RESUMO
The renal thiazide-sensitive NaCl cotransporter, NCC, is the major pathway for salt reabsorption in the distal convoluted tubule. The activity of this cotransporter is critical for regulation of several physiological variables such as blood pressure, serum potassium, acid base metabolism, and urinary calcium excretion. Therefore, it is not surprising that numerous hormone-signaling pathways regulate NCC activity to maintain homeostasis. In this review, we will provide an overview of the most recent evidence on NCC modulation by aldosterone, angiotensin II, vasopressin, glucocorticoids, insulin, norepinephrine, estradiol, progesterone, prolactin, and parathyroid hormone.
Assuntos
Hormônios/metabolismo , Túbulos Renais Distais/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Animais , Hormônios Esteroides Gonadais/metabolismo , Hormônios/farmacologia , Humanos , Túbulos Renais Distais/efeitos dos fármacos , Receptores de Peptídeos/efeitos dos fármacos , Receptores de Peptídeos/metabolismo , Sistema Renina-Angiotensina , Membro 3 da Família 12 de Carreador de Soluto/efeitos dos fármacosRESUMO
INTRODUCTION: Receptors for natriuretic peptides have been demonstrated as potential targets for the treatment of male erectile dysfunction. AIM: This study investigates the relaxant effects of the atrial natriuretic peptide (ANP) and uroguanylin (UGN), and expression of natriuretic peptide receptors on strips of human corpora cavernosa (HCC). MAIN OUTCOME MEASURES: Quantitative analysis of natriuretic receptor expression and relaxation of precontracted strips were used to assess the membrane-bound guanylate cyclase-cyclic guanosine monophosphate (cGMP) pathway in HCC strips. METHODS: HCC was obtained from a cadaver donor at the time of collection of organs for transplantation (14-47 years) and strips were mounted in organ baths for isometric studies. RESULTS: ANP and UGN both induced concentration-dependent relaxation on HCC strips with a maximal response attained at 300 nM, corresponding to 45.4±4.0% and 49±4.8%, respectively. The relaxation is not affected by 30 µM 1H-[1,2,4]oxaolodiazolo[4,3-a]quinoxalin-1-one (ODQ) (a soluble guanylate cyclase inhibitor), but it is significantly blocked by 10 µM isatin, a nonspecific particulate guanylate cyclase (pGC) inhibitor. UGN was unable to potentiate electrical field stimulation (EFS) or acetylcholine-induced relaxations. The potential role of pGC activation and cGMP generation in this effect is reinforced by the potentiation of this effect by phosphodiesterase-5 inhibitor vardenafil (55.0±7.5-UGN vs. 98.6±1.4%-UGN+vardenafil; P<0.05). The relaxant effect was also partially (37.6%) blocked by the combination iberitoxin-apamin but was insensitive to glybenclamide. The expression of guanylate cyclase receptors (GC-A, GC-B, GC-C) and the expression of the natriuretic peptide "clearance" receptor (NPR-C) were confirmed by real-time polymerase chain reaction. The exposure of HCC strips to ANP (1 µM) and UGN (10 µM) significantly increased cGMP, but not cyclic adenosine monophosphate (cAMP) levels. CONCLUSIONS: UGN relaxes HCC strips by a guanylate cyclase and K(ca)-channel-dependent mechanism. These findings obtained in HCC reveal that the natriuretic peptide receptors are potential targets for the development of new drugs for the treatment of erectile dysfunction.
Assuntos
Fator Natriurético Atrial/metabolismo , Disfunção Erétil/tratamento farmacológico , Peptídeos Natriuréticos/farmacologia , Pênis/cirurgia , Adolescente , Adulto , Fator Natriurético Atrial/efeitos dos fármacos , Cadáver , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Disfunção Erétil/enzimologia , Disfunção Erétil/metabolismo , Guanilato Ciclase/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , Relaxamento Muscular/fisiologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Peptídeos Natriuréticos/metabolismo , Pênis/efeitos dos fármacos , Receptores do Fator Natriurético Atrial , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Peptídeos/efeitos dos fármacos , Receptores de Peptídeos/metabolismo , Guanilil Ciclase Solúvel , Adulto JovemRESUMO
1. A short review is given of the chemical, physical, and pharmacological development of the idea that target cell lipid membranes may catalyze the interaction between regulatory peptides (or other pharmacologic agents) and their cell surface receptors. 2. The message-address and the membrane compartments concepts explain the observed correlations between the three-dimensional structures of peptides induced by a membrane surface and their preference for a certain receptor subtype. 3. Examples are given for opioid peptides (enkephalin, dynorphin, etc.), tachykinin peptides (substance P, neurokinin A, etc.), and melanocortin peptides (ACTH, alpha-MSH, etc.). 4. Relationships between the conformation of substance P induced by membrane association and that of a non-peptide substance P mimetic are discussed. Possible reasons for the difference between agonistic and antagonistic properties in the peptide field are revealed by this case.
Assuntos
Lipídeos de Membrana/farmacologia , Peptídeos/farmacologia , Animais , Interações Medicamentosas , Humanos , Ligantes , Lipídeos de Membrana/química , Peptídeos/química , Conformação Proteica , Receptores de Peptídeos/química , Receptores de Peptídeos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
GM1 ganglioside has been identified as the receptor for cholera toxin (CT) and heat-labile (LT) enterotoxin of Escherichia coli in many cell types. Using the radial immune hemolysis (RIH) and indirect hemagglutination (IH) tests described for the detection of these enterotoxins, a study was conducted on the 100% inhibition of these reactions by pre-incubating these enterotoxins with GM1, GD1a and GT1 gangliosides. GM1 was found to be much more efficient than the other two. With respect to the RIH test, GT1 was more efficient than GD1a as an inhibitor of enterotoxin binding. Similar results were obtained with the IH test. These data also showed that sheep red blood cells provide a good model system for the study of receptors for CT, LT and probably other enterotoxins which bind to gangliosides.
Assuntos
Toxina da Cólera/antagonistas & inibidores , Enterotoxinas/antagonistas & inibidores , Escherichia coli , Gangliosídeos/farmacologia , Guanilato Ciclase , Animais , Toxina da Cólera/imunologia , Depressão Química , Estabilidade de Medicamentos , Enterotoxinas/imunologia , Eritrócitos/efeitos dos fármacos , Eritrócitos/imunologia , Testes de Hemaglutinação , Técnica de Placa Hemolítica , Temperatura Alta , Humanos , Receptores de Enterotoxina , Receptores Acoplados a Guanilato Ciclase , Receptores de Peptídeos/efeitos dos fármacos , Receptores de Peptídeos/imunologia , Ovinos , SuínosRESUMO
1. A short review is given of the chemical, physical, and pharmacological development of the idea that target cell lipid membranes may catalyze the interaction between regulatory peptides (or other pharmacologic agents) and their cell surface receptors. 2. The message-address and the membrane compartments concepts explain the observed correlations between the three-dimensional structures of peptides induced by a membrane surface and their preference for a certain receptor subtype. 3. Examples are given for opioid peptides (enkephalin, dynorphin, etc.), tachykinin peptides (substance P, neurokinin A, etc.), and melanocortin peptides (ACTH, alpha-MSH, etc.). 4. Relationships between the conformation of substance P induced by membrane association and that of a non-peptide substance P mimetic are discussed. Possible reasons for the difference between agonistic and antagonistic properties in the peptide field are revealed by this case