title: KMUP-1 inhibits hypertension-induced left ventricular hypertrophy through regulation of nitric oxide synthases, ERK1/2, and calcineurin.
abstract: Hypertension can induce left ventricular hypertrophy (LVH), and the nitric oxide (NO) pathway plays an important role in the pathogenesis of cardiac hypertrophy. This study aimed to examine whether KMUP-1, a novel xanthine-based derivative, could inhibit LVH in spontaneously hypertensive rats (SHRs) and to investigate potential mechanisms underlying its antihypertrophic effects. Two groups of animals with chronic or subacute LVH were treated. In the chronic LVH group, KMUP-1 (10 or 30 mg/kg/d orally) was administered for 28 days to both normotensive rats and SHRs. In the subacute LVH group, KMUP-1 (0.5 mg/kg/d intraperitoneally) or sildenafil (0.7 mg/kg/d intraperitoneally) was administered for 10 days with or without co-treatment with the nitric oxide synthase (NOS) inhibitor N-omega-nitro-l-arginine (L-NNA; 20 mg/L orally). After treatment, the effects of KMUP-1 or sildenafil on hypertension, cardiac hypertrophy, survival, expression of the NO/soluble guanylate cyclase (sGC)/protein kinase G (NO/sGC/PKG) pathway in the aorta andleft ventricle, and calcineurin A/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in the left ventricle were examined. In the chronic LVH group, the SHRs developed hypertension with LVH over the 28 days. KMUP-1 attenuated the hypertension and LVH, increased survival rate, enhanced endothelial NOS/cyclic guanosine monophosphate/PKG (eNOS/cGMP/PKG) and decreased inducible NOS (iNOS) expression in the aorta and left ventricle of the SHRs. In the subacute LVH group, both KMUP-1 and sildenafil administered for 10 days attenuated the LVH in SHRs, with enhanced eNOS/cGMP/PKG and suppressed iNOS/calcineurin A/ERK1/2 expression in the left ventricle. In addition, both KMUP-1 and sildenafil attenuated L-NNA-induced LVH. KMUP-1 inhibition of hypertension-induced LVH with associated upregulation of eNOS, downregulation of iNOS in both the aorta and left ventricle, and attenuation of calcineurin A and ERK1/2 signaling in the left ventricle.
authors.affiliation: Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
authors.forename: Chung-Pin
authors.initials: CP
authors.lastname: Liu
authors.forename: Jong-Hau
authors.initials: JH
authors.lastname: Hsu
authors.forename: Ching-Jiunn
authors.initials: CJ
authors.lastname: Tseng
authors.forename: Ping-Ju
authors.initials: PJ
authors.lastname: Wu
authors.forename: Yi-Ya
authors.initials: YY
authors.lastname: Wang
authors.forename: Jiunn-Ren
authors.initials: JR
authors.lastname: Wu
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D010880:Piperidines; D014970:Xanthines; C439304:KMUP 1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019703:Calcineurin