title: Combined oral contraceptive and nitric oxide synthesis inhibition synergistically causes cardiac hypertrophy and exacerbates insulin resistance in female rats.
abstract: Combined oral contraceptive (COC) use or inhibition of nitric oxide (NO) synthesis has been shown to cause hypertension and insulin resistance. However, the concomitant effects of COC and NO deficiency on the heart and glucose regulation are not well known. We therefore hypothesized that COC treatment during NO deficiency would lead to the development of cardiac hypertrophy that is associated with aggravated glucose deregulation, pro-inflammatory and pro-fibrotic biomarkers. Eight-week-old female Wistar rats were randomly allotted into control, NO deficient (NG-nitro-l-arginine methyl ester: L-NAME; 20.0mg/kg b.w.), COC-treated (1.0μg ethinylestradiol+5.0μg levonorgestrel, p.o) and L-NAME+COC-treated groups. The animals were treated daily for 6 weeks. Systolic blood pressure was estimated by tail-cuff plethysmography, insulin resistance (IR) and β-cell function were estimated by homeostatic model of assessment (HOMA-IR and HOMA-β). Pro-inflammatory (C-reactive protein; CRP and uric acid) and pro-fibrotic (plasminogen activator inhibitor-1; PAI-1) biomarkers were estimated in the plasma. Cardiac histological examination was also done. Results show that COC or L-NAME treatments led to increased blood pressure, HOMA-IR, impaired β-cell function, PAI-1, CRP and uric acid, without significant effect on cardiac mass. L-NAME+COC-treated group had significantly higher blood pressure, HOMA-IR, impaired β-cell function, PAI-1, CRP and cardiac mass than COC- or L-NAME-treated groups. Histological examination validated that COC use during NO deficiency causes cardiac hypertrophy. The present study demonstrates that COC treatment and NO deficiency synergistically causes cardiac hypertrophy that is associated with aggravated glucose deregulation, atherogenic dyslipidemia, pro-inflammatory and pro-fibrotic markers.
authors.affiliation: Cardiovascular Research Laboratory, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria. Electronic address: tunjilaw@unilorin.edu.ng.
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Olatunji
authors.affiliation: Cardiovascular Research Laboratory, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.
authors.forename: Kehinde S
authors.initials: KS
authors.lastname: Olaniyi
authors.affiliation: Cardiovascular Research Laboratory, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria; Cardiovascular Unit, Department of Physiology, College of Health Sciences, Osun State University, Osogbo, Nigeria.
authors.forename: Taofeek O
authors.initials: TO
authors.lastname: Usman
authors.affiliation: Cardiovascular Research Laboratory, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.
authors.forename: Bilikis A
authors.initials: BA
authors.lastname: Abolarinwa
authors.affiliation: Cardiovascular Research Laboratory, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria.
authors.forename: Caleb J
authors.initials: CJ
authors.lastname: Achile
authors.affiliation: Department of Pharmacology & Cardiovascular Research Institute, Kyungpook National University School of Medicine, Daegu 700-842, Republic of Korea.
authors.forename: In-Kyeom
authors.initials: IK
authors.lastname: Kim
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002097:C-Reactive Protein / Q000032:analysis; D006332:Cardiomegaly / Q000097:blood / Q000139:chemically induced*; D003277:Contraceptives, Oral, Combined / Q000494:pharmacology*; D004958:Estradiol / Q000097:blood; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D005260:Female; D007333:Insulin Resistance; D016912:Levonorgestrel / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000172:deficiency*; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D017208:Rats, Wistar; D014527:Uric Acid / Q000097:blood
chemical_list: D003277:Contraceptives, Oral, Combined; D017395:Plasminogen Activator Inhibitor 1; D014527:Uric Acid; D009569:Nitric Oxide; D004997:Ethinyl Estradiol; D004958:Estradiol; D016912:Levonorgestrel; D002097:C-Reactive Protein; D019331:NG-Nitroarginine Methyl Ester
keywords: Cardiac hypertrophy; Inflammation; Nitric oxide; Oral contraceptive; Profibrotic biomarker