Long-term effects of perindopril on metabolic parameters and the heart in the spontaneously hypertensive/NIH-corpulent rat with non—insulin-dependent diabetes mellitus and hypertension

Striffler, John S.; Bhathena, Sam J.; Michaelis, Otho E.; Campbell, Joaquin D.; Hansen, Carl T.; Scalbert, Elizabeth; Thibault, Nancy; Velasquez, Manuel T.

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Volume 47, Issue 10 , Pages 1199-1204, October 1998

Long-term effects of perindopril on metabolic parameters and the heart in the spontaneously hypertensive/NIH-corpulent rat with non—insulin-dependent diabetes mellitus and hypertension☆

John S. Striffler
- Department of Medicine, George Washington University Medical Center, Washington, DC, USA
- Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD, USA
- Veterinary Research Program, National Institutes of Health, Bethesda, MD, USA
- Institut de Recherches Internationales Servier & Compagnie-Development, Paris, France
- Current address for J.S.S.: Department of Diabetes, Endocrinology and Metabolism, City of Hope Medical Center, Duarte, CA 91010.
Sam J. Bhathena
- Department of Medicine, George Washington University Medical Center, Washington, DC, USA
- Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD, USA
- Veterinary Research Program, National Institutes of Health, Bethesda, MD, USA
- Institut de Recherches Internationales Servier & Compagnie-Development, Paris, France
Otho E. Michaelis IV
- Department of Medicine, George Washington University Medical Center, Washington, DC, USA
- Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD, USA
- Veterinary Research Program, National Institutes of Health, Bethesda, MD, USA
- Institut de Recherches Internationales Servier & Compagnie-Development, Paris, France
- Deceased.
Joaquin D. Campbell
- Department of Medicine, George Washington University Medical Center, Washington, DC, USA
- Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD, USA
- Veterinary Research Program, National Institutes of Health, Bethesda, MD, USA
- Institut de Recherches Internationales Servier & Compagnie-Development, Paris, France
Carl T. Hansen
- Department of Medicine, George Washington University Medical Center, Washington, DC, USA
- Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD, USA
- Veterinary Research Program, National Institutes of Health, Bethesda, MD, USA
- Institut de Recherches Internationales Servier & Compagnie-Development, Paris, France
Elizabeth Scalbert
- Department of Medicine, George Washington University Medical Center, Washington, DC, USA
- Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD, USA
- Veterinary Research Program, National Institutes of Health, Bethesda, MD, USA
- Institut de Recherches Internationales Servier & Compagnie-Development, Paris, France
Nancy Thibault
- Department of Medicine, George Washington University Medical Center, Washington, DC, USA
- Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD, USA
- Veterinary Research Program, National Institutes of Health, Bethesda, MD, USA
- Institut de Recherches Internationales Servier & Compagnie-Development, Paris, France
Manuel T. Velasquez
- Address reprint requests to Manuel T. Velasquez, MD, Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University Medical Center, 2150 Pennsylvania Ave NW, Washington, DC 20037.
- Department of Medicine, George Washington University Medical Center, Washington, DC, USA
- Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture, Beltsville, MD, USA
- Veterinary Research Program, National Institutes of Health, Bethesda, MD, USA
- Institut de Recherches Internationales Servier & Compagnie-Development, Paris, France

Received 11 October 1997; accepted 2 April 1998.

Abstract

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic model that exhibits both non—insulin-dependent diabetes mellitus (NIDDM) and hypertension. To determine the impact of long-term treatment with the long-acting angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the glucose metabolism, lipid levels, and heart in this model, studies were performed in three groups of SHR/N-cp rats maintained on a diet containing 54% carbohydrate with 18% sucrose and 36% starch. One group of obese rats received PE (0.5 to 1.0 mg/kg body weight/d) for 3 to 4 months, a second group of obese rats received no treatment, and a third group of lean rats were used as controls. The mean systolic blood pressure (SBP) increased gradually in both untreated obese and lean rats, with lean animals showing slightly higher levels compared with untreated obese rats. By contrast, SBP was reduced to normal levels in PE-treated obese rats throughout the treatment period. Compared with lean rats, obese rats showed significantly higher body weight and fasting serum levels of glucose, insulin, total cholesterol (TC), and triglyceride (TG). However, no significant differences were observed in these metabolic parameters between PE-treated and untreated obese rats. Plasma renin activity measured at the end of the treatment period was significantly higher in PE-treated rats compared with untreated obese and untreated lean rats. The mean heart weight and left ventricular weight, expressed in absolute terms or indexed to body weight, were significantly lower in PE-treated versus untreated obese and untreated lean rats. To further determine whether glucose metabolism is directly affected by PE treatment, in vitro glycogen sythesis was evaluated in isolated soleus muscles obtained from three additional groups of animals. The basal rate of muscle glycogen synthesis was significantly lower in obese compared with lean rats (P < .05), but did not differ between PE-treated and untreated obese rats. Maximal insulin-stimulated glycogen synthesis increased threefold in PE-treated obese rats, but this increase did not differ from the increases observed in untreated obese and learn rats. In conclusion, the present study shows that long-term PE treatment in obese SHR/N-cp rats with NIDDM and hypertension effectively controlled systemic arterial pressure and resulted in a significant reduction in left ventricular weight. However, these favorable effects of PE were not associated with significant improvement in glucose tolerance, hyperinsulinemia, and hyperlipidemia in this model. PE also had no direct stimulatory effects on either basal or insulin-mediated glycogen synthesis in the isolated soleus muscle of obese rats, perhaps because of the severe insulin-resistant state of the animals. Our results support the clinical observations that antihypertensive therapy with ACE inhibitors has neutral effects on glucose metabolism and insulin sensitivity in patients with combined hypertension and NIDDM.

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