RESUMO
Inhibition of the sphingosine-1-phosphate (S1P)-catabolizing enzyme S1P lyase (S1PL) elevates the native ligand of S1P receptors and provides an alternative mechanism for immune suppression to synthetic S1P receptor agonists. S1PL inhibition is reported to preferentially elevate S1P in lymphoid organs. Tissue selectivity could potentially differentiate S1PL inhibitors from S1P receptor agonists, the use of which also results in bradycardia, atrioventricular block, and hypertension. But it is unknown if S1PL inhibition would also modulate cardiac S1P levels or cardiovascular function. The S1PL inhibitor 6-[(2R)-4-(4-benzyl-7-chlorophthalazin-1-yl)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile was used to determine the relationship in rats between drug concentration, S1P levels in select tissues, and circulating lymphocytes. Repeated oral doses of the S1PL inhibitor fully depleted circulating lymphocytes after 3 to 4 days of treatment in rats. Full lymphopenia corresponded to increased levels of S1P of 100- to 1000-fold in lymph nodes, 3-fold in blood (but with no change in plasma), and 9-fold in cardiac tissue. Repeated oral dosing of the S1PL inhibitor in telemeterized, conscious rats resulted in significant bradycardia within 48 hours of drug treatment, comparable in magnitude to the bradycardia induced by 3 mg/kg fingolimod. These results suggest that S1PL inhibition modulates cardiac function and does not provide immune suppression with an improved cardiovascular safety profile over fingolimod in rats.
Assuntos
Aldeído Liases/antagonistas & inibidores , Bradicardia/induzido quimicamente , Inibidores Enzimáticos/efeitos adversos , Coração/efeitos dos fármacos , Lisofosfolipídeos/metabolismo , Miocárdio/metabolismo , Esfingosina/análogos & derivados , Animais , Bradicardia/metabolismo , Relação Dose-Resposta a Droga , Feminino , Coração/fisiologia , Masculino , Piperazinas/efeitos adversos , Ratos , Ratos Sprague-Dawley , Esfingosina/metabolismoRESUMO
A novel series of N-type calcium channel inhibitors have been discovered. Optimization of potency and HT-ADME properties provides 4-aminocyclopentapyrrolidines with analgesic efficacy after oral dosing.
Assuntos
Analgésicos/química , Analgésicos/uso terapêutico , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo N/metabolismo , Neuralgia/tratamento farmacológico , Administração Oral , Analgésicos/síntese química , Analgésicos/metabolismo , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/metabolismo , Humanos , Microssomos/metabolismo , Ratos , Relação Estrutura-AtividadeRESUMO
ABT-869 [N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea] is a novel multitargeted inhibitor of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptor tyrosine kinase family members. ABT-869 demonstrates tumor growth inhibition in multiple preclinical animal models and in early clinical trials. VEGF receptor inhibition is also associated with reversible hypertension that may limit its benefit clinically. To evaluate optimal therapeutic approaches to prevent hypertension with VEGF receptor inhibition, we characterized the dose-dependent effects of seven antihypertensive agents from three mechanistic classes [angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs)] on hypertension induced by ABT-869 in conscious telemetry rats. We report that ABT-869-induced hypertension can be prevented and reversed with subtherapeutic or therapeutic doses of antihypertensive drugs with a general rank order of ACEi > ARB > CCB. In SCID mice, the ACE inhibitor, enalapril (C(20)H(28)N(2)O(5) x C(4)H(4)O(4)) at 30 mg/kg, prevented hypertension, with no attenuation of the antitumor efficacy of ABT-869. These studies demonstrate that the adverse cardiovascular effects of the VEGF/PDGF receptor tyrosine kinase inhibitor, ABT-869, are readily controlled by conventional antihypertensive therapy without affecting antitumor efficacy.
Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Indazóis/farmacologia , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Acrilatos/farmacologia , Anlodipino/farmacologia , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Relação Dose-Resposta a Droga , Enalapril/farmacologia , Humanos , Imidazóis/farmacologia , Indazóis/efeitos adversos , Indazóis/uso terapêutico , Lisinopril/farmacologia , Masculino , Camundongos , Camundongos SCID , Neoplasias/patologia , Nifedipino/farmacologia , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Ramipril/farmacologia , Ratos , Ratos Sprague-Dawley , Telmisartan , Tiofenos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
ABT-869 is a novel multitargeted inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases (RTKs) with potent antiangiogenic properties that slow tumor progression. Vascular endothelial growth factor receptor blockade has been shown to produce hypertension. Atrasentan is a potent and selective endothelin (ETA) receptor antagonist that lowers blood pressure and affects tumor growth. To assess the utility of ETA receptor blockade in controlling hypertension with RTK inhibition, we evaluated the ability of atrasentan to block hypertension with ABT-869 in conscious, telemetry-instrumented rats. Changes in mean arterial pressure (MAP) and heart rate (HR) were evaluated using mean values and the area under the curve (AUC). Atrasentan (0.5, 1.5, and 5.0 mg kg(-1) d(-1) for 5 days) elicited dose-dependent decreases in MAP-AUC (-16.7 +/- 1.3, -20.94 +/- 3.68, and -30.12 +/- 3.57 mm Hg x day, respectively) compared with vehicle. ABT-869 (1, 3, 10, 30 mg kg(-1) d(-1) for 5 days) increased MAP compared with vehicle (MAP-AUC values of -5.52 +/- 3.75, 12.7 +/- 8.4, 37.5 +/- 4.4, and 63.8 +/- 3.3 mm Hg x day, respectively). Pretreatment with atrasentan (5 mg/kg for 5 days) prevented and abolished the hypertensive effects of ABT-869. Thus, ETA receptor blockade effectively alleviated hypertension with RTK inhibition and may serve a dual therapeutic role by preventing hypertension and slowing tumor progression.
Assuntos
Inibidores da Angiogênese/farmacologia , Antagonistas do Receptor de Endotelina A , Hipertensão/prevenção & controle , Indazóis/farmacologia , Compostos de Fenilureia/farmacologia , Pirrolidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Inibidores da Angiogênese/efeitos adversos , Animais , Área Sob a Curva , Atrasentana , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Indazóis/efeitos adversos , Masculino , Compostos de Fenilureia/efeitos adversos , Pirrolidinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , TelemetriaRESUMO
A new structural series of histamine H3 receptor antagonist was developed. The new compounds are based on a quinoline core, appended with a required basic aminoethyl moiety, and with potency- and property-modulating heterocyclic substituents. The analogs have nanomolar and subnanomolar potency for the rat and human H3R in various in vitro assays, including radioligand competition binding as well as functional tests of H3 receptor-mediated calcium mobilization and GTPgammaS binding. The compounds possessed favorable drug-like properties, such as good PK, CNS penetration, and moderate protein binding across species. Several compounds were found to be efficacious in animal behavioral models of cognition and attention. Further studies on the pharmaceutic properties of this series of quinolines discovered a potential problem with photochemical instability, an issue which contributed to the discontinuation of this series from further development.
Assuntos
Pirazóis/síntese química , Pirimidinas/síntese química , Quinolinas/síntese química , Receptores Histamínicos H3/metabolismo , Animais , Atenção/efeitos dos fármacos , Aprendizagem da Esquiva/efeitos dos fármacos , Proteínas Sanguíneas/metabolismo , Barreira Hematoencefálica/metabolismo , Cálcio/metabolismo , Linhagem Celular , Cognição/efeitos dos fármacos , Cães , Agonismo Inverso de Drogas , Estabilidade de Medicamentos , Haplorrinos , Humanos , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos SHR , Reconhecimento Psicológico/efeitos dos fármacos , Comportamento Social , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
BACKGROUND/AIMS: Vitamin D receptor activators (VDRAs) may suppress renin expression and VDR-mediated renin inhibitors may offer a novel mechanism to control the RAS. METHODS: We delineated the effects of paricalcitol and calcitriol on PTH, renin, and iCa(2+) in C57/BL6 mice administered vehicle, paricalcitol, or calcitriol (0.01, 0.03, 0.10, 0.33, 1.0 microg/kg s.c.) 3 days/week for 9 days. RESULTS: Paricalcitol produced PTH suppression from 0.03 to 1.0 microg/kg (values between 9.7 +/- 3.3 and 20.7 +/- 4.7 pg/ml; vehicle = 88.0 +/- 16.9) and elicited dose-dependent reductions in renin/GAPDH expression at 0.33 and 1.0 microg/kg (0.037 +/- 0.002, 0.027 +/- 0.003; vehicle = 0.054 +/- 0.003) but produced no increases iCa(2+) at any dose tested. Calcitrol produced PTH suppression at all doses tested (between 6.4 +/- 1.2 and 29.5 +/- 17.2 pg/ml) and renin suppression at 0.10, 0.33, and 1.0 microg/kg (0.029 +/- 0.002, 0.031 +/- 0.003, and 0.038 +/- 0.02). However, at 0.33 and 1.0 mg/kg, calcitriol produced increases iCa(2+) (1.31 +/- 0.03 and 1.48 +/- 0.02 mmol/l; vehicle = 1.23 +/- 0.02 mmol/l). CONCLUSIONS: Paricalcitol produces significant, dose-dependent suppression of renin expression in the absence of hypercalcemia at doses 10-fold above those necessary for PTH suppression. Calcitriol also produced suppression of renin at doses at least 10-fold above those required for PTH suppression, but increases in iCa(2+) were observed at doses only 3-fold above those necessary to elicit renin suppression.
Assuntos
Calcitriol/administração & dosagem , Cálcio/metabolismo , Ergocalciferóis/administração & dosagem , Rim/metabolismo , Hormônio Paratireóideo/metabolismo , Renina/metabolismo , Ativação Transcricional/fisiologia , Animais , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Rim/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Renina/genética , Ativação Transcricional/efeitos dos fármacosRESUMO
Improvements have been made to the safety and efficacy of bumped kinase inhibitors, and they are advancing toward human and animal use for treatment of cryptosporidiosis. As the understanding of bumped kinase inhibitor pharmacodynamics for cryptosporidiosis therapy has increased, it has become clear that better compounds for efficacy do not necessarily require substantial systemic exposure. We now have a bumped kinase inhibitor with reduced systemic exposure, acceptable safety parameters, and efficacy in both the mouse and newborn calf models of cryptosporidiosis. Potential cardiotoxicity is the limiting safety parameter to monitor for this bumped kinase inhibitor. This compound is a promising pre-clinical lead for cryptosporidiosis therapy in animals and humans.
Assuntos
Criptosporidiose/tratamento farmacológico , Cryptosporidium parvum/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Administração Oral , Animais , Animais Recém-Nascidos , Bovinos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Coração/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Interferon gama/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Testes de Mutagenicidade , Gravidez , Ligação Proteica , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/toxicidade , SegurançaRESUMO
Screening novel, poorly soluble small-molecule candidates for cardiovascular liabilities represents a key challenge in early drug discovery. This report describes a novel vehicle composed of 20% N,N-Dimethylacetamide (DMA)/40% Propylene glycol (PG)/40% Polyethylene Glycol (PEG-400) (DPP) for administration of new chemical entities (NCEs) by slow intravenous (i.v.) infusion in a preclinical anesthetized rat model. The vehicle was designed considering both available excipient safety information and solubilization potential for poorly soluble NCEs. DPP solubilized 11 drugs, 8 of which were insoluble in 5% dextrose in water (D5W), and 5 insoluble in PEG-400 to a target concentration of 30mg/mL. DPP elicits no adverse cardiovascular responses in the anesthetized rat model despite containing 40% PEG-400, a commonly used organic solvent which elicits hypertension and bradycardia that often confounds interpretation of drug effects. Three compounds demonstrating adequate solubility in both DPP and D5W were screened in the anesthetized rat model. When normalized to plasma exposure, atenolol, sotalol and enalaprilat exhibited comparable mean arterial pressure, heart rate, and cardiac contractility responses regardless of formulation. While the antihypertensive effect of nifedipine was evident with both DPP and PEG-400 formulations, pressor effects from PEG-400 confounded interpretation of the magnitude of nifedipine's response. Plasma concentrations of atenolol and enalaprilat were greater in D5W formulation whereas sotalol exposures were greater when using DPP as a vehicle. These results demonstrate the utility of DPP as an intravenous vehicle for formulating poorly soluble compounds in early preclinical screening for cardiovascular safety studies.
Assuntos
Portadores de Fármacos/química , Excipientes/química , Hemodinâmica/efeitos dos fármacos , Modelos Cardiovasculares , Preparações Farmacêuticas/administração & dosagem , Bibliotecas de Moléculas Pequenas/administração & dosagem , Acetamidas/administração & dosagem , Acetamidas/química , Acetamidas/toxicidade , Animais , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/toxicidade , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Excipientes/administração & dosagem , Excipientes/toxicidade , Infusões Intravenosas , Dose Letal Mediana , Masculino , Preparações Farmacêuticas/sangue , Preparações Farmacêuticas/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/toxicidade , Propilenoglicol/administração & dosagem , Propilenoglicol/química , Propilenoglicol/toxicidade , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/efeitos adversos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , SolubilidadeRESUMO
Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.
Assuntos
Ciclobutanos/síntese química , Ciclobutanos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Cálcio/metabolismo , Ciclobutanos/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Conformação Molecular , Piridinas/química , Relação Estrutura-Atividade , Canais de Cátion TRPV/metabolismoRESUMO
Blockade of voltage-gated Ca²âº channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²âº channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC50=0.8 µM and 1.4 µM, respectively) and T-type (IC50=4.6 µM and 1.2 µM, respectively) Ca²âº channels in FLIPR based Ca²âº flux assays. A-686085 also potently blocked L-type Ca²âº channels (EC50=0.6 µM), however, A-1048400 was much less active in blocking this channel (EC50=28 µM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC50=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²âº currents in rat dorsal root ganglion neurons (IC50=3.0 µM and 1.6 µM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²âº channels coupled with pharmacological selectivity vs. L-type Ca²âº channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function.
Assuntos
Analgésicos/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Hemodinâmica/fisiologia , Neurônios/fisiologia , Medição da Dor , Piperidonas/administração & dosagem , Piperidonas/química , Administração Oral , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Neurônios/efeitos dos fármacos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-DawleyRESUMO
Transient receptor potential vanilloid type 1 (TRPV1) is a ligand-gated ion channel that functions as an integrator of multiple pain stimuli including heat, acid, capsaicin and a variety of putative endogenous lipid ligands. TRPV1 antagonists have been shown to decrease inflammatory pain in animal models and to produce limited hyperthermia at analgesic doses. Here, we report that ABT-102, which is a potent and selective TRPV1 antagonist, is effective in blocking nociception in rodent models of inflammatory, post-operative, osteoarthritic, and bone cancer pain. ABT-102 decreased both spontaneous pain behaviors and those evoked by thermal and mechanical stimuli in these models. Moreover, we have found that repeated administration of ABT-102 for 5-12 days increased its analgesic activity in models of post-operative, osteoarthritic, and bone cancer pain without an associated accumulation of ABT-102 concentration in plasma or brain. Similar effects were also observed with a structurally distinct TRPV1 antagonist, A-993610. Although a single dose of ABT-102 produced a self-limiting increase in core body temperature that remained in the normal range, the hyperthermic effects of ABT-102 effectively tolerated following twice-daily dosing for 2 days. Therefore, the present data demonstrate that, following repeated administration, the analgesic activity of TRPV1 receptor antagonists is enhanced, while the associated hyperthermic effects are attenuated. The analgesic efficacy of ABT-102 supports its advancement into clinical studies.
Assuntos
Analgésicos/administração & dosagem , Febre/tratamento farmacológico , Indazóis/administração & dosagem , Limiar da Dor/efeitos dos fármacos , Dor/tratamento farmacológico , Canais de Cátion TRPV/metabolismo , Ureia/análogos & derivados , Animais , Temperatura Corporal/efeitos dos fármacos , Neoplasias Ósseas/complicações , Cálcio/metabolismo , Modelos Animais de Doenças , Interações Medicamentosas , Febre/induzido quimicamente , Inflamação/complicações , Masculino , Camundongos , Camundongos Endogâmicos C3H , Atividade Motora/efeitos dos fármacos , Osteoartrite/complicações , Dor/etiologia , Medição da Dor , Ratos , Ratos Sprague-Dawley , Canais de Cátion TRPV/antagonistas & inibidores , Ureia/administração & dosagemRESUMO
Levosimendan enhances cardiac contractility via Ca(2+) sensitization and induces vasodilation through the activation of ATP-dependent K(+) and large-conductance Ca(2+)-dependent K(+) channels. However, the hemodynamic effects of levosimendan, as well as its metabolites, OR-1896 and OR-1855, relative to plasma concentrations achieved, are not well defined. Thus levosimendan, OR-1896, OR-1855, or vehicle was infused at 0.01, 0.03, 0.1, and 0.3 mumol.kg(-1).30 min(-1), targeting therapeutic to supratherapeutic concentrations of total levosimendan (62.6 ng/ml). Results were compared with those of the beta(1)-agonist dobutamine and the phosphodiesterase 3 inhibitor milrinone. Peak concentrations of levosimendan, OR-1896, and OR-1855 were 455 +/- 21, 126 +/- 6, and 136 +/- 6 ng/ml, respectively. Levosimendan and OR-1896 produced dose-dependent reductions in mean arterial pressure (-31 +/- 2 and -42 +/- 3 mmHg, respectively) and systemic resistance without affecting pulse pressure, effects paralleled by increases in heart rate; OR-1855 produced no effect at any dose tested. Dobutamine, but not milrinone, increased mean arterial pressure and pulse pressure (17 +/- 2 and 23 +/- 2 mmHg, respectively). Regarding potency to elicit reductions in time to peak pressure and time to systolic pressure recovery: OR-1896 > levosimendan > milrinone > dobutamine. Levosimendan and OR-1896 elicited dose-dependent increases in change in pressure over time (118 +/- 10 and 133 +/- 13%, respectively), concomitant with reductions in left ventricular end-diastolic pressure and ejection time. However, neither levosimendan nor OR-1896 produced increases in myocardial oxygen consumption at inotropic and vasodilatory concentrations, whereas dobutamine increased myocardial oxygen consumption (79% above baseline). Effects of the levosimendan and OR-1896 were limited to the systemic circulation; neither compound produced changes in pulmonary pressure, whereas dobutamine produced profound increases (74 +/- 13%). Thus levosimendan and OR-1896 are hemodynamically active in the anesthetized dog at concentrations observed clinically and elicit cardiovascular effects consistent with activation of both K(+) channels and Ca(2+) sensitization, whereas OR-1855 is inactive on endpoints measured in this study.
Assuntos
Acetamidas/farmacologia , Cardiotônicos/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Dobutamina/farmacologia , Hidrazonas/farmacologia , Milrinona/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Piridazinas/farmacologia , Resistência Vascular/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Cálcio/metabolismo , Débito Cardíaco/efeitos dos fármacos , Cardiotônicos/sangue , Sistema Cardiovascular/metabolismo , Cães , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Hidrazonas/sangue , Masculino , Contração Miocárdica/efeitos dos fármacos , Potássio/metabolismo , Canais de Potássio/efeitos dos fármacos , Canais de Potássio/metabolismo , Circulação Pulmonar/efeitos dos fármacos , Piridazinas/sangue , Simendana , Fatores de Tempo , Vasodilatadores/sangue , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Calcium-sensing receptor (CaR) activation decreases serum parathyroid hormone (PTH) and Ca2+ and, despite long-term reductions in mean arterial blood pressure (MAP), may produce acute hypertension in rats, an effect we hypothesized was mediated by constriction of multiple vascular beds. Rats were subjected to 5/6 nephrectomy (NX) or no surgery (Normal); at 7 to 8 weeks, uremia animals were anesthetized and instrumented to record MAP and regional blood flow (carotid, mesenteric, and hindlimb). Cinacalcet [N-(1-naphthalen-1-ylethyl)-3-[3-(trifluoromethyl)phenyl]-propan-1-amine; 1, 3, and 10 mg/kg; 30 min/dose] was infused over 90 min. In NX rats, cinacalcet dose-dependently decreased ionized calcium (iCa2+), elicited a 90% reduction in PTH, and produced dose-dependent self-limiting increases in MAP (from 119 +/- 6 to 129 +/- 5, 142 +/- 4, and 145 +/- 3 mm Hg at the end of each infusion). At 1 mg/kg, carotid vascular resistance (CVR) and mesenteric vascular resistance (MVR) increased to 16 +/- 6 and 18 +/- 6% above baseline, respectively. Hindlimb vascular resistance (HVR) also trended upward (13 +/- 8%). At 3 mg/kg, increases in CVR (38 +/- 10%), MVR (40 +/- 8%), and HVR (39 +/- 14%) were exacerbated; at 10 mg/kg, values remained at or near these levels. The effects of cinacalcet in Normal rats were similar to NX and were attenuated by ganglionic blockade with hexamethonium at low doses but remained significantly elevated at higher doses. Thus, CaR activation acutely increases MAP in uremic and nonuremic rats, responses that occur in parallel to vasoconstriction in multiple vascular beds through both a central and peripheral mechanism of action. Moreover, subsequent mechanistic studies suggest that increases in MAP produced by cinacalcet may be mediated by reduced tonic NO synthase-dependent NO production subsequent to reductions in blood iCa2+.
Assuntos
Vias Aferentes/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Vias Eferentes/fisiologia , Tono Muscular/efeitos dos fármacos , Músculo Liso Vascular , Naftalenos/farmacologia , Receptores de Detecção de Cálcio/metabolismo , Uremia , Animais , Cálcio/sangue , Cinacalcete , Frequência Cardíaca/efeitos dos fármacos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/inervação , Hormônio Paratireóideo/sangue , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Uremia/tratamento farmacológico , Uremia/metabolismo , Uremia/fisiopatologia , Resistência Vascular/efeitos dos fármacosRESUMO
The net contribution of endothelin type A (ET(A)) and type B (ET(B)) receptors in blood pressure regulation in humans and experimental animals, including the conscious mouse, remains undefined. Thus we assessed the role of ET(A) and ET(B) receptors in the control of basal blood pressure and also the role of ET(A) receptors in maintaining the hypertensive effects of systemic ET(B) blockade in telemetry-instrumented mice. Mean arterial pressure (MAP) and heart rate were recorded continuously from the carotid artery and daily (24 h) values determined. At baseline, MAP ranged from 99 +/- 1 to 101 +/- 1 mmHg and heart rate ranged between 547 +/- 15 and 567 +/- 19 beats/min (n = 6). Daily oral administration of the ET(B) selective antagonist A-192621 [10 mg/kg twice daily] increased MAP to 108 +/- 1 and 112 +/- 2 mmHg on days 1 and 5, respectively. Subsequent coadministration of the ET(A) selective antagonist atrasentan (5 mg/kg twice daily) in conjunction with A-192621 (10 mg/kg twice daily) decreased MAP to baseline values on day 6 (99 +/- 2 mmHg) and to below baseline on day 8 (89 +/- 3 mmHg). In a separate group of mice (n = 6) in which the treatment was reversed, systemic blockade of ET(B) receptors produced no hypertension in animals pretreated with atrasentan, underscoring the importance of ET(A) receptors to maintain the hypertension produced by ET(B) blockade. In a third group of mice (n = 10), ET(A) blockade alone (atrasentan; 5 mg/kg twice daily) produced an immediate and sustained decrease in MAP to values below baseline (baseline values = 101 +/- 2 to 103 +/- 2 mmHg; atrasentan decreased pressure to 95 +/- 2 mmHg). Thus these data suggest that ET(A) and ET(B) receptors play a physiologically relevant role in the regulation of basal blood pressure in normal, conscious mice. Furthermore, systemic ET(B) receptor blockade produces sustained hypertension in conscious telemetry-instrumented mice that is absent in mice pretreated with an ET(A) antagonist, suggesting that ET(A) receptors maintain the hypertension produced by ET(B) blockade.