RESUMO
A series of 3-(phenylsulfonyl)-1-phenylimidazolidine-2,4-dione derivatives have been synthesized and evaluated for their ability to selectively inhibit human heart chymase. The structure-activity relationship studies on these compounds gave the following results. The 1-phenyl moiety participates in a hydrophobic interaction where an optimum size is required. At this position, 3,4-dimethylphenyl is the best moiety for inhibiting chymase and showed high selectivity compared with chymotrypsin and cathepsin G. A 3-phenylsulfonyl moiety substituted with hydrogen-bond acceptors such as nitrile and methoxycarbonyl enhances its activity. Molecular-modeling studies on the interaction of 3-[(4-chlorophenyl)sulfonyl]-1-(4-chlorophenyl)-imidazolidine-2,4-dione (29) with the active site of human heart chymase suggested that the 1-phenyl moiety interacts with the hydrophobic P1 pocket, the 3-phenylsulfonyl moiety resides in the S1'-S2' subsites, and the 4-carbonyl of the imidazolidine ring and sulfonyl group interact with the oxyanion hole and the His-45 side chain of chymase, respectively. The complex model is consistent with the structure-activity relationships.
Assuntos
Imidazóis/síntese química , Miocárdio/enzimologia , Serina Endopeptidases/química , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/síntese química , Sulfonamidas/síntese química , Sítios de Ligação , Quimases , Gráficos por Computador , Humanos , Imidazóis/química , Imidazóis/farmacologia , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Método de Monte Carlo , Conformação Proteica , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
All Wistar rats showed hypertension when they were given heat-stress and administered metyrapone (200 micrograms/kg/day), a cholesterol-11-beta-hydroxylase inhibitor. The addition of saline loading potentiated the hypertensive state. The hypertension in MH-rats was blocked by a low dose (1 mg/kg) of propranolol, a dose which was insufficient to cure the Spontanous Hypertensive rats, and by a very low dose (20 ng/kg) of 1-dopa with carbidopa treatment, but not by haloperidol, sulpiride, or prazosin. Striatal dopamine (DA) of MH-rats was increased significantly. These results suggested that the hypertension of MH-rats was related to the inhibition of central DA release. Since MH-rats showed the availability of propranolol clearly, this may be a useful model for hypertension.
Assuntos
Encéfalo/metabolismo , Dopamina/metabolismo , Temperatura Alta/efeitos adversos , Hipertensão/etiologia , Metirapona/farmacologia , Animais , Modelos Animais de Doenças , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Propranolol/uso terapêutico , Ratos , Ratos Endogâmicos , Cloreto de Sódio/administração & dosagemRESUMO
To elucidate the mechanism, cardiac function and prognosis of complete left bundle branch block (CLBBB), 32 patients with CLBBB were studied using echocardiographic and vectorcardiographic methods. They were classified into 5 types: according to the presence or absence of early systolic notch and paradoxical motion of interventricular septum. Type I, an early systolic notch and paradoxical motion of the interventricular septum; type II, an early systolic notch and a flat septal motion, type III, an early systolic notch but no paradoxical motion; type IV, an early systolic notch of a slight degree but no paradoxical motion; type V, showed neither early systolic notch nor paradoxical motion. Type I patients had enlarged left ventricular dimension, severe cardiac damage and poor prognosis while type IV patients had a good ventricular function and prognosis with no complications. In type V patients, intraventricular conduction disturbances were apparent; a wide QRS loop in horizontal plane with no significant terminal delay. In type II and III, there were no typical findings. The histology revealed that the left bundle branch block was located at the bifurcation.