Alterations in coronary artery vascular reactivity of hypertensive Ren-2 transgenic rats.

Tschudi, Marcel R.; Noll, Georg; Arnet, U.; Novosel, Dragutin; Ganten, Detlev; Lüscher, Thomas F.

doi:10.1161/01.cir.89.6.2780

Cited by 23 publications

(10 citation statements)

References 29 publications

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“…Considering other models of hypertension, isolated coronary arteries from hypertensive Ren-2 transgenic rats relax normally in response to acetylcholine, but basal NO dilatory function is reduced in comparison with controls [32]. Additionally, small coronary arteries from pigs with a renal model of hypertension display normal endothelium-dependent relaxations in response to bradykinin, substance P and 5-HT [33], which demonstrates that abnormal endothelium-mediated responses are not a consistent feature of the coronary vasculature in hypertension.…”

Section: Discussionmentioning

confidence: 91%

Influence of Mode of Contraction on the Mechanism of Acetylcholine-Mediated Relaxation of Coronary Arteries from Normotensive and Spontaneously Hypertensive Rats

Bund

1998

Clinical Science

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1. Endothelium-dependent acetylcholine-mediated relaxations of small coronary arteries (approximately 200 microns internal diameter) from 20 weeks old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls were compared under pressurized no-flow conditions after the development of myogenic tone or constriction with the thromboxane A2 mimetic U46619. 2. Relaxations of WKY and SHR arteries following development of myogenic tone did not differ and were not significantly influenced by indomethacin alone (10 mumol/l) or in combination with N omega-nitro-L-arginine (L-NNA, 0.1 mmol/l). Maximum relaxations were significantly attenuated by 30 mmol/l K+ in the SHR, from 85 +/- 7% (n = 11) to 20 +/- 8% (n = 8), P < 0.001, and in the WKY from 86 +/- 5% (n = 9) to 39 +/- 14% (n = 8), P < 0.01. 3. Relaxations following constriction with U46619 were also similar in both rat strains. Maximum relaxations were 50 +/- 11% (n = 8) in SHR and 60 +/- 7% (n = 6) in WKY. Indomethacin did not influence these relaxations. The combination of indomethacin and L-NNA attenuated relaxations in WKY (P < 0.01), but in the SHR the attenuation did not achieve statistical significance (P = 0.07) compared with controls; the maximum responses were reduced to 25 +/- 7% (n = 8) and 14 +/- 11% (n = 6) in the SHR and WKY respectively, but only in the WKY was this reduction significant (P < 0.05). 4. These data demonstrate that, under control conditions, SHR and WKY coronary arteries relax equally effectively, regardless of mode of contraction, and also that the mechanism of acetylcholine-mediated relaxation differs according to the mode of contraction. Acetylcholine relaxes myogenic tone by a K(+)-sensitive mechanism in both WKY and SHR, consistent with a role for endothelium-derived hyperpolarizing factor; NO contributes substantially to the relaxation of U46619-induced tone by acetylcholine in the WKY, but to a diminished extent in the SHR. 5. These data indicate that the choice of vasoconstrictor agent is of critical concern when assessing mechanisms of endothelium-dependent relaxation and abnormalities thereof in hypertension.

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Section: Discussionmentioning

confidence: 91%

Influence of Mode of Contraction on the Mechanism of Acetylcholine-Mediated Relaxation of Coronary Arteries from Normotensive and Spontaneously Hypertensive Rats

Bund

1998

Clinical Science

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“…Endothelium-dependent relaxation in response to acetylcholine has been reported to be impaired in one study of aorta. 31 In contrast, responses to endothelium-dependent agonists in TGR(mRen2)27 were not impaired in another study of aorta 32 and studies of coronary arteries 33 and the mesenteric circulation. 34 Responses to endothelium-dependent agonists were enhanced in the renal circulation of TGR(mRen2)27 compared with nontransgenic controls.…”

Section: Vascular Responses In Control and R؉/a؉ Micementioning

confidence: 89%

Impaired Endothelial Function in Transgenic Mice Expressing Both Human Renin and Human Angiotensinogen

Didion

Sigmund

Faraci

2000

Stroke

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Background and Purpose-Chronic hypertension is a risk factor for carotid vascular disease and stroke. Mechanisms that account for alterations in carotid and cerebral vascular function during hypertension are poorly defined and based almost exclusively on studies in the spontaneously hypertensive rat, a model in which hypertension has an unknown etiology and in which the genetic background is dissimilar to the most commonly used normotensive control, the Wistar-Kyoto rat. Methods-In this study we examined vascular function in a defined model of hypertension, double transgenic mice that overexpress both human renin (Rϩ) and human angiotensinogen (Aϩ). We studied vessels in vitro from Rϩ/Aϩ mice as well as nontransgenic (RϪ/AϪ) and single transgenic (RϪ/Aϩ or Rϩ/AϪ) littermate controls. Results-After submaximal precontraction with U46619 or prostaglandin F 2␣ , acetylcholine, which produces relaxation mediated by endothelial nitric oxide synthase, produced marked relaxation of carotid arteries in control mice but was impaired in Rϩ/Aϩ mice. For example, 1 mol/L acetylcholine relaxed the carotid artery by 79Ϯ4% versus 44Ϯ7% (PϽ0.01) in control and Rϩ/Aϩ mice, respectively. Impaired responses to acetylcholine in Rϩ/Aϩ mice could be restored toward normal with indomethacin (10 mol/L). In contrast, relaxation of the carotid artery in response to nitroprusside and papaverine was similar in Rϩ/Aϩ mice and control mice. Conclusions-These findings indicate that acetylcholine-induced relaxation of carotid artery is impaired selectively in mice made hypertensive by expression of human renin and human angiotensinogen. The mechanism of this impairment may involve production of a cyclooxygenase-derived contracting factor. (Stroke. 2000;31:760-765.)Key Words: acetylcholine Ⅲ endothelium Ⅲ hypertension Ⅲ nitric oxide Ⅲ nitroprusside C hronic hypertension is a major risk factor for carotid vascular disease and stroke. 1,2 For reasons that are not clear, hypertension is more strongly associated with stroke than with myocardial infarction. 3 Recent findings suggest that carotid artery disease (carotid wall thickening) is associated with impairment of endothelium-dependent relaxation in patients with hypertension. 4 In addition, a genetic analysis demonstrated cosegregation of impaired endotheliumdependent relaxation and a stroke-prone phenotype in chronically hypertensive rats. 5 These findings reaffirm the importance of studying mechanisms of endothelial dysfunction in carotid artery and cerebral blood vessels under pathophysiological conditions, including hypertension.At present, our understanding of changes in carotid and cerebral vascular function during hypertension is based almost exclusively on studies in spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP), models in which hypertension has an unknown etiology and in which the genetic background is dissimilar to the most commonly used normotensive control, the WistarKyoto rat (WKY). 6 The first goal of the present study was to See E...

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“…22 In contrast to baseline effects, acetylcholine (ACh)-stimulated dilation of the coronary circulation was similar in normotensive and hypertensive animals, and was abolished in Hypertension, NO, and coronary endothelium Dovepress submit your manuscript | www.dovepress.com Dovepress both groups by L-NAME, suggesting stimulated NO release and/or bioavailability may be unaltered by hypertension in this vascular bed. 50 Further analysis revealed, however, that the relationship between CVR and NO production is altered in SHR hearts so a greater amount of NO production occurs despite a persistently much higher CVR than in WKY controls. 18 Furthermore, inhibition of eNOS with l-arginine analogues also blunts constrictory responses in the majority of the coronary perfusion studies in hypertensive hearts, 19,21 suggesting that NO is contributing to constrictory responses in the hypertensive coronary vascular bed likely via its destruction by superoxide and the consequent effects of reactive species formed.…”

Section: Nitric Oxide Bioavailability In the Control Of Coronary Hemomentioning

confidence: 96%

“…Indeed, in general, endothelium-mediated (drug-and shear stress-stimulated) dilation of isolated coronary arteries is reduced in hypertensive humans 11,[53][54][55][56][57] and animals, 19,21,32,36,45,51,52,[58][59][60][61][62] while the endothelium-independent vasodilatory responses to sodium nitroprusside and adenosine are often unaltered. 21,32,45,55,63 There are exceptions to these general observations 18,33,50,[63][64][65][66] and the vessel type (conduit vs resistance artery), 45,57 the mode of precontraction, 33 and the vasodilator protocol 45,56,61,67 or eliminated 58,68,69 by inhibitors of eNOS in isolated coronary vessels from hypertensive animals, suggesting that NO remains an important component of vascular function even when its bioavailability is reduced in hypertension. In isolated pressurized coronary microvessels it was observed that removal of the endothelium increased the amount of myogenic constriction to a greater extent in SHR than in WKY over a wide pressure range.…”

Section: Nitric Oxide-mediated Vasomotor Function Of Isolated Coronarmentioning

confidence: 97%

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Levy

Chung²,

Kroetsch

et al. 2009

VHRM

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This review highlights a number of nitric oxide (NO)-related mechanisms that contribute to coronary vascular function and that are likely affected by hypertension and thus become important clinically as potential considerations in prevention, diagnosis, and treatment of coronary complications of hypertension. Coronary vascular resistance is elevated in hypertension in part due to impaired endothelium-dependent function of coronary arteries. Several lines of evidence suggest that other NO synthase isoforms and dilators other than NO may compensate for impairments in endothelial NO synthase (eNOS) to protect coronary artery function, and that NO-dependent function of coronary blood vessels depends on the position of the vessel in the vascular tree. Adaptations in NOS isoforms in the coronary circulation to hypertension are not well described so the compensatory relationship between these and eNOS in hypertensive vessels is not clear. It is important to understand potential functional consequences of these adaptations as they will impact the efficacy of treatments designed to control hypertension and coronary vascular disease. Polymorphisms of the eNOS gene result in significant associations with incidence of hypertension, although mechanistic details linking the polymorphisms with alterations in coronary vasomotor responses and adaptations to hypertension are not established. This understanding should be developed in order to better predict those individuals at the highest risk for coronary vascular complications of hypertension. Greater endothelium-dependent dilation observed in female coronary arteries is likely related to endothelial Ca 2+ control and eNOS expression and activity. In hypertension models, the coronary vasculature has not been studied extensively to establish mechanisms for sex differences in NO-dependent function. Genomic and nongenomic effects of estrogen on eNOS and direct and indirect antioxidant activities of estrogen are discussed as potential mechanisms of interest in coronary circulation that could have implications for sex-and estrogen status-dependent therapy for hypertension and coronary dysfunction. The current review identifies some important basic knowledge gaps and speculates on the potential clinical relevance of hypertension adaptations in factors regulating coronary NO function.

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Alterations in coronary artery vascular reactivity of hypertensive Ren-2 transgenic rats.

Abstract: Ren-2 transgenic rats develop fulminant hypertension that is associated with a selective decrease in endothelium-dependent contractions in response to L-NAME, whereas endothelium-dependent relaxations in response to acetylcholine as well as smooth muscle function remain unaffected.

Cited by 23 publications

References 29 publications

Influence of Mode of Contraction on the Mechanism of Acetylcholine-Mediated Relaxation of Coronary Arteries from Normotensive and Spontaneously Hypertensive Rats

Influence of Mode of Contraction on the Mechanism of Acetylcholine-Mediated Relaxation of Coronary Arteries from Normotensive and Spontaneously Hypertensive Rats

Impaired Endothelial Function in Transgenic Mice Expressing Both Human Renin and Human Angiotensinogen

Nitric oxide and coronary vascular endothelium adaptations in hypertension

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