Marcos A. Mayer

Chronic infusion of angiotensin-(1–7) improves insulin resistance and hypertension induced by a high-fructose diet in rats

The current study was undertaken to determine whether Ang-(1-7) is effective in improving metabolic parameters in fructose-fed rats (FFR), a model of metabolic syndrome. Six-week-old male Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of either diet, control and FFR were implanted with subcutaneous osmotic pumps that delivered Ang-(1-7) (100 ng.kg(-1).min(-1)). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We measured systolic blood pressure (SBP) together with plasma levels of insulin, triglycerides, and glucose. A glucose tolerance test (GTT) was performed, with plasma insulin levels determined before and 15 and 120 min after glucose administration. In addition, we evaluated insulin signaling through the IR/IRS-1/PI3K/Akt pathway as well as the phosphorylation levels of IRS-1 at inhibitory site Ser(307) in skeletal muscle and adipose tissue. FFR displayed hypertriglyceridemia, hyperinsulinemia, increased SBP, and an exaggerated release of insulin during a GTT, together with decreased activation of insulin signaling through the IR/IRS-1/PI3K/Akt pathway in skeletal muscle, liver, and adipose tissue, as well as increased levels of IRS-1 phospho-Ser(307) in skeletal muscle and adipose tissue, alterations that correlated with increased activation of the kinases mTOR and JNK. Chronic Ang-(1-7) treatment resulted in normalization of all alterations. These results show that Ang-(1-7) ameliorates insulin resistance in a model of metabolic syndrome via a mechanism that could involve the modulation of insulin signaling.

Recent advances in obesity pharmacotherapy.

Obesity is considered a worldwide epidemic. Weight reduction by means of lifestyle changes is difficult to achieve, and pharmacotherapy is frequently needed. Although all currently approved anti-obesity agents have proven to be effective to achieve some degree of weight reduction and improve cardiometabolic risk factors, different compounds differ in their mechanism of action and safety profile. However, it is still difficult to achieve and maintain therapeutic objectives along time. The aim of the present article is to summarize the main characteristics of available anti-obesity agents and to explore novel agents that may provide significant clinical benefits in the future.

Angiotensin-(1-7) improves cardiac remodeling and inhibits growth-promoting pathways in the heart of fructose-fed rats.

The present study examined whether chronic treatment with angiotensin (ANG)-(1-7) reduces cardiac remodeling and inhibits growth-promoting signaling pathways in the heart of fructose-fed rats (FFR), an animal model of insulin resistance. Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of the corresponding diet, control and FFR were implanted with osmotic pumps that delivered ANG-(1-7) (100 ng.kg(-1).min(-1)). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We determined heart weight, myocyte diameter, interstitial fibrosis, and perivascular collagen type III deposition as well as the phosphorylation degree of ERK1/2, JNK1/2, and p38MAPK. FFR showed a mild hypertension that was significantly reduced after ANG-(1-7) treatment. Also, FFR displayed higher ANG II circulating and local levels in the heart that remained unaltered after chronic ANG-(1-7) infusion. An increased heart-to-body weight ratio, myocyte diameter, as well as left ventricular fibrosis and perivascular collagen type III deposition were detected in the heart of FFR. Interestingly, significant improvements in these cardiac alterations were obtained after ANG-(1-7) treatment. Finally, FFR that received ANG-(1-7) chronically displayed significantly lower phosphorylation levels of ERK1/2, JNK1/2, and p38MAPK. The beneficial effects obtained by ANG-(1-7) were associated with normal values of Src-homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) activity in the heart. In conclusion, chronic ANG-(1-7) treatment ameliorated cardiac hypertrophy and fibrosis and attenuated the growth-promoting pathways in the heart. These findings show an important protective role of ANG-(1-7) in the heart of insulin-resistant rats.

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

The I kappaB kinase-beta (IKK-beta)/nuclear factor-kappaB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3beta. This was accompanied by a decrease in phosphorylation of IR on serine (Ser) 994, a residue that seems to be implicated in the regulation of IR kinase in OZR. In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. TBK1 was found to co-immunoprecipitate with the IR, in the liver of OZR supporting an in vivo association between the IR and TBK1. Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes.

Cardiovascular Drugs Inducing QT Prolongation: Facts and Evidence

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

In Vitro and In Vivo Pharmacodynamic Properties of Metoprolol in Fructose-fed Hypertensive Rats

This study of metoprolol pharmacokinetic and pharmacodynamic properties investigates cardiac β1-adrenoceptors activity and its involvement in the hypertensive stage in 6-week-old fructose-fed male Sprague-Dawley rats. Methods: A microdialysis probe was inserted in the carotid artery to monitor metoprolol levels, blood pressure, and heart rate after drug administration (3-10 mg/kg intravenously). The relationship between levels and cardiovascular effects was studied using a pharmacokinetic-pharmacodynamic model with effect compartment. Dissociation constant and inverse agonism were evaluated in isolated atria. Results: Metoprolol pharmacokinetics were similar in both groups. Metoprolol induced a greater hypotensive effect in fructose-fed animals (Emax: −24 ± 1 mm Hg, n = 6, P < 0.05 vs. control) than in control rats (Emax: −14 ± 1 mm Hg, n = 6). Bradycardic response was similar in both groups; metoprolol chronotropic potency was greater in fructose-fed rats (IC50: 123 ± 15 ng/mL, P < 0.05 vs. control) compared to control animals (IC50: 216 ± 36 ng/mL) after administration of 3 mg/kg. Metoprolol constants of dissociation for β1-adrenoceptors and inverse agonism were similar in both groups. Conclusion: Results demonstrate the β1-adrenoceptors involvement in the fructose hypertension. A greater potency to metoprolol in vivo chronotropic effect was found in fructose-fed rats. This greater potency was not caused by alteration in the activity of β1-adrenoceptors.

Therapeutic Implications of Beta-Adrenergic Receptor Pharmacodynamic Properties

In the last decades new pharmacodynamic properties of beta-adrenoceptors have been discovered that could greatly impact in the use of beta-adrenergic agents in the clinical practice. Concepts such as multiple binding sites, constitutive activity, polymorphism and intracellular signaling of betaadrenoceptors may contribute in the discovery of more efficacious pharmacological agents for treatment of heart failure and asthma. beta-Adrenoceptors show a relative high constitutive activity in both cardiac and pulmonar tissues. Most beta-blockers exert an inverse agonist action that could contribute to their beneficial effects in the treatment of heart failure. Recently, the existence of multiple affinity sites has been described for beta1-adrenoceptor. It was proposed that beta-blockers that show agonist properties at the beta1L-adrenoceptors binding site may exert neutral or harmful effects when used for treatment of heart failure. Considering the cardiac effect of beta1L-adrenoceptors, activation of the low-affinity state of beta1-adrenoceptor could be deleterous in cardiovascular pharmacology. The ability of beta2-adrenoceptor to couple to Gs or Gi-protein gives the possibility that different agonists can activate different signaling cascades. Full beta2-adrenoceptor agonists would be highly useful for improvement bronchodilatation in the acute treatment of asthma. Polymorphic variants of beta-adrenoceptors have profound impact in the understanding of normal physiology and pathophysiology. Genotypic characterization of patients could improve selection of patients during beta-adrenergic pharmacotherapies. The aim of the present review is to describe new insights in pharmacological and biochemical properties of beta-adrenoceptors and their impact on the use of beta-adrenergic agents in the treatment of cardiovascular and respiratory diseases.

ROLE OF HYPOTHALAMIC α2-ADRENOCEPTOR ACTIVITY IN FRUCTOSE-INDUCED HYPERTENSION

1 The aim of the present study was to investigate the effects of the α2‐adrenoceptor antagonist yohimbine on blood pressure and heart rate (HR) regulation, as well as on adrenergic and serotoninergic neurotransmission, in fructose hypertensive (F) rats. 2 The anterior hypothalamic area of control (C) and F rats was perfused with Ringers solution containing 10 and 100 µg/mL yohimbine through a microdialysis concentric probe. The effects of yohimbine on mean arterial pressure (MAP) and HR, as well as on hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5‐hydroxyindole acetic acid (5‐HIAA) levels, were measured according to perfusion time. 3 Although intrahypothalamic perfusion of yohimbine increased blood pressure in C rats (ΔMAP 9 ± 1 and 11 ± 2 mmHg for 10 and 100 µg/mL yohimbine, respectively; P < 0.05 vs Ringers perfusion), the α‐adrenoceptor antagonist did not modify MAP in F. Intrahypothalamic yohimbine had no effect on HR at either concentration tested. Intrahypothalamic perfusion of 10 and 100 µg/mL yohimbine increased DOPAC levels in C rats (135 ± 6 and 130 ± 5% of basal levels, respectively; both n = 6; P < 0.05 vs Ringers perfusion), but not in F animals (115 ± 6 and 102 ± 6% of basal levels, respectively; both n = 6). In both C and F rats, yohimbine administration induced an increase in 5‐HIAA dialysate levels. 4 The results of the present study support the notion that α2‐adrenoceptor tone of the anterior hypothalamus of normotensive rats, which contributes to normal blood pressure regulation, is not involved in the control of HR in either normotensive C or hypertensive F rats. The absence of changes in MAP after yohimbine perfusion in F rats suggests that the α2‐adrenoceptor tone could be decreased in this group of rats and that this may be responsible for the maintenance of hypertension in this model. Intrahypothalamic perfusion of yohimbine increased DOPAC in the dialysate only in C rats, suggesting changes in presynaptic α2‐adrenoceptor activity in fructose‐overloaded rats. Conversely, increased 5‐HIAA levels did not differ between C and F groups.

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic–pharmacodynamic (PK–PD) modeling. Male Sprague–Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1–3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK–PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK–PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats. Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.

Enantioselective pharmacokinetic–pharmacodynamic modelling of carvedilol in a NG-nitro-l-arginine methyl ester rat model of secondary hypertension

Objectives  The role of vascular sympatholytic activity of carvedilol in its antihypertensive effect in NG‐nitro‐l‐arginine methyl ester (L‐NAME) hypertensive rats was assessed by means of enantioselective pharmacokinetic–pharmacodynamic (PK‐PD) modelling.