Enhanced acetylcholine and P2Y-receptor stimulated vascular EDHF-dilatation in congestive heart failure

Malmsjö, Malin; Bergdahl, Anders; Zhao, Xiao-He; Sun, Xingshu; Hedner, Thomas; Edvinsson, Lars; Erlinge, David

doi:10.1016/s0008-6363(99)00062-0

Cited by 62 publications

(52 citation statements)

References 40 publications

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“…In contrast, EDHF-mediated vasodilation in PH was reduced in arterioles but unchanged in SAs, and the relative contribution of EDHF to vasodilation was increased in both arterioles and SAs. This robust and sustained vasodilatory action of EDHF in PH is consistent with the suggestion that EDHF might be a crucial compensatory or reserve mechanism for maintaining organ blood flow in situations of NO dysfunction (7,23,25). In a preliminary study, we demonstrated that the RV coronary capillary flow response to ACh in spontaneously hypertensive rats was preserved in the absence of NO by robust EDHF activity (10).…”

Section: Discussionsupporting

confidence: 80%

Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats

Kajiya¹,

Hirota²,

Inai³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats. Am J Physiol Heart Circ Physiol 292: H2737-H2744, 2007. First published January 12, 2007; doi:10.1152/ajpheart.00548.2006.-Pulmonary hypertension (PH) causes right ventricular (RV) hypertrophy and, according to the extent of pressure overload, eventual heart failure. We tested the hypothesis that the mechanical stress in PH-RV impairs the vasoreactivity of the RV coronary microvessels of different sizes with increased superoxide levels. Five-week-old male Sprague-Dawley rats were injected with monocrotaline (n ϭ 126) to induce PH or with saline as controls (n ϭ 114). After 3 wk, coronary arterioles (diameter ϭ 30 -100 m) and small arteries (diameter ϭ 100 -200 m) in the RV were visualized using intravital videomicroscopy. We evaluated ACh-induced vasodilation alone, in the presence of N -nitro-Larginine methyl ester (L-NAME), in the presence of tetraethylammonium (TEA) or catalase with or without L-NAME, and in the presence of SOD. The degree of suppression in vasodilation by L-NAME and TEA was used as indexes of the contributions of endothelial nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF), respectively. In PH rats, ACh-induced vasodilation was significantly attenuated in both arterioles and small aretries, especially in arterioles. This decreased vasodilation was largely attributable to reduced NOmediated vasoreactivity, whereas the EDHF-mediated vasodilation was relatively robust. The suppressive effect on arteriolar vasodilation by catalase was similar to TEA in both groups. Superoxide, as measured by lucigenin chemiluminescence, was significantly elevated in the RV tissues in PH. SOD significantly ameliorated the impairment of ACh-induced vasodilation in PH. Robust EDHF function will play a protective role in preserving coronary microvascular homeostasis in the event of NO dysfunction with increased superoxide levels. acetylcholine; N -nitro-L-arginine methyl ester; tetraethylanmonium; catalase; superoxide dimutase; endothelium-derived hyperpolarizing factor PULMONARY HYPERTENSION (PH) causes pressure overload and hypertrophy, finally leading to failure, in the right ventricle (RV) of the heart. Although the right coronary perfusion pressure remains relatively unchanged, the high pressure and hypertrophy of the RV affect the coronary hemodynamics (8, 13), and patients with PH and RV hypertrophy might have symptoms indistinguishable from those of angina pectoris (4, 30). In chronic PH, coronary flow regulation is the only mechanism that maintains the oxygen supply to the RV, since no further increase in the absorption of oxygen is possible (31). The endothelium-dependent vasodilation of coronary small arteries (SAs, diameter ϭ 100 -200 m) isolated from the RV has been shown to be lower in rats with chronic PH (33), whereas in acute PH, endogenous nitric oxide (NO) regulates right coronary blood flow (37). However, the contri...

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Section: Discussionsupporting

confidence: 80%

Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats

Kajiya¹,

Hirota²,

Inai³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…In HF, the contribution of EDHF relative to NO for inducing vasorelaxation is increased, partly because NO is reduced (21). This was also indicated in our study.…”

Section: Endothelial-mediated No-and Prostacyclin-independent Vasorelsupporting

confidence: 86%

Exercise training and losartan improve endothelial function in heart failure rats by different mechanisms

Kemi

Haram

Høydal

et al. 2013

Scandinavian Cardiovascular Journal

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Objectives: To investigate the mechanisms of losartan-and exercise training-induced improvements on endothelial dysfunction in heart failure.Design: Sprague-Dawley rats subjected to left coronary artery ligation inducing myocardial infarction and heart failure were randomized to losartan treatment, high-intensity exercise training, or both.Results: Losartan, but not exercise training, reduced the heart failure-associated elevation in left ventricular end-diastolic pressure (26±2 mmHg vs. 19±1 mmHg after losartan). In contrast, both exercise training and losartan improved exercise capacity, by 40% and 20%, respectively; no additional effects were observed when exercise training and losartan were combined. Aortic segments were mounted on a force transducer to determine vasorelaxation.Heart failure impaired endothelium-dependent vasorelaxation, observed as a 1.9-fold reduced response to acetylcholine (EC 50 ). Exercise and losartan improved acetylcholine-mediated vasorelaxation to the same extent, but by different mechanisms. Exercise training upregulated the nitric oxide pathway, whereas losartan upregulated a non-nitric oxide or -prostacyclin pathway; possibly involving the endothelium-dependent hyperpolarizing factor.

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“…47 Experimental evidence supports this proposal, as a shift away from NO-mediated endothelium-dependent relaxation toward EDHF-dependent relaxation has been reported in microvessels from cardiomyopathic hamsters, 106 as well as in coronary arteries from rats with congestive heart failure. 107 A similar phenomenon has been described for bradykinininduced changes in forearm blood flow in essential hypertensive patients 108 and in arterioles removed from patients with coronary artery disease, where vasodilatation is mediated entirely by a mechanism sensitive to both CYP and K ϩ Ca channel inhibitors. 24 Such findings indicate that in the absence of NO, vascular tone can be regulated by an EDHF-like mechanism.…”

Section: Cyp and Cardiovascular Diseasementioning

confidence: 53%

Cytochrome P450 and Vascular Homeostasis

Fleming

2001

Circulation Research

339

296

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Abstract-Since the initial reports that renal cytochrome P450 (CYP) enzymes can metabolize arachidonic acid to substances which affect arterial tone, it has become increasingly clear that CYP enzymes expressed within the cardiovascular system play a crucial role in the modulation of vascular homeostasis. There is strong evidence suggesting that the activation of a CYP epoxygenase in endothelial cells is an essential step in nitric oxide and prostacyclinindependent vasodilatation of several vascular beds, particularly in the heart and kidney. A smooth muscle CYP -hydroxylase, on the other hand, generates a vasoconstrictor eicosanoid that is central to the myogenic response. Moreover, CYP epoxygenase and -hydroxylase products, as well as CYP-derived reactive oxygen species, are intracellular signal transduction molecules involved in several signaling cascades affecting numerous cellular processes, including vascular cell proliferation and angiogenesis. This review summarizes the vascular effects of epoxyeicosatrienoic acids and 20-hydroxyeicosatetraenoic acid, both of which are CYP-derived metabolites of arachidonic acid, endogenously generated within endothelial and vascular smooth muscle cells. Although the link between CYP expression/activity and cardiovascular disease is currently tentative, the evidence being accumulated to suggest that CYP pathways are altered in animal models of hypertension and atherosclerosis can no longer be ignored. The development of selective pharmacological tools is, however, a prerequisite for the analysis of the involvement of specific CYP isoforms in the regulation of vascular homeostasis in human subjects. Key Words: endothelial dysfunction Ⅲ endothelium-derived hyperpolarizing factor Ⅲ epoxyeicosatrienoic acids Ⅲ free radicals Ⅲ 20-hydroxyeicosatetraenoic acid C ytochrome P450 (CYP) enzymes are membrane-bound, heme-containing terminal oxidases in a multienzyme system that also includes a FAD/FMN-containing NADPHcytochrome P450 reductase and cytochrome b 5 . CYP enzymes oxidize, peroxidize, and/or reduce cholesterol, vitamins, steroids, xenobiotics, and numerous pharmacological substances in an oxygen-and NADPH-dependent manner. Some CYP isoforms are fairly specific in their choice of substrates but many, particularly those in the endoplasmic reticulum, catalyze a large number of chemical reactions and can use an almost unlimited number of biologically occurring and synthetic compounds. Because many CYP isozymes are also capable of metabolizing arachidonic acid to biologically active products, 1,2 CYP enzymes are often described as the third pathway of arachidonic acid metabolism (ie, in addition to cyclooxygenases and lipoxygenases), although they also oxidize other endogenous lipids such as retinoic and linoleic acid. CYP products derived from substrates other than arachidonic acid also elicit physiological responses. For example, the epoxygenase CYP 2J2 can generate epoxyeicosatrienoic acids (EETs) from arachidonic acid and epoxyeicosaquatraenoic acids from eicosapentaenoic ac...

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Enhanced acetylcholine and P2Y-receptor stimulated vascular EDHF-dilatation in congestive heart failure

Cited by 62 publications

References 40 publications

Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats

Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive rats

Exercise training and losartan improve endothelial function in heart failure rats by different mechanisms

Cytochrome P450 and Vascular Homeostasis

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