Role of Endothelin-1 in Blood Pressure Regulation in a Rat Model of Visceral Obesity and Hypertension

Abstract

Abstract-Endothelial dysfunction has been suggested to play an important role in the development of obesity-induced hypertension. Because endothelin release increases in response to endothelial damage, we examined whether endothelin-1 contributes to increased arterial pressure in a model of visceral obesity produced by feeding SpragueDawley rats a high-fat (HF) diet (40% fat w/w, nϭ6) for 12 months. Arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 hours per day and intravenous infusions. After a 5-day control period, rats were infused with the selective endothelin-1 type A receptor (ET-A) blocker ABT-627 (2.5 mg/kg per day, IV) for 9 days, followed by a recovery period. Rats fed a standard chow (normal fat, or NF, group: nϭ6) for 12 months were also infused with ET-A blocker and were used as controls. Compared with NF rats, HF rats had higher MAP (113Ϯ4 versus 98Ϯ2 mm Hg), increased visceral fat (18.7Ϯ2.0 versus 10.8Ϯ1.4 g), and 3.2-fold increase in plasma leptin despite similar total body weight gain. Long-term ET-A blockade markedly reduced MAP in HF (Ϫ14Ϯ3 mm Hg) and NF (Ϫ14Ϯ2 mm Hg), but it had no effect on HR, GFR, or PRA. These results indicate that a long-term HF diet may cause visceral obesity and increased MAP, even in the absence of major changes in total body weight. Endothelin-1 appears to play an important role in the maintenance of arterial pressure in rats fed HF and NF diets, but it does not appear to contribute to increased MAP in this model of diet-induced hypertension. Key Words: hypertension Ⅲ renin Ⅲ kidney Ⅲ diet Ⅲ obesity C onsiderable evidence suggest that excess weight gain is the most common cause of human essential hypertension. Risk estimates from the Framingham Heart Study, for example, indicate that Ϸ78% of hypertension in men and 65% in women can be directly attributed to obesity.

Obesity-Associated Hypertension

“…This indicates a selective enhancement of ET A receptor-dependent vasoconstrictor tone in obese hypertensive patients. 43 In contrast, da Silva et al 44 found that long-term blockade of ET A receptors reduced arterial pressure similarly in a rat model of visceral obesity and in control normotensive animals, suggesting that endothelin-1 does not contribute to the elevation of arterial pressure in this model of central obesity. These data may also indicate that endothelin antagonism alone is not sufficient to restore the impaired NO bioavailability in obesity.…”

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

“…Overweight and obese humans have enhanced ET-1-mediated endothelial dysfunction (194). An ET A receptor antagonist attenuated HFD-induced hypertension in rats having increased visceral obesity and leptin levels (34). Indirect evident suggests that this pathway is augmented in obese preeclamptic situations.…”

Increasing or stabilizing renal epoxyeicosatrienoic acid production attenuates abnormal renal function and hypertension in obese rats

“…However, the mechanisms whereby obesity causes hypertension are not fully understood. To better understand those mechanisms, different investigators have used a rat model fed an HF diet (2,4,33). We have chosen this model because it mimics the effects of human HF-food consumption; rats develop characteristic features of human obesity-induced hypertension, including increased renal tubular reabsorption and glomerular filtration rate (GFR) (8).…”