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Pathway Description
Isosorbide Mononitrate Action Pathway
Homo sapiens
Drug Action Pathway
Isosorbide mononitrate is an organic nitrate and an antianginal drug used to treat Angina Pectoris through vasodilation. It is an active metabolite of isosorbide dinitrate. As a organic nitrate, it is a prodrug for nitric oxide, which is a gas that is a potent vasodilator. Isosorbide works on arteries and veins, but predominately acts on veins to reduce cardiac preload. It has a longer duration of action compared to nitroglycerin.
Isosorbide mononitrate enters the smooth muscle cell or myocyte through an unknown transporter. It is then metabolized in the cytosol into nitric oxide by P450 enzymes, xanthine oxidoreductase (XO), glutathione-S-transferase (GST), or cytosolic aldehyde dehydrogenase isoforms. Nitric oxide activates Guanylate cyclase which catalyzes GTP into cGMP. cGMP activates cGMP-dependent protein kinase. Activated protein kinase has many interactions within the myocyte. Protein kinase activates potassium channels which causes potassium to leave the myocyte. This causes hyperpolarization in the cell. This prevents the voltage-gated calcium channels from opening and allowing calcium into the cell. This is also prevented by protein kinase inhibiting the voltage-gated calcium channels. This along with the activation of calcium pumps out of the cell and into the sarcoplasmic reticulum causes the cytosolic concentration of calcium to be very low. Low concentrations of calcium cannot bind to calmodulin which means calmodulin cannot activate myosin light chain kinase. With myosin light chain kinase unable to activate, myosin light chain cannot be phosphorylated which means that it is dephosphorylated by myosin light chain phosphatase. The accumulation of myosin light chain causes myosin to unbind from actin and the muscle to relax. The relaxation of smooth muscles around blood vessels causes vasodilation. This leads to the effects of decreased cardiac oxygen consumption, redistribution coronary flow toward ischemic areas via collaterals, and the relief of coronary spasms.
References
Isosorbide Mononitrate Pathway References
Munzel T, Steven S, Daiber A: Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction. Vascul Pharmacol. 2014 Dec;63(3):105-13. doi: 10.1016/j.vph.2014.09.002. Epub 2014 Oct 14.
Kenkare SR, Benet LZ: Tolerance to nitroglycerin in rabbit aorta. Investigating the involvement of the mu isozyme of glutathione S-transferases. Biochem Pharmacol. 1996 May 17;51(10):1357-63. doi: 10.1016/0006-2952(96)00058-5
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
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