Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracts of mammalian atria, but not ventricles, induce marked diuresis, natriuresis, and reduction in blood pressure when infused systemically in rats and dogs. These extracts also inhibit aldosterone biosynthesis and renal renin release. Natriuretic peptides, 21 amino acids and longer, have been isolated from atria of rodents and man, and share a nearly homologous amino acid sequence at the carboxyterminus. Natriuretic activity resides in a 17-amino acid ring formed by a disulfide bridge, and the C-terminal Phe-Arg appears necessary for full biological potency. The deoxyribonucleic acid-encoding atrial natriuretic peptides have been cloned and the gene structure elucidated. Reduction of the diuretic and natriuretic responses to an acute volume load by right atrial appendectomy first suggested a role for atrial peptides in the physiological response to plasma volume expansion. Subsequently, release of peptides with natriuretic and spasmolytic properties from isolated heart preparations in response to right atrial distension was demonstrated by bioassay and radioimmunoassay. The presence of these peptides in normal rat and human plasma in concentrations of 20-100 pM, and the findings of increased levels in response to acute and chronic plasma volume expansion, rapid atrial tachyarrhythmias, systemic hypertension, congestive heart failure, and renal insufficiency imply that they play an important role in body fluid homeostasis. The mechanisms by which atrial peptides increase renal salt and water excretion are as yet unclear. Renal vascular effects have been consistently demonstrated, and limited evidence for direct actions on tubule ion transport has also been reported recently. In vitro, these peptides cause precontracted vascular and nonvascular smooth muscle to relax, mediated by a direct action on smooth muscle cells. Specific receptors for these peptides have been characterized in crude membranes prepared from whole kidney homogenates and adrenal glomerulosa cells, in intact glomeruli and cultured glomerular mesangial cells, and in intact bovine aortic smooth muscle and endothelial cells. Natriuretic peptides stimulate cyclic guanosine monophosphate accumulation in target tissues, and augment particulate guanylate cyclase activity in membrane fractions, suggesting that cyclic guanosine monophosphate is the second messenger mediating their cellular action.
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PMID:George E. Brown memorial lecture. Role of atrial peptides in body fluid homeostasis. 301 7

The vascular endothelium achieved a critical place in the understanding of vascular physiology and pathophysiology, after the discovery of the production of prostacyclin by endothelial cells, followed by the recognition that substances like acetylcholine, assumed to be direct vasodilators, could only trigger dilation in the presence of an intact endothelium. The endothelium-derived relaxing factor (EDRF) behaves as an endogenous nitrovasodilator and causes vasodilatation through stimulation of guanylyl cyclase and cellular accumulation of cyclic GMP. Subsequently, it was demonstrated that the EDRF is nitric oxide (NO), produced through the metabolism of the aminoacid L-arginine by the nitric oxide synthases (NOS). Three isoforms of this enzyme were discovered and cloned: a constitutive neuronal isoform (nNOS); an inducible isoform (iNOS), ubiquitous in cells stimulated by certain cytokines; and an endothelial isoform (eNOS). The importance of the different isoforms is well demonstrated in animal models; more recently, human studies unveiled the importance of these enzymes. The endothelium produces other vasodilators besides NO and prostacyclin; furthermore, it produces several vasoconstrictors. There is a delicate balance between these factors, which can be disturbed: several well known cardiovascular aggressors, like arterial hypertension, diabetes, smoking, dyslipidemia or renal insufficiency, can alter several invasive or non-invasive tests of endothelial function. The fact that an intervention on these factors may reverse endothelial dysfunction as measured by these tests, raises hope that they may be surrogate markers of global cardiovascular risk. If correlation of these tests with clinical outcomes proves to be robust, they may become extensively used in clinical practise.
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PMID:[Vascular endothelium: the history of a recent revolution in angiology]. 1607 83