/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND AND OBJECTIVE: Hyperactivity of the brain renin-angiotensin (Ang) system has been implicated in the development and maintenance of hypertension. AngIII, one of the main effector peptides of the brain renin-Ang system, exerts a tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme generating brain AngIII, represents a new therapeutic target for the treatment of hypertension. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. When given orally in acute treatment in hypertensive rats, RB150 crosses the gastrointestinal and blood-brain barriers, enters the brain, inhibits brain APA activity and decreases BP. We investigate, here, the antihypertensive effects of chronic oral RB150 (50âmg/kg per day) treatment over 24 days in alert hypertensive deoxycorticosterone acetate-salt rats. METHODS: We measured variations in Brain APA enzymatic activity, SBP, plasma arginine vasopressin levels and metabolic parameters after RB150 chronic administration. RESULTS: This resulted in a significant decrease in SBP over the 24-day treatment period showing that no tolerance to the antihypertensive RB150 effect was observed throughout the treatment period. Chronic RB150 treatment also significantly decreased plasma arginine vasopressin levels and increased diuresis, which participate to BP decrease by reducing the size of fluid compartment. Interestingly, we observed an increased natriuresis without modifying both plasma sodium and potassium levels. CONCLUSION: Our results strengthen the interest of developing RB150 as a novel central-acting antihypertensive agent and evaluating its efficacy in salt-sensitive hypertension.
Asunto(s)
Antihipertensivos/uso terapéutico , Encéfalo/enzimología , Disulfuros/uso terapéutico , Glutamil Aminopeptidasa/metabolismo , Hipertensión/tratamiento farmacológico , Ácidos Sulfónicos/uso terapéutico , Administración Oral , Animales , Arginina Vasopresina/sangre , Presión Sanguínea/efectos de los fármacos , Acetato de Desoxicorticosterona , Inhibidores Enzimáticos/uso terapéutico , Glutamil Aminopeptidasa/antagonistas & inhibidores , Hipertensión/sangre , Hipertensión/fisiopatología , Masculino , Natriuresis/efectos de los fármacos , RatasRESUMEN
Hypertension affects one-third of the adult population and is a growing problem due to the increasing incidence of obesity and diabetes. Brain RAS (renin-angiotensin system) hyperactivity has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We have identified in the brain RAS that APA (aminopeptidase A) and APN (aminopeptidase N), two membrane-bound zinc metalloproteases, are involved in the metabolism of AngII (angiotensin II) and AngIII (angiotensin III) respectively. The present review summarizes the main findings suggesting that AngIII plays a predominant role in the brain RAS in the control of BP (blood pressure). We first explored the organization of the APA active site by site-directed mutagenesis and molecular modelling. The development and the use in vivo of specific and selective APA and APN inhibitors EC33 and PC18 respectively, has allowed the demonstration that brain AngIII generated by APA is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in conscious hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, which has led to the development of potent orally active APA inhibitors, such as RB150. RB150 administered orally in hypertensive DOCA (deoxycorticosteroneacetate)-salt rats or SHRs (spontaneously hypertensive rats) crosses the intestinal, hepatic and blood-brain barriers, enters the brain, generates two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and normalize BP for several hours. The decrease in BP involves two different mechanisms: a decrease in vasopressin release into the bloodstream, which in turn increases diuresis resulting in a blood volume reduction that participates in the decrease in BP and/or a decrease in sympathetic tone, decreasing vascular resistance. RB150 constitutes the prototype of a new class of centrally acting antihypertensive agents and is currently being evaluated in a Phase Ib clinical trial.
Asunto(s)
Disulfuros/uso terapéutico , Glutamil Aminopeptidasa/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Inhibidores de Proteasas/uso terapéutico , Ácidos Sulfónicos/uso terapéutico , Angiotensina III/metabolismo , Angiotensina III/fisiología , Animales , Sitios de Unión , Presión Sanguínea , Barrera Hematoencefálica , Encéfalo/efectos de los fármacos , Ensayos Clínicos Fase I como Asunto , Diseño de Fármacos , Glutamil Aminopeptidasa/química , Humanos , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Inhibidores de Proteasas/farmacocinética , RatasRESUMEN
AIMS: In rats post-myocardial infarction (MI), activation of angiotensinergic pathways in the brain contributes to sympathetic hyperactivity and progressive left ventricle (LV) dysfunction. The present study examined whether angiotensin III (Ang III) is one of the main effector peptides of the brain renin-angiotensin system controlling these effects. METHODS AND RESULTS: After coronary artery ligation, Wistar rats were infused intracerebroventricularly for 4 weeks via minipumps with vehicle, the aminopeptidase A (APA) inhibitor RB150 (0.3 mg/day), which blocks the formation of brain Ang III, or losartan (0.25 mg/day). Blood pressure (BP), heart rate, and renal sympathetic nerve activity in response to air stress and acute changes in BP were measured, and LV function was evaluated by echocardiography and Millar catheter. At 4 weeks post-MI, brain APA activity was increased, sympatho-excitatory and pressor responses to air stress enhanced, and arterial baroreflex function impaired. LV end-diastolic pressure (LVEDP) was increased and ejection fraction (EF) and maximal first derivative of change in pressure over time (dP/dt(max)) were decreased. Central infusion of RB150 during 4 weeks post-MI normalized brain APA activity and responses to stress and baroreflex function, and improved LVEDP, EF, and dP/dt(max). Central infusion of losartan had similar effects but was somewhat less effective, and had no effect on brain APA activity. CONCLUSION: These results indicate that brain APA and Ang III appear to play a pivotal role in the sympathetic hyperactivity and LV dysfunction in rats post-MI. RB150 may be a potential candidate for central nervous system-targeted therapy post-MI.
Asunto(s)
Angiotensina III/antagonistas & inhibidores , Encéfalo/metabolismo , Progresión de la Enfermedad , Infarto del Miocardio/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Disfunción Ventricular Izquierda/prevención & control , Disfunción Ventricular Izquierda/fisiopatología , Aldosterona/metabolismo , Angiotensina III/efectos de los fármacos , Animales , Barorreflejo/efectos de los fármacos , Barorreflejo/fisiología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Disulfuros/administración & dosificación , Disulfuros/farmacología , Glutamil Aminopeptidasa/antagonistas & inhibidores , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Infusiones Intraventriculares , Ratas , Ratas Wistar , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Volumen Sistólico/efectos de los fármacos , Volumen Sistólico/fisiología , Ácidos Sulfónicos/administración & dosificación , Ácidos Sulfónicos/farmacología , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We reported previously in the brain that aminopeptidase A and aminopeptidase N are involved in the metabolism of angiotensin II and angiotensin III, respectively. By using in vivo specific and selective aminopeptidase A and aminopeptidase N inhibitors, we showed that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting a tonic stimulatory control more than blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential target for the treatment of hypertension. We demonstrated here the antihypertensive effects of RB150, a prodrug of the specific and selective aminopeptidase A inhibitor, EC33, in spontaneously hypertensive rats, a model of human essential hypertension. Oral administration of RB150 in conscious spontaneously hypertensive rats inhibited brain aminopeptidase A activity, demonstrating the central bioavailability of RB150 and its ability to generate EC33 into the brain. Oral RB150 treatment dose-dependently reduced blood pressure in spontaneously hypertensive rats with an ED(50) of 30 mg/kg, lasting for several hours. This decrease in blood pressure is partly attributed to a decrease in sympathetic tone, reducing vascular resistance. This treatment did not modify systemic renin-angiotensin system activity. Concomitant oral administration of RB150 with a systemic renin-angiotensin system blocker, enalapril, potentiated the RB150-induced blood pressure decrease achieved in <2 hours. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents that might be used in combination with classic systemic renin-angiotensin system blockers to improve blood pressure control.
Asunto(s)
Antihipertensivos/uso terapéutico , Disulfuros/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Glutamil Aminopeptidasa/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Ácidos Sulfónicos/uso terapéutico , Administración Oral , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Disulfuros/administración & dosificación , Disulfuros/farmacología , Relación Dosis-Respuesta a Droga , Enalapril/administración & dosificación , Enalapril/farmacología , Enalapril/uso terapéutico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Glutamil Aminopeptidasa/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Ácidos Sulfónicos/administración & dosificación , Ácidos Sulfónicos/farmacologíaRESUMEN
Hypertension affects 26% of adults and is in constant progress related to increased incidence of obesity and diabetes. One-third of hypertensive patients may be successfully treated with one antihypertensive agent, one-third may require two agents and in the remaining patients will need three agents for effective blood pressure (BP) control. The development of new classes of antihypertensive agents with different mechanisms of action therefore remains an important goal. Brain renin-angiotensin system (RAS) hyperactivity has been implicated in hypertension development and maintenance in several types of experimental and genetic hypertension animal models. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III have similar affinities for type 1 (AT1) and type 2 (AT2) Ang II receptors. Following intracerebroventricular (i.c.v.) injection, Ang II and Ang III similarly increase arginine-vasopressin (AVP) release and BP. Blocking the brain RAS may be advantageous as it simultaneously (1) decreases sympathetic tone and consequently vascular resistance, (2) decreases AVP release, reducing blood volume and vascular resistance and (3) blocks angiotensin-induced baroreflex inhibition, decreasing both vascular resistance and cardiac output. However, as Ang II is converted to Ang III in vivo, the exact nature of the active peptide is not precisely determined. We summarize here the main findings identifying AngIII as one of the major effector peptides of the brain RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP in hypertensive rats, identifying brain aminopeptidase A (APA), the enzyme generating brain Ang III, as a potentially candidate target for hypertension treatment. This has led to the development of potent orally active APA inhibitors, such as RB150--the prototype of a new class of centrally acting antihypertensive agents.
Asunto(s)
Antihipertensivos/uso terapéutico , Encéfalo/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Sistema Renina-Angiotensina , Angiotensina III/antagonistas & inhibidores , Angiotensina III/metabolismo , Animales , Encéfalo/efectos de los fármacos , Resistencia a Medicamentos , Glutamil Aminopeptidasa/antagonistas & inhibidores , Humanos , Terapia Molecular Dirigida , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Inhibidores de Proteasas/uso terapéutico , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
Overactivity of the brain renin-angiotensin system has been implicated in the development and maintenance of hypertension. We reported previously that angiotensin II is converted to angiotensin III by aminopeptidase A in the mouse brain. We then used specific and selective aminopeptidase A inhibitors to show that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting tonic stimulatory control over blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential candidate central nervous system target for the treatment of hypertension. Given this possible clinical use of aminopeptidase A inhibitors, it was, therefore, important to investigate their pharmacological activity after oral administration. We investigated RB150, a dimer of the selective aminopeptidase A inhibitor, EC33, generated by creating a disulfide bond. This chemical modification allows prodrug to cross the blood-brain barrier when administered by systemic route. Oral administration of RB150 in conscious DOCA-salt rats inhibited brain aminopeptidase A activity, resulting in values similar to those obtained with the brains of normotensive rats, demonstrating the central bioavailability of RB150. Oral RB150 treatment resulted in a marked dose-dependent reduction in blood pressure in DOCA-salt but not in normotensive rats, with an ED(50) in the 1-mg/kg range, achieved in <2 hours and lasting for several hours. This treatment also significantly decreased plasma arginine-vasopressin levels and increased diuresis, which may participate to the blood pressure decrease by reducing the size of fluid compartment. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Glutamil Aminopeptidasa/antagonistas & inhibidores , Hipertensión/tratamiento farmacológico , Administración Oral , Animales , Arginina Vasopresina/sangre , Presión Sanguínea/fisiología , Modelos Animales de Enfermedad , Disulfuros/administración & dosificación , Disulfuros/farmacología , Disulfuros/uso terapéutico , Diuresis/efectos de los fármacos , Diuresis/fisiología , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Líquidos/fisiología , Inhibidores Enzimáticos/administración & dosificación , Glutamil Aminopeptidasa/efectos de los fármacos , Glutamil Aminopeptidasa/metabolismo , Hipertensión/enzimología , Hipertensión/fisiopatología , Masculino , Ratas , Ratas Endogámicas Dahl , Ratas Endogámicas WKY , Ácidos Sulfónicos/administración & dosificación , Ácidos Sulfónicos/farmacología , Ácidos Sulfónicos/uso terapéuticoRESUMEN
Among the main bioactive peptides of the brain renin-angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for the type 1 and type 2 Ang receptors. Both peptides, injected intracerebroventricularly, cause similar increase in blood pressure (BP). Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarized recent insights into the predominant role of brain AngIII in the central control of BP underlining the fact that brain aminopeptidase A (APA), the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension. This led to the development of potent, systematically active APA inhibitors, such as RB150, as a prototype of a new class of centrally acting antihypertensive agents for the treatment of certain forms of hypertension.