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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Guanylate cyclase of every fraction studied showed an absolute requirement for Mn2+ ions for optimal activity; with Mg2+ or Ca2+ reaction was barely detectable. Triton X-100 stimulated the particulate enzyme much more than the supernatant enzyme and solubilized the particulate-enzyme activity. 2. Substantial amounts of guanylate cyclase were recovered with the washed particulate fractions of cardiac muscle (63-98%), skeletal muscle (77-93%), cerebral cortex (62-88%) and liver (60-75%) of various species. The supernatants of these tissues contained 7-38% of total activities. In frog heart, the bulk of guanylate cyclase was present in the supernatant fluid. 3. Plasma-membrane fractions contained 26, 21, 22 and 40% respectively of the total homogenate guanylate cyclase activities present in skeletal muscle (rabbit), cardiac muscle (guinea pig), liver (rat) and cerebral cortex (rat). In each case, the specific activity of this enzyme in plasma membranes showed a five- to ten-fold enrichment when compared with homogenate specific activity. 4. These results suggest that guanylate cyclase, like adenylate cyclase, and ouabain-sensitive Na+ + K+-dependent ATPase (adenosine triphosphatase), is associated with the surface membranes of cardiac muscle, skeletal muscle, liver and cerebral cortex; however, considerable activities are also present in the supernatant fractions of these tissues which contain very little adenylate cyclase or ouabain-sensitive Na+ + K+-dependent ATPase activities.
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PMID:Guanylate cyclase. Subcellular distribution in cardiac muscle, skeletal muscle, cerebral cortex and liver. 1 Aug 90

Administration of atrial natriuretic factor (ANF) in animals results in increases in renal blood flow, natriuresis, and a decrease in arterial blood pressure, supporting a role for the atrial peptide system in cardiovascular regulation. However, little is known about the vascular effects of synthetic ANF (26 amino acid) on coronary artery smooth muscle. We studied the coronary vascular effects of synthetic ANF in feline artery preparations in vitro. In isolated coronary arteries perfused at constant flow, ANF (3-300 nM) concentration dependently decreased perfusion pressure ranging from 2.6 +/- 0.7 mm Hg (p less than 0.02) at 3 nM to 28.6 +/- 3.7 mm Hg (p less than 0.001) at 300 nM. Perfusion with the prostacyclin analog, iloprost (20-100 nM), failed to alter the coronary vasodilator response to ANF. ANF also relaxed feline coronary helical strips when contracted by U-46,619 (an endoperoxide analog), serotonin, and leukotriene D4. This relaxant effect was independent of the presence of endothelial cells and occurred in the presence of a guanylate cyclase inhibitor, methylene blue. The ANF had no direct effect on electrically driven isolated feline papillary muscles, signifying a lack of direct inotropic activity of ANF in cat cardiac muscle. These results suggest that ANF may produce coronary vasodilation that therefore could contribute to coronary regulation, without directly altering myocardial performance.
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PMID:Coronary vascular actions of synthetic atrial natriuretic factor in isolated vascular preparations. 244 81

Elevation of cyclic GMP by muscarinic agonists has been suggested to be responsible for the negative inotropic effects of these agents in cardiac muscle, and for the endothelium-dependent relaxation caused by these agents in vascular smooth muscle. These relationships were studied by monitoring the effects of muscarinic agonists on tension and cyclic GMP levels in rabbit left atrial strips and aortic rings, in the presence and absence of the cyclic GMP lowering agent, LY83583. LY83583 completely blocked both the cyclic GMP increase and the relaxation caused by acetylcholine in rabbit aortic rings with intact endothelial cells. Acetylcholine-induced cyclic GMP elevation and relaxation in these preparations were also blocked by quinacrine and nordihydroguaiaretic acid (NDGA), but neither response was blocked by the 5-lipoxygenase inhibitor U-60257. In the experiments with rabbit left atrium, LY83583 blocked the acetylcholine-induced cyclic GMP elevation but did not block the negative inotropic effects of the drug. Quinacrine, NDGA, and a guanylate cyclase inhibitor, methylene blue, failed to block either the cyclic GMP increase or the decrease in contractile force caused by carbachol in atrial strips. These results support the suggestion that an increase in cyclic GMP may be responsible for the endothelium-dependent relaxation of rabbit aorta by muscarinic agonists, but not for the direct negative inotropic effects of these drugs in rabbit atrium. Muscarinic agents appear to increase cyclic GMP levels in rabbit atrium and aorta by different mechanisms. Although both are blocked by LY83583, they differ not only in their requirements for endothelial cells, but also in their susceptibility to other blocking agents.
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PMID:Effects of LY83583, nordihydroguaiaretic acid, and quinacrine on cyclic GMP elevation and inhibition of tension by muscarinic agonists in rabbit aorta and left atrium. 282 46

The potassium-channel openers comprise a large number of molecules that can be classified into three basic groups: (1) agents like levcromakalim that open a small-conductance (10-30 pS) glibenclamide-sensitive K+ channel currently known as the ATP-sensitive K+ channel, KATP; (2) hybrid molecules, such as nicorandil, that open KATP channels and that also activate the enzyme-soluble guanylate cyclase; (3) molecules like dehydrosaponin 1 that open the large-conductance (100-150 pS) calcium-dependent K+ channel, BKCa. K(+)-channel openers in groups 1 and 2 are most potent on smooth muscle, but KATP channels in cardiac muscle, neurones and the pancreatic beta cell are also affected. In vivo, moderate to high doses produce a fall in diastolic pressure with reflex tachycardia; low doses may exert selective dilator effects on specific vascular beds with little effect on systemic pressure. In vitro, all smooth muscles are relaxed with loss of spontaneous electric and mechanical activity; hyperpolarization to the region of EK is often observed. These effects can be antagonized by glibenclamide and also by imidazolines and guanidines, such as phentolamine, guanethidine, and antazoline, agents that also inhibit the smooth muscle delayed rectifier channel, KV. The mode and site of action of the group 1 and 2 K(+)-channel openers is the subject of intense study. Irrespective of their specific mode of action, the K(+)-channel openers, especially the hybrid molecules such as nicorandil, constitute a novel and promising approach to the treatment of cardiovascular disease.
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PMID:Pharmacology of the potassium channel openers. 764 22

Nitric oxide (NO) acts as an autocrine- and paracrine-acting signaling autacoid that, among other functions, has been shown to regulate cardiac contractile responsiveness to beta-adrenergic and muscarinic cholinergic agonists. Nitric oxide (NO) is formed by the oxidation of one of two equivalent guanidino nitrogens in L-arginine by O2 to form NO and L-citrulline. This reaction is catalyzed by a family of enzymes termed NO synthases. Three distinct isoforms of NOS have been identified, each the product of a separate gene. Cellular constituents of cardiac muscle, including ventricular myocytes as well as microvascular endothelial cells, have been shown to express the "endothelial constitutive" isoform of NO synthase (ecNOS or NOS3) in vivo, and both cell types also express the NO synthase isoform induced by specific inflammatory cytokines (iNOS or NOS2) in vivo and in vitro. While NO-dependent intracellular signalling in cardiac myocytes clearly involves the activation of guanylate cyclase and downstream signalling by cGMP, there is accumulating evidence that non-cGMP-dependent regulatory signalling events are also initiated by NO. In addition, decreased contractile responsiveness of cardiac myocytes to beta-adrenergic agonists, following induction of NOS2 by inflammatory cytokines, requires the presence of insulin and the co-induction of enzymes responsible for production of tetrahydrobiopterin, a NOS co-factor. Inappropriate or excessive production of NO by cardiac myocytes and by microvascular endothelial cells likely contributes to the cardiac contractile dysfunction characteristic of the systemic inflammatory response syndrome and cardiac allograft rejection.
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PMID:The role of the NO pathway in the control of cardiac function. 895 72

Nitric oxide (NO) is an ubiquitous signaling molecule produced from L-arginine by NO synthase (NOS). In the vasculature, NO mediates parasympathetic endothelium-dependent vasodilation. NO may also mediate the parasympathetic control of myocardial function. This is supported by the observations that NOS3, the endothelial constitutive NOS, is expressed in normal cardiac myocytes from rodents and human, and NOS and/or guanylyl cyclase inhibitors antagonize the effect of muscarinic agonists on heart rate, atrio-ventricular conduction, contractility and L-type calcium current. Here we examine the autonomic regulation of the heart in genetically engineered mice deficient in NOS3 (NOS3-KO). We show that the chronotropic and inotropic responses to both beta-adrenergic and muscarinic agonists were unaltered in isolated cardiac tissue preparations from NOS3-KO mice, although these mice have a defective parasympathetic regulation of vascular tone. Similarly, beta-adrenergic stimulation and muscarinic inhibition of the calcium current did not differ in cardiac myocytes from NOS3-KO mice and those from wild-type mice. RT-PCR did not demonstrate upregulation of other NOS isoforms. Similarly, Gi/Go proteins and muscarinic receptor density were unaltered. These data refute the idea that NOS3 is obligatory for the normal autonomic control of cardiac muscle function.
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PMID:Muscarinic and beta-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase. 1008 91

Nitric oxide (NO)-derived species could potentially react with arachidonic acid to generate novel vasoactive metabolites. We studied the reaction of arachidonic acid with nitrogen dioxide (NO2), a free radical that originates from NO oxidation. The reaction mixture contained lipid products that relaxed endothelium-removed bovine coronary arteries. Relaxation to the lipid mixture was inhibited approximately 20% by indomethacin and approximately 70% by a soluble guanylate cyclase (sGC) inhibitor (ODQ). Thus, novel lipid products, which activate sGC presumably through a mechanism involving NO, appeared to have contributed to the observed vasorelaxation. Lipids that eluted at 9 to 12 min during high-performance liquid chromatography fractionation accounted for about one-half of the vasodilator activity in the reaction mixture, which was inhibited by ODQ. Lipid products in fractions 9 to 12 were identified by electrospray tandem mass spectrometry to be eight isomers having molecular weight of 367 and a fragmentation pattern indicative of arachidonic acid derivatives containing nitro and hydroxy groups and consistent with the structures of vicinal nitrohydroxyeicosatrienoic acids. These lipids spontaneously released NO (183 +/- 12 nmol NO/15 min/micromol) as detected by head space/chemiluminescence analysis. Mild alkaline hydrolysis of total lipids extracted from bovine cardiac muscle followed by isotopic dilution gas chromatography/mass spectrometry analysis detected basal levels of nitrohydroxyeicosatrienoic acids (6.8 +/- 2.6 ng/g tissue; n = 4). Thus, the oxidation product of NO, NO2, reacts with arachidonic acid to generate biologically active vicinal nitrohydroxyeicosatrienoic acids, which may be important endogenous mediators of vascular relaxation and sGC activation.
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PMID:Vicinal nitrohydroxyeicosatrienoic acids: vasodilator lipids formed by reaction of nitrogen dioxide with arachidonic acid. 1160 73

Recent studies identified that GATA-4 is a stress responsive transcription factor and can exert cell survival signaling in cardiac myocytes. The present study was designed to examine whether GATA-4 is modulated by ischemic preconditioning (PC), and ischemia/reperfusion (I/R). PC of isolated rat hearts was elicited by perfusing with Krebs-Henseleit bicarbonate buffer with four cyclic episodes of 5 min ischemia and 10 min reperfusion. Some hearts were then subjected to 30 min ischemia followed by 2 h reperfusion. PC increased the DNA binding activity of GATA-4 compared to control, while I/R downregulated GATA-4 expression. Activation was associated with post-translational modifications of GATA-4 via acetylation. As nitric oxide (NO) may be involved in PC and I/R, we examined whether NO could modulate GATA-4 in HL-1 cardiac muscle cells. An NO donor, sodium nitroprusside (SNP), downregulated GATA activity and GATA-4 mRNA expression. We cloned the 5'-flanking region of human GATA-4 gene and found that the luciferase activity controlled by this region was also suppressed by NO. A protein kinase G (PKG) inhibitor KT5823 inhibited SNP-induced downregulation of GATA-4, while YC-1 (guanylyl cyclase activator) and dibutyryl cGMP (PKG activator) downregulated GATA-4. Thus, GATA-4 is modulated by PC, I/R and NO, and might regulate cardiac myocyte survival and apoptosis.
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PMID:GATA-4 regulation of myocardial survival in the preconditioned heart. 2786 47

Na(+)/Ca(2+) exchanger 1 (NCX1) is a plasma membrane transporter involved in regulating intracellular Ca(2+) concentrations. NCX1 is critical for Ca(2+) regulation in cardiac muscle, vascular smooth muscle and nerve fibers. However, little is known about the physiological role of NCX1 in gastrointestinal motility. To determine the role of NCX1 in gastrointestinal tissues, we examined electric field stimulation (EFS)-induced responses in the longitudinal smooth muscle of the distal colon in smooth muscle-specific NCX1 transgenic mice (Tg). Tg show that NCX1 protein was overexpressed in the distal colon at a level twofold greater than that of endogenous NCX1. We found that the amplitudes of EFS-induced relaxation that persisted during EFS were greater in Tg than in wild-type mice (WT). Under the nonadrenergic, noncholinergic condition, the EFS-induced relaxation in Tg was also greater than that in WT. Inhibition of NO synthase, CO synthase, soluble guanylate cyclase (sGC), and protein kinase G (PKG) all attenuated the enhanced relaxation in Tg, demonstrating the importance of NCX1 in NO/sGC/PKG signaling. The action of NOR-1, an NO donor, induced enhanced relaxation in Tg compared with that in WT. Unlike NOR-1, pituitary adenylate cyclase-activating peptide and vasoactive intestinal peptide induced a similar relaxation in Tg compared with that in WT. In this study, we demonstrate that NCX1 plays an important role in smooth muscle motility in the mouse distal colon.
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PMID:Na/Ca(2+) exchanger 1 transgenic mice display increased relaxation in the distal colon. 2542 75

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