Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neonatal rat atrial and ventricular cardiocytes in primary culture secrete proatrial natriuretic factor (proANF), the 126-amino acid precursor of atrial natriuretic factor (ANF). The cellular mechanisms of proANF secretion differ in the two cell types: atrial cardiocytes store proANF in abundant secretory granules before secretion, whereas ventricular cardiocytes secrete the precursor rapidly after synthesis. In this study, we used the Na+-K+-adenosinetriphosphatase (ATPase) inhibitor ouabain to investigate the functional significance of these differing secretory mechanisms. Ouabain increased immunoreactive ANF (iANF) secretion by atrial cardiocytes 1.5- to 2.4-fold. Metabolic labeling studies demonstrated that proANF was the form of iANF released in response to ouabain. Ventricular secretion of iANF was unaffected by the Na+-K+-ATPase inhibitor. These observations are consistent with a model in which atrial cardiocytes are able to release proANF via a regulated secretory pathway, whereas ventricular cardiocytes utilize a constitutive secretory pathway. The ability of ouabain to stimulate proANF secretion suggests that an increase in intracellular calcium concentration may promote fusion of secretory granules with atrial cell membranes thereby mediating exocytosis of stored proANF.
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PMID:Ouabain induces secretion of proatrial natriuretic factor by rat atrial cardiocytes. 297 23

Atrial natriuretic factor (ANF) inhibits basal and stimulated aldosterone synthesis in adrenal glomerulosa cells. ANF probably acts through specific membrane receptors. Alterations in cyclic GMP and cyclic AMP levels do not account for ANF's inhibitory effect. ANF does not block angiotensin II (AngII) receptors nor does it interfere with phosphoinositide metabolism or calcium movements stimulated by adrenal agonists. ANF does not inhibit protein synthesis nor does it work by inhibiting NA+,K+-ATPase or depleting cell potassium. ANF decreases conversion of endogenous cholesterol to pregnenolone, the step stimulated by adrenocorticotropin and AngII. ANF does not affect the conversion of 20-alpha-hydroxycholesterol, which easily penetrates mitochondrial membranes to the site of the cholesterol side-chain cleavage enzyme. These results suggest that ANF inhibits the ability of endogenous cholesterol to reach or interact with the side-chain cleavage enzyme. ANF does not act like a calcium channel-blocking agent. However, ANF is less effective at high-calcium concentrations, which suggests that it may inhibit a step that calcium stimulates. Understanding ANF action will probably require identification of the specific biochemical changes (mediators) that it induces. Parallel efforts to understand how other agents stimulate steroidogenesis (particularly in the areas of protein synthesis, protein phosphorylation, and cholesterol movements) will further this understanding.
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PMID:Inhibition of aldosterone synthesis by atrial natriuretic factor. 301 92

Two independent series of biomedical investigations have led to the discovery that the atria constitute a peptide-secreting endocrine gland. The first investigation is mainly morphological and started with the finding that mammalian atrial (but not ventricular) cardiocytes contain "dense bodies." These "dense bodies," later called "specific granules," were found to be different from lysosomes; to be made up of proteins; and to incorporate both 3H-leucine and 3H-fucose in a pattern typical of peptide-secreting endocrine cells. The finding that rat atrial granulation varied with the sodium and water balance led to the crucial observation that atrial extracts have natriuretic and diuretic effects. In less than five years, this new natriuretic hormone has been purified, sequenced and synthesized, and its CDNA and gene have been cloned. The atrial natriuretic factor (ANF) gene has been assigned to the distal short arm of chromosome 1 in band 1P36, while the mouse gene is localized in chromosome 4. The native and synthetic hormones exert identical wide ranging effects (possibly through particulate guanylate cyclase stimulation and adenylate cyclase inhibition) on the kidney, blood vessels, adrenal cortex, and pituitary. Physiopathologic implications of the hormone in experimental hypertension, congestive heart failure, and expansion of blood volume are already beginning to emerge. Concurrently, the search for the function of natriuretic hormones or factors (through studies of negative pressure breathing, atrial distension experiments, head-out water immersion, expansion of blood volume, Na+/K+-ATPase inhibition, and parabiosis experiments in Dahl rats) has provided a general framework within which to interpret this new cardiac function.
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PMID:The heart as an endocrine gland. 302 9

Control of the contraction/relaxation cycle in vascular smooth muscle is regulated by Ca2+ and the cyclic nucleotides, cAMP and cGMP. For the most part, the effectors of these intracellular messengers are the protein kinases. Four major protein kinases (myosin light chain kinase, protein kinase C, cAMP dependent protein kinase, and cGMP dependent protein kinase) have been identified in vascular smooth muscle. Substantial biochemical and physiological evidence exists supporting the involvement of Ca2+/calmodulin-mediated activation of myosin light chain kinase and phosphorylation of the 20,000 dalton P-light chain of myosin in the regulation of vascular contractile activity. However, alternative hypotheses exist which suggest that additional Ca2+ dependent regulatory mechanisms reside at other contractile protein sites. Calcium also activates protein kinase C, which requires phospholipid and diacylglycerol as co-factors instead of calmodulin. Protein kinase C also phosphorylates smooth muscle myosin P-light chain; however, phosphorylation occurs at a different site on the P-light chain and represses ATPase activity which has been stimulated by myosin light chain kinase-catalyzed phosphorylation. The precise physiological role of protein kinase C in modulating vascular smooth muscle contractile activity remains to be elucidated. Relaxation of vascular smooth muscle by some different relaxants is linked to either cAMP or cGMP formation. Correlative evidence also links activation of cAMP dependent protein kinase with relaxation. Two isozymes of cAMP dependent protein kinase exist in arterial smooth muscle; potential specific roles for each isozyme have not been elucidated. Mechanistically, relaxation mediated by both cyclic nucleotide-regulated protein kinases most likely involves primary effects on Ca2+ ion flux regulation rather than direct effects on contractile protein interactions. Activation of cGMP dependent protein kinase may be important in mediating the relaxant effects of endothelium derived relaxant factor or atrial natriuretic factor. Direct pharmacological modulation of smooth muscle vascular protein kinase activity represents an approach towards developing novel vasodilator agents. Various classes of agents, including phenothiazine antipsychotics, antidepressants, naphthalene sulfonamides, and certain lipophilic Ca2+ antagonists, inhibit myosin light chain kinase activity primarily by competition with the enzyme for Ca2+-calmodulin. However, additional inhibition via binding to the myosin P-light chain may also occur with some of these agents.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of contractile activity in vascular smooth muscle by protein kinases. 302 13

In this review, we first summarized the evidence from animals and man for and against a role for dietary sodium in the genesis and treatment of hypertension. The evidence for a role for dietary sodium in the genesis of hypertension is strongest in those subjects with impaired ability to excrete sodium due to organic renal disease or mineralocorticoid excess. Here restriction of dietary sodium promptly lowers arterial pressure. Its role in the genesis of essential hypertension is still controversial. Nevertheless, it appears that some patients with mild to moderate essential hypertension respond to moderate sodium restriction with a modest fall in blood pressure. This restriction also seems to reduce the amount of antihypertensive medication needed to keep blood pressure under control. We next considered the mechanism of the pressure response to dietary sodium chloride, concentrating upon the increase in extracellular fluid volume, potassium depletion, and increased plasma levels of prohypertensive sodium pump inhibitor and antihypertensive atrial natriuretic factor. We next summarized the evidence for a primary role for dietary potassium in the genesis of hypertension and pointed out that certain subsets of subjects with a high incidence of hypertension also have a lower dietary potassium intake. Some investigators find that dietary potassium supplementation lowers blood pressure in established hypertension. This may result from natriuresis and from vasodilation subsequent to stimulation of Na+, K+-ATPase in vascular smooth muscle and adrenergic nerve terminals. We then considered practical aspects of dietary sodium restriction and dietary potassium supplementation in the therapy for established hypertension. The review concludes with comments on their possible roles in the prevention of hypertension.
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PMID:Dietary sodium and potassium in the genesis, therapy, and prevention of hypertension. 329 78

The effects of a natriuretic factor contained in extracts of the atrial myocardium on an isolated renal Na+, K+-ATPase enzyme system were evaluated. Ultrafiltrates (molecular weight less than 30,000) of boiled extract of rat atria and ventricles were prepared. Infusion of 100 microliters of the atrial ultrafiltrate into bioassay rats resulted in a prompt, short-lived natriuresis and diuresis. However, addition of 100 microliters of the atrial ultrafiltrate to 900 microliters of a suspension containing Na+, K+-ATPase had no significant effect on enzymatic activity. Similarly, ultrafiltrates of ventricular extract also had no significant effect on Na+, K+-ATPase activity. These results indicate that the atrial natriuretic factor does not alter renal tubular sodium reabsorption by directly inhibiting the Na+, K+-ATPase enzyme system.
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PMID:Failure of atrial myocardial extract to inhibit renal Na+, K+-ATPase. 631 33

Atrial cardiocytes contain specific atrial granules ( SAGs ) which are the storage site of atrial natriuretic factor (ANF). The purpose of the present study was to determine whether ANF produces natriuresis by inhibiting Na+-K+ pump activity and whether this factor is similar to the humoral sodium transport inhibiting factor ( HSTIF ) previously demonstrated in acutely volume expanded animals and humans as well as in experimental and human essential hypertension. Our results indicate that, in contrast to the HSTIF , ANF does not inhibit membrane Na+,K+-ATPase, vascular smooth muscle cell Na+-K+ pump activity, or sodium transport in the toad bladder. Intravenous infusion of ANF in the bilaterally nephrectomized, hexamethonium-treated rat produces only a small transient pressor response, probably due to potentiation of endogenous norepinephrine. These findings strongly suggest that the ANF is not the same as the HSTIF detected on acute volume expansion and in some forms of hypertension. They also suggest that the diuretic and natriuretic effects of ANF are due to mechanism(s) other than blood pressure elevation and inhibition of Na+-K+ pump activity.
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PMID:Effects of rat atrial extract on sodium transport and blood pressure in the rat. 632 56

We investigated the possible central interaction of atrial natriuretic factor (ANF) and an endogenous Na+, K(+)-ATPase (Na-pump) inhibitor in normal rats. Release of an endogenous Na-pump inhibitor associated with deoxycorticosterone acetate-salt hypertension may be regulated in the anteroventral third ventricle (AV3V) area of the CNS. We reported earlier that bolus injection of synthetic 26-amino acid ANF (Arg101-Tyr126, 6 micrograms/250 g rat) into the lateral brain ventricle (ICV) promotes the appearance in the plasma of a Na-pump inhibitor in rats. To determine whether the AV3V area of the brain is involved in the ICV effect of ANF, we introduced electrolytic lesions in this area. This treatment abolished the appearance of the Na-pump inhibitor after intraventricular injection of ANF. To further localize the area and the pathways involved in the interaction of ANF and the Na-pump inhibitor, we produced bilateral medial coronal knife cuts designed to transect the medially coursing pathway through the periventricular tissue of the AV3V region between the level of the medial preoptic area and the anterior hypothalamic nuclei. These knife cuts also abolished the appearance of the Na-pump inhibitor after ICV injection of ANF. Our data to date indicate that centrally administered ANF promotes the appearance of a Na-pump inhibitor in the plasma. A central site of interaction between ANF and the Na-pump inhibitor appears to be the AV3V area and a medial pathway coursing caudally from the AV3V region.
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PMID:Effect of hypothalamic lesions on interaction of centrally administered ANF and the circulating sodium-pump inhibitor. 750 25

Mononuclear cell infiltration and local cytokine elaboration are hallmarks of inflammatory and immunologic heart diseases. To test the hypothesis that cytokines can modulate cardiac myocyte growth and phenotype, myocytes cultured from neonatal rat hearts were exposed to IL-1 beta, an inflammatory cytokine prevalent in myocardial inflammation. IL-1 beta (2 ng/ml, 24 h) increased [3H]leucine incorporation by 30 +/- 4% (P < 0.001, n = 29) and net cellular protein content by 20 +/- 4% (P < 0.001, n = 27), but had no effect on DNA synthesis. Northern hybridization showed that IL-1 beta increased prepro-atrial natriuretic factor (ANF) mRNA (5.8 +/- 1.5-fold, P < 0.01, n = 13) and beta-myosin heavy chain (beta-MHC) mRNA (> 10-fold, n = 4), and decreased mRNA levels for sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) (-46 +/- 7%; P < 0.001; n = 11), calcium release channel (CRC) (-65 +/- 11%, P < 0.001, n = 8) and voltage-dependent calcium channel (VDCC) (-53 +/- 7%, P < 0.001, n = 8). NG-monomethyl-L-arginine (1 mM), an inhibitor of nitric oxide (NO) synthesis, did not inhibit the IL-1 beta-induced protein synthesis or changes in mRNA levels. In ventricular myocardium obtained from adult rats treated with lipopolysaccharide (4 mg/kg intraperitoneally 18 h) to stimulate systemic cytokine production, there were changes in the mRNA levels for beta-MHC (6 +/- 1-fold, P < 0.01, n = 4), SERCA2 (-65 +/- 4%, P < 0.0001, n = 4), CRC (-67 +/- 5%, P < 0.001, n = 4), and VDCC (-58 +/- 5%, P < 0.001; n = 4) that were qualitatively similar to those observed in cultured myocytes. Thus, IL-1 beta, acting via an NO-independent mechanism, caused myocyte hypertrophy associated with induction of fetal genes (ANF and beta-MHC) and downregulation of three important calcium regulatory genes (SERCA2, CRC, and VDCC). IL-1 beta may contribute to the abnormal structural and functional alterations of cardiac myocytes in conditions marked by mononuclear cell infiltration.
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PMID:Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes. 763 44

The present investigation was designed to determine 1) if dimethyl sulfoxide (DMSO) inhibits renal cortical and medullary Na(+)-K(+)-ATPase at the ouabain binding site and 2) if this inhibition of Na(+)-K(+)-ATPase by. DMSO involves atrial natriuretic peptides or prostaglandins. DMSO (10%) inhibited renal cortical and medullary Na(+)-K(+)-ATPase 31% and 29.5%, respectively. Ouabain (0.5 mM) inhibited renal cortical and medullary Na(+)-K(+)-ATPase 32% and 35%, respectively. When DMSO and ouabain were added together the inhibition of renal cortical and medullary Na(+)-K(+)-ATPase was 55% and 59%, respectively. Atrial natriuretic peptides consisting of amino acids 1-30 (i.e., long acting natriuretic peptide), 31-67 (vessel dilator), 79-98 (kaliuretic peptide) and 99-126 (atrial natriuretic factor, ANF) of the 126 amino acid ANF prohormone inhibited renal cortical Na(+)-K(+)-ATPase 27.5%, 20%, 37.5% and 0% at a 10(-11)M concentration. The addition of DMSO caused a doubling (P < 0.05) of this inhibition. Likewise, these same atrial peptides inhibited renal medullary Na(+)-K(+)-ATPase 27.8%, 19.2%, 39.5%, and 0% with DMSO doubling (P < 0.05) their Na(+)-K(+)-ATPase inhibition. There was not any additive effect of any of the atrial peptides with ouabain. Naproxen, a prostaglandin inhibitor, completely blocked atrial peptides and ouabain's inhibition of Na(+)-K(+)-ATPase but not DMSO's. Each of the atrial peptides except ANF increased prostaglandin E2 synthesis while DMSO did not increase prostaglandin E2 synthesis. This investigation suggests that DMSO has its inhibiting effect at a site different from the ouabain binding site on renal Na(+)-K(+)-ATPase since it has an additive effect with ouabain in inhibiting Na(+)-K(+)-ATPase while the atrial peptides appear to have their effect at the ouabain binding site. As opposed to the atrial peptides, DMSO's mechanism of inhibiting Na(+)-K(+)-ATPase does not appear to involve prostaglandin E2.
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PMID:Dimethyl sulfoxide inhibits renal Na(+)-K(+)-ATPase at a site different from ouabain and atrial peptides. 764 19


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