Lawrence A. Olatunji

GPER-1 agonist G1 induces vasorelaxation through activation of epidermal growth factor receptor-dependent signalling pathway.

The G protein‐coupled oestrogen receptor‐1 (GPER‐1) agonist G1 induces endothelium‐dependent relaxation. Activation of the epidermal growth factor (EGF) receptor leads to transduction of signals from the plasma membrane for the release of nitric oxide. We tested the hypothesis that G1 induces endothelium‐dependent vasorelaxation through activation of the EGF receptor.

Combined estrogen–progestogen but not progestogen-only oral contraceptive alters glucose tolerance and plasma lipid profile in female rats

Women are exposed to sex steroids in several formulations such as oral contraceptives (OCs) and hormone replacement therapies. Estrogen is believed to have cardiometabolic protection effect; but its beneficial effects have recently been queried. The aim of the present study was to clarify whether or not the altered glucose tolerance and plasma lipid profile was associated with OC and due to the estrogenic or progestogenic-component and if that was dose-dependent in 7-8 weeks old female rats. Rats were divided into vehicle-treated (control), high dose combined OC-treated (HCOC; receiving 1.5μg ethinyl estradiol/15.0μg norgestrel), low dose combined OC-treated (LCOC; receiving 0.15μg ethinyl estradiol/1.5μg norgestrel), high dose progestogen OC-treated (HOC; receiving 35.0μg levonorgestrel) and low dose progestogen OC-treated (LOC; receiving 3.5μg levonorgestrel) groups. Rats were given (p.o.) vehicle (distilled water), HCOC, LCOC, HOC and LOC daily for 6 weeks. When compared with the controls, HCOC treatment led to significant decreases in glucose tolerance and plasma high-density lipoprotein-cholesterol. However, HCOC-treated and LCOC-treated groups had significantly higher plasma triglyceride levels when compared with the control group. Fasting blood glucose, plasma total cholesterol, and low-density lipoprotein-cholesterol were comparable among groups. Body weight gain appeared to be attenuated by OC treatments, particularly in LOC-treated rats. In conclusion, our findings demonstrate that combined estrogen-progestogen but not progestogen-only OC use resulted in impaired glucose tolerance that was associated with increased triglyceride and decreased high-density lipoprotein-cholesterol. The effects on glucose tolerance and high-density lipoprotein-cholesterol were dose-dependent while that on triglyceride was not.

Anti-inflammatory and antithrombotic effects of nicotine exposure in oral contraceptive-induced insulin resistance are glucocorticoid-independent

BACKGROUNDnReports showed that estrogen-progestin oral contraceptive (COC) or tobacco smoking causes increased risk of cardiovascular diseases (CVD) in premenopausal women. Studies also suggest that nicotine, a major tobacco alkaloid, may worsen or improve atherothrombotic CVD. Altered hemorheology, prothrombotic and pro-inflammatory biomarkers, have been implicated in the development of atherothrombotic CVD events. However, the effect of non-smoking nicotine exposure on these biomarkers during COC treatment is not yet established. We therefore sought to determine the effects of nicotine exposure during COC treatment on these biomarkers, and also tested the hypothesis that the nicotine effects would be glucocorticoid-dependent.nnnMETHODSnFemale Sprague-Dawley rats aged 10 weeks were given (po) vehicle, low-dose nicotine (0.1 mg/kg) or high-dose nicotine (1.0 mg/kg) with or without COC steroids (5.0 μg/kg ethinylestradiol and 25.0 μg/kg levonorgestrel) daily for 6 weeks.nnnRESULTSnCOC treatment or nicotine exposure led to increased insulin resistance (IR), hemorheological (blood viscosity, hematocrit and plasma viscosity), prothrombotic (plasminogen activator inhibitor-1), pro-inflammatory (uric acid, C-reactive protein, neutrophil/lymphocyte and platelet/lymphocyte ratios) biomarkers and corticosterone. However, these effects except that on corticosterone were abrogated by nicotine exposure during COC treatment.nnnCONCLUSIONSnOur study indicates that nicotine- or COC-induced IR may be mediated via inflammatory/thrombotic pathway. The results imply that nicotine exposure could impact negatively on atherothrombotic biomarkers in COC non-users, whereas the impact in COC users could be positive. The results also suggest that the anti-inflammatory, antithrombotic and blood viscosity-lowering effects of nicotine exposure during COC use is circulating glucocorticoid-independent.BACKGROUNDnReports showed that estrogen-progestin oral contraceptive (COC) or tobacco smoking causes increased risk of cardiovascular diseases (CVD) in premenopausal women. Studies also suggest that nicotine, a major tobacco alkaloid, may worsen or improve atherothrombotic CVD. Altered hemorheology, prothrombotic and pro-inflammatory biomarkers, have been implicated in the development of atherothrombotic CVD events. However, the effect of non-smoking nicotine exposure on these biomarkers during COC treatment is not yet established. We therefore sought to determine the effects of nicotine exposure during COC treatment on these biomarkers, and also tested the hypothesis that the nicotine effects would be glucocorticoid-dependent.nnnMETHODSnFemale Sprague-Dawley rats aged 10 weeks were given (po) vehicle, low-dose nicotine (0.1mg/kg) or high-dose nicotine (1.0mg/kg) with or without COC steroids (5.0μg/kg ethinylestradiol and 25.0μg/kg levonorgestrel) daily for 6 weeks.nnnRESULTSnCOC treatment or nicotine exposure led to increased insulin resistance (IR), hemorheological (blood viscosity, hematocrit and plasma viscosity), prothrombotic (plasminogen activator inhibitor-1), pro-inflammatory (uric acid, C-reactive protein, neutrophil/lymphocyte and platelet/lymphocyte ratios) biomarkers and corticosterone. However, these effects except that on corticosterone were abrogated by nicotine exposure during COC treatment.nnnCONCLUSIONSnOur study indicates that nicotine- or COC-induced IR may be mediated via inflammatory/thrombotic pathway. The results imply that nicotine exposure could impact negatively on atherothrombotic biomarkers in COC non-users, whereas the impact in COC users could be positive. The results also suggest that the anti-inflammatory, antithrombotic and blood viscosity-lowering effects of nicotine exposure during COC use is circulating glucocorticoid-independent.

High-calcium diet reduces blood pressure, blood volume and preserves vasorelaxation in oral contraceptive-treated female rats.

Cardiovascular complications are the major clinical challenges among users of synthetic steroids in oral contraceptive (OC) formulations. Interventions that reduce blood volume and improve vasorelaxation have been shown to reduce hypertension and the associated risk factors. The aim of the present study was to investigate the influence of increasing dietary calcium from 0.9 to 3.0% on the development of OC-induced high blood pressure and associated changes in female Sprague-Dawley rats treated with a combination of OC steroids (1 microg ethinyl estradiol and 10 microg norgestrel; p.o.) daily for 10 weeks. Results showed that OC administration led to significant increases in blood pressure, blood volume and cardiac weight. Conversely, OC caused significant reductions in body weight, urinary excretion of water, plasma levels of calcium, 17beta-estradiol and progesterone. Increased dietary calcium attenuated the elevation in blood pressure induced by OC and abrogated the associated changes in blood volume, cardiac weight, plasma calcium and urinary excretion of water. The endothelium-dependent relaxation responses to acetylcholine and endothelium-independent relaxation responses to sodium nitroprusside in noradrenaline-precontracted aortic rings were not significantly different among the groups. The results indicate that increased calcium intake abrogated the development of high blood pressure and associated increased blood volume and cardiac weight during OC treatment. The beneficial effect of increased dietary calcium during OC use may be explained by improved diuretic and preserved vasorelaxant responses.

Combined oral contraceptive and nitric oxide synthesis inhibition synergistically causes cardiac hypertrophy and exacerbates insulin resistance in female rats

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.

Nicotine exposure suppresses hyperinsulinemia and improves endothelial dysfunction mediators independent of corticosteroids in insulin-resistant oral contraceptive-treated female rats

Abstract Estrogen-progestin oral contraceptives (COC) or tobacco smoking has been associated with hypertension and endothelial dysfunction resulting in increased risk of cardiovascular diseases (CVD). Contrasting effects of nicotine exposure on endothelial function have been reported. The effect of non-smoking nicotine exposure on endothelial dysfunction during COC treatment remains to be fully elucidated. We therefore, sought to determine the effects of nicotine exposure during COC treatment on endothelial dysfunction mediators and circulating corticosteroids. Female Wistar rats aged 10u2009weeks were given (po) vehicle, nicotine (1.0u2009mg/kg) with or without COC steroids (1.0u2009µg ethinylestradiol and 5.0u2009µg levonorgestrel) daily for 6u2009weeks. Nicotine exposure caused 113.3% increase in insulinemia whereas COC treatment led to 76.9% increased insulinemia compared with control. Furthermore, COC treatment or nicotine exposure led to glucose deregulation, insulin resistance, reduced nitric oxide bioavailability, elevated plasminogen activator inhibitor-1, uric acid, oxidative stress, atherogenic dyslipidemia, and corticosteroids. However, COCu2009+u2009NIC treatment led to 41.2% decrease in insulemina compared with COC-treated rats. Furthermore, all other alterations were alleviated by nicotine exposure in COC-treated female rats with the exception of corticosteroids.

Low-dose spironolactone ameliorates insulin resistance and suppresses elevated plasminogen activator inhibitor-1 during gestational testosterone exposure

Abstract Context: Elevated gestational circulating testosterone has been associated with pathological pregnancies that increase the risk of development of cardiometabolic disorder in later life. Objective: We hypothesised that gestational testosterone exposure, in late pregnancy, causes glucose deregulation and atherogenic dyslipidaemia that would be accompanied by high plasminogen activator inhibitor-1 (PAI-1). The study also hypothesise that low-dose spironolactone treatment would ameliorate these effects. Methods: Pregnant Wistar rats received vehicle, testosterone (0.5u2009mg/kg; sc), spironolactone (0.5u2009mg/kg, po) or testosterone and spironolactone daily between gestational days 15 and 19. Results: Gestational testosterone exposure led to increased HOMA-IR, circulating insulin, testosterone, 1-h post-load glucose, atherogenic dyslipidaemia, PLR, PAI-1 and MDA. However, all these effects, except that of circulating testosterone, were ameliorated by spironolactone. Conclusions: These results demonstrate that low-dose spironolactone ameliorates glucose deregulation and atherogenic dyslipidaemia during elevated gestational testosterone exposure, at least in part, by suppressing elevated PAI-1.

Sodium acetate improves disrupted glucoregulation and hepatic triglyceride content in insulin-resistant female rats: involvement of adenosine deaminase and dipeptidyl peptidase-4 activities

Combined oral contraceptive (COC) treatment has been shown to be associated with glucose deregulation and increased triglyceride levels, but the mechanisms are elusive. Soluble dipeptidyl peptidase-4 (sDPP-4) and adenosine deaminase (ADA) are involved in the initiation and/or progression of cardiometabolic disorders. We therefore, hypothesized that increased DPP-4 and ADA activities are involved in glucose deregulation and hepatic triglyceride accumulation induced by COC treatment. This study also investigated whether short-chain fatty acid, acetate, would protect against COC-induced dysmetabolic effects. Female Wistar rats received (p.o.) vehicle and COC (1.0xa0μg ethinylestradiol plus 5.0xa0μg levonorgestrel) with or without sodium acetate (ACE; 200xa0mg) for 8xa0weeks. Treatment with COC led to increased plasma triglyceride-glucose index, 1-h postload glucose response, insulin, free fatty acid, insulin resistance, and impaired glucose tolerance. COC treatment also resulted in increased plasma and hepatic triglycerides (TG), TG/HDL-cholesterol ratio, malondialdehyde, uric acid, lactate dehydrogenase, DPP-4, ADA, and xanthine oxidase (XO) activities. On the other hand, COC led to reduction in nitric oxide level. However, ACE significantly ameliorated the alterations induced by COC treatment, but XO activity remains elevated during COC treatment. This result also demonstrates that increased DPP-4 and ADA activities are at least in part involved in glucose deregulation and hepatic TG accumulation induced by COC treatment. Therefore, sodium acetate would impact positively on cardiometabolic disorders, at least in part, by inhibition of DPP-4 and ADA activities.

Gestational glucocorticoid exposure disrupts glucose homeostasis that is accompanied by increased endoglin and DPP-4 activity instead of GSK-3 in rats

Gestational glucocorticoid (GC) treatment has been associated with cardiometabolic disorder (CMD) in offsprings in later life. Elevated dipeptidyl peptidase-4 (DPP-4) activity, endoglin and glycogen synthase kinase-3 (GSK-3) has also been implicated in the development of insulin resistance (IR) and/or vascular inflammation. We aimed to investigate the impact of GC exposure on glucose metabolism and the circulating levels of inflammatory biomarkers, DPP-4 activity and GSK-3 in pregnant rats. Pregnant Wistar rats received either vehicle or dexamethasone (DEX; 0.2u202fmg/kg; po) between gestational days 14 and 19. Gestational GC exposure resulted in impaired glucose homeostasis that is accompanied with elevated circulating levels of inflammatory biomarkers (endoglin, uric acid, and platelet/lymphocyte ratio), oxidative stress (malondialdehyde), blood viscosity, reduced NO level and increased DPP-4 activity. However, these effects were associated with atherogenic dyslipidemia and reduced GSK-3.We conclude that plasma endoglin, a marker of vascular inflammation, and plasma DPP-4 activity are increased in pregnant rats treated with GC during late gestation. Therefore, glucose deregulation associated with gestational GC exposure is through endoglin-/DPP-4-dependent but GSK-3-independent pathway.

Neck circumference is independently associated with relative systemic hypertension in young adults with sickle cell anaemia

BackgroundA seemingly interesting observation in patients with sickle cell anaemia (SCA) is that they usually have lower systemic blood pressures (BP) and insulin resistance than persons in the general population in spite of chronic inflammation and vasculopathy. However, relative systemic hypertension (rHTN) has been linked to pulmonary hypertension, increased blood viscosity and renal insufficiency, which could indicate a risk of developing cardiometabolic disorder (CMD) in SCA.We therefore hypothesized that neck circumference (NC) and CMD marker; triglyceride glucose (TyG) index would independently predict rHTN in young adults with SCA in steady state.MethodsWe compared the anthropometrical, hematological, hemorheological and CMD markers between SCA patients with normal BPu2009<u2009120/70xa0mmHg; nHTN, nu2009=u200965) and those with rHTN (BPu2009≥u2009120/70xa0mmHg, nu2009=u200932).ResultsOur results showed that SCA with rHTN had significantly higher body weight, waist circumference, NC, plasma viscosity, systolic and diastolic BP. Results also indicated that NC (OR: 2.98; 95% CI 1.46 to 6.10, pu2009<u20090.01) was a predictor of rHTN in SCA independent of gender, age, weight, waist circumference, BMI, blood viscosity, triglyceride or TyG. A receiver operating characteristic curve analysis also showed that NC was the most efficient predictor of rHTN than other CMD markers.ConclusionThe present study demonstrates that increased NC is a salient risk factors that is independently associated with rHTN in SCA. The finding therefore underscores the utility of NC in early detection and stratification of systemic hypertension, particularly in individuals with SCA.