Tempol augments angiotensin II-induced AT2 receptor-mediated relaxation in diabetic rat thoracic aorta

Arun, K.H.S.; Kaul, Chamanlal; Ramarao, P.

doi:10.1097/00004872-200411000-00017

Cited by 26 publications

(33 citation statements)

References 37 publications

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“…Cosentino et al (2005) suggested that the losartan-unmasked AT 2 receptor-mediated vasodilatation seen in the aorta isolated from SHR may contribute to the beneficial hemodynamic effects of AT 1 receptor blockade. Arun et al (2004) noted that ANG IIinduced relaxation, evident only in the presence of the AT 1 blocker, was enhanced in aortic rings isolated from diabetic rats but not control rats, the response being attenuated by L-NAME or ATP-sensitive K ϩ channel blockers and abolished by treatment with both inhibitors. [ 3 H]ANG II saturation binding at the AT 2 receptor was enhanced in aortic membranes from diabetic rats compared with control rats.…”

Section: Angiotensin-induced Endothelium-derived Relaxing Factomentioning

confidence: 99%

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

2007

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Section: Angiotensin-induced Endothelium-derived Relaxing Factomentioning

confidence: 99%

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

2007

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“…12 We have shown previously that the balance between NO and cyclooxygenase (COX) derivatives is modified in hypertension 13 and may involve the inducible form of the enzyme, COX-2. 14 Thus, in this study, we investigated the possible roles of ROS and COX-2 in alterations of AT2R-dependent dilation in resistance arteries from type 2 diabetic rats.…”

mentioning

confidence: 99%

Reactive Oxygen Species and Cyclooxygenase 2-Derived Thromboxane A2 Reduce Angiotensin II Type 2 Receptor Vasorelaxation in Diabetic Rat Resistance Arteries

et al. 2010

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Abstract-Angiotensin II has a key role in the control of resistance artery tone and local blood flow. Angiotensin II possesses 2 main receptors. Although angiotensin II type 1 receptor is well known and is involved in the vasoconstrictor and growth properties of angiotensin II, the role of the angiotensin II type 2 receptor (AT2R) remains much less understood. Although AT2R stimulation induces vasodilatation in normotensive rats, it induces vasoconstriction in pathological conditions involving oxidative stress and cyclooxygenase 2 expression. Thus, we studied the influence of cyclooxygenase 2 on AT2R-dependent tone in diabetes mellitus. Mesenteric resistance arteries were isolated from Zucker diabetic fatty (ZDF) and lean Zucker rats and studied using in vitro using wire myography. In ZDF rats, AT2R-induced dilation was lower than in lean rats (11% versus 21% dilation). Dilation in ZDF rats returned to the control (lean rats) level after acute superoxide reduction (Tempol and apocynin), cyclooxygenase 2 inhibition (NS398), or thromboxane A 2 synthesis inhibition (furegrelate). Cyclooxygenase 2 expression and superoxide production were significantly increased in ZDF rat arteries compared with arteries of lean rats. After chronic treatment with Tempol, AT2R-dependent dilation was equivalent in ZDF and lean rats. Chronic treatment of ZDF rats with NS398 also restored AT2R-dependent dilation to the control (lean rats) level. Plasma thromboxane B 2 (thromboxane A 2 metabolite), initially high in ZDF rats, was decreased by chronic Tempol and by chronic NS398 to the level found in lean Zucker rats. Thus, in type 2 diabetic rats, superoxide and thromboxane A 2 reduced AT2R-induced dilation. These findings are important to take into consideration when choosing vasoactive drugs for diabetic patients. Key Words: type 2 diabetes mellitus Ⅲ angiotensin II Ⅲ angiotensin II type 2 receptor Ⅲ cyclooxygenase 2 Ⅲ oxidative stress Ⅲ thromboxane A2 Ⅲ resistance arteries R esistance arteries play a key role in vascular homeostasis. They possess a basal tone modulated by neurohormonal systems, among which the renin-angiotensin system has a major role. This basal tone is modified in hypertension, ischemic disease, myocardial infarction, and diabetes mellitus. In diabetes mellitus, blockade of the renin-angiotensin system efficiently reduces vascular damage. 1 In addition, in the microcirculation, angiotensin-converting enzyme inhibition has a dual positive effect by increasing postischemic angiogenesis and reducing retinal microvascular damage induced by diabetes mellitus. 2 Angiotensin II (Ang II) acts on 2 receptors, the type 1 receptor (AT1R) and the type 2 receptor (AT2R). 3 Stimulation of the AT1R is associated with vasoconstriction and vascular cell growth, 4 and its blockade explains a large part of the positive effects of targeting of the renin-angiotensin system in diabetes mellitus. Because AT2R has been shown to induce vasodilatation and stimulate antigrowth effects, 3 its stimulation may exert an additional positive effect...

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“…Ang II plays a fundamental role in controlling the functional and structural integrity of arterial wall and contributes significantly to the pathological mechanisms underlying vascular complications of diabetes (1,2,11,87). Recent studies suggest that cardiac myocytes and vascular smooth muscles contain RAS, which is activated under diabetic conditions (82).…”

Section: Role Of Angiotensin II (Ang Ii) In Diabetic Vascular Complicmentioning

confidence: 99%

“…We are proposing that chronic release of Ang II leads to changes in ionic currents and action potentials and stimulates excessive collagen synthesis in human vascular smooth muscle cells and that these effects can be reversed by blocking the formation or action of Ang II. The apparent benefits of Ang II receptor blockade or ACE inhibition in diabetes are cardiac (26,70) and vascular protection (2). Ang II can activate NADPH oxidase, whose product superoxide anion (O 2 -) quenches nitric oxide (NO) resulting in peroxynitrite (ONOO -) formation (48,61).…”

Section: Role Of Angiotensin II (Ang Ii) In Diabetic Vascular Complicmentioning

confidence: 99%

“…The various sources of ROS include NADP(H) oxidases, hemeoxygenase-1, cyclooxygenase, lipoxygenase, xanthine oxidase, mitochondrial oxidation, cytochrome P450 monooxygenases, oxidation of polyunsaturated fatty acids, and glucose auto-oxidation. We have previously reported attenuation of Ang II-induced enhanced vascular responses in diabetic (72) and in spontaneously hypertensive rats (SHR) (68) by tempol [a cell permeable superoxide dismutase (SOD) mimetic] and observed the involvement of cysteinyl leukotrienes and dihydropyridine (DHP) sensitive L-type calcium channels in supersensitivity to Ang II (2,69). It appears, therefore, that Ang II is likely to affect vascular dynamics quantitatively different in diabetic/hypertensive patients than in normal individuals ( Table 3).…”

Section: Introductionmentioning

confidence: 99%

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2005

Cardiovascular Drug Reviews

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Current understanding of the genesis of diabetic vascular disease suggests that vascular complications, such as atherosclerosis and hypertension, are associated with changes in structural and functional parameters. Experimental and epidemiological data suggest that activation of the renin-angiotensin-aldosterone system plays an important role in the development of micro-and macro-vascular complications. Most of the negative cardiovascular actions of angiotensin II are mediated through AT 1 receptors, whereas the AT 2 receptors mediate largely beneficial effects. Hence, compared to angiotensin converting enzyme inhibitors (ACEIs), selective AT 1 receptor blockers (ARBs) should provide additional end organ protection via AT 2 receptors activation. Although ACEIs are useful therapeutically, they are being currently displaced by ARBs.Enhanced calcium ion channel activity is reported in vascular smooth muscles from diabetic animal models. Clinical benefits of calcium channel blockers (CCBs) in diabetic hypertensive patients are controversial, but there is increasing experimental evidence for the beneficial effects of dihydropyridine-type CCBs. Although the treatment of hypertension in diabetics reduces cardiovascular and microvascular complications, the ideal strategy for treating hypertension in diabetics has not been well defined and warrants a combination approach. Only limited clinical data regarding the use of ARBs in combination with CCBs in diabetics are available. The experimental data suggest that combination of a CCB and an AT 1 receptor blocker, or a hypothetical dual blocker of AT 1 receptors as well as of calcium channels would be an ideal regimen. There is, however, no conclusive 99

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Tempol augments angiotensin II-induced AT2 receptor-mediated relaxation in diabetic rat thoracic aorta

Cited by 26 publications

References 37 publications

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation

Reactive Oxygen Species and Cyclooxygenase 2-Derived Thromboxane A2 Reduce Angiotensin II Type 2 Receptor Vasorelaxation in Diabetic Rat Resistance Arteries

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