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)

1. To date, no method exists for preventing the injury-induced, accelerated atherogenesis that can occur as a "late complication" after initially successful invasive cardiovascular therapy (e.g. coronary angioplasty, endarterectomy). The problems intrinsic to some of the therapeutic approaches that are presently being developed have been analyzed, and the need for an alternative approach is evident. 2. An hypothesis is advanced, providing a novel conceptual basis for developing preventive therapy for accelerated atherogenesis, as well as for other chronic (degenerative) disease states, using agents that selectively inhibit the actions and metabolic transformations of excessive amounts of endogenously-derived and/or exogenously-acquired nitric oxide (NO). 3. It is considered that excess NO can damage tissue by enhancing the formation of hydroxyl radicals (OH.) via the peroxynitrite pathway and alpha-hydroxynitrosamines via nitrosation processes, and that it can stimulate cell proliferation by activating guanyl cyclase. These actions would facilitate the process of accelerated atherogenesis. 4. Selectivity for opposing the effects and metabolic handling of excess NO, regardless of its origin (endogenous via the action of constitutive or inducible NO synthase, or exogenous), rather than selectivity for inhibiting the activity of inducible versus constitutive NO synthase, is considered to be the key element required of candidate therapeutic agents. 5. The vitamin C derivative, 2-O-octadecylascorbic acid, which could protect that part of the NO mechanism that is essential for normal function by scavenging superoxide anion-radicals (O2-., while preventing the formation of OH. and potentially toxic nitrosamines via metabolic reactions involving excess NO, represents a model compound for developing effective therapy.
Gen Pharmacol 1995 Jul
PMID:Excess EDRF/NO, a potentially deleterious condition that may be involved in accelerated atherogenesis and other chronic disease states. 763 42

1. Contribution of cyclic GMP generation to the relaxation by nipradilol of vascular smooth muscle was studied in the isolated rabbit aorta contracted by phenylephrine (10(-7) M) or prostaglandin F2 alpha (PGF2 alpha, 3 x 10(-6) M). 2. Nipradilol-induced relaxation in both contractions and increase in cyclic GMP content were inhibited by methylene blue (10(-5) M). 3. The relations between the increase in cyclic GMP and the relaxation produced by nipradilol and nitroglycerin were fitted to sigmoid curves. The increase in cyclic GMP at 50% relaxation by nipradilol was smaller than that by nitroglycerin (1.2-fold increase as against 3-fold increase). 4. These results suggest a smaller contribution of cyclic GMP generation through activation of soluble guanylate cyclase to nipradilol-induced relaxation in the rabbit aorta.
Gen Pharmacol 1995 Jan
PMID:Contribution of cyclic GMP generation to the relaxation by nipradilol in the rabbit aorta. 771 70

1. SKPYMRFamide, a novel FMRFamide-like endogenous peptide reversibly decreases excitatory responses (depolarization and inward current) evoked by local ionophoretic application of acetylcholine (ACh) onto the soma of identified neurons F1, F2, F4 and F5/6 of the land snail, Helix aspersa. 2. Threshold concentrations of SKPYMRFamide for an inhibitory action on ACh-induced responses are 0.5-1 mumoll-1. This modulatory action of peptide is dose- and time-dependent. 3. It is concluded that SKPYMRFamide inhibits ACh receptors through activation of specific binding sites on the plasma membrane. 4. The possible role of different second messengers in the modulatory influence of SKPYMRFamide on ACh receptors was tested using 13 modulators of different second messenger systems. 5. The results indicate that SKPYMRFamide may inhibit ACh receptors through activation of one or more of the following systems: phospholipases C, A2, NO-synthase, soluble guanylate cyclase and lipoxygenases which elevate basal intracellulal levels of NO, cGMP, arachidonic acid, acyclic eicosanoids, inositol-1,4,5-trisphosphate (I(1,4,5)P3), I(1,4,5)P3-dependent Ca(2+)-mobilization followed by activation of calmodulin and Ca2+/calmodulin-dependent protein kinase II. Protein kinases A, C and cyclic eicosanoids do not appear to participate in modulatory action of SKPYMRFamide.
Gen Pharmacol 1995 May
PMID:Inhibitory action of SKPYMRFamide on acetylcholine receptors of Helix aspersa neurons: role of second messengers. 778 22

1. We further investigated our earlier proposal that NO- and NO2-carrying molecules potentiate photorelaxation using isolated rabbit corpus cavernosum. 2. Corporal smooth muscle, in the presence or absence of endothelium, relaxed only slightly upon u.v. light (366 nm) irradiation. But, NO- and/or NO2-containing compounds such as streptozotocin and NG-nitro-L-arginine methyl ester significantly (P < 0.01) enhanced photorelaxation in this tissue. In addition, NG-nitro-D-arginine methyl ester, known to lack inhibitory action on NO synthase, showed concentration-dependent potentiation of the photorelaxation. 3. Oxygen radical generating system via xanthine+xanthine oxidase and guanylate cyclase inhibitor, methylene blue, significantly (P < 0.05) inhibited the streptozotocin-potentiated photorelaxation. 4. Nitrite was accumulated by photolysis of streptozotocin, NG-nitro-L-arginine methyl ester and NG-nitro-D-arginine methyl ester, in a concentration and exposure time-dependent manner. 5. These observations indicate that NO is a potent relaxant of rabbit corpus cavernosum and further support our hypothesis that NO is released by photolysis from NO- and NO2-carrying molecules.
Gen Pharmacol 1994 Sep
PMID:Photo-induced adequate nitric oxide (PIANO)-mediated relaxation in isolated rabbit corpus cavernosum. 783 33

1. This study was designed to investigate whether relaxation of isolated guinea-pig sphincter of Oddi preparation by nitrates is mediated by guanylate cyclase activation indirectly by nitric oxide (NO), as in vascular tissues. 2. Sodium nitroprusside, isosorbide dinitrate and amyl nitrite induced dose-dependent relaxations of Oddi's sphincter precontracted by potassium chloride (150 mM). Methylene blue (5 x 10(-5) M), an inhibitor of guanylate cyclase, did not significantly inhibit the relaxations caused by nitrovasodilators. 3. Unlike potassium chloride, acetylcholine (10(-7) - 10(-3) M) induced unsustained contractions which were significantly increased by methylene blue. NG-monomethyl-L-arginine (L-NMMA; 4 x 10(-4) M), an inhibitor of NO biosynthesis, also increased the contractile response to acetylcholine. 4. These results suggest that another mechanism rather than inhibition of guanylate cyclase is involved in the nitrovasodilators-induced relaxations and that acetylcholine releases a relaxing factor, possibly NO, that may modulate its own contraction in this preparation.
Gen Pharmacol 1994 Sep
PMID:The action of amyl nitrite and isosorbide dinitrate on the contractility of sphincter of Oddi of guinea-pigs. 783 50

We measured currents under voltage clamp in intact retinal rod photoreceptors with tight seal electrodes in the perforated patch mode. In the dark, membrane depolarization to voltages > or = +20 mV activates a time- and voltage-dependent outward current in the outer segment. This dark voltage-activated current (DVAC) increases in amplitude with a sigmoidal time course that is voltage dependent. DVAC reaches its maximum enhancement of approximately 30% in 4-6 s at +60 mV. DVAC is entirely suppressed by light and its current-voltage curve and reversal potential are the same as those of the photocurrent. Therefore, DVAC arises from the opening in darkness of the cGMP-gated channels of the outer segment. DVAC is blocked by BAPTA loaded into the cell's cytoplasm and is enhanced by lowering extracellular Ca2+ concentration. Because the cGMP-gated channels are not directly gated by voltage and because BAPTA blocks DVAC, we suggest this signal arises from a voltage-dependent decrease in cytoplasmic Ca2+ concentration that, in turn, activates guanylyl cyclase and causes cGMP synthesis. In rods loaded with high cytoplasmic Na+, membrane depolarization in darkness to voltages > or = +20 mV inactivates the outward current in the outer segment with an exponential time course. We call this DVIC (dark, voltage-inactivated current). DVIC reflects voltage-dependent closing of the cGMP-gated channel in the dark. DVIC, too, is blocked by cytoplasmic BAPTA, and it arises from a voltage-dependent rise in cytoplasmic Ca2+ in darkness, which occurs only if cytoplasmic Na is high. We develop a quantitative model to calculate the rate and extent of the voltage-dependent change in cytoplasmic Ca2+ concentration in a normal rod. We assume that this concentration is controlled by the balance between Ca2+ influx through the cGMP-gated channels and its efflux through a Na+/Ca2+, K+ exchanger. Lowered cytoplasmic Ca2+ is linked to guanylyl cyclase activation with characteristics determined from biochemical studies. The model considers the cytoplasmic buffering of both Ca2+ and cGMP. Simulated data generated by the model fit well DVAC measured in rods and also DVAC previously measured in cones. DVAC in cones is larger in magnitude and faster in time course than that in rods. The successful fit of DVAC by the model leads us to suggest that the activity and Ca2+ dependence of the enzymes of transduction are not different in rods and cones, but the quantitative features of Ca2+ homeostasis in the outer segment of the two receptor types differ profoundly.(ABSTRACT TRUNCATED AT 400 WORDS)
J Gen Physiol 1994 Nov
PMID:Differences in calcium homeostasis between retinal rod and cone photoreceptors revealed by the effects of voltage on the cGMP-gated conductance in intact cells. 787 28

1. The relaxation by nitroglycerin (GTN) and nitric oxide (NO) of aortic smooth muscles from rabbit and rat contracted by phenylephrine was inhibited by LY 83583 (LY) and methylene blue (MB) (the same applied to guinea-pig aorta), while the relaxation by SNP was not inhibited in rabbit. The relaxation by ANP was not inhibited. 2. All these agents produced concentration-dependent increases in cyclic GMP. While the increases by GTN and NO were inhibited by LY and MB, the increases by SNP were inhibited only in rat and those by ANP were not inhibited. 3. Thus, LY behaved essentially similar to MB, indicating that the substance is an inhibitor of activation of soluble guanylate cyclase by NO and NO-related vasodilators. It was assumed that, like MB, LY facilitated intracellular release of NO from SNP in rabbit.
Gen Pharmacol 1994 Nov
PMID:Modification by LY 83583 and methylene blue of relaxation induced by nitric oxide, glyceryl trinitrate, sodium nitroprusside and atriopeptin in aortae of the rat, guinea-pig and rabbit. 789 47

1. Bradykinin and related kinins possess two different types of action (consisting of relaxation and contraction) in the isolated rat duodenum via their specific receptors. However, the mechanisms of these actions have not been fully elucidated. The present study was undertaken to investigate the effects of the agents affecting cyclic nucleotide metabolism on bradykinin-induced relaxations and on bradykinin- and des-Arg9-bradykinin-induced contractions. 2. Des-Arg9-bradykinin, B1 receptor agonist, and high concentrations of bradykinin elicited dose-dependent contractile responses in the rat duodenum, while low concentrations of bradykinin caused a dose-dependent relaxation in this tissue. 3. Nicotinic acid, an inhibitor of adenylate cyclase, inhibited the relaxation of rat duodenum induced by bradykinin at low concentrations in a non-competitive manner. However, the inhibitory efficacy of nicotinic acid against bradykinin was limited by 39.9% and this inhibition was not further increased by higher concentrations of nicotinic acid up to 10(-3) M. 4. Imidazole, an activator of cyclic nucleotide phosphodiesterase, caused a slight inhibition of the relaxant responses to low concentrations of bradykinin and of the contractile responses to des-Arg9-bradykinin and high concentrations of bradykinin in isolated rat duodenum. These inhibitions were also limited in efficacies and not increased by higher concentrations of imidazole. 5. Methylene blue, an agent that inhibits soluble guanylate cyclase, suppressed the contractions of rat duodenum induced by des-Arg9-bradykinin and high concentrations of bradykinin in a non-competitive manner. Again, these inhibitions were limited and further increase in the inhibitory efficacy was not observed in spite of increasing the methylene blue concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Gen Pharmacol 1994 Nov
PMID:Effects of the agents affecting cyclic nucleotide metabolism on the bradykinin- and des-Arg9-bradykinin-induced relaxations and contractions in isolated rat duodenum. 789 50

We measured outer segment currents under voltage clamp in solitary, single cone photoreceptors isolated from the retina of striped bass. In darkness, changes in membrane voltage to values more positive than 10 mV activate a time- and voltage-dependent outward current in the outer segment. This dark, voltage-activated current (DVAC) increases in amplitude with a sigmoidal time course up to a steady-state value, reached in 0.75-1.5 s. DVAC is entirely suppressed by light, and its current-voltage characteristics and reversal potential are the same as those of the light-sensitive currents. DVAC, therefore, arises from the activation by voltage in the dark of the light-sensitive, cGMP-gated channels of the cone outer segment. Since these channels are not directly gated by voltage, we explain DVAC as arising from a voltage-dependent decrease in cytoplasmic Ca concentration that, in turn, activates only guanylate cyclase and results in net synthesis of cGMP. This explanation is supported by the finding that the Ca buffer BAPTA, loaded into the cytoplasm of the cone outer segment, blocks DVAC. To link a decrease in cytoplasmic Ca concentration to the synthesis of cGMP and the characteristics of DVAC, we develop a quantitative model that assumes cytoplasmic Ca concentration can be continuously calculated from the balance between passive Ca influx via the cGMP-gated channel and its active efflux via a Na/Ca,K exchanger, and that further assumes that guanylate cyclase is activated by decreasing cytoplasmic Ca concentration with characteristics identical to those described for the enzyme in rods. The model successfully simulates experimental data by adjusting the Ca conductance of the cGMP-gated channels as a function of voltage and the Ca buffering power of the cytoplasm. This success suggests that the activity of guanylate cyclase in cone outer segments is indistinguishable from that in rods.
J Gen Physiol 1993 Jun
PMID:In retinal cones, membrane depolarization in darkness activates the cGMP-dependent conductance. A model of Ca homeostasis and the regulation of guanylate cyclase. 810 Dec 10

This study examines the regulation of cGMP by illumination and by calcium during signal transduction in vertebrate retinal photoreceptor cells. We employed an electropermeabilized rod outer segment (EP-ROS) preparation which permits perfusion of low molecular weight compounds into the cytosol while retaining many of the features of physiologically competent, intact rod outer segments (ROS). When nucleotide-depleted EP-ROS were incubated with MgGTP, time- and dose-dependent increases in intracellular cGMP levels were observed. The steady state cGMP concentration in EP-ROS (0.007 mol cGMP per mol rhodopsin) approached the cGMP concentration in intact ROS. Flash illumination of EP-ROS in a 250-nM free calcium medium resulted in a transient decrease in cGMP levels; this occurred in the absence of changes in calcium concentration. The kinetics of the cGMP response to flash illumination of EP-ROS were similar to that of intact ROS. To further examine the effects of calcium on cGMP metabolism, dark-adapted EP-ROS were incubated with MgGTP containing various concentrations of calcium. We observed a twofold increase in cGMP steady state levels as the free calcium was lowered from 1 microM to 20 nM; this increase was comparable to the behavior of intact ROS. Measurements of guanylate cyclase activity in EP-ROS showed a 3.5-fold increase in activity over this range of calcium concentrations, indicating a retention of calcium regulation of guanylate cyclase in EP-ROS preparations. Flash illumination of EP-ROS in either a 50- or 250-nM free calcium medium revealed a slowing of the recovery time course at the lower calcium concentration. This observation conflicts with any hypothesis whereby a reduction in free calcium concentration hastens the recovery of cytoplasmic cGMP levels, either by stimulating guanylate cyclase activity or by inhibiting phosphodiesterase activity. We conclude that changes in the intracellular calcium concentration during visual transduction may have more complex effects on the recovery of the photoresponse than can be accounted for solely by guanylate cyclase activation.
J Gen Physiol 1994 Jan
PMID:Regulation of intracellular cyclic GMP concentration by light and calcium in electropermeabilized rod photoreceptors. 816 98


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