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)

Nitroglycerin and the organic nitrates (RONO2) can be considered prodrugs that require conversion to an active intracellular moiety that initiates vascular smooth muscle relaxation. Vasodilation of veins and arteries occurs when the enzyme guanylate cyclase (GC) is activated, initiating the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP); this is the final pathway for vascular dilation caused by the nitrovasodilators (organic nitrates, sodium nitroprusside, and molsidomine) as well as endothelium-derived relaxing factor (EDRF). The common denominator appears to be the intracellular production of nitric oxide (NO), which is the activated product of organic nitrate denitration. Nitrate tolerance has been associated with a relative depletion or unavailability of thiol groups that are involved in the initial step of denitration of RONO2. Sulfhydryl groups (SH) are oxidized during this process; with continuous nitrate exposure, decreased nitrate metabolism within the vascular smooth muscle cell occurs as a direct result of the depletion of reduced SH groups. Thus, less NO is formed and cGMP production is diminished, with a subsequent decrease or absence of vasodilation. In addition, SH groups or thiols are required for the production of S-nitrosothiols (RSNO). These short-lived compounds have been identified as an end product of organic nitrate metabolism and as possibly obligatory for the induction of GC. It is unclear, however, as to whether S-nitrosothiols are a necessary by-product of NO production from organic nitrates. It appears that RSNO can be formed outside the cell membrane and may be able to induce vasorelaxation after penetrating the cell and initiating GC activation. Exogenous SH donors, particularly N-acetylcysteine (NAC), have been employed to provide intracellular thiols in efforts to prevent or reverse nitrate tolerance. Nitrate physiologic actions are accentuated following NAC administration in the absence of tolerance. Although controversial, the concept that NAC or other thiols might be able to prevent the development of nitrate tolerance is being actively studied in laboratories around the world. Methionine has also been utilized as an SH donor with some success. Not all data are consistent, however, and the ultimate role of thiol donors for the prevention or reversal of nitrate tolerance remains uncertain. Finally, there has been considerable interest in supplying thiols by use of the SH-containing angiotensin converting enzyme inhibitors, such as captopril. This approach does not seem promising, probably because insufficient thiol can be supplied by therapeutic dosages of these drugs.
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PMID:Interactions between organic nitrates and thiol groups. 192

It has been deduced (Lancaster, Proc. Natl. Acad. Sci. USA 91 (1994) 8137-8141), from a consideration of Fick's law of diffusion, that the very effective scavenging of nitric oxide (NO) by haemoglobin in red blood cells prevents any NO from endothelial cells migrating outwards into vascular smooth muscle. This conclusion has led some authors to suggest that endothelium-derived relaxing factor (EDRF) is not free NO. We have reconsidered the application of Fick's law to the migration of NO in the vasculature, making allowance for the reaction of NO with guanylate cyclase and for the layer of red blood-free plasma next to the endothelium. The source of NO is taken as an infinite cylinder. Calculations for vessels of various diameters indicate that a substantial amount of NO migrates outwards in spite of very effective scavenging by haemoglobin and that the relative amount of NO migrating outwards depends upon the radius of the vessel. The view that locally produced NO is not responsible for vascular dilation has not been sustained.
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PMID:Diffusion of nitric oxide and scavenging by blood in the vasculature. 981 7

This study investigated vildagliptin-induced vasodilation and its related mechanisms using phenylephrine induced precontracted rabbit aortic rings. Vildagliptin induced vasodilation in a concentration-dependent manner. Pretreatment with the large-conductance Ca2+-activated K+ channel blocker paxilline, ATP-sensitive K+ channel blocker glibenclamide, and inwardly rectifying K+ channel blocker Ba2+ did not affect the vasodilatory effects of vildagliptin. However, application of the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine significantly reduced the vasodilatory effects of vildagliptin. In addition, application of either of two sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors, thapsigargin or cyclopiazonic acid, effectively inhibited the vasodilatory effects of vildagliptin. These vasodilatory effects were not affected by pretreatment with adenylyl cyclase, protein kinase A (PKA), guanylyl cyclase, or protein kinase G (PKG) inhibitors, or by removal of the endothelium. From these results, we concluded that vildagliptin induced vasodilation via activation of Kv channels and the SERCA pump. However, other K+ channels, PKA/PKG-related signaling cascades associated with vascular dilation, and the endothelium were not involved in vildagliptin-induced vasodilation.
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PMID:Vildagliptin, an Anti-diabetic Drug of the DPP-4 Inhibitor, Induces Vasodilation via Kv Channel and SERCA Pump Activation in Aortic Smooth Muscle. 3051 10