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)

Carbon monoxide (CO) is well known as a relaxing substance in the vasculature, where it is released during the heme oxygenase (HO) reaction. Little is known about the tissue-specific targets of CO in smooth muscles. To date the functional role of CO in the coronary artery remains unclear. The expression of HO-2, the constitutive isoform of HO, but not of HO-1 (inducible HO isoform) was demonstrated by immunohistochemical reaction. Contractile studies, performed under isometrical conditions, showed that CO, as well as hemin (given as a substrate for HO), relax de-endothelized coronary smooth muscle after the blockade of neuronal transmission. The action of hemin was antagonized by preliminary treatment of the vessel with SnPPIX--a competitive inhibitor of HO. The relaxatory effects of hemin were abolished in the presence of guanylyl-cyclase or protein kinase G antagonists. Patch-clamp studies revealed that hemin caused activation of iberiotoxin-blockable K outward current (I(K)) via guanylyl-cyclase and protein-kinase-G-dependent mechanisms. This activation coincided with hyperpolarization of the plasma membrane of single coronary smooth muscle cells by 8+/-3 mV, which was prevented by preliminary exposure of cells to 10 microM SnPPIX. The I(K)-augmenting effect of hemin was not affected by pretreatment of cells with cyclopiazonic acid and/or ryanodine, blockers of phospholipase C or heparin (applied via pipette), but was not observed when ATP was omitted from the dialyzing solution, or in the presence of Na-free, ATP-containing pipette solution. The omission of Ca(2+) from the bath or the replacement of Na with Li in both pipette and bath media also prevented the I(K)-activating effect of hemin. These results suggest that the constitutive HO-2 in coronary artery smooth muscle cells plays role in the modulation of tone. At the level of smooth muscle cells CO and its precursor hemin may cause hyperpolarization of the plasma membrane by activation of iberiotoxin-sensitive I(K) presumably via PKG-dependent activation of the Na/Ca exchanger. This activation is thought to increase the submembrane Ca(2+) concentration in the vicinity of large-conductance, Ca(2+)-sensitive K channels, thus causing voltage-dependent inhibition of Ca(2+) entry and subsequent relaxation of the vessel.
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PMID:Role of constitutively expressed heme oxygenase-2 in the regulation of guinea pig coronary artery tone. 1276 25

The present studies compared the effects of CO-releasing molecule (CORM-1), authentic CO, and nonadrenergic noncholinergic (NANC) nerve stimulation in the internal anal sphincter (IAS). Functional in vitro experiments and Western blot studies were conducted in rat IAS smooth muscle. We examined the effects of CORM-1 (50-600 microM) and authentic CO (5-100 microM) and NANC nerve stimulation by electrical field stimulation (EFS; 0.5-20 Hz, 0.5-ms pulse, 12 V, 4-s train). The experiments were repeated after preincubation of the tissues with the neurotoxin TTX, the guanylate cyclase inhibitor 1H-(1,2,4)oxadiazolo-(4,3-a)quinoxalin-1-one (ODQ), the selective heme oxygenase (HO) inhibitor tin protoporphyrin IX (SnPP-IX), the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (L-NNA), and SnPP-IX + L-NNA. We also investigated the effects of the HO substrate hematin (100 microM). CORM-1, as well as CO, produced concentration-dependent IAS relaxation, whereas hematin had no effect. TTX abolished and L-NNA significantly blocked IAS relaxation by EFS without any effect on CORM-1 and CO. ODQ blocked IAS relaxation by CORM-1, authentic CO, and EFS. SnPP-IX had no significant effect on IAS relaxation by CORM-1, CO, or EFS. The presence of neuronal nitric oxide synthase, HO-1, and HO-2 in IAS smooth muscle was confirmed by Western blot studies. CORM-1 and CO, as well as NANC nerve stimulation, produced IAS relaxation via guanylate cyclase/cGMP-dependent protein kinase activation. The advent of CORM-1 with potent effects in the IAS has significant implications in anorectal motility disorders with regard to pathophysiology and therapeutic potentials.
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PMID:Mechanism of internal anal sphincter relaxation by CORM-1, authentic CO, and NANC nerve stimulation. 1533 53

We used the patch-clamp technique to examine the role of carbon monoxide (CO) in regulating Ca(2+)-activated big-conductance K (BK) channels in the principal cell of the cortical collecting duct (CCD). Application of CORM3 or CORM2, a CO donor, activated BK channels in the CCD, whereas adding inactivated CORM2/3 had no effect. Superfusion of the CCD with CO-bubbled bath solution also activated the BK channels in the cell-attached patches. The effect of CO on BK channels was not dependent on nitric oxide synthase (NOS) because the effect of CORM3 was also observed in the CCD treated with l-NAME, an agent that inhibits the NOS. Adding a membrane-permeable cGMP analog, 8-bromo-cGMP, significantly increased the BK channel in the CCD. However, inhibition of soluble guanylate cyclase failed to abolish the stimulatory effect of CORM3 on BK channels. Moreover, inhibition of cGMP-dependent protein kinase G did not block the stimulatory effect of CORM3 on the BK channels, suggesting that the stimulatory effect of CO on the BK channels was, at least partially, induced by a cGMP-independent mechanism. Western blot demonstrated that heme oxygenase type 1 (HO-1) and HO-2 were expressed in the kidney. Moreover, a high-K (HK) intake increased the expression of HO-1 but not HO-2 in the kidney. A HK intake also increased renal HO activity defined by NADPH-dependent CO generation following addition of heme in the cell lysate from renal cortex and outer medulla. The role of HO in regulating BK channel activity in the CCD was also suggested by experiments in which application of hemin increased the BK channels. The stimulatory effect of hemin on the BK channels was blocked by SnMP, a HO inhibitor. But, adding CORM3 was still able to activate the BK channels in the presence of SnMP. We conclude that CO activates the BK channels, at least partially, through a NO-cGMP-independent pathway and that HO plays a role in mediating the effect of HK intake on the BK channels in the CCD.
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PMID:Carbon monoxide stimulates Ca2+ -dependent big-conductance K channels in the cortical collecting duct. 2323 81