LY83583 is a membrane-permeable soluble guanylate cyclase (sGC) inhibitor. LY83583 reduces cGMP production and interferes with NO/cGMP signaling. LY83583 generates superoxide and inhibits leukotriene synthesis and neutrophil chemotaxis. LY83583 can be used in research on cardiovascular diseases, platelet activation, vascular smooth muscle dysfunction and inflammation[1-4].
In vitro, 100µM LY83583 and 100mM DMPO were used to stimulate HUVEC cells for 10 minutes to 24 hours. LY83583 generated DMPO/OH adduct signals and induced reactive oxygen species production in HUVEC cells[5]. 786-0 cells were treated with 0.03-1µM LY83583 for 24-96 hours. LY83583 reduced cell number and induced apoptosis in a time- and dose-dependent manner, caused MEK1/2 and ERK1/2 dephosphorylation, decreased Elk-1 phosphorylation and downregulated COX-2, increased ROS formation, decreased Bcl-xL and increased Bax, and promoted cytochrome c release, procaspase-3 processing and AIF translocation into the nucleus[6]. HN33 cells were pretreated with 1µM LY83583 for 1 hour and then treated with 50µM hemin for 24 hours. LY83583 attenuated hemin-induced neuroglobin protein and mRNA expression[7].
In vivo, Wistar rats received a single intravenous injection of 4.0-40.0μmol/kg LY83583. LY83583 did not affect resting diastolic blood pressure, nor did it affect the pressor response induced by 3.13nmol/kg norepinephrine or the pressor response induced by spinal sympathetic nerve stimulation[8]. Sprague-Dawley rats received a single intracerebroventricular injection of 1μg-100μg LY83583. LY83583 increased non-rapid eye movement sleep slow-wave activity, promoted non-rapid eye movement sleep during the light phase and suppressed rapid eye movement sleep[9]. Long Evans rats received an intravenous bolus of 1mg/kg LY83583 followed by infusion of 3mg/kg·hr LY83583 for 2 hours. LY83583 reduced plasma cGMP concentration[10].
References:
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[2] Shi R, Gao S, Smith AH, et al. Superoxide-induced Type I Collagen Secretion Depends on Prolyl 4-Hydroxylases. Biochem Biophys Res Commun. 2020 Sep 3;529(4):1011-7.
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[4] Kajimura M, Michel CC. Flow modulates the transport of K+ through the walls of single perfused mesenteric venules in anaesthetised rats. J Physiol. 1999 Dec 1;521(3):665-77.
[5] Horinouchi Y, Tsuchiya K, Taoka C, et al. Antioxidant effects of photodegradation product of nifedipine. Chem Pharm Bull. 2011 Feb;59(2):208-214.
[6] Ambrose M, Ryan A, O'Sullivan GC, et al. Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38δ/γ, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor. Mol Pharmacol. 2006 Jun;69(6):1879-90.
[7] Zhu Y, Sun Y, Jin K, et al. Hemin induces neuroglobin expression in neural cells. Blood. 2002 Oct 1;100(7):2494-8.
[8] Abdullah K, Cawley T, Connolly C, et al. Comparison of the effects of nitric oxide synthase inhibition and guanylate cyclase inhibition on vascular contraction in vitro and in vivo in the rat. Naunyn Schmiedebergs Arch Pharmacol. 1997;356(4):481-7.
[9] Ribeiro AC, Kapás L. The effects of intracerebroventricular application of 8-Br-cGMP and LY-83,583, a guanylyl cyclase inhibitor, on sleep-wake activity in rats. Brain Res. 2005 Jun 7;1049(1-2):25-33.
[10] Brandt MA, Conrad KP. In vivo and in vitro studies of a putative inhibitor of cyclic guanosine 3',5'-monophosphate production. Proc Soc Exp Biol Med. 1991;196(1):30-34.