Antihypertensive effects of CS-045 treatment in obese Zucker rats

doi:10.1016/0026-0495(93)90175-N

Metabolism

Volume 42, Issue 1, January 1993, Pages 75-80

https://doi.org/10.1016/0026-0495(93)90175-N Get rights and content

Abstract

The association of hypertension with obesity has been well recognized, but the etiology remains poorly understood. Obesity is characterized by hyperinsulinemia, which reflects peripheral insulin resistance. Insulin resistance may participate in the development of hypertension with obesity. CS-045 [(I)-5-[4-(5-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]-2,4-thiazolidiendion] is a new orally effective antidiabetic agent that potentiates insulin action and reduces insulin resistance in obese Zucker rats and other obese diabetic animals. In this study, we examined the antihypertensive effect of CS-045 in obese male and female Zucker rats as a model of hypertension associated with obesity. CS-045 was administered as a food admixture (∼16 and ∼70 mg/kg/d) for 4 weeks (female) and (∼15 and ∼67 mg/kg/d) 8 weeks (male) in obese Zucker rats at 5 to 7 months of age. CS-045 slightly but significantly decreased plasma glucose levels. Plasma insulin levels were significantly decreased in obese male rats, but were not significantly decreased in obese female rats. Drug administration led to significant decreases in plasma triglyceride and cholesterol levels and systolic blood pressure (SBP) in a dose-dependent manner from 1 week after administration in obese Zucker rats. CS-045 increased urinary sodium excretion, sodium/potassium ratio, and creatinine clearance in a dose-dependent manner, and also led to a remarkable decrease in urinary protein excretion. However, CS-045 did not reduce urinary catecholamine excretion. These data indicate that CS-045 may promote renal sodium excretion and improve decreased glomerular filtration rates, which may reflect the amelioration of insulin resistance. Since the obese Zucker rat may be a useful animal model for hypertension associated with obesity, CS-045 may provide a new pharmacologic approach to the management of hypertension in obesity and/or non-insulin-dependent diabetes mellitus.

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PPARs are known widely for their roles in lipid metabolism and inflammation. Agonist ligands for PPARα and PPARγ have been used clinically for the management of dyslipidemia and control of glycemia in patients with type 2 diabetes [30,31]. More recently, attention to pleiotropic effects of these agents has grown with evidence that PPARγ is a negative regulator of cardiomyocyte hypertrophy through its interaction with NFATc4, an important transcription factor that is both necessary and sufficient for development of cardiomyocyte hypertrophy [13,25,32–34].
Peroxisome proliferator-activated receptor alpha (PPARα) has been implicated in the pathogenesis of cardiac hypertrophy, although its mechanism of action remains largely unknown. To determine the effect of PPARα activation on endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy and explore its molecular mechanisms, we evaluated the interaction of PPARα with nuclear factor of activated T-cells c4 (NFATc4) in nuclei of cardiomyocytes from neonatal rats in primary culture. In ET-1-stimulated cardiomyocytes, data from electrophoretic mobility-shift assays (EMSA) and co-immunoprecipitation (co-IP) revealed that fenofibrate (Fen), a PPARα activator, in a concentration-dependent manner, enhanced the association of NFATc4 with PPARα and decreased its interaction with GATA-4, in promoter complexes involved in activation of the rat brain natriuretic peptide (rBNP) gene. Effects of PPARα overexpression were similar to those of its activation by Fen. PPARα depletion by small interfering RNA abolished inhibitory effects of Fen on NFATc4 binding to GATA-4 and the rBNP DNA. Quantitative RT-PCR and confocal microscopy confirmed inhibitory effects of PPARα activation on elevation of rBNP mRNA levels and ET-1-induced cardiomyocyte hypertrophy. Our results suggest that activated PPARα can compete with GATA-4 binding to NFATc4, thereby decreasing transactivation of NFATc4, and interfering with ET-1 induced cardiomyocyte hypertrophy.
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The administration of a glitazone was found to be renal protective in the obese Zucker rat model of type 2 diabetes. In these animals, troglitazone decreased urine protein excretion and reduced blood glucose, blood pressure, plasma insulin, and plasma lipids [94]. Since then, a beneficial effect of glitazones on diabetic nephropathy has been consistently reported for in animal models of both type 1 and type 2 diabetes.
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Balaglitazone is a novel thiazolidinedione in clinical development for the treatment of type 2 diabetes. Common side effects associated with PPARγ receptor agonists are weight gain, oedema and adipogenesis. Balaglitazone is a selective partial PPARγ agonist and it has been speculated that such compounds have a more favourable safety margin than full agonists. We have compared impact of equi-efficacious antihyperglycaemic doses of balaglitazone with full PPARγ agonist rosiglitazone on body fluid accumulation, cardiac enlargement, and adipogenesis. Equi-efficacious antihyperglycaemic doses (ED₉₀) of balaglitazone (3 mg/kg/day) and rosiglitazone (6 mg/kg/day) were determined in male diabetic db/db mice. In adult male rats treated for up to 42 days, feeding, drinking, anthropometry, and plasma volumes were measured. Total plasma volume was measured with dye dilution technique. Compared to vehicle, rosiglitazone consistently increased food intake throughout the 42 day treatment period. In contrast, balaglitazone increased food intake in the last week of the experiment. However, both rosiglitazone and balaglitazone increased water intake. After 42 days, rosiglitazone treated rats displayed significantly elevated adiposity. Rosiglitazone increased total blood and plasma volumes throughout the treatment. Twenty-one days of balaglitazone treatment had no significant impact on blood or plasma volumes, whilst 42 days of balaglitazone increased plasma volume but to a significantly lesser extent than seen for rosiglitazone (vehicle: 46.1 ± 1.5; balaglitazone: 50.8 ± 1.21; rosiglitazone: 54.6 ± 1.6 ml/kg). Heart weight was significantly elevated only in rosiglitazone treated animals. At doses inducing comparable antihyperglycaemic control, the full PPARγ agonist, rosiglitazone, induces more pronounced body fluid retention and heart enlargement than seen for the partial PPARγ agonist, balaglitazone. Thus, partial agonists may pose safer alternative to current anti-diabetic therapy with full PPARγ agonist.
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Antihypertensive effects of CS-045 treatment in obese Zucker rats

Abstract

Metabolism

Am J Med

The relation of adiposity to blood pressure and development of hypertension: The Framingham Study

Ann Intern Med

Weight and blood pressure: Findings in hypertension screening of 1 million Americans

JAMA

Insulin and blood pressure in obesity

Hypertension

Postprandial hyperinsulinemia in patients with mild essential hypertension

Hypertension

Hyperinsulinemia: A link between hypertension, obesity and glucose intolerance

J Clin Invest

Evidence for an association of high blood pressure and hyperinsulinemia in obese man

J Clin Endocrinol Metab

Resistance to insulin-stimulated glucose uptake in patients with hypertension

J Clin Endocrinol Metab

Insulin resistance in essential hypertension

N Engl J Med

Role of insulin resistance in human disease

Diabetes

The Zucker-fatty rat: A review

The Zucker fatty rat as a genetic model of obesity and hypertension

Hypertension

Characterization of new oral antidiabetic agent CS-045: Studies in KK and obob mice and Zucker fatty rats

Diabetes

Studies on hindered phenols and analogues: 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation

J Med Chem

Metabolic effects of a new oral hypoglycemic agent, CS-045, in non-insulin-dependent diabetic subjects

Diabetes Care

Characterization of new oral antidiabetic agent CS-045: Studies in KK and $ob ob$ mice and Zucker fatty rats