(Hypertension. 1995;25:146-150.)
© 1995 American Heart Association, Inc.
Articles |
Wistar Fatty Rat Is Obese and Spontaneously Hypertensive
From the Third Department of Internal Medicine (T.Y., S.-i.T., Y.Y., K.U., H.S.); Second Department of Internal Medicine (K.T., S.U., M.I.); the Laboratory Animal Facility (Y.K.), Yokohama City University School of Medicine; the Health Science Research Institute (F.I.), Yokohama; and the Department of Pediatric and Cardiovascular Thoracic Surgery, Toho University School of Medicine, Tokyo, Japan.
Correspondence to Shun-ichi Tanaka, MD, Third Department of Internal Medicine, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236, Japan.
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Abstract |
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Abstract The purpose of this study was to determine whether genetically obese Wistar fatty rats have higher blood pressure than their lean littermates and if so to elucidate the mechanism of this obesity-related hypertension. We measured blood glucose and plasma insulin levels, blood pressure, and catecholamine and sodium excretions in age-matched female Wistar fatty and lean rats. After 12 weeks of age, the body weight of Wistar fatty rats was significantly greater than that of their lean counterparts. Fasting blood glucose and plasma insulin concentrations were higher in the fatty than the lean rats throughout the observation period (8 to 24 weeks of age). Systolic blood pressure of fatty rats measured by the tail-cuff method was similar to that of lean rats at 8 weeks of age (135±2 [mean±SEM] versus 134±3 mm Hg) but significantly higher at 16 (158±2 versus 136±3 mm Hg, P<.01) and 24 (166±5 versus 142±2 mm Hg, P<.01) weeks of age. Urinary norepinephrine excretion was significantly increased in the fatty rats at both 16 (1755±173 versus 977±128 ng/24 h, P<.05) and 24 (1907±283 versus 737±173 ng/24 h, P<.01) weeks of age. The ratio of urinary norepinephrine excretion to body weight was also significantly increased in the fatty rats. These results show that with increasing body weight Wistar fatty rats develop hypertension, which may be attributable to an increased sympathetic nerve activity. Since these characteristics are similar to those observed in human obesity–related hypertension, we consider that this rat may be a good model for further analysis of the mechanism of obesity-related hypertension.
Key Words: hypertension, spontaneous • obesity • rats, inbred strains • insulin resistance • catecholamine
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Introduction |
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The incidence of essential hypertension is greater among obese than nonobese individuals even when the groups are matched for age, gender, and race.1 2 3 4 5 Studies demonstrate that excessive body weight is associated with elevated blood pressure in both animals and humans and that weight reduction normalizes blood pressure.2 6 7 However, the mechanisms of obesity-related hypertension have not yet been fully identified.
Recently, it has been proposed that insulin resistance and subsequent compensatory hyperinsulinemia might be important in the etiology of obesity-associated hypertension.2 8 9 Obesity-related metabolic abnormalities, including dyslipidemia and glucose intolerance, are also associated with insulin resistance and hyperinsulinemia.10 11 12 13 In experimental models, obesity and hypertension are not definitely associated.14 15 Thus, it is important to find an appropriate new obese hypertensive animal model with the characteristics observed in human obesity.
In 1981, Ikeda et al16 developed a new model of obesity-related non–insulin-dependent diabetes mellitus, the Wistar fatty rat (WFR). This strain was derived from crosses between obese Zucker (13M strain, fa/fa) and Wistar-Kyoto rats. The WFR (fa/fa) develops obesity and obesity-related features, such as hyperinsulinemia and hyperlipemia, in a manner similar to the obese Zucker rat. Male WFR show severe hyperglycemia, glucosuria, and polyuria as early as 8 week of age. Female WFR show only insulin resistance and mild glucose tolerance.17 Epidemiological and clinical evidence documents a close association among hypertension, obesity, impaired glucose intolerance, and non–insulin-dependent diabetes mellitus.10 Although the pathogenic interactions among these conditions are only partly understood, it has been proposed that insulin resistance and subsequent compensatory hyperinsulinemia might be important in the etiology of obesity-associated hypertension.2 8 9 On the other hand, some researchers showed that diabetes mellitus and hypertension are closely linked independent of obesity.10 Thus, because the mechanism by which hypertension develops in male WFR is more complex, the female WFR is thought to be more appropriate for studying the mechanisms of obesity-related hypertension without the influence of diabetes. In the present study, we compared systolic blood pressure (SBP) in female WFR and Wistar lean rats (WLR) and show that WFR spontaneously develop hypertension with obesity.
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Methods |
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Animals
Wistar (fa/-) rats were originally obtained from the breeding colony at the Biological Institute of Takeda Pharmaceutical Co in June 1989. All were maintained at the Laboratory Animal Facility, Yokohama City University School of Medicine. Female WFR (fa/fa) and age-matched WLR (fa/+ or +/+) (individually marked) were used. All had free access to water and standard rat chow pellets and were housed under controlled temperature (22±1°C) and humidity (50% to 60%) with a photoperiod from 7 AM to 7 PM. Body weight was measured every 4 weeks. Fasting blood glucose and plasma insulin concentrations were measured at 8, 16, and 24 weeks of age.
Blood Pressure Measurement
Indirect blood pressure measurements were made at 8, 16, and 24
weeks of age. SBP was measured by a tail-cuff sphygmomanometer
(UR-5000, Ueda Co, Ltd) in conscious rats between 3 and 6
PM.
Arterial blood pressure was also measured at the end of the study by direct carotid artery catheterization. Rats were first anesthetized with 40 mg/kg IP pentobarbital. An arterial catheter was placed in the left carotid artery for measurement of mean arterial pressure. On recovery from anesthesia, each rat was placed in an individual cage for a 24-hour recovery and habituation period. The arterial catheter was then attached to a pressure transducer (Gould P23 ID, Gould-Statham) for monitoring of arterial blood pressure on a physiological recorder (model 7746, NEC San-ei Ltd).
Urinary Measurements
Twenty-four–hour urinary measurements were conducted at
8, 16, and 24 weeks of age. Rats were housed individually in metabolic
cages equipped with drinking bottles and food cups outside the cage so
that urine could be collected without contamination from food and
water. Twenty-four–hour urine samples were collected into flasks
containing 6N HCl. Twenty-four–hour sodium excretion was calculated
from urine volume and urinary sodium concentration measured by flame
photometry. Total 24-hour sodium intake was calculated from the amount
of food consumed. Urinary catecholamines were measured by a
high-performance liquid chromatographic (HPLC) method using an
automated HPLC analyzer (Tosoh Co). Details on this HPLC analyzer have
been previously reported.18
Biochemical Measurements
Blood samples were obtained from the subclavicular vein at 8,
16, and 24 weeks of age. Samples were centrifuged, aliquoted, frozen,
and later assayed for sodium, potassium, and insulin. Plasma sodium and
potassium levels were determined with a Hitachi 736 autoanalyzer. Serum
creatinine levels were determined by a method described by
Yatzidis.19 Blood glucose concentrations were measured by
a glucose oxidase method with a Beckman glucose analyzer. Plasma
insulin levels were measured by radioimmunoassay (Amersham).
Heart and Kidney Weights
Hearts and kidneys of WFR and WLR were weighed at 8, 16, and 24
weeks of age.
Statistical Analysis
Data are expressed as mean±SEM. Statistical analyses of
differences were performed using an unpaired t test.
Applicability of the t test to the data was verified by the
F test and Welch's correction.
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Results |
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WFR showed a progressive increase in body weight. After 12 weeks of age, the difference between mean body weights of WFR and WLR were statistically significant (Fig 1).
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SBP was significantly higher in WFR than WLR at 16 (158±2 versus 136±3 mm Hg, P<.01) and 24 (166±5 versus 142±2 mm Hg, P<.01) weeks of age but not at 8 weeks of age (135±2 versus 134±3 mm Hg) (Fig 2). Intra-arterial mean blood pressure measured directly at 24 weeks of age was also higher in WFR than WLR (141±6 versus 125±5 mm Hg, P<.05).
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As shown in Table 1, mean fasting blood glucose concentration was significantly higher in WFR than WLR at all ages (P<.001), but it was not more than 11.0 mmol/L. WFR also showed significantly higher fasting plasma insulin concentrations at 16 and 24 weeks of age (P<.01). Plasma sodium, potassium, chloride, and creatinine levels did not differ significantly between the groups.
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Urinary sodium and potassium excretions are also shown in Table 1. Excretion of each electrolyte was similar in both groups throughout the observation period.
Urinary epinephrine, norepinephrine, and dopamine excretions at 8, 16, and 24 weeks of age were examined. At both 8 and 16 weeks of age, urinary epinephrine excretion was not different between WFR and WLR. Although urinary epinephrine excretion was significantly increased at 24 weeks of age in WFR compared with WLR (P<.05), at all ages the ratio of epinephrine excretion to body weight was not different between the groups (Table 2). Urinary norepinephrine excretion increased significantly with age in WFR but not WLR. In addition, the ratio of urinary norepinephrine excretion to body weight was also significantly higher in WFR than WLR at 16 and 24 weeks of age (P<.01). Urinary dopamine excretion was not different between groups (data not shown).
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Heart and kidney weights were significantly greater in WFR than WLR at 16 (P<.05) and 24 (P<.01) weeks of age. However, the ratios of both heart weight and kidney weight to body weight were significantly decreased in WFR compared with WLR (Table 1).
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Discussion |
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We designed this study to determine whether WFR are hypertensive compared with their lean littermates and if so to investigate the mechanism of the blood pressure increase. The results demonstrate that although at 8 weeks of age slight obesity, mild hyperglycemia, and hyperinsulinemia were observed in WFR, SBP was not different between WFR and WLR. After 16 weeks of age, SBP was significantly higher in WFR, as were body weight and plasma insulin level. Thus, it was suggested that hypertension in WFR might be induced by obesity-related changes, such as hyperinsulinemia and insulin resistance. Although the ratio of epinephrine excretion to body weight was not increased, the ratio of norepinephrine excretion to body weight and norepinephrine excretion in WFR were significantly greater than in WLR at 16 and 24 weeks of age, suggesting that the sympathetic nervous system (SNS) was activated in WFR compared with WLR.
In the past 20 years a large number of genetically inherited forms of obesity have been studied. Obese Zucker rats develop obesity with hyperinsulinemia, insulin resistance, hyperphagia, and hyperlipidemia at an early age.20 21 22 Although glucose intolerance is also found, their blood glucose levels are normal throughout their life.23 Many researchers have reported the blood pressure in obese Zucker rats. Some show blood pressure to be significantly higher in obese Zucker rats compared with their lean littermates,24 25 26 27 28 whereas others show no such difference.29 30 Thus, it still remains controversial whether the obese Zucker rat is definitely hypertensive or not. The obese spontaneously hypertensive rat (Koletsky's rat), in addition to elevated blood pressure, exhibits genetic obesity, endogenous hyperlipemia, endocrine gland dysfunction, and metabolic abnormalities and develops premature atherosclerosis.31 However, blood pressure is actually lower in Koletsky's rats than in their lean littermates, indicating that factors other than obesity cause hypertension in this model.32 LA/N and SHR/N-corpulent rats develop spontaneous insulin resistance, obesity, impaired glucose tolerance, hypertriglyceridemia, and atherosclerosis.33 34 35 However, both rat strains are essentially normotensive. Dietary-induced obese rats (Sprague-Dawley rat) have been shown to develop mild hypertension in association with hyperinsulinemia and insulin resistance when on a diet containing high concentrations of sugars such as fructose or sucrose.22 Although these models have allowed some detailed examinations of the relations among plasma insulin, insulin resistance, body fat content, and blood pressure, they do not replicate one important component of human obesity: genetic predisposition.
It is well known that obesity is closely related to hypertension. However, the mechanisms by which hypertension develops remain unknown. In the past decade, hyperinsulinemia and insulin resistance have been suggested to be the link between obesity and hypertension. Several mechanisms of hyperinsulinemia-induced hypertension have been hypothesized. First, insulin has been shown to increase renal tubular reabsorption of sodium and lead to a positive salt and water balance.13 36 37 Second, the activation of the SNS by hyperinsulinemia is proposed to be involved in obesity-induced hypertension.38 39 40 Third, hyperinsulinemia elevates intracellular Ca2+ concentration in vascular smooth muscle cells, causing vasoconstriction and increased blood pressure.41 Fourth, insulin or insulin-like growth factor stimulates vascular and cardiac myocyte growth, resulting in arteriolar narrowing and cardiac hypertrophy.42 In the present study, we examined 24-hour urinary sodium and catecholamine excretions to investigate the first two mechanisms. Although urinary sodium excretion showed no significant difference between WFR and WLR, catecholamine excretion and plasma insulin concentration were significantly increased in WFR. These results suggest that hypertension in WFR might be attributable to an increase in sympathetic nerve activity rather than an insulin-induced increase in renal sodium retention.
Although SNS activity is reported to be enhanced in both human and animal obesity, these results remain undefined. Some studies have provided evidence for elevated SNS activity,43 44 but others have not.45 46 In WFR, we also examined SNS activity. Plasma catecholamine level, however, is considered to be regulated by many factors. Thus, the blood sampling conditions are critical, especially in animals. Various stresses, such as sounds, pain, and posture, affect plasma catecholamine level. No definite sampling method has been established even though several methods have been proposed, such as sampling after death, sampling with rats under anesthesia, and sampling through an intravenous catheter from a conscious rat. On the other hand, 24-hour norepinephrine excretion may represent an integrated measure of averaged sympathetic activity. Therefore, we studied 24-hour urinary norepinephrine excretion instead of plasma norepinephrine concentration. Interestingly, with the use of 24-hour urinary norepinephrine excretion as an index of SNS activity, a positive relation has been demonstrated between the abdominal form of obesity and urinary norepinephrine excretion.47 48 However, no correlation was found if plasma norepinephrine was used as the index. Our present results are consistent with these reports.
Although several investigators have indicated a correlation between hyperinsulinemia and insulin resistance and SNS activity,38 39 40 48 49 50 it remains controversial whether hyperinsulinemia and insulin resistance would cause hypertension. A few reports on the long-term effects of insulin injection on blood pressure have suggested that hyperinsulinemia per se cannot fully account for obesity-induced hypertension.51 52 WFR show persistent hyperinsulinemia and hypertension after 16 weeks of age and may be a good model to elucidate the precise relation between hyperinsulinemia and hypertension.
In conclusion, we have shown that blood pressure of WFR is elevated significantly compared with that of WLR and the pathogenesis of the hypertension might be related to an increase in sympathetic nerve activity. Since the characteristics of female WFR, including hyperinsulinemia, insulin resistance, mild hyperglycemia, hyperlipidemia, and mild hypertension, are similar to those observed in human obese hypertension, this rat might be a good model for analysis of the mechanism of obesity-related hypertension.
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Acknowledgments |
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This study was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan and by the Kihara Memorial Foundation. Dr Kouichi Tamura is supported by a Research Fellowship of the Japan Society for the Promotion of Science for Young Scientists. We wish to thank Drs Manabu Ishihara, Atushi Sugiyama, Mari Kimura, Kenichirou Sekigawa, Yasuo Tokita, and Koichi Sugimoto for technical assistance.
Received May 2, 1994; first decision June 1, 1994; accepted September 8, 1994.
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