Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine

Loke, Kit E.; Messina, Edward J.; Shesely, Edward G.; Kaley, Gabor; Hintze, Thomas H.

doi:10.1016/s0008-6363(00)00196-6

Cited by 14 publications

(11 citation statements)

References 45 publications

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“…The findings of the present study support our previous work indicating that BK activates eNOS to regulate cardiac O 2 consumption and that this does not occur in the eNOS knockout mouse heart (16,18). More importantly, we demonstrated previously the transfer of NO from dog coronary microvessels coincubated with eNOS knockout mouse heart regulates tissue O 2 consumption (21).…”

Section: Discussionsupporting

confidence: 92%

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O₂ consumption

Adler

Huang

Wang

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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.-We investigated the role of nitric oxide (NO) in the control of myocardial O 2 consumption in the hearts of female Xenopus frogs, which lack a coronary vascular endothelium and in which the endocardial endothelium is the only source of NO to regulate cardiac myocyte function. Hence, frogs are an ideal model in which to explore the role of diffusion of NO from the endocardial endothelium (EE) without vascular endothelial or cardiac cell NO production. In Xenopus hearts we examined the regulation of cardiac O 2 consumption in vitro at 25°C and 37°C. The NO-mediated control of O2 consumption by bradykinin or carbachol was significantly (P Ͻ 0.05) lower at 25°C (79 Ϯ 13 or 73 Ϯ 11 nmol/min) than at 37°C (159 Ϯ 26 or 201 Ϯ 13 nmol/min). The response to the NO donor S-nitroso-Nacetyl penicillamine was also markedly lower at 25°C (90 Ϯ 8 nmol/min) compared with 37°C (218 Ϯ 15 nmol/min). When Triton X-100 was perfused into hearts, the inhibition of myocardial O 2 consumption by bradykinin (18 Ϯ 2 nmol/min) or carbachol (29 Ϯ 4 nmol/min) was abolished. Hematoxylin and eosin slides of Triton X-100-perfused heart tissue confirmed the absence of the EE. Although endothelial NO synthase protein levels were decreased to a variable degree in the Triton X-100-perfused heart, NO 2 production (indicating eNOS activity) decreased by Ͼ80%. It appears that the EE of the frog heart is the sole source of NO to regulate myocyte O 2 consumption. When these cells are removed, the ability of NO to regulate O2 consumption is severely limited. Thus our results suggest that the EE produces enough NO, which diffuses from the EE to cardiac myocytes, to regulate myocardial O 2 consumption. Because of the close proximity of the EE to underlying myocytes, NO can diffuse over a distance and act as a messenger between the EE and the rest of the heart to control mitochondrial function and O 2 consumption. nitric oxide; Western blot analysis; Triton X-100; mitochondria; Griess reaction THE ENDOCARDIAL ENDOTHELIUM (EE) plays a vital role in the regulation of myocardial performance and electrical activity as recently reviewed by Brutsaert (3). Located between luminal blood and the underlying cardiac muscle, the EE synthesizes and releases nitric oxide (NO) in amounts sufficient to regulate myocardial contraction under basal conditions (4,24). NO is also known to regulate O 2 consumption under a variety of conditions (2,12,15,22,25). This regulation of myocardial metabolism may be one of NO's most significant roles. We have proposed that endothelial NO synthase (eNOS), which is the most highly expressed isoform of NOS in vascular tissue under physiological conditions, contributes to the control of tissue O 2 consumption by NO (16,25).As a model to determine the significance of the diffusion of NO in the control of cardiac cell O 2 consumption, the frog heart is of much interest because it has no coronary circulation and can therefore be used to study the interaction between the EE and the myocardium without interference from the vascular endothelium (...

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Section: Discussionsupporting

confidence: 92%

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O₂ consumption

Adler

Huang

Wang

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…NO has a number of beneficial effects in various systems and importantly functions as a physiological vasodilator in the coronary artery vascular bed, a regulator of mitochondrial respiration, a modulator of myocardial contractility, and a key metabolite in blood pressure regulation (1,30,32,59). Most of the functions for NO in the cardiovascular system are attributable to the enzyme eNOS, which is expressed in the endothelium as well as the cardiomyocyte.…”

Section: Discussionmentioning

confidence: 99%

“…Taylor et al (58) demonstrated that under hypoxic conditions, ATP and phosphocreatine are depleted significantly more in rat hearts with decreased concentration of functional Mb compared with hearts with normal levels of Mb. Several additional studies (1,32,59) have demonstrated that NO modulates oxygen mitochondrial respiration in the heart. NO has been shown to directly inhibit mitochondrial oxidative phosphorylation through reversible binding to cytochrome c oxidase (complex IV), where NO competes with dioxygen to bind at the binuclear Cu B /Fe a3 2ϩ site of cytochrome c oxidase (4-6, 11, 12, 46, 54, 56, 65).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice

Mammen¹,

Kanatous²,

Yuhanna³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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. Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice. Am J Physiol Heart Circ Physiol 285: H2132-H2141, 2003. First published July 24, 2003 10.1152/ajpheart.00147.2003.-Myoglobin-deficient mice are viable and have preserved cardiac function due to their ability to mount a complex compensatory response involving increased vascularization and the induction of the hypoxia gene program (hypoxia-inducible factor-1␣, endothelial PAS, heat shock protein27, etc.). To further define and explore functional roles for myoglobin, we challenged age-and gender-matched wild-type and myoglobin-null mice to chronic hypoxia (10% oxygen for 1 day to 3 wk). We observed a 30% reduction in cardiac systolic function in the myoglobin mutant mice exposed to chronic hypoxia with no changes observed in the wild-type control hearts. The cardiac dysfunction observed in the hypoxic myoglobin-null mice was reversible with reexposure to normoxic conditions and could be prevented with treatment of an inhibitor of nitric oxide (NO) synthases. These results support the conclusion that hypoxia-induced cardiac dysfunction in myoglobin-null mice occurs via a NO-mediated mechanism. Utilizing enzymatic assays for NO synthases and immunohistochemical analyses, we observed a marked induction of inducible NO synthase in the hypoxic myoglobin mutant ventricle compared with the wild-type hypoxic control ventricle. These new data establish that myoglobin is an important cytoplasmic cardiac hemoprotein that functions in regulating NO homeostasis within cardiomyocytes.

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“…Loke et al 56 sought to determine whether amlodipine-derived NO regulated oxygen consumption in the heart from eNOSϪ/Ϫ mice. Amlodipine, like ramiprilat, had no effect on oxygen consumption in the eNOSϪ/Ϫ mouse heart.…”

Section: Stimulation Of No Synthesis By Amlodipinementioning

confidence: 99%

Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists

Mason

Marché

Hintze

2003

ATVB

156

117

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Abstract-Calcium channel blockers (CCBs) were developed as vasodilators, and their use in cardiovascular disease treatment remains largely based on that mechanism of action. More recently, with the evolution of second-and third-generation CCBs, pleiotropic effects have been observed, and at least some of CCBs' benefit is attributable to these mechanisms. Understanding these effects has contributed greatly to elucidating disease mechanisms and the rationale for CCB use. Furthermore, this knowledge might clarify why drugs are useful in some disease states, such as atherosclerosis, but not in others, such as heart failure. Although numerous drugs used in the treatment of vascular disease, including statins and angiotensin-converting-enzyme inhibitors, have well-described pleiotropic effects universally accepted to contribute to their benefit, little attention has been paid to CCBs' potentially similar effects.Accumulating evidence that at least 1 CCB, amlodipine, has pharmacologic actions distinct from L-type calcium channel blockade prompted us to investigate the pleiotropic actions of amlodipine and CCBs in general. There are several areas of research; foci here are (1) the physicochemical properties of amlodipine and its interaction with cholesterol and oxidants; (2) the mechanism by which amlodipine regulates NO production and implications; and (3) amlodipine's role in controlling smooth muscle cell proliferation and matrix formation.

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Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine

Abstract: These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine.

Cited by 14 publications

References 45 publications

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O₂ consumption

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O₂ consumption

Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice

Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists

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Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine

Abstract: These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine.

Cited by 14 publications

References 45 publications

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O2 consumption

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O2 consumption

Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice

Novel Vascular Biology of Third-Generation L-Type Calcium Channel Antagonists

Contact Info

Product

Resources

About

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O₂ consumption

Endocardial endothelium in the avascular frog heart: role for diffusion of NO in control of cardiac O₂ consumption