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)

We have investigated the effect of NZ-107, an inhibitor of bronchoconstriction induced by slow reacting substance of anaphylaxis (SRS-A), on tracheal responses to adenosine in the guinea pig. In the presence of an adenosine uptake inhibitor, dipyridamole (1 microM), NZ-107 (0.3-1 microM) enhanced adenosine-induced relaxation in 30 nM leukotriene D4 (LTD4)-precontracted trachea, whereas aminophylline (AP, 10-30 microM), an adenosine receptor antagonist, markedly inhibited it. NZ-107 (1 microM) also enhanced the relaxation induced by forskolin, an adenylate cyclase activator, but not that by nitroprusside (NP), a guanylate cyclase activator. AP (30 microM) affected neither forskolin- nor NP-induced relaxation. NZ-107 (1 microM) and AP (30 microM) inhibited to about the same extent the contractile response to an adenosine A1 receptor agonist, the R(-)-enantiomer of N6-(2-phenylisopropyl)-adenosine (R-PIA). The R-PIA-induced contraction was completely blocked by 5 microM indomethacin. NZ-107 (1 microM) did not affect the contraction induced by PGD2, but significantly reduced that of PGF2 alpha. AP (30 microM) had no effect on PGF2 alpha- and PGD2-induced contractions. These results suggest that NZ-107 may have a unique profile for adenosine responses in bronchial asthma.
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PMID:Effects of NZ-107 on tracheal responses to adenosine in the guinea pig. 188 Sep 89

PAF elicits a rapid, concentration-dependent elevation of platelet cytosolic free calcium ([Caf]), measured by quin2. Elevation of [Caf] is transient, and the rate of reversal increases with agonist concentration. Adenylate cyclase stimulants (PGI2, PGD2) and 8-bromo cAMP; a guanylate cyclase stimulant (sodium nitroprusside) and 8-bromo cGMP; and a protein kinase C stimulant (phorbol myristate acetate) block the elevation of [Caf] induced by PAF, and accelerate its reversal. These results suggest that cAMP, cGMP and 1,2-diacylglycerol (DAG) could act as second messengers to regulate [Caf] in platelets. As PAF is known to stimulate platelet phosphoinositide hydrolysis (ergo DAG formation) but fails to elevate platelet cAMP or cGMP, it is proposed that DAG, via activation of protein kinase C, may act as an endogenous modulator of platelet [Caf]: an action that contributes to the role of DAG as a bi-directional regulator of platelet reactivity.
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PMID:Regulation of platelet cytosolic free calcium by cyclic nucleotides and protein kinase C. 299 27

Samples of blood, urine and ovarian tissues of non-pregnant cycling guinea-pigs were obtained from day 3 before until day 2 after oestrus. In addition placental specimens were obtained from 49- to 62-day pregnant guinea-pigs. In a separate series of experiments blood samples of normally menstruating and dysmenorrhoeic women were collected daily during the last one week preceding and the first two days of the menstrual cycle. Plasma and tissue samples were analyzed simultaneously for ascorbic acid (AA) and prostaglandins (PGs) E2 and F2 alpha. The urine and leukocyte samples were estimated for AA only. The results demonstrate that the ovarian AA depletion at ovulation is not associated with a rise in urinary, plasma or leukocyte levels. From about the 8th week of pregnancy in the guinea-pig the placental levels of AA start to decline, while the concentrations of PGs start to rise. During the late luteal phase, the plasma of normally cycling women has a PGD2 alpha/PGE2 ratio of about 0.6. In the dysmenorrhoeic women this ratio varies from 0.9 to 1.3. In addition, the plasma and leukocyte levels of AA in the dysmenorrhoeic women are lower than the levels found in the normally cycling women. The results of both animal and human studies indicate that an inverse relationship exists between the levels of AA and the amount of PGF2 alpha synthesized and/or released in the body tissues. It is suggested that AA acts to control the ratio between PGF2 alpha and PGE2 and therefore forms an integral part of the adenyl/guanylate cyclase system. The mechanism for the fall in tissue ascorbic acid is however not known. The results suggest that this is due to increased break-down and/or rapid consumption of AA in the body tissues. In addition the reduction in placental tissue levels of AA near term could be due to its redistribution from maternal to foetal tissues.
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PMID:Interactions of ascorbic acid with prostaglandins. 681 84

The role of blood platelets in the pathogenesis of atherosclerosis, thrombosis, thromboembolism and stroke (hemorrhagic/thrombotic) is well established. In view of this recognized role played by platelets in the complications associated with coronary artery disease and cerebrovascular disease, there is considerable interest in the pharmacology of platelet activation inhibitory drugs. These drugs exert their effect by blocking several different activation signalling mechanisms. Some of the known compounds that modulate platelet function include: inhibitors of arachidonic acid metabolism (nonsteroidal anti-inflammatory drugs and thromboxane synthetase inhibitors), drugs that alter membrane phospholipid composition (omega 3 fatty acids), stimulators of adenylyl cyclase and guanylyl cyclase (PGE1, PGI2, PGD2/ERRF [nitric oxide], nitroglycerin, nitroprusside), phosphodiesterase inhibitors (dipyridamole and methylxanthines) and calcium antagonists (verapamil, nifedipine, diltiazem). Current research on the pharmacology of platelet activation inhibitory drugs is focused on the development of specific receptor antagonists (antibodies, peptides, receptor antagonists). Since platelets have multiple mechanisms for achieving activation, and the process of thrombosis involves multicellular modulation of platelet activity, it will be rather difficult to develop a compound that is capable of causing complete inhibition of activation mechanisms. Therefore, future research will be devoted to development of designer drugs that will be used for preventing discrete platelet responses. This approach may be useful as total inhibition of platelet activation, although it may prevent thrombotic events, may possibly precipitate hemorrhagic conditions. A better understanding of cell signalling pathways and the mechanisms involved in the pathogenesis of cardiovascular cerebrovascular disease will facilitate the development of efficient antiplatelet drugs.
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PMID:Pharmacology of platelet activation-inhibitory drugs. 806 66

We studied the putative relaxant effects of several isoprostanes (8-iso-PGE1, and 8-iso-PGE2, 8-iso-PGF1alpha, 8-iso-PGF1beta, 8-iso-PGF2alpha, and 8-iso-PGF2beta) on pulmonary (PA), mesenteric (MA), coronary (CA) arteries and pulmonary veins (PV), from newborn and 2-week-old piglets. Isoprostanes were compared with agonists of the EP (PGE1, PGE2, and misoprostol), DP (PGD2), and IP (iloprost) receptors. Isoprostane-induced relaxation was only observed when TP receptors were occupied (by U46619) or blocked (by SQ 29,548). Under these conditions, 8-iso-PGE2 induced a relaxation of PA (but not PV or MA) that increased with postnatal age. 8-iso-PGE1, 8-iso-PGE2, and 8-iso-PGF2alpha evoked modest relaxations in CA. 8-iso-PGE2-induced relaxation of PA was impaired by endothelium removal and by the presence of blockers of NO synthase (L-NAME), guanylate cyclase (ODQ), or EP receptor (AH6809). PGE1, PGE2, and misoprostol (but not PGD2 or iloprost) induced a relaxation of PA that increased with age. In conclusion, occupancy or blockade of TP receptors unmasked a relaxant effect of 8-iso-PGE2 in piglet PA. This relaxation increased with postnatal age, was endothelium-dependent and involved EP receptors and NO.
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PMID:Age-related changes in isoprostane-mediated relaxation of piglet blood vessels. 2003 85