Intact female stroke-prone hypertensive rats lack responsiveness to mineralocorticoid receptor antagonists

Rigsby, Christine S.; Burch, Ashley E.; Ogbi, Safia; Pollock, David M.; Dorrance, Anne M.

doi:10.1152/ajpregu.00145.2007

Cited by 26 publications

(26 citation statements)

References 60 publications

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“…The thread was left in place and the rats were allowed to recover. MCAO was confirmed by laser Doppler flowmetery (Rigsby et al, 2007a). Post-occlusion (24 hours) the area of the infarction was quantified using 2,3,5-triphenyltetrazolium (TTC) staining, the cerebral infarct size was corrected for the presence of edema using the following equation, % Hemisphere Infarcted = ((V L −V C )/V C ) * 100 where V L is the volume of the lesioned hemisphere and V C is the volume of the control hemisphere (Swanson et al, 1990).…”

Section: Methodsmentioning

confidence: 99%

Diet-induced obesity causes cerebral vessel remodeling and increases the damage caused by ischemic stroke

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Portik-Dobos

Smith

et al. 2009

Microvascular Research

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Hypertension, elevated fasting blood glucose and plasma insulin develop in rats fed a high fat (HF) diet. Our goal was to assess the effects of obesity, beginning in childhood, on the adult cardiovascular system. We hypothesized that rats fed a HF diet would have larger ischemic cerebral infarcts and middle cerebral artery (MCA) remodeling. Three-week-old male Sprague Dawley rats were fed a HF (Obese) or control diet for 10 weeks. Cerebral ischemia was induced by MCA occlusion (MCAO). MCA structure was assessed by pressure myography and cerebral vessel matrix metalloproteinase (MMP) activity and expression and collagen levels were measured in vessels from rats that did not undergo MCAO. The cerebral infarct was greater in the obese rats than the control (46.0±2.1 vs 28.0±7.5 percent of the hemisphere infarcted, obese vs control p<0.05). The MCAs from obese rats had smaller lumens (232±7.2 vs 254±7.8μm obese vs control p<0.05) and thicker walls (19.6±0.8 vs 17.8± 0.9μm obese vs control p<0.05) and were less compliant than MCAs from control rats. MMP-2 activity and collagen I expression were increased in vessels from obese rats and MMP-13 expression was reduced. These results suggest obesity, beginning in childhood, causes inward vessel remodeling with a concomitant increase in vessel stiffness due to increased collagen deposition. These changes in MCA structure may be responsible for the increase in the ischemic damage after MCAO.

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Section: Methodsmentioning

confidence: 99%

Diet-induced obesity causes cerebral vessel remodeling and increases the damage caused by ischemic stroke

Deutsch

Portik-Dobos

Smith

et al. 2009

Microvascular Research

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“…Mechanical properties of third-order mesenteric artery segments were studied in a small vessel arteriograph (Living Systems Instrumentation) as described previously (Rigsby et al, 2007). In brief, after a 30-min equilibration period at 50 mm Hg pressure, pressure-dependent (5-120 mm Hg) changes in lumen diameter were measured under active (Ca 2ϩ -containing Krebs-HEPES buffer) and passive (Ca 2ϩ -free Krebs-HEPES buffer) conditions.…”

Section: Methodsmentioning

confidence: 99%

Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes

Sachidanandam

Hutchinson

Elgebaly³

et al. 2008

J Pharmacol Exp Ther

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Type 2 diabetes and dyslipidemia oftentimes present in combination. However, the relative roles of diabetes and diet-induced dyslipidemia in mediating changes in vascular structure, mechanics, and function are poorly understood. Our hypothesis was that addition of a high-fat diet would exacerbate small artery remodeling, compliance, and vascular dysfunction in type 2 diabetes. Vascular remodeling indices [media/lumen (M/L) ratio, collagen abundance and turnover, and matrix metalloproteinase dynamics], mechanical properties (vessel stiffness), and reactivity to pressure and vasoactive factors were measured in third-order mesenteric arteries in control Wistar and type 2 diabetic Goto-Kakizaki (GK) rats fed either a regular or high-fat diet. M/L ratios, total collagen, and myogenic tone were increased in diabetes. Addition of the high-fat diet altered collagen patterns (mature versus new collagen) in favor of matrix accumulation. Addition of a high-fat diet caused increased constriction to endothelin-1 (0.1-100 nM), showed impaired vasorelaxation to both acetylcholine (0.1 nM-1 M) and sodium nitroprusside (0.1 nM-1 M), and increased cardiovascular risk factors in diabetes. These results suggest that moderate elevations in blood glucose, as seen in our lean GK model of type 2 diabetes, promote resistance artery remodeling resulting in increased medial thickness, whereas addition of a high-fat diet contributes to diabetic vascular disease predominantly by impairing vascular reactivity in the time frame used for this study. Although differential in their vascular effects, both hyperglycemia and diet-induced dyslipidemia need to be targeted for effective prevention and treatment of diabetic vascular disease.It is estimated that over 23 million Americans are affected by type 2 diabetes. Obesity, insulin resistance, and hypertension often cluster along with type 2 diabetes, resulting in a condition known as metabolic syndrome or syndrome X, thus imposing an enormous task from a therapeutic standpoint (Muhammad, 2004). Although studies with obese Zucker rats (Frisbee, 2003;Stepp et al., 2004;Bouvet et al., 2007) and ob/ob mice (Schä fer et al., 2004) provide important evidence about complications of obesity, insulin resistance, hypertension, and prediabetes in the systemic microvasculature, the relative contributions of the individual components of metabolic syndrome to diabetes-associated complications cannot be dissected. Furthermore, effects of hyperglycemia and high-fat diet on the structure and mechanics of contractile medial layer are less understood. To define specific targets and develop therapeutic strategies to treat vascular complications, it is very important that the relative contributions of hyperglycemia and hyperlipidemia to vascular structure and function independent of atherosclerotic changes are well defined. The Goto-Kakizaki (GK) rat, being a spontaneous model of type 2 diabetes without the presence of comorbid complications, thus offers an excellent opportunity to study the individual role of...

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“…Blood pressure is already elevated and LVH present by 12 weeks of age in SP-SHRs, and urinary norepinephrine excretion is higher than that of agematched normotensive Wistar-Kyoto rats. 18 SP-SHRs were used in the present study at 16 to 24 weeks of age, at the compensatory phase, 11,19 when LVH can reduce wall stress and maintain cardiac function in the face of the hemodynamic overload. In agreement with previous reports, these rats had increased blood pressure and LVH.…”

Section: Discussionmentioning

confidence: 99%

Hemodynamic and Cardiac Effects of Chronic Eprosartan and Moxonidine Therapy in Stroke-Prone Spontaneously Hypertensive Rats

Mukaddam‐Daher

Ménaouar²,

Paquette³

et al. 2009

Hypertension

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Abstract-The renin-angiotensin and sympathetic nervous systems play critical interlinked roles in the development of left ventricular hypertrophy, fibrosis, and dysfunction. These studies investigated the hemodynamic and cardiac effects of monoblockade and coblockade of renin-angiotensin and sympathetic nervous systems. Stroke-prone spontaneously hypertensive rats (16 weeks old; male; nϭ12 per group) received the sympatholytic imidazoline compound, moxonidine (2.4 mg/kg per day); the angiotensin-receptor blocker eprosartan (30 mg/kg per day), separately or in combination; or saline vehicle for 8 weeks, SC, via osmotic minipumps. Blood pressure and heart rate were continuously measured by radiotelemetry. After 8 weeks, in vivo cardiac function and structure were measured by transthoracic echocardiography and a Millar conductance catheter, and the rats were then euthanized and blood and heart ventricles collected for various determinations. Compared with vehicle, the subhypotensive dose of moxonidine resulted in lower (PϽ0.01) heart rate, left ventricular hypertrophy, cardiomyocyte cross-sectional area, interleukin 1␤, tumor necrosis factor-␣, and mRNA for natriuretic peptides. Eprosartan reduced pressure (PϽ0.01), as well as extracellular signal-regulated kinase (ERK) 44 phosphorylation, Bax/Bcl-2, and collagen I/III, and improved left ventricular diastolic function (PϽ0.03). Combined treatment resulted in greater reductions in blood pressure, heart rate, left ventricular hypertrophy, collagen I/III, and inhibited inducible NO synthase and increased endothelial NO synthase phosphorylation, as well as reduced left ventricular anterior wall thickness, without altering the other parameters. Thus, in advanced hypertension complicated with cardiac fibrosis, sympathetic inhibition and angiotensin II blockade resulted in greater reduction in blood pressure and heart rate, inhibition of inflammation, and improved left ventricular pathology but did not add to the benefits of angiotensin II blockade on cardiac function. Key Words: hypertension Ⅲ hypertrophy Ⅲ hemodynamics Ⅲ natriuretic peptides Ⅲ moxonidine Ⅲ eprosartan I ncreased activities of the renin-angiotensin-aldosterone system and the sympathetic nervous system have been considered as important contributors to the pathogenesis of hypertension, as well as to the development of left ventricular hypertrophy (LVH). 1,2 Both angiotensin II, the primary effector molecule of the renin-angiotensin system, and the neurotransmitter norepinephrine exert hemodynamic effects by actions on several organs implicated in pressure and volume regulation, causing vasoconstriction and sodium retention. In addition, neurohormonal activation of cardiac adrenergic receptors and angiotensin type 1 (AT-1) receptors promotes growth of the cardiac muscle by direct hypertrophic and proliferative action on cardiomyocytes and fibroblasts and stimulation of biosynthesis of collagen and connective tissue and indirectly through inflammatory cell activation and stimulation of cytokine synthesis and ...

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Intact female stroke-prone hypertensive rats lack responsiveness to mineralocorticoid receptor antagonists

Cited by 26 publications

References 60 publications

Diet-induced obesity causes cerebral vessel remodeling and increases the damage caused by ischemic stroke

Diet-induced obesity causes cerebral vessel remodeling and increases the damage caused by ischemic stroke

Differential Effects of Diet-Induced Dyslipidemia and Hyperglycemia on Mesenteric Resistance Artery Structure and Function in Type 2 Diabetes

Hemodynamic and Cardiac Effects of Chronic Eprosartan and Moxonidine Therapy in Stroke-Prone Spontaneously Hypertensive Rats

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