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Short-term therapy with rosiglitatzone, a PPAR-¿ agonist improves metabolic profile
and vascular function in non-obese lean wistar rats
Naderali, Mohammad M.; Itua, Imose; Abubakari, Abdul-Razak; Naderali, Ebrahim K.
Published in: ISRN Pharmacology Publication date: Document Version Publisher's PDF, also known as Version of record Citation for published version (APA): Naderali, M. M., Itua, I., Abubakari, A-R., & Naderali, E. K. (2012). Short-term therapy with rosiglitatzone, aPPAR-¿ agonist improves metabolic profile and vascular function in non-obese lean wistar rats. ISRN Pharmacology, 2012, [130347]. 10.5402/2012/130347 General rights
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Download date: 07. Oct. 2016 International Scholarly Research NetworkISRN PharmacologyVolume 2012, Article ID 130347, 7 pagesdoi:10.5402/2012/130347 Research Article
Short-Term Therapy with Rosiglitazone, a PPAR-γ Agonist,
Improves Metabolic Profile and Vascular Function in Nonobese
Lean Wistar Rats
Mohammad M. Naderali,1 Imose Itua,2 Abdul-Razak Abubakari,2 and Ebrahim K. Naderali2
1 Calderstones School, Harthill Road, Liverpool L18 3HS, UK2 Department of Health Sciences, Liverpool Hope University, Hope Park, Liverpool L16 9JD, UK Correspondence should be addressed to Ebrahim K. Naderali, [email protected] Received 19 May 2012; Accepted 21 June 2012 Academic Editors: H. Cerecetto, K. Lutfy, and F. G. M. Russel Copyright 2012 Mohammad M. Naderali et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.
A number of preclinical and clinical studies have reported blood-pressure-lowering benefits of thiazolidinediones in diabeticsubjects and animal models of diabetes. This study was designed to further elucidate vascular effects of rosiglitazone, on healthynonobese, lean animals. Adult male Wistar rats were randomized and assigned to control and rosiglitazone-treated groups andwere dosed daily with either vehicle or rosiglitazone (10 mg kg−1 day−1) by oral gavage for 5 days. Compared with control group,rosiglitazone treatment significantly reduced plasma levels of triglycerides (>240%) and nonesterified free fatty acids (>268%)(both, P < 0.001). There were no changes in vascular contractility to KCl or noradrenaline between two groups. However,rosiglitazone therapy improved carbamylcholine-induced vasorelaxation (93 ± 3% versus control 78 ± 2, P < 0.01) an effectwhich was abolished by L-NAME. There was no difference in sodium nitroprusside-induced vasorelaxation between the controland rosiglitazone-treated animals. These results indicate that short-term rosiglitazone therapy improves both metabolic profile andvascular function in lean rats. The vascular effect of rosiglitazone appears to be mediated by alteration in NO production possiblyby activation of endothelial PPARγ. This increased NO production together with improved lipid profile may explain mechanism(s)of blood-pressure-lowering effects of thiazolidinediones on both human and experimental animals.
include nitric oxide (NO) and endothelin, both of whichacting on the underlying vascular smooth muscle to mod- Metabolic syndrome (syndrome X), known as a cluster of ulate arterial contractility, is well understood. Impaired insulin resistance, abnormal glucose tolerance, abdominal endothelium-dependent vasorelaxation has been demon- obesity, dyslipidaemia, and arterial disease [1], is associated strated in obesity, type 2 diabetes, and hypertension [5– with substantially increased risk of cardiovascular disease 7] with the most striking abnormality being attenuation of resulting in increased morbidity and premature mortality.
Insulin resistance is thought to be the primary abnormality Thiazolidinediones (TZDs), such as pioglitazone and in syndrome X. The increased cardiovascular disorders seen rosiglitazone, are effective in the management of type in syndrome X are thought to be consequences of at least 2 diabetes mellitus. They bind to the nuclear peroxi- (a) alterations in direct effects of insulin on vascular smooth some proliferator-activated receptor-γ (PPAR-γ), and con- muscle proliferation [2], (b) indirect effects via activation sequential improvements in insulin resistance and glucose of the sympathetic nervous system [3], and (c) resistance to metabolism are principally attributed to decreased free vasodilator effects of insulin [4].
fatty acid concentrations [8, 9]. They improve metabolic The role of endothelium in the regulation of vascular abnormalities in animal models of insulin resistance and tone by producing various vasoactive mediators which type 2 diabetes [5, 10] and in human subjects with type ISRN Pharmacology 2 diabetes mellitus [11, 12]. A variety of studies have incubated in a 5 mL organ bath containing physiological salt suggested that thiazolidinediones may also have independent solution (PSS; composition [in mM]: NaCl 119, KCl 4.7, beneficial effects on the vasculature. These included lowering CaCl2 2.5, MgSO4 1.17, NaHCO3 25, KH2PO4 1.18, EDTA of blood pressure in fatty Zucker rats [13], genetically obese 0.026 and glucose 5.5) gassed with 95% O2 and 5% CO2 at diabetic rats [14], diet-induced hypertensive rats [15], and, Dahl salt-sensitive rats [16]. Moreover, TZDs have been After 30 min equilibration, the length-tension character- reported to reduce vascular adverse remodeling, and preserve istics for each vessel were determined as described previously intramyocardial vascularization in renovascular hypertensive [23]. The computer also calculated the target tension that rats (2K1C model) [17] as well as direct vasorelaxant effect each vessel should develop in response to a maximal and endothelial protective effects on arteries from obese stimulus. Arteries were then allowed a further 30 min to equi- Zucker rats [18, 19]. Similar studies in human subjects with librate before being depolarized twice with high-potassium type 2 diabetes mellitus have reported endothelial function physiological salt solution (KPSS, 125 mM), in which NaCl improvement [20, 21]. Therefore, it appears that TZDs have in normal PSS was replaced by an equimolar concentration a significantly positive effects on vascular function.
of KCl. Any vessel failing to reach its predetermined target On examination of the effects of the TZD on metabolic tension in response to vasoconstriction with KCl (125 mM) and/or cardiovascular function, a vast majority of the animal was discarded. Cumulative concentration-response curves to or human studies are performed on well-established disease either KCl (10–125 mM) or noradrenaline (NA, 0.5–6 μM) status. Thus, it is not possible to extrapolate if an early were then carried out.
intervention by TZD's would also have a significant effecton cardiovascular function in prediabetic status. Hence, this 2.3. Assessment of Endothelium-Dependent and -Independent study was designed to evaluate vascular effects of acute (5 Vascular Relaxation. Changes in endothelial-dependent and day) administration of rosiglitazone in chowfed male Wistar -independent vascular functions were assessed by observ- rats. In this study, resistance arteries were deployed to mea- ing any alterations invascular reactivity to carbamyl- sure vascular function, as these vessels represent endothelial choline (CCh), and sodium nirtoprusside (SNP) in NA- function throughout the vasculature and are believed to be preconstricted arteries. Arteries were contracted with a involved in determining the increase in peripheral resistance supramaximal concentration of NA (8 μM). When con- that leads to the development of hypertension [22].
traction reached a plateau after 2 minutes, concentration-response curves were carried out to either CCh or SNP 2. Material and Methods
(for both, 10 nM–100 μM). Vascular responses to CCh weremeasured in absence or presence of L-NAME (100 μM).
2.1. Animals. Adult (12-week-old) male Wistar rats (n = 20)were randomized and assigned to a control group (n = 2.4. Reagents. Noradrenaline, carbamylcholine, sodium 10, 300.2 ± 5.4 g) and a rosiglitazone-treated group (n = nitroprusside (SNP), N(G)-nitro-L-arginine methyl ester 10, 302.5 ± 4.9 g). All animals had free access to standard (L-NAME), rosiglitazone, and carboxymethyl cellulose were laboratory pelleted diet (CRM Biosure, Cambridge, UK) all obtained from Sigma Chemicals (UK). Noradrenaline, and water. They were housed in pairs under controlled CCh, SNP, and L-NAME were all dissolved in double distilled environmental conditions (19–22◦C; 30–40% humidity) and water. Both noradrenaline and SNP were kept away from a 12-hour light/dark cycle (lights on at 08:00 h). All animals light throughout the experiment. All water-soluble solutions were dosed at 08:00 daily for 5 days with either vehicle were freshly made on the day of the experiment.
(1% carboxymethyl cellulose at 3 mL kg−1 body weight) orrosiglitazone (10 mg kg−1 day−1) by oral gavage.
The rats were killed 2 hours after last dose by CO2 2.5. Data Interpretation and Statistical Analyses. Vasocon- inhalation. Blood was removed by cardiac puncture into striction in response to NA and KCl were expressed as abso- cold heparinized tubes and hematocrit levels were measured.
lute force generated. Vasorelaxation responses to CCh and The gonadal and perirenal fat pads and the gastrocnemius SNP were calculated as the percentage reduction from the muscle were dissected and weighed. Plasma was immediately maximal tension generated in response to the supramaximal separated by centrifugation before being frozen for later concentration of NA (8 μM). Data are expressed as mean measurements of nonesterified free fatty acids (NEFA) and ± S.E.M. Statistical significance was tested using repeated- triglycerides (TG), using commercially available diagnostic measures ANOVA or the Mann-Whitney test, as appropriate.
kits (Roche & Sigma Diagnostics, resp.).
Results were considered statistically significant at the P < 0.05levels.
2.2. Assessment of Vascular Function. Four third-ordermesenteric arteries (<250 μm diameter, 2 mm lengths) were 3. Results
carefully dissected from each animal. Each artery was freedof fat and connective tissue and mounted on two 40 μm 3.1. Body Weight and Metabolic Data. There were no signif- diameter stainless-steel wires in an automated myograph icant differences in body weight (P = 0.399), and perirenal (Cambustion, Cambridge, UK), based on the principle of fat pad mass (P = 0.239), and gastrocnemius muscle mass the Mulvany myograph. The vessels (in duplicate) were (P = 0.659) between two experimental groups (Table 1).
ISRN Pharmacology Table 1: Physiological and metabolic characteristics of the 2 improved vasorelaxation in arteries from rosiglitazone- experimental groups. Data are mean ± SEM.
treated animals was abolished in the presence of L-NAME(rosiglitazone-treated: 73 ± 2% versus control 77 ± 2 (Figure 2(b)).
300.2 ± 5.4 302.7 ± 4.9 3.5. Endothelium-Independent Relaxation. The shapes of 325.5 ± 5.6 339.9 ± 8.7 concentration response curves to SNP were almost identicalin both groups. Moreover, there were no significant differ- Gonadal fat-pad mass (g) 1.13 ± 0.06 1.47 ± 0.09a ences in maximum SNP-induced vasorelaxation between the Perirenal fat-pad mass (g) 1.12 ± 0.08 1.31 ± 0.12 two groups (rosiglitazone-treated: 88 ± 2% versus control 91 Gastrocnemius muscle mass (g) 1.86 ± 0.05 1.92 ± 0.06 ± 2% (Figure 3).
Fat/lean ratio∗ 1.23 ± 0.07 1.45 ± 0.08 Plasma triglycerides (mM) 1.34 ± 0.11 0.50 ± 0.04b 0.20 ± 0.01 0.08 ± 0.00b Total cholesterol 2.33 ± 0.10 2.40 ± 0.96 Rosiglitazone, a thiazolidinedione insulin-sensitizing agent 0.92 ± 0.08 1.01 ± 0.08 which acts by stimulating PPAR-γ, has been shown to 2.12 ± 0.20 2.66 ± 0.17 improve endothelial function in both human and animals 45.9 ± 0.2 41.8 ± 0.5b [20, 24, 25]. Despite reports of expression and function of PPARγ in rat and human vascular smooth muscle cells [26], Fat/Lean ratio = sum of white fat pad masses/gastrocnemius muscle mass; aP < 0.01, bP < 0.001 versus controls.
studies in human and rodents have failed to show a directvasorelaxant effect of rosiglitazone [27].
The beneficial vascular effects of rosiglitazone involve vasorelaxation but not vasocontraction mechanism(s). In However, compared with control groups, rosiglitazone- fact, it is reported that rosiglitazone had no effect on treated animals, had significantly higher gonadal fat pad contractile responses to NA, but markedly increased sensi- mass (P < 0.01), and lower hematocrit (P < 0.001) (Table 1).
tivity to Acetylcholine- (Ach-) induced vasorelaxation [28].
The increase in gonadal fat pad mass in turn translated to Interestingly similar effects of rosiglitazone were seen in this an increase in fat/lean ratio in rosiglitazone-treated animals, study, where five-day rosiglitazone treatment did not alter compared with their counterpart control group. However, contractile responses to NA or KCl, while it significantly this increase in fat/lean ratio was not statistically significant improved CCh-induced vasorelaxation indicating a role for from that of control group (P = 0.0830) (Table 1).
rosiglitazone in improving endothelial function which may Rosiglitazone significantly lowered plasma levels of involve upregulation of Akt/eNOS pathways [29].
triglycerides (>240%) and NEFA (>268%) (for both, P < Although rosiglitazone improved CCh-induced vasore- 0.001) than control animals; however, it had no effects on laxation, it failed to significantly affect SNP-induced vasore- plasma levels of total cholesterol, LDL, and HDL.
laxation suggesting that rosiglitazone does not influ-ence vasorelaxation via smooth muscle cyclic guanosine 3.2. Vascular Responses. There were no significant differences monophosphate (cGMP) pathway. Interestingly a recent in arterial diameter between two groups in this study.
study reported blunting of rosiglitazone effects in lower-ing blood pressure and vasorelaxation in animals lackingendothelial but not smooth muscle PPARγ (SM22Cre/flox 3.3. Contractile Responses. There were no significant dif- mice) [30], indicating that beneficial effects of rosiglitazone ferences in KCl-induced arterial contraction between the are mediated via activation of specific endothelial PPARγ two groups. KCl concentration-response curves in both receptors. Moreover, in streptozotocin- (STZ-) induced groups produced similar maximal contractile generated diabetic rats rosiglitazone significantly reversed blunting of forces (control: 7.29 ± 0.50 versus rosiglitazone-treated: 7.23 ACh-induced vasorelaxation [31], further highlighting role 0.38 mN). Similar outcome was also seen with NA- of PPARγ agonists in protecting endothelial function. Similar induced contractility. NA-induced contractile curves were effects have also been described on genetically modified similar between control and rosiglitazone-treated animals, mice where regulation of blood pressure and heart rate producing comparable maximal contractions between two under stressed conditions are consequence of activation groups (control: 13.99 ± 1.21 versus rosiglitazone-treated: of endothelial PPARγ receptors [32]. Furthermore, stress- 13.33 ± 0.89) (Figure 1).
induced (transplantation-induced) endothelial dysfunctionis completely restored by rosiglitazone [33] highlighting improvement of endothelial function by activation of PPARγ rosiglitazone-treated rats showed significant (P < 0.001) increase in vasorelaxation response to CCh compared In our study, the increased CCh-induced vasorelaxant with that of control animals (rosiglitazone-treated: 93 effect of rosiglitazone therapy was abolished in the presence ± 3% versus control 78 ± 2 (Figure 2(a)). However, this of L-NAME. This is in agreement with a previous study ISRN Pharmacology Figure 1: The effects of (a) KCl (10–125 mM) and (b) noradrenaline (NA; 0.5–6 μM) on arteries from 5-day rosiglitazone-treated anduntreated control animals. There were no significant differences between the two groups. Data represent mean ± S.E.M.
Figure 2: Relaxation curves for carbamylcholine (CCh) on arteries from 5-day rosiglitazone-treated and untreated control animals in (a)absence or (b) presence of L-NAME. Arteries were first precontracted with NA (8 μM). When contraction reached a plateau after 2 minutes,concentration-response curves to CCh were carried out in the presence or absence of L-NAME (100 μM). Data represent mean ± S.E.M. Theconcentration-response curves between untreated controls and rosiglitazone-treated animals differ significantly (by ANOVA, ∗P < 0.01) inthe absence of L-NAME but not in the presence of L-NAME.
where presence of L-NAME blocked ACh-induced relax- by pioglitazone [35] and rosiglitazone [36], leading to ation in pioglitazone-treated STZ-diabetic rats [34]. Taken together, these data suggest that PPARγ activation improves Rosiglitazone treatment had no effects on total body endothelial function, thereby facilitating production and/or weight and gastrocnemius muscle mass. Measurements of release of nitric oxide (NO) vasorelaxant. Although we did fat pad masses indicated an increase in gonadal but not not measure NO levels in this study, others have shown in perirenal fat pad mass suggesting selective changes in an increased basal nitric oxide release in TZD-treated STZ- adiposity in response to rosiglitazone therapy. The impor- diabetic rats suggesting inhibition of NO breakdown and/or tance of this selective increase in fat pad remains to be increase of basal and agonist-stimulated production of NO elucidated. However, in agreement with previous reports ISRN Pharmacology In summary, short-term rosiglitazone therapy improves both metabolic profile and vascular function in lean nondia-betic rats. The beneficial effect of rosiglitazone on vascular reactivity is mediated by activation of endothelial PPARγreceptors leading to increased NO synthesis and production.
This increased NO production may, at least in part, explainmechanism(s) of blood-pressure-lowering effects of thiazo-lidinediones on both human and animals models. Moreover, improved vasorelaxant effect seen by rosiglitazone therapyin this study appears to be a class effect shared with other Conflict of Interests
The authors have declared that there is no conflict of Figure 3: Relaxation curves for sodium nitroprusside (SNP)on arteries from 5-day rosiglitazone-treated and untreated con- The authors wish to express their gratitude to Miss. Mahdieh trol animals. NA (8 μM)-precontracted arteries were subjected Naderali for her editorial assistance in preparing this paper.
to increasing concentration of SNP. There were no significantdifferences between the two groups. Data represent mean ± S.E.
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