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)

The activity of soluble guanylate cyclase (GC) of rat heart and the regulatory activity of dithiothreitol (DTT) and sodium nitroprusside under ischemic myocardium damage caused by ligation of left coronary artery has been investigated. After coronary occlusion the GC activity in the presence of Mn2+ or Mg2+ decreases both in ischemic and in intact zones (40% from normal) in 15 min, in 24 h it more diminishes (up to 30%) in the ischemic zone, in intact zone it partially normalizes (up to 70%). The stimulatory effect of DTT on the GC activity in studied heart zones doesn't differ from control. The activation of GC by nitroprusside in ischemic zone decreases in 15 min, it is practically absent in 24 h. The decrease of GC activation in intact zone is less expressed. It is suggested that the reduction of GC activation by sodium nitroprusside is due to the loss of the heme by the enzyme during ischemia.
 ...
PMID:[Cardiac guanylate cyclase in rats with ischemic damage to the myocardium]. 197 76

Nitric oxide (NO), generated by endothelial (e) NO synthase (NOS) and neuronal (n) NOS, plays a ubiquitous role in the body in controlling the function of almost every, if not every, organ system. Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), induce inducible (i) NOS synthesis that produces massive amounts of NO toxic to the invading viruses and bacteria, but also host cells by inactivation of enzymes leading to cell death. The actions of all forms of NOS are mediated not only by the free radical oxidant properties of this soluble gas, but also by its activation of guanylate cyclase (GC), leading to the production of cyclic guanosine monophosphate (cGMP) that mediates many of its physiological actions. In addition, NO activates cyclooxygenase and lipoxygenase, leading to the production of physiologically relevant quantities of prostaglandin E2 (PGE2) and leukotrienes. In the case of iNOS, the massive release of NO, PGE2, and leukotrienes produces toxic effects. Systemic injection of LPS causes induction of interleukin (IL)-1 beta mRNA followed by IL-beta synthesis that induces iNOS mRNA with a latency of two and four hours, respectively, in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood-brain barrier, and shortly thereafter, in hypothalamic regions, such as the temperature-regulating centers, paraventricular nucleus containing releasing and inhibiting hormone neurons, and the arcuate nucleus, a region containing these neurons and axons bound for the median eminence. We are currently determining if LPS similarly activates cytokine and iNOS production in the cardiovascular system and the gonads. Our hypothesis is that recurrent infections over the life span play a significant role in producing aging changes in all systems outside the blood-brain barrier via release of toxic quantities of NO. NO may be a major factor in the development of coronary heart disease (CHD). Considerable evidence has accrued indicating a role for infections in the induction of CHD and, indeed, patients treated with a tetracycline derivative had 10 times less complications of CHD than their controls. Stress, inflammation, and infection have all been shown to cause induction of iNOS in rats, and it is likely that this triad of events is very important in progression of coronary arteriosclerosis leading to coronary occlusion. Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone, melatonin, respectively, may be caused by NO. The induction of iNOS in the temperature-regulating centers by infections may cause the decreased febrile response in the aged by loss of thermosensitive neurons. iNOS induction in the paraventricular nucleus may cause the decreased nocturnal secretion of growth hormone (GH) and prolactin that occurs with age, and its induction in the arcuate nucleus may destroy luteinizing hormone-releasing hormone (LHRH) neurons, thereby leading to decreased release of gonadotropins. Recurrent infections may play a role in aging of other parts of the brain, because there are increased numbers of astrocytes expressing IL-1 beta throughout the brain in aged patients. IL-1 and products of NO activity accumulate around the plaques of Alzheimer's, and may play a role in the progression of the disease. Early onset Parkinsonism following flu encephalitis during World War I was possibly due to induction of iNOS in cells adjacent to substantia nigra dopaminergic neurons leading to death of these cells, which, coupled with ordinary aging fall out, led to Parkinsonism. The central nervous system (CNS) pathology in AIDS patients bears striking resemblance to aging changes, and may also be largely caused by the action of iNOS. Antioxidants, such as melatonin, vitamin C, and vitamin E, probably play an important acute and chronic role in reducing or eliminating the oxidant damage produced by NO.
 ...
PMID:The nitric oxide hypothesis of aging. 995 25

In a previous study nitroglycerin failed to dilate coronary collateral vessels during exercise. This study tested the hypothesis that failure of nitroglycerin to increase collateral flow occurred because endogenous nitric oxide (NO) had activated the guanylate cyclase vasodilator pathway so that additional NO from nitroglycerin could have no additional effect. Six dogs were collateralized using intermittent 2-min occlusions of the left anterior descending coronary artery followed by permanent occlusion. One week after permanent coronary occlusion, dogs were exercised on a treadmill (heart rate 202 +/- 5 beats/min), while blood flow was measured with radioactive microspheres. Blood flow to the collateral zone during control exercise was 1.90 +/- 0.11 ml. min(-1). g(-1) compared with 2.28 +/- 0.15 ml. min(-1). g(-1) in the normal zone (P < 0.05); systolic wall thickening was 23 +/- 3% in the collateral zone compared with 27 +/- 2% in the normal zone. When N(G)-nitro-L-arginine (L-NNA; 20 mg/kg iv) was administered to block NO production, collateral zone flow during exercise decreased to 1. 43 +/- 0.20 ml. min(-1). g(-1) (P < 0.05), and systolic wall thickening decreased to 12 +/- 4% (P < 0.05). A subsequent infusion of nitroglycerin (2 microg. kg(-1). min(-1) iv) increased collateral zone blood flow to 1.65 +/- 0.16 ml. min(-1). g(-1) (P < 0.05) and increased systolic wall thickening to 22 +/- 5% (P < 0.05). These findings demonstrate that endogenous NO contributes to collateral zone blood flow during exercise. If endogenous NO synthesis is blocked, then nitroglycerin is effective in improving collateral zone blood flow and contractile function during exercise.
 ...
PMID:Nitroglycerin dilates coronary collateral vessels during exercise after blockade of endogenous NO production. 1048 11

Natriuretic peptides are regulatory autacoids in the mammalian myocardium whose functions, mediated via particulate guanylyl cyclase/cGMP, may include cytoprotection against ischaemia-reperfusion injury. Previous work has identified that B-type natriuretic peptide (BNP) limits infarct size when administered prior to and during coronary occlusion through a K(ATP) channel-dependent mechanism. The present study examined the hypothesis that the protection afforded by BNP is mediated specifically at reperfusion in a postconditioning-like manner. Langendorff-perfused rat hearts were subjected to 35 min coronary artery occlusion and 120 min reperfusion, and infarct size was determined by tetrazolium staining. Postconditioning was effected by applying six 10-second periods of global ischaemia at the onset of reperfusion.Treatment with either BNP 10 nM or the NO donor S-nitroso-N-acetylpenicillamine (SNAP) 1-10 microM was commenced 5 min prior to reperfusion and continued until 10 min after reperfusion. Control infarct size (% of ischaemic risk zone) was 40.8 +/- 3.7%.BNP at reperfusion induced a significant limitation of infarct size (BNP 22.9 +/- 4.1% P<0.05 vs. control). Co-treatment at reperfusion with BNP and the K(ATP) channel blockers 5-hydroxydecanote (5HD, 100 microM), glibenclamide (Glib; 10 microM) or HMR1098 (10 microM) abolished the infarct-limiting effect of BNP (BNP + 5HD 41.0 +/- 3.9%, BNP + Glib 39.8 +/- 5.6%, BNP + HMR 1098 46.0 +/- 7.1%,P < 0.05 vs. BNP). BNP given together with L-NAME (100 microM) at reperfusion resulted in a marked loss of protection (BNP + L-NAME 53.1 +/- 3.8% P < 0.001 vs. BNP). In a second series of experiments, SNAP (1-10 microM) given at reperfusion was found not to be protective (SNAP 1 microM 30.2 +/- 4.9%, SNAP 2 microM 27.5 +/- 9.5%, SNAP 5 microM 39.2 +/- 5.7%, SNAP 10 microM 33.7 +/- 6.4%, not significant vs. control). In a third series of experiments, postconditioning significantly limited infarct size (14.9 +/- 3.6 % vs. control 34.5 +/- 4.9%, P < 0.01) and this effect of postconditioning was abolished in the presence of isatin (100 microM), a non-specific blocker of particulate guanylyl cyclases (35.1 +/- 6%, P < 0.05 vs. postconditioning). In conclusion, pharmacological activation of pGC by BNP can effectively induce protection against reperfusion injury, by mechanisms involving K(ATP) channel opening and endogenous NO synthase activation. Furthermore, endogenous activation of pGC could play a role in the mechanism of postconditioning.
 ...
PMID:B-type natriuretic peptide at early reperfusion limits infarct size in the rat isolated heart. 1789 17