Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present studies we sought to determine if cicletanine, which is an antihypertensive agent of unknown mechanism, could alter cGMP metabolism via inhibition of cGMP phosphodiesterases (PDE) in vascular smooth muscle. Cicletanine was determined to be a mixed (competitive, noncompetitive) inhibitor of both calmodulin-regulated and cGMP-specific PDEs from monkey aortic smooth muscle with Ki values of 450 to 700 microM. Cicletanine also potentiated vasorelaxation by the guanylate cyclase activators sodium nitroprusside and atrial natriuretic peptide in isolated rat aortas. Potentiation was not dependent upon the contractile agonists nor was it indomethacin-sensitive. Neither potentiation nor inhibition of cGMP PDEs was stereoselective. Methylene blue attenuated a component of cicletanine-induced vasorelaxation, but did not completely obviate relaxation. Both cicletanine and the cGMP-PDE inhibitor zaprinast potentiated sodium nitroprusside-mediated cGMP formation and relaxation, although the increase in cGMP content was markedly greater with zaprinast compared to cicletanine. In further studies, cicletanine did not potentiate cGMP activation of cGMP-dependent protein kinase, but did inhibit calmodulin-activated myosin light chain kinase and protein kinase C at relatively high concentrations (approximately 1 mM). In summary, these data demonstrate that cicletanine inhibits vascular cGMP PDEs, potentiates vasorelaxation, and to a limited extent, cGMP formation by guanylate cyclase activators in vascular smooth muscle. However, these relationships for cicletanine are dissimilar from the reference cGMP PDE inhibitor, zaprinast. Thus, other mechanisms may also contribute to the vasorelaxant action of cicletanine.
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PMID:Inhibition of low Km cGMP phosphodiesterases and Ca+(+)-regulated protein kinases and relationship to vasorelaxation by cicletanine. 185 Apr 74

The effects of sodium nitroprusside (SNP) on Ca2+-dependent K+ (KCa) channels in cultured bovine adrenal chromaffin cells were investigated using single channel recording patch-clamp techniques. KCa channels were activated by application of 100 microM SNP to the extracellular side of cell-attached patches. Methylene blue (300 microM), an inhibitor of soluble guanylate cyclase, or H-8 (1 microM), a protein kinase inhibitor with relative specificity for cGMP-dependent protein kinase, diminished but did not completely abolish the SNP-induced KCa channel activation. Diethylamine/NO complex (DEA/NO), an NO donor, also activated KCa channels in cell-attached patches. Furthermore, application of 100 microM SNP or 100 nM DEA/NO to the intracellular surface of excised inside-out patches also activated KCa channels in the bath solution which contained 1 microM Ca2+. These results indicate that SNP is capable of activating the KCa channel via cGMP-dependent and -independent mechanisms. These studies demonstrate that NO may serve as an important regulatory mechanism for catecholamine secretion in chromaffin cells via the activation of KCa channels.
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PMID:Nitric oxide activates Ca2+-activated K+ channels in cultured bovine adrenal chromaffin cells. 965 59

Prostaglandin E(1) (PGE(1)) has cardioprotective effects on the ischemic-reperfused heart. To clarify the mechanisms underlying the protective action of PGE(1) on myocardium, we examined the effect of PGE(1) on the L-type Ca(2+) current (I(Ca)) using single atrial cells from rabbits. PGE(1) did not show a significant effect on basal I(Ca) but inhibited the I(Ca) prestimulated by isoproterenol (Iso, 30 nM). This inhibition was concentration dependent (EC(50) = 0.027 microM). Both sulprostone, a specific PGE receptor subtype (EP(1) and EP(3)) agonist, and 11-deoxy-PGE(1), an EP(3) agonist, inhibited the Iso-stimulated I(Ca), similar to PGE(1). Pretreatment with pertussis toxin (PTX) abolished the PGE(1) inhibition of I(Ca). Both the application of forskolin plus IBMX and intracellular dialysis with 8-bromoadenosine 3',5'-cyclic monophosphate eliminated the effect of PGE(1). PGE(1) did not show any further inhibition of I(Ca) when the effect of Iso was almost fully antagonized by acetylcholine. Methylene blue (guanylate cyclase inhibitor), KT-5823 (cGMP-dependent protein kinase inhibitor), and erythro-9-(2-hydroxy-3-nonyl)adenine (type II phosphodiesterase inhibitor) did not significantly change the inhibitory effect of PGE(1). These findings suggest that 1) PGE(1) inhibits Iso-stimulated I(Ca) by binding to the EP(3) receptor and 2) the PTX-sensitive and cAMP-dependent pathway is involved in the PGE(1) inhibition of I(Ca), but the nitric oxide-cGMP-dependent pathway is not. The PGE(1)-induced antiadrenergic effect shown in this study may contribute to the PGE(1) protection of myocardium against ischemia.
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PMID:EP receptor-mediated inhibition by prostaglandin E(1) of cardiac L-type Ca(2+) current of rabbits. 1051 71

1.Voltage-gated K+ channels containing Kv3 subunits play specific roles in the repolarization of action potentials. Kv3 channels are expressed in selective populations of CNS neurons and are thought to be important in facilitating sustained and/or repetitive high frequency firing. Regulation of the activity of Kv3 channels by neurotransmitters could have profound effects on the repetitive firing characteristics of those neurons. 2.Kv3 channels are found in several neuronal populations in the CNS that express nitric oxide synthases (NOSs). We therefore investigated whether Kv3 channels are modulated by the signalling gas nitric oxide (NO). 3. We found that Kv3.1 and Kv3.2 currents are potentially suppressed by D-NONOate and other NO donors. The effects of NO on these currents are mediated by the activation of guanylyl cyclase (GC), since they are prevented by Methylene Blue, an inhibitor of GC, and by ODQ, a specific inhibitor of the soluble form of GC. Moreover, application of 8-Br-cGMP, a permeant analogue of cGMP, also blocked Kv3.1 and Kv3.2 currents. 4.KT5283, a cGMP-dependent protein kinase (PKG) blocker, prevented the inhibition of Kv3.1 and Kv3.2 currents by D-NONOate and 8-Br-cGMP. This indicates that activation of PKG as a result of the increase in intracellular cGMP levels produced by D-NONOate or 8-Br-cGMP is necessary for channel block. 5. Although the effects of NO on Kv3.1 and Kv3.2 channels require PKG activity, two observations suggest that they are not mediated by phosphorylation of channel proteins: (a) the reagents affect both Kv3.2 and Kv3.1 channels, although only Kv3.2 proteins have a putative PKA-PKG phosphorylation site, and (b) mutation of the PKA-PKG phosphorylation site in Kv3.2 does not interfere with the effects of NO or cGMP. 6. The inhibitory effects of NO and cGMP on Kv3.1 and Kv3.2 currents appear to be mediated by the activation of serine-threonine phosphatase, since they are blocked by low doses of okadaic acid. Furthermore, direct intracellular application of the catalytic subunit of protein phosphatase 2A inhibited Kv3.2 currents, indicating that activity of PKG-induced phosphatase is necessary and sufficient to inhibit these channels. 7. The results suggest that basal phosphorylation of Kv3 channel proteins is required for proper channel function. Activation of phosphatases via NO or other signals that increase cGMP might be a potent mechanism to regulate Kv3 channel activity in neurons.
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PMID:Modulation of Kv3 potassium channels expressed in CHO cells by a nitric oxide-activated phosphatase. 1128 Nov 23

This study investigated the hypothesis that atrial natriuretic peptide (ANP) responses are mediated by particulate guanylate cyclase in the pulmonary vascular bed of the cat. When tone in the pulmonary vascular bed was raised to a high steady level with the thromboxane mimic U-46619, injections of ANP caused dose-related decreases in lobar arterial pressure. After administration of HS-142-1, an ANP-A- and ANP-B-receptor antagonist, vasodilator responses to ANP were reduced. The nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) enhanced ANP vasodilator responses, suggesting that inhibition of NO modulates ANP responses. L-NAME administration with constant 8-bromo-cGMP infusion attenuated the increased vasodilator response to ANP, suggesting that supersensitivity to ANP occurs upstream to activation of a cGMP-dependent protein kinase. In pulmonary arterial rings, ANP produced concentration-related vasorelaxant responses with and without endothelium. Methylene blue, L-NAME, or N(omega)-monomethyl-L-arginine did not alter ANP vasorelaxant responses. These data show that ANP supersensitivity observed in the intact pulmonary vascular bed is not seen in isolated pulmonary arterial segments, suggesting that it may only occur in resistance vessel elements. These results suggest that ANP responses occur through activation of ANP-A and/or -B receptors in an endothelium-independent manner and are modulated by NO in resistance vessel elements in the pulmonary vascular bed of the cat.
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PMID:L-NAME enhances responses to atrial natriuretic peptide in the pulmonary vascular bed of the cat. 1135 72