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)

Adrenomedullin (ADM) is a vasodilator produced by vascular endothelium and smooth muscle cells. Although plasma ADM levels are increased in patients with hypertension, heart failure, and myocardial infarction, little information exists regarding the microvascular response to ADM in the human heart. In the present study we tested the hypothesis that ADM produces coronary arteriolar dilation in humans and examined the mechanism of this dilation. Human coronary arterioles were dissected and cannulated with micropipettes. Internal diameter was measured by video microscopy. In vessels constricted with ACh, the diameter response to cumulative doses of ADM (10(-12)-10(-7) M) was measured in the presence and absence of human ADM-(22-52), calcitonin gene-related peptide-(8-37), N(omega)-nitro-L-arginine methyl ester (L-NAME), indomethacin (Indo), (1)H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, SQ-22536, or KCl (60 mM). ADM dilated human coronary arterioles through specific ADM receptors (maximum dilation = 69 +/- 11%). L-NAME or N-monomethyl-L-arginine attenuated dilation to ADM (for L-NAME, maximum dilation = 66 +/- 7 vs. 41 +/- 13%, P < 0.05). Thus the mechanism of ADM-induced dilation involves generation of nitric oxide. However, neither (1)H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one, SQ-22536, nor Indo alone altered dilation to ADM. High concentrations of KCl blocked dilation to ADM. The magnitude of ADM dilation was reduced in subjects with hypertension. We propose that, in human coronary arterioles, ADM elicits vasodilation in part through production of nitric oxide and in part through activation of K(+) channels, with little contribution from adenylyl cyclase. The former dilator mechanism is independent of the more traditional pathway involving activation of soluble guanylate cyclase.
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PMID:Human coronary arteriolar dilation to adrenomedullin: role of nitric oxide and K(+) channels. 1108 13

Atrial myocytes synthesise atrial natriuretic factor prohormone consisting of 126 amino acids (ANP1-126) which is subsequently processed to several fragments. Atrial natriuretic factor (ANF, ANP99-126) originating from the C-terminal portion of prohormone is a best described atrial peptide. However, several peptides originating from the N-terminus of this precursor also circulate and produce significant diuresis, natriuresis and vasodilatation. These are: long acting natriuretic peptide (ANP1-30), vessel dilator (ANP31-67) and kaliuretic peptide (ANP79-98). ANP1-98 and ANP68-98 also circulate. Kaliuretic peptide specifically stimulates urinary potassium excretion. These peptides are slowly metabolised and their plasma concentration is higher than ANF suggesting their important role in water-electrolyte homeostasis and regulation of vascular tone. N-terminal atrial peptides don't bind to classical natriuretic peptide receptors, each of them has probably its own unique receptors. Although these peptides activate particulate guanylate cyclase in a number of tissues, some of their effects, for example natriuresis, are not mediated by cGMP but rather by prostaglandin E2. Plasma concentration of N-terminal atrial peptides may be useful in diagnosis and risk stratification in patients with heart failure and after myocardial infarction. Recently N-terminal fragment of brain natriuretic peptide (BNP1-76) was identified in the blood. This peptide is secreted together with its C-terminal partner, BNP77-108 by ventricular myocytes. Some studies suggest that N-terminal BNP may be also a useful diagnostic tool in cardiovascular diseases.
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PMID:[N-terminal atrial natriuretic peptides]. 1122 84

Among the traditional risk factors, dyslipidaemia and coagulation disorders play an important role in increasing the risk of coronary heart disease (CHD) in patients with type 2 diabetes. The lipid abnormalities of patients with insulin resistance and type 2 diabetes include increased triglycerides, lower high density lipoprotein (HDL)-cholesterol and the predominance of small dense low density lipoprotein (LDL)-particles. The composition of HDL particles is different from healthy controls and the concentration of the larger, more anti-atherogenic particles is decreased in patients with insulin resistance and type 2 diabetes. Subgroup analyses of several large studies have shown that lowering LDL-cholesterol with statin treatment decreased cardiovascular events in patients with type 2 diabetes. In other studies, gemfibrozil decreased cardiovascular events in a subgroup of patients with diabetes, although the decreases were not always statistically significant. Platelets from patients with diabetes are more sensitive to several aggregating agents, have increased numbers of glycoprotein receptors and a lower activity of guanylate cyclase. These factors may contribute to the documented hyperreactivity of platelets in patients with type 2 diabetes. Other factors in patients with type 2 diabetes include alterations in serum fibrinogen, PAI-1, tissue-type plasminogen activator (tPa) and factors V, II and VII, which have all been linked to the risk of myocardial infarction. Increased D-dimer, von Willebrand factor (vWf) antigen, A-II anti-plasmin and decreased anti-thrombin III were also reported in patients with type 2 diabetes. This pro-thrombotic risk profile of the circulating blood in type 2 diabetes patients, together with the lipid abnormalities, contributes to the increased risk of vascular events in this population.
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PMID:Dyslipidaemia and coagulation defects of insulin resistance. 1196 26

Since the early 1970s, increasing evidence has suggested that the consumption of moderate amounts of alcohol is inversely correlated with mortality from myocardial infarction. There is also some evidence that the protective effects of wine might be more pronounced than those of other alcoholic beverages. These observations prompted us to investigate the cardioprotective activity of Vitis vinifera seeds in experimental ischemia-reperfusion injury. An isolated rabbit heart preparation paced electrically was used to evaluate the effects of a highly purified, high molecular weight fraction of oligomeric procyanidins isolated from Vitis vinifera seeds on myocardial reperfusion injury after 40 min of low-flow (1 ml/min) ischemia. Infusion of the heart with 100 or 200 microg/ml procyanidins dose-dependently reduced left ventricular end-diastolic pressure during ischemia, decreased coronary perfusion pressure, improved cardiac mechanical performance upon reperfusion, increased the release of 6-Keto-prostaglandin F1alpha into the perfusate in both the preischemic and the reperfusion periods and suppressed rhythm irregularity. Procyanidins dose-dependently relaxed human internal mammary aortic (IMA) rings (with intact endothelium) precontracted with norepinephrine. This effect was completely abolished in IMA-rings without functional endothelium or when this vascular tissue was pretreated with nitric oxide synthase inhibitor (NG-monomethyl-L-arginine) or with guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). In conclusion, these results indicate that procyanidins could be of therapeutical potential in cardiovascular diseases. However, further investigations are required for a better definition of the mode of action of these oligomers.
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PMID:Procyanidins from Vitis vinifera seeds display cardioprotection in an experimental model of ischemia-reperfusion damage. 1513 76

Erectile dysfunction (ED) tends to be associated with other diseases, the common basis of which is endothelial dysfunction. ED is also frequently combined with LUTS and the common basis for both conditions seems to be elevation of Rho-kinase activity and decrease of NO concentration. Because all three PDE 5 inhibitors sildenafil, tadalafil, and vardenafil have a common mode of action, i.e., inhibition of PDE 5, they are not different in terms of their efficacy and safety profile except for color vision disturbances which are more common after sildenafil and back pain/myalgia more often observed after tadalafil. The main differentiating characteristics among the three PDE 5 inhibitors are their pharmacokinetics. These are ultimately responsible for the observation that in head-to-head comparative trials depending on the respective study design the overwhelming majority of the patients opted either for tadalafil as the longest acting PDE 5 inhibitor (36 h) or for vardenafil as a relatively rapidly acting drug. All published studies so far have shown that in terms of the cardiovascular risk profile (myocardial infarction rate) all three PDE 5 inhibitors performed better than placebo although the results were not statistically significant. Without any exception it applies to all three PDE 5 inhibitors that they are absolutely contraindicated in patients taking nitrate- or molsidomine-containing medications and that they may interact in particular with non-uroselective alpha-adrenoceptor blockers. This is why their simultaneous application with PDE 5 inhibitors has to be avoided.In the near future chronic (daily) application of a PDE 5 inhibitor may show advantages, at least in those 50-60% of all patients in whom there is a high likelihood of endothelial dysfunction due to the diagnostic (penile duplex Doppler) outcome. Possible new developments in the management of ED with a time frame of 5-8 years until their market approval are guanylate cyclase activators, Rho-kinase inhibitors, melanocortin receptor agonists, gene therapy, and tissue engineering.
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PMID:[Erectile dysfunction. New drugs with special consideration of the PDE 5 inhibitors]. 1519 47

Three types of natriuretic peptides (NP) have been isolated: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The NP family elicits a number of vascular, renal and endocrine effects that help to maintain blood pressure and extracellular fluid volume. These effects are mediated by the specific binding of NP to cell surface receptors that have been characterized, purified and cloned from cells of the vasculature, kidney, adrenal gland and brain. There are 3 subtypes of NP receptors: type A natriuretic peptide receptor (NPRA), type B natriuretic peptide receptor (NPRB), and type C natriuretic peptide receptor (NPRC). All 3 subtypes affect cellular second messenger activity. NPRA and NPRB are guanylyl cyclase receptors, and their activation increases cGMP levels. Activation of NPRC results in inhibition of adenylyl cyclase activity. Human NPRA has a high structural homology with human NPRB, and contains a highly-conserved guanylyl cyclase domain. ANP and BNP bind primarily to NPRA, which is found in the vasculature, causing vasodilation and inhibition of vascular smooth muscle cell proliferation. The present paper contains a review of NPs and their receptors and the genetic contribution of the NP system to cardiovascular diseases such as essential hypertension and myocardial infarction.
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PMID:The genetic contribution of the natriuretic peptide system to cardiovascular diseases. 1575 53

Although plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated early after myocardial infarction (MI), the significance is not fully understood. We therefore investigated the function of natriuretic peptides after induction of MI in knockout (KO) mice lacking the natriuretic peptide receptor guanylyl cyclase-A, the receptor for ANP and BNP. KO and wild-type (WT) mice were subjected to left coronary artery ligation and then followed up for 4 weeks. Irrespective of genotype, almost all deaths occurred within 1 week after induction of MI. KO mice showed significantly higher mortality because of a higher incidence of acute heart failure, which was associated with diminished water and sodium excretion and with higher cardiac levels of mRNAs encoding ANP, BNP, transforming growth factor-beta1, and type I collagen. By 4 weeks after infarction, left ventricular remodeling, including myocardial hypertrophy and fibrosis, and impairment of left ventricular systolic function were significantly more severe in KO than WT mice. Notably, the enhanced myocardial fibrosis seen in KO mice was virtually absent in infarcted double-KO mice, lacking guanylyl cyclase-A and angiotensin II type 1a receptors, although there was no improvement in survival and no attenuation of cardiac hypertrophy. Thus, guanylyl cyclase-A activation by endogenous cardiac natriuretic peptides protects against acute heart failure and attenuates chronic cardiac remodeling after MI. These beneficial effects are mediated partly through inhibition of the renin-angiotensin system (RAS), although RAS-independent protective actions of guanylyl cyclase-A are also suggested.
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PMID:Role of natriuretic peptide receptor guanylyl cyclase-A in myocardial infarction evaluated using genetically engineered mice. 1599 9

Postinfarct remodeling impairs mechanisms of ischemic preconditioning. We examined whether myocardial response to activation of the erythropoietin (EPO) receptor is modified by postinfarct remodeling. Four weeks after induction of myocardial infarction (MI) by coronary ligation in post-MI group (post-MI) or a sham operation in sham group (sham), rat hearts were isolated and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area (i.e., left ventricle) from which scarred infarct was excluded (%I/R). The heart weight was 15% larger in post-MI, but there was no intergroup difference in plasma EPO levels or myocardial EPO receptor levels. EPO infusion (5 U/ml) significantly reduced %I/R from 59.9 +/- 4.1 to 36.2 +/- 4.2 in sham and from 58.1 +/- 5.0 to 35.2 +/- 4.0 in post-MI. This EPO-induced protection was sensitive to a phosphatidylinositol 3-kinase (PI3K) inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), in sham. However, neither LY294002 nor wortmannin inhibited the EPO-induced protection in post-MI. Phosphorylation of Janus kinase 2 by EPO was attenuated and phosphorylation of Akt was not detected in post-MI. A guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, and a mitochondrial ATP-sensitive K(+) channel (mitoK(ATP) channel) blocker, 5-hydroxydecanoate, inhibited EPO-induced protection in both sham and post-MI. Suppressor of cytokine signaling (SOCS)-1 protein level was higher by 50% in post-MI than in sham, although SOCS-3 levels were similar. These findings suggest that postinfarct remodeling disrupts cellular signaling from the EPO receptor to PI3K, presumably by increased SOCS-1. However, in the remodeled myocardium, lack of PI3K/Akt activation by the EPO receptor seems to be compensated by a mechanism upstream of the guanylyl cyclase-mitoK(ATP) channel pathway to achieve EPO-induced protection.
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PMID:Alteration in erythropoietin-induced cardioprotective signaling by postinfarct ventricular remodeling. 1637 61

Myocardial infarction is a manifestation of necrotic cell death as a result of opening of the mitochondrial permeability transition (MPT). Receptor-mediated cardioprotection is triggered by an intracellular signaling pathway that includes phosphatidylinositol 3-kinase, endothelial nitric-oxide synthase, guanylyl cyclase, protein kinase G (PKG), and the mitochondrial K(ATP) channel (mitoK(ATP)). In this study, we explored the pathway that links mitoK(ATP) with the MPT. We confirmed previous findings that diazoxide and activators of PKG or protein kinase C (PKC) inhibited MPT opening. We extended these results and showed that other K(+) channel openers as well as the K(+) ionophore valinomycin also inhibited MPT opening and that this inhibition required reactive oxygen species. By using isoform-specific peptides, we found that the effects of K(ATP) channel openers, PKG, or valinomycin were mediated by a PKCepsilon. Activation of PKCepsilon by phorbol 12-myristate 13-acetate or H(2)O(2) resulted in mitoK(ATP)-independent inhibition of MPT opening, whereas activation of PKCepsilon by PKG or the specific PKCepsilon agonist psiepsilon receptor for activated C kinase caused mitoK(ATP)-dependent inhibition of MPT opening. Exogenous H(2)O(2) inhibited MPT, because of its activation of PKCepsilon, with an IC(50) of 0.4 (+/-0.1) microm. On the basis of these results, we propose that two different PKCepsilon pools regulate this signaling pathway, one in association with mitoK(ATP) and the other in association with MPT.
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PMID:The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition. 1672 May 72

Nitric oxide (NO) participates in the control of contractility and heart rate, limits cardiac remodeling after an infarction and contributes to the protective effect of ischemic pre- and postconditioning. Low concentrations of NO, with production of small amounts of cGMP, inhibit phosphodiesterase III, thus preventing the hydrolysis of cAMP. The subsequent activation of a protein-kinase A causes the opening of sarcolemmal voltage-operated and sarcoplasmic ryanodin receptor Ca(2+) channels, thus increasing myocardial contractility. High concentrations of NO induce the production of larger amounts of cGMP which are responsible for a cardiodepression in response to an activation of protein kinase G (PKG) with blockade of sarcolemmal Ca(2+) channels. NO is also involved in reduced contractile response to adrenergic stimulation in heart failure. A reduction of heart rate is an evident effect of NO-synthase (NOS) inhibition. It is noteworthy that the direct effect of NOS inhibition can be altered if baroreceptors are stimulated by increases in blood pressure. Finally, NO can limit the deleterious effects of cardiac remodeling after myocardial infarction possibly via the cGMP pathway. The protective effect of NO is mainly mediated by the guanylyl cyclase-cGMP pathway resulting in activation of PKG with opening of mitochondrial ATP-sensitive potassium channels and inhibition of the mitochondrial permeability transition pores. NO acting on heart is produced by vascular and endocardial endothelial NOS, as well as neuronal and inducible synthases. In particular, while in the basal control of contractility, endothelial synthase has a predominant role, the inducible isoform is mainly responsible for the cardiodepression in septic shock.
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PMID:Nitric oxide and cardiac function. 1770 39


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