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

---

Query: EC:2.7.11.12 (PKG)
2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.
...
PMID:Mechanisms of action of nitrates. 787 67

Nitric oxide inhibits proliferation and migration of vascular smooth muscle cells and contractility of cardiomyocytes in vitro. In spontaneously hypertensive rats (SHR), evidence suggests intrinsic abnormalities of the L-arginine-nitric oxide axis, such as low cGMP-dependent protein kinase in the heart and abnormal L-arginine metabolism. To investigate the in vivo effect of L-arginine on cardiac hypertrophy, 30 SHR and 30 Wistar-Kyoto rats (WKY) were randomly grouped to receive L-arginine (7.5 g/L in drinking water) or vehicle for 12 weeks. L-Arginine treatment did not affect body weight or arterial pressure in either strain. In vehicle-treated animals, the heart/body weight ratio was significantly higher in SHR than in WKY (P < .01). L-Arginine treatment decreased the heart/body weight ratio in SHR (P < .05) but did not affect it in WKY. Expression of skeletal alpha-actin mRNA, known to be expressed in the hypertrophied myocardium, was attenuated in L-arginine-treated SHR compared with vehicle-treated SHR. Cardiac cGMP content and nitrate/nitrite content were less in SHR than WKY. L-Arginine treatment increased these levels only in SHR, suggesting enhanced nitric oxide production. Thus, chronic L-arginine administration attenuated cardiac hypertrophy independently of blood pressure and increased myocardial content of cGMP and nitrate/nitrite. Our results suggest that abnormality of the cardiac L-arginine-nitric oxide axis may play an important role in the pathogenesis of cardiac hypertrophy in SHR.
...
PMID:Chronic L-arginine administration attenuates cardiac hypertrophy in spontaneously hypertensive rats. 859 77

Whether organic nitrates are bioactivated to NO in cardiac muscle cells and may thus directly affect cardiac contractile function has remained an open question. Therefore, we determined the effects of the organic nitrates glyceryl trinitrate (100 mumol/L), pentaerythritol tetranitrate (10 mumol/L), and isosorbide-5-mononitrate on electrically stimulated contractile response (CR) and cAMP and cGMP content of isolated adult rat ventricular cardiomyocytes compared with different concentrations of the spontaneous NO donors S-nitroso-N-acetyl-d,1-penicillamine (SNAP) and 2,2-diethyl-1-hydroxy-1-nitroso-hydrazine (DEA/NO). A high concentration of spontaneous NO donors (100 mumol/L caused a large increase in cGMP content that was accompanied by a decrease in CR to 73.8 +/- 6.7% (SNAP) and 80.9 +/- 6.1% (DEA/NO) of the control values. Inhibition of cGMP-dependent protein kinase by 10 mumol/L KT 5822 converted this effect into a pronounced improvement of CR (163.5 +/- 14.0%) By contrast, the organic nitrates caused a small but significant increase in cGMP, which was accompanied by an increase in cAMP and CR identical to that induced by 10 nmol/L isoprenaline (141.6 +/- 6.4%) A similar effect was observed with a low concentration (1 mumol/L of SNAP and DEA/NO. All increases in CR induce by nitrates were abolished after inhibition of cAMP-dependent protein kinase by Rp-cAMPS (10 mumol/L). The positive contractile effect of isoprenaline was enhanced by 1 mumol/L SNAP. This effect was also demonstrated in isolated rat papillary muscles. These results indicate that in cardiac muscle (1) organic nitrate are bioactivated to NO; (2) this results in a moderate increase in cGMP, which causes an improved CR by increasing cAMP and activating cAMP-dependent protein kinase; and (3) a large increase in cGMP, produced by high doses of NO donors, reduces CR because of the activation of CGMP-dependent protein kinase.
...
PMID:Low increase in cGMP induced by organic nitrates and nitrovasodilators improves contractile response of rat ventricular myocytes. 860 11

We examined whether dipyridamole affected interleukin-1beta-stimulated nitric oxide (NO) production by cultured rat vascular smooth muscle cells. Interleukin-1beta stimulated the production of nitrite and nitrate, stable metabolites of NO, in a dose- and time-dependent manner in vascular smooth muscle cells. Dipyridamole (1-100 mu M) enhanced interleukin-1beta-induced nitrite production in a dose- and time-dependent manner. The mRNA expression of inducible NO synthase was up-regulated by dipyridamole (0.3-10 mu M) treatment in a dose-dependent manner. Both 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) and dibutyryl adenosine 3',5'-cyclic monophosphate (db-cAMP) enhanced the nitrite production in the presence of interleukin-1beta. Dipyridamole up-regulated the effect of both 8-bromo-cGMP and db-cAMP on the interleukin-1beta-induced nitrite production. Dipyridamole increased the intracellular cAMP content in the presence of interleukin-1beta (10 ng/ml), but did not affect the intracellular cGMP content. 8R*,9S*,11S*-(-)-9-hydroxy-9-n-hexyloxy-8-methyl-2,3,9,10- tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo-(a,g)-cy cloocta ++-(c,d,e)-trinden-1-one (KT 5720), a selective inhibitor of cAMP-dependent protein kinase, abolished the enhancement of interleukin-1beta-induced nitrite production by dipyridamole, whereas 8R*,9S*,11S*-(-)-9-methoxy-carbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-ep oxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cyclo-octa-(c,d,e)-tr inden-1-one (KT 5823), an inhibitor of cGMP-dependent protein kinase, did not attenuate the enhancement. Furthermore, Rolipram and 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro-20-1724), cAMP-specific phosphodiesterase type IV inhibitors, augmented the interleukin-1beta-induced nitrite production. We concluded that dipyridamole enhanced the interleukin-1beta-induced NO production via an increase in intracellular cAMP content in cultured rat vascular smooth muscle cells.
...
PMID:Dipyridamole enhances interleukin-1beta-stimulated nitric oxide production by cultured rat vascular smooth muscle cells. 890 84

Tumor necrosis factor (TNF)-alpha, a pluripotent cytokine implicated in the pathogenesis of airway inflammation, has been shown to provoke hypersecretion of mucin by airway epithelial cells in vitro. In this study, we investigated potential signaling pathways mediating TNF-alpha-induced mucin secretion using guinea pig tracheal epithelial (GPTE) cells in air-liquid interface culture. Exogenously applied TNF-alpha (human recombinant) stimulated mucin secretion in a concentration-dependent manner, with maximal effects at 10 to 15 ng/ml (286 to 429 U/ml). The pathway of stimulated secretion appeared to involve generation of intracellular nitric oxide (NO), activation of soluble guanylate cyclase (GC-S), production of cyclic guanosine monophosphate (cGMP), and activation of cGMP-dependent protein kinase (PKG). TNF-alpha increased production of nitrite and nitrate by GPTE cells; both mucin secretion and cGMP production were attenuated by NG-monomethyl-L-arginine (1 mM), a competitive inhibitor of nitric oxide synthase (NOS), or by the GC-S inhibitor LY83583 (50 microM); and mucin secretion in response to TNF-alpha or to the cGMP analogue dibutyryl cGMP (100 and 500 microM) was attenuated by the specific PKG inhibitor KT5823 (1 microM). Increased mucin secretion and increased cGMP production in response to TNF-alpha both appeared to be mediated by a phospholipase C that hydrolyzes phosphatidylcholine (PC-PLC), and by protein kinase C (PKC), since both responses were attenuated by either D609 (10 and 20 microg/ml), a specific PC-PLC inhibitor, or by each of three PKC inhibitors: Calphostin C (0.3 and 0.5 microM), bisindoylmaleimide (GF 109203X, Go 6850; 20 nM), or Ro31-8220 (10 microM). Collectively, the results suggest that TNF-alpha stimulates secretion of mucin by GPTE cells via a mechanism(s) dependent on PC-PLC and PKC, and involving activation of NOS, generation of NO, production of cGMP, and activation of PKG.
...
PMID:Tumor necrosis factor-alpha stimulates mucin secretion and cyclic GMP production by guinea pig tracheal epithelial cells in vitro. 1003 Aug 39

NO, constitutively produced by endothelial NO synthase (eNOS), plays a key regulatory role in vascular wall homeostasis. We generated transgenic (Tg) mice overexpressing eNOS in the endothelium and reported the presence of reduced NO-elicited relaxation. The purpose of this study was to clarify mechanisms of the reduced response to NO-mediated vasodilators in eNOS-Tg mice. Thoracic aortas of Tg and control mice were surgically isolated for vasomotor studies. Relaxations to acetylcholine and sodium nitroprusside were significantly reduced in Tg vessels compared with control vessels. Relaxations to atrial natriuretic peptide and 8-bromo-cGMP were also significantly reduced in Tg vessels. Reduced relaxations to these agents were restored by chronic N(G)-nitro-L-arginine methyl ester treatment. Basal cGMP levels of aortas were higher in Tg mice than in control mice, whereas soluble guanylate cyclase (sGC) activity in Tg vessels was approximately 50% of the activity in control vessels. Moreover, cGMP-dependent protein kinase (PKG) protein levels and PKG enzyme activity were decreased in Tg vessels. These observations indicate that chronic overexpression of eNOS in the endothelium resulted in resistance to the NO/cGMP-mediated vasodilators and that at least 2 distinct mechanisms might be involved: one is reduced sGC activity, and the other is a decrease in PKG protein levels. We reported for the first time that increased NO release from the endothelium reduces sGC and PKG activity in mice. These data may provide a new insight into the mechanisms of nitrate tolerance and cross tolerance to nitrovasodilators.
...
PMID:Mechanisms of reduced nitric oxide/cGMP-mediated vasorelaxation in transgenic mice overexpressing endothelial nitric oxide synthase. 1090 19

BAY 41-8543 is a novel, highly specific and so far the most potent NO-independent stimulator of sGC. Here we report the effects of BAY 41-8543 on the isolated enzyme, endothelial cells, platelets, isolated vessels and Langendorff heart preparation. BAY 41-8543 stimulates the recombinant sGC concentration-dependently from 0.0001 microM to 100 microM up to 92-fold. In combination, BAY 41-8543 and NO have synergistic effects over a wide range of concentrations. Similar results are shown in implying that BAY 41-8543 stimulates the sGC directly and furthermore makes the enzyme more sensitive to its endogenous activator NO. In vitro, BAY 41-8543 is a potent relaxing agent of aortas, saphenous arteries, coronary arteries and veins with IC(50)-values in the nM range. In the rat heart Langendorff preparation, BAY 41-8543 potently reduces coronary perfusion pressure from 10(-9) to 10(-6) g ml(-1) without any effect on left ventricular pressure and heart rate. BAY 41-8543 is effective even under nitrate tolerance conditions proved by the same vasorelaxing effect on aortic rings taken either from normal or nitrate-tolerant rats. BAY 41-8543 is a potent inhibitor of collagen-mediated aggregation in washed human platelets (IC(50)=0.09 microM). In plasma, BAY 41-8543 inhibits collagen-mediated aggregation better than ADP-induced aggregation, but has no effect on the thrombin pathway. BAY 41-8543 is also a potent direct stimulator of the cyclic GMP/PKG/VASP pathway in platelets and synergizes with NO over a wide range of concentrations. These results suggest that BAY 41-8543 is on the one hand an invaluable tool for studying sGC signaling in vitro and on the other hand its unique profile may offer a novel approach for treating cardiovascular diseases.
...
PMID:Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies. 1181 68

The aim of this study was to determine the molecular mechanism of nitric oxide (NO) in preventing cardiomyocytes from hypertrophic response induced by angiotensin II (Ang II). Hypertrophic response of neonatal rat cardiomyocytes was assayed by protein synthesis rate and expression of atrial natriuretic peptide (ANP) mRNA. The level of NO was shown by the content of nitrate and nitrite in cardiac myocytes. The protein expression of MKP-1 and the gene expression of eNOS were measured with Western blotting and RT-PCR, respectively. The results are as follows. (1) L-arginine (L-Arg) induced a dose-dependent increase in NO by 16% and 31% at the concentrations of 10 micromol/L and 100 micromol/L, respectively. L-Arg also increased the gene expression of eNOS. However, these effects were inhibited by L-NAME, the inhibitor of NOS. (2) The gene expression and the protein synthesis of ANP induced by Ang II (0.1 micromol/L) were inhibited by L-Arg (100 micromol/L). The inhibitory action of L-Arg was abolished after pretreatment with antisense oligoneucleotide against MKP-1. (3) L-Arg (100 micromol/L) increased the protein expression of MKP-1 by 225%, which was inhibited by L-NAME, an NOS inhibitor, and KT-5823, a cGMP-dependent protein kinase (PKG) inhibitor. However, Ang II enhanced the effect induced by L-Arg. The above results show that NO may activate PKG, and thereby promote the protein expression of MKP-1 and inactivate MAPK, resulting in an inhibition of cardiomyocyte hypertrophic response induced by Ang II.
...
PMID:[Molecular mechanism of nitric oxide in preventing cardiomyocytes from hypertrophic response induced by angiotensin II]. 1207 67

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted due to the development of nitrate tolerance. With initiation of nitroglycerin therapy one can detect neurohormonal activation and signs for intravascular volume expansion. These so called pseudotolerance mechanisms may compromise nitroglycerin's vasodilatory effects. Long-term treatment with nitroglycerin is also associated with a decreased responsiveness of the vasculature to nitroglycerin's vasorelaxant potency suggesting changes in intrinsic mechanisms of the tolerant vasculature itself may also contribute to tolerance. More recent experimental work defined new mechanisms of tolerance such as increased vascular superoxide production and increased sensitivity to vasoconstrictors secondary to an activation of the intracellular second messenger protein kinase C. As potential superoxide producing enzymes, the NADPH oxidase and the nitric oxide synthase have been identified. Nitroglycerin-induced stimulation of oxygen-derived free radicals together with NO derived from nitroglycerin may lead to the formation of peroxynitrite, which may be responsible for the development of tolerance as well as for the development of cross tolerance to endothelium-dependent vasodilators. The oxidative stress concept of tolerance and cross tolerance may explain why radical scavengers such as vitamin C or substances which reduce oxidative stress, such as ACE-inhibitors, AT1 receptor blockers or folic acid, are able to beneficially influence both tolerance and nitroglycerin-induced endothelial dysfunction. New aspects concerning the role of oxidative stress in nitrate tolerance and nitrate induced endothelial dysfunction and the consequences for the NO/cyclicGMP downstream target, the cGMP-dependent protein kinase will be discussed.
...
PMID:Mechanisms underlying nitrate-induced endothelial dysfunction: insight from experimental and clinical studies. 1237 19

Nitrate tolerance (NT) in hypertension is attributed to reduced activity of soluble guanylyl cyclase (sGC). We examined NT in basilar artery vascular smooth muscle cells (VSMCs) from control rats, rats infused with angiotensin II (Ang; 240 microg/kg per hour for 4 days), which were normotensive, and Ang-hypertensive rats (AHR; 240 microg/kg per hour for 28 days). Ca2+-activated K+ (Maxi-K) channels in VSMCs from AHR showed reduced activation by NO donor, consistent with NT. The concentration-response relationship for 8-Br-cGMP was shifted 2.5-fold to the right, indicating that abnormal sGC alone could not account for NT. Inside-out patches from AHR showed normal activation with exogenous cGMP-dependent protein kinase I (cGKI), suggesting no abnormality downstream of cGKI. We hypothesized that the reduction in apparent affinity of 8-Br-cGMP for cGKI in AHR might be due to a change in relative amounts of cGKIalpha versus cGKIbeta, since cGKIbeta is less sensitive to cGMP activators than cGKIalpha. This was substantiated by showing the following in AHR: (1) reduced effect of the cGKIalpha-selective activator 8-APT-cGMP; (2) reduced total cGKI protein (both isoforms), but an increase in cGKIbeta protein in quantitative immunofluorescence and Western blots; (3) similar changes in cGKI isoforms immunoisolated with Maxi-K channels; and (4) a large increase in cGKIbeta mRNA and a decrease in cGKIalpha mRNA in real-time PCR and Northern blots. Upregulation of cytosolic cGKIbeta was evident 4 days after Ang infusion, before development of hypertension. Our data identify a functional role for cGKIbeta in VSMCs previously ascribed exclusively to cGKIalpha. Ang-induced alternative splicing of cGKI represents a novel mechanism for reducing sensitivity to NO/cGMP.
...
PMID:Alternative splicing of cGMP-dependent protein kinase I in angiotensin-hypertension: novel mechanism for nitrate tolerance in vascular smooth muscle. 1464 36


1 2 3 Next >>

---