The Vascular Renin-Angiotensin System as a Possible Source of Vascular Inflammation in Fructose-Fed Rats

375 Hypertens Res Vol.30 (2007) No.5 p.375-376 Editorial Comment The Vascular Renin-Angiotensin System as a Possible Source of Vascular Inflammation in Fructose-Fed Rats Shun ISHIBASHI1) (Hypertens Res 2007; 30: 375–376) Key Words: angiotensin, hypertension, fructose, oxidative stress, captopril Increased consumption of carbohydrates underlies the pandemic increase in the number of people with obesity in the industrialized world. Obesity is frequently associated with other metabolic derangements, thereby leading to more morbid cardiovascular diseases. Hypertension is one of the key derangements clustered in obesity and/or insulin resistance (1). Why is that increased consumption of carbohydrates, rather than salt, raises blood pressure? This question has puzzled researchers for some time. Fortunately, we can use fructose-fed rats (FFR) (2), which develop hypertension, dyslipidemia and insulin resistance, as an ideal model to address this question. Pharmacological studies suggest that activation of the sympathetic nervous system (2, 3) as well as the renin-angiotensin system (RAS) is involved in the development of hypertension in this model. In particular, the angiotensin II (Ang II) type 1 (AT1) receptor in the cardiovascular system has emerged as a central player of this link (4). In an article appearing in this issue of Hypertension Research (5), Nyby et al. provide a fresh look at the role of the vascular AT1 receptor in vascular dysfunction, oxidative stress and inflammation in FFR. They show that the increased oxidative stress and inflammation in the aorta of FFR are associated with the increased expression of tissue AT1 receptor. Captopril, an angiotensin-converting enzyme (ACE) inhibitor, reversed hypertension and all of these vascular abnormalities. These results suggest that vascular dysfunction and vascular oxidative stress in FFR are mediated by vascular RAS. It is widely accepted that inflammation underlies both insu- lin resistance and accelerated atherosclerosis in obesity and type 2 diabetes (6). From this point of view, it is noteworthy that the treatment with captopril did not alleviate hyperinsulinemia or glucose intolerance, which is in keeping with a previous study (7). Although insulin sensitivity was not directly measured by more sophisticated techniques such as glucose clamp, these findings have several implications. First, the anti-inflammatory effects of captopril seem more prominent in vascular tissues than in adipose tissues and skeletal muscles, since the drug did not affect systemic insulin resistance, which conceivably correlates RAS signaling in the latter two tissues. Second, neither hyperinsulinemia nor hyperglycemia per se mediate vascular inflammation in this model. This notion appears to contradict the hypothesis that hyperinsulinemia selectively stimulates MAP kinase signaling in vascular tissues in Zucker fatty rats (8), thereby aggravating cell proliferation and atherosclerosis. As suggested by Nyby et al. (5), vascular inflammation may be directly determined by the activity of vascular RAS. However, some investigators have reported that other ACE inhibitors such as enalapril (9, 10), quinapril (11) and temocapril (12), and AT1 receptor antagonists such as losartan (4, 13) and olmesartan (12, 14), reverse insulin resistance as well as hypertension. Therefore, further studies may be warranted to clarify the differential effects of various RAS-blocking agents on insulin resistance. In addition to antihypertensive agents, fish oil (15), troglitazone (16), and pioglitazone (17) have been reported to alleviate hypertension in FFR, suggesting that oxidative stress From the 1)Division of Endocrinology and Metabolism, Jichi Medical University School of Medicine, Shimotsuke, Japan. Address for Reprints: Shun Ishibashi, M.D., Ph.D., Division of Endocrinology and Metabolism, Jichi Medical University School of Medicine, 3311–1 Yakushiji, Shimotsuke 329–0498, Japan. E-mail: Received May 7, 2007. 376 Hypertens Res Vol. 30, No. 5 (2007) and insulin resistance per se are involved in the development of hypertension in FFR. Deciphering the precise relationship between RAS and each of these other targets for unconventional blood pressure–lowering therapy should provide us with further insight into the pathophysiology of metabolic syndrome, and ultimately lead to an ideal strategy for alleviating aortic blood pressure in patients with metabolic syndrome. References 1. 2. 3. 4. 5. 6. 7. 8. Reaven GM: Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595–1607. Hwang IS, Ho H, Hoffman BB, Reaven GM: Fructoseinduced insulin resistance and hypertension in rats. Hypertension 1987; 10: 512–516. Takatori S, Zamami Y, Mio M, Kurosaki Y, Kawasaki H: Chronic hyperinsulinemia enhances adrenergic vasoconstriction and decreases calcitonin gene−related peptide− containing nerve−mediated vasodilation in pithed rats. Hypertens Res 2006; 29: 361–368. Shinozaki K, Ayajiki K, Nishio Y, Sugaya T, Kashiwagi A, Okamura T: Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertension 2004; 43: 255–262. Nyby MD: Vascular angiotensin type 1 receptor expression is associated with vascular dysfunction, oxidative stress and inflammation in fructose-fed rats. Hypertens Res 2007; 30: 451–457. Hotamisligil GS: Inflammation and metabolic disorders. Nature 2006; 444: 860–867. Kobayashi R, Nagano M, Nakamura F, et al: Role of angiotensin II in high fructose-induced left ventricular hypertrophy in rats. Hypertension 1993; 21: 1051–1055. Jiang ZY, Lin YW, Clemont A, et al: Characterization of selective resistance to insulin signaling in the vasculature of obese Zucker (fa/fa) rats. J Clin Invest 1999; 104: 447–457. Rosenthal T, Erlich Y, Rosenmann E, Grossman E, Cohen A: Enalapril improves glucose tolerance in two rat models: a new hypertensive diabetic strain and a fructose-induced hyperinsulinaemic rat. Clin Exp Pharmacol Physiol Suppl 1995; 22: S353–S354. 10. Erlich Y, Rosenthal T: Contribution of nitric oxide to the beneficial effects of enalapril in the fructose-induced hyperinsulinemic rat. Hypertension 1996; 28: 754–757. 11. Uchida T, Okumura K, Ito T, et al: Quinapril treatment restores the vasodilator action of insulin in fructose-hypertensive rats. Clin Exp Pharmacol Physiol 2002; 29: 381– 385. 12. Higashiura K, Ura N, Takada T, et al: The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist on insulin resistance in fructose-fed rats. Am J Hypertens 2000; 13: 290–297. 13. Navarro-Cid J, Maeso R, Perez-Vizcaino F, et al: Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertensive rat. Hypertension 1995; 26: 1074–1078. 14. Okada K, Hirano T, Ran J, Adachi M: Olmesartan medoxomil, an angiotensin II receptor blocker ameliorates insulin resistance and de (...truncated)