Abstract

Myocardial infarction (MI) results in alterations in cardiac structure and function that not only impact the infarcted area, but also result in changes in the remote, remodelled myocardium. These changes also encompass structural changes in the coronary vascular tree and an increase in extravascular compressive forces acting on the microcirculation, thereby blunting myocardial flow reserve. Moreover, regulation of microvascular tone in the remote coronary vasculature is altered after MI. The alterations in regulation of microvascular tone appear to be principally the result of a loss of NO bioavailability in conjunction with an increased reactive oxygen species production. Interestingly, a reduced influence of a number of vasoconstrictors, including PDE5 and endothelin, serves to blunt the abnormalities in myocardial oxygen balance in remodelled myocardium after MI. Nevertheless, the overall changes in control of microvascular tone perturb the myocardial perfusion, resulting in impaired myocardial O2 delivery to the non-infarcted regions. The accompanying cardiomyocyte contractile dysfunction and/or enhanced apoptosis may contribute to the progression of cardiac dysfunction after MI.

Introduction

The incidence and prevalence of heart failure are increasing, principally due to an increased survival of acute myocardial infarction (MI) in conjunction with an ageing population. Particularly, in patients with a large MI, left ventricular (LV) function continues to deteriorate over time. The mechanisms that contribute to the transition of LV dysfunction towards overt heart failure remain incompletely understood, but may involve (i) loss of cardiomyocytes through apoptosis,1 (ii) a primary reduction in contractile function of the surviving myocardium,2 and/or (iii) alterations in extracellular matrix leading to progressive LV dilation.3 These alterations in LV structure and function not only impact the infarcted area, but also result in changes in the remote, remodelled myocardium. Thus, myocardial blood flow (MBF) abnormalities, resulting in impaired myocardial O2 delivery to the non-infarcted regions (leading to secondary contractile dysfunction and/or enhanced apoptosis), have been suggested to contribute to the progression of LV dysfunction after MI.4 A significant reduction in MBF reserve has been shown in the surviving remodelled LV myocardium in patients with overt heart failure.5 Furthermore, even in patients with only asymptomatic LV dysfunction, flow reserve is reduced in the non-stenotic myocardial regions.6 In line with these clinical observations, we observed in a porcine model of post-infarct remodelling that during increased O2-demand induced by exercise, the increase in coronary blood flow was impaired resulting in perturbations in oxygen delivery (Figure 1).7,8

Figure 1

Schematic drawing of the coronary microvasculature and the alterations in control mechanisms of microvascular tone in post-infarct remodelled myocardium. In red are shown the mechanisms that contribute to microvascular dysfunction; in green are shown the counteracting mechanisms that blunt the increased microvascular tone; in black are shown mechanisms that are unchanged as compared with normal hearts. See text for further explanation.

Figure 1

Schematic drawing of the coronary microvasculature and the alterations in control mechanisms of microvascular tone in post-infarct remodelled myocardium. In red are shown the mechanisms that contribute to microvascular dysfunction; in green are shown the counteracting mechanisms that blunt the increased microvascular tone; in black are shown mechanisms that are unchanged as compared with normal hearts. See text for further explanation.

Mechanisms of flow perturbations in post-myocardial infarction remodelled myocardium

The reduction in flow reserve and the associated perturbation in oxygen delivery during exercise are likely caused by the physical interaction between the coronary vasculature and the surrounding myocardium, in conjunction with structural and functional changes in the coronary microvasculature. It is evident that the coronary vasculature is compressed by the surrounding myocardium during systole.9,10 Hence, diastolic time fraction is an important determinant of myocardial perfusion.11,12 However, the coronary microvasculature is particularly sensitive for the compression that occurs during diastole, as a result of changes in LV diastolic function, i.e. elevated LV diastolic pressures7 and changes in the rate of relaxation.13 Structural changes of the remote coronary vasculature involve both inward, hypertrophic remodelling of the existing vessels14 as well as insufficient adaptations of the vasculature to keep up with the post-MI eccentric myocardial hypertrophy. The latter results in increased length of the coronary vascular tree in the presence of a maintained arteriolar density and even a decreased capillary density in the remote remodelled myocardium.7

The increased extravascular compression and structural changes in the coronary vasculature result in an increased minimal coronary microvascular resistance and a decreased myocardial perfusion, particularly in the subendocardial layers as the maximal subendocardial blood flow was blunted by 40% in anaesthetized swine with heart failure 3 weeks after an MI.15 This impairment of flow reserve is particularly important during exercise, when myocardial oxygen demand and extravascular compression increase simultaneously. Although MBF increases during exercise in the remote coronary vasculature after MI, this increase in flow did not completely match the increase in myocardial oxygen demand, as evidenced by an increase in myocardial oxygen extraction. Moreover, MBF was redistributed away from the subendocardium in favour of the subepicardium in post-MI as compared with normal swine,7 suggesting that the increase in myocardial oxygen extraction occurred predominantly at the subendocardium. Impaired perfusion of the subendocardium is likely to be, at least in part, responsible for the deterioration of LV function because local interstitial oedema and disruption of collagen fibres resemble the ultrastructural changes that occur with recurrent ischaemia.16,17 Furthermore, a decrease in maximal force development was observed in cardiomyocytes isolated from the subendocardium but not the subepicardium.18

In addition to changes in myocardial compressive forces and structural changes in the coronary vasculature, we have studied neurohumoral and metabolic alterations in the regulation of coronary vasomotor tone after MI as reviewed by Duncker et al.19 In the remainder of this review, we will focus on novel insights into the role of endothelial dysfunction in the altered regulation of coronary blood flow in the remote remodelled myocardium after MI (Figure 1).

Alterations in endothelial function in post-myocardial infarction remodelled myocardium

A healthy endothelium is a key factor in vascular homeostasis. The endothelium not only constitutes the inner lining of the vasculature, but is also a highly active endocrine and paracrine organ that releases a variety of factors that are anti-inflammatory, anti-coagulant, and/or involved in regulation of vascular tone. Thus, the endothelium releases vasoactive factors such as nitric oxide (NO), prostacyclin, endothelin (ET), thromboxane, reactive oxygen species (ROS), and the recently discovered factor uridine adenosine tetra-phosphate (Up4A).10,20 The balance between endothelium-derived vasodilators and vasoconstrictors is continuously modulated by haemodynamic factors such as shear stress, locally secreted inflammatory mediators, as well as circulating neurohormones such as norepinephrine and angiotensin II, thereby influencing vasomotor tone. Numerous studies have shown that endothelial dysfunction, i.e. an imbalance between endothelium-derived vasodilators and constrictors contributes to the aetiology cardiovascular disease.

After MI, oxidative stress is increased even in the remote myocardium,21,22 and this increased oxidative stress contributes to endothelial dysfunction not only in isolated large coronary arteries23 but also in the coronary microvasculature.24 Superoxide generation occurs in all layers of the vascular wall.25 Because it is highly reactive, non-membrane permeable, and because anti-oxidant defence mechanisms are abundantly present, the actions of superoxide are restricted to the sub-cellular compartment in the proximity of its source of generation.26 Superoxide influences vascular tone through several mechanisms. First, superoxide can oxidatively alter various K+ channels in vascular smooth muscle cells,27,28 thereby depolarizing the membrane potential and resulting in vasoconstriction. Second, it can react with the Sarco(Endo)Plasmic Reticulum Ca2+ pump in smooth muscle cells, which depletes the SR from Ca and thereby induces vasodilation.29,30 Finally, superoxide can react with NO to form ONOO, thereby limiting NO bioavailability and decreasing NO-mediated vasodilation.31 In healthy subjects, superoxide levels are tightly controlled by superoxide dismutase (SOD).32,33 SOD catalyses the reaction of superoxide into H2O2 and O2. H2O2, a potent vasodilator,34–36 is not only more stable than superoxide, but also membrane-permeable. Superoxide, derived from the respiratory chain of the mitochondria in the cardiac myocytes, when converted to the vasodilator H2O2, can diffuse to the microvasculature and is responsible for the coupling of increased myocardial metabolism to vasodilation of the coronary microvessels.36,37 Administration of an SOD mimetic had no effect on coronary vasomotor tone in awake dogs either at rest or during exercise,38 indicating optimal efficiency of endogenous SOD in converting superoxide to H2O2. However, in the porcine coronary circulation, free radical scavenging with N-2-mercaptopropionyl glycine (MPG) did have a small but significant vasodilator effect both at rest and during exercise, indicating that the O2·− that is generated in the coronary microvasculature may not be (completely) converted to H2O2, and exerts a net vasoconstrictor effect on the coronary vasculature.24 These data are in accordance with the observation that the reaction between NO and superoxide to form ONOO (thereby causing vasoconstriction) is 3–4 times faster than the reduction of superoxide by SOD (which would cause vasodilation).39 This coronary vasodilator effect of ROS-scavenging with MPG,24 as well as the dihydroethidium staining of the remote myocardium,22 was increased in swine with MI as compared with normal swine, indicating an increased production of ROS even in the microvasculature supplying the remote, non-infarcted myocardium. These data are in accordance with findings that superoxide production is increased in the remote coronary arteries of rats with MI23 as well as in monocytes/macrophages within the intima, media, and adventitia in vessels with coronary artery disease (CAD).40

The increased oxidative stress in the porcine coronary microvasculature after MI was accompanied by uncoupling of eNOS.24 eNOS uncoupling occurs through oxidation of its co-factor BH4 and results in generation of superoxide by eNOS rather than NO,41,42 thereby further contributing to oxidative stress.24 Consistent with a role of eNOS in generation of superoxide, the vasodilator effect of MPG in swine with MI disappeared after eNOS-inhibition. However, despite eNOS uncoupling, eNOS inhibition still resulted in significant, albeit reduced,24,43,44 coronary vasoconstriction at rest and during exercise, indicating eNOS-mediated NO production was still dominant over ROS production. Moreover, agonists are still capable of inducing NO-dependent coronary vasodilation, although this vasodilation was impaired in the remote coronary vasculature after MI.45 The latter data are consistent with the blunted vasodilator responses to endothelium-dependent receptor-mediated vasodilators (particularly acetylcholine) in the microcirculation of the LV myocardium in clinical studies in patients with chronic heart failure.46 A causal relation between the loss of NO-mediated vasodilation and the progression of LV dysfunction to heart failure is suggested by studies in dogs with pacing-induced dilated cardiomyopathy, in which the loss of basal NO production in the LV myocardium coincided with the progression from LV dysfunction to overt heart failure.47,48

The vasodilator effect of NO on the vasculature is principally mediated by activation of soluble guanylyl cyclase (sGC) and formation of cGMP in vascular smooth muscle.49 cGMP signalling is terminated through breakdown of cGMP by phosphodiesterase 5 (PDE5) and to a lesser extent by PDE1.50 PDE5 is predominantly present in vascular smooth muscle and skeletal muscle51,52 although there are some reports of its presence in cardiomyocytes53 and endothelial cells.54 PDE5-inhibition results in vasodilation of the large coronary arteries in both humans55 and swine.56 In healthy swine, PDE5-inhibition also causes coronary microvascular vasodilation both at rest and during exercise that was reduced (but not abolished) after inhibition of eNOS, indicating that NO is indeed an important activator of cGMP production. In contrast to these findings in swine, human studies fail to show an increase in coronary blood flow in response to PDE5-inhibition under resting conditions,55,57–59 potentially because all human studies involved patients with some degree of endothelial dysfunction in the coronary microcirculation. Hence, the lower levels of NO, and consequently cGMP production, could potentially explain the lack of effect of PDE5-inhibition in the coronary microvasculature of CAD patients. Indeed, even in patients with mild CAD who showed little effect of PDE5-inhibition under basal conditions, PDE5-inhibition enhanced the, NO-mediated, vasodilation by acetylcholine of both the large epicardial coronary arteries and the coronary microcirculation.55

Both PDE5 mRNA expression and vasodilation induced by PDE5-inhibition were reduced in the coronary microvasculature of the remote non-infarcted myocardium after MI.44 The reduced PDE5 gene expression and the blunted vasoconstrictor influence of PDE5 after MI suggest that PDE5 is down-regulated to prolong the biological availability of cGMP and to maintain the vasodilator influence of NO. This implies that the amount of NO required for this vasodilator influence is reduced. Moreover, our data suggest that, although inhibition of eNOS does result in vasoconstriction in swine with MI, the main vasodilator effect of NO was not mediated by increasing cGMP, as the effect of eNOS inhibition was similar in the presence and absence of PDE5 inhibition.44 It is therefore likely that the principal vasodilator effect of NO in the remote coronary circulation of swine with MI is mediated through limiting the vasoconstrictor effects of ET.43,60

Although circulating plasma levels ET are increased after MI, the vasoconstrictor influence of endogenous as well as exogenous ET on the remote coronary vasculature is reduced after MI in vivo.8 Paradoxically, in coronary small arteries isolated from the remote myocardium of swine with MI, ET-induced contraction was enhanced,8 suggesting that there are factors in vivo that modulate ET-sensitivity of the coronary vasculature. An ET-mediated vasoconstrictor influence was unmasked in MI swine after inhibition of either eNOS or cyclooxygenase (COX),43 confirming that NO, prostanoids and ET interact in regulation of coronary vasomotor tone.8 Indeed, it has been shown that both NO61,62 and prostanoids63 are capable of inhibiting ET production and release via a cGMP-dependent pathway. Moreover, NO reduces the ET receptor binding affinity in the human vasculature.64,65 Consistent with the reduced eNOS activity, the suppression of ET-mediated coronary vasoconstriction by NO was reduced in swine with a recent MI as compared with normal swine.43

In contrast to the reduced effect of NO, the suppression of ET by prostanoids was enhanced, while the overall vasodilator effect of prostanoids was unaltered in the remote coronary vasculature after MI.43 COX-1 is constitutively expressed in the healthy coronary vasculature,66,67 while COX-2 is mainly induced by shear stress and at sites of inflammation and could therefore become more important after MI. Indeed, the contribution of prostanoids to regulation of coronary vascular tone in humans increases with the progression of CAD. Distal to angiographically minimally diseased coronary arteries inhibition of prostanoid production induces mild vasoconstriction at rest that increases during exercise,68 whereas vasoconstriction is most pronounced in patients with CAD at rest69–71 and during exercise.69–71 COX-1 and COX-2 end-products influence the ET system at various levels, for instance, thromboxane A2 stimulates the production of pre-pro-ET72 the precursor of the vasoactive ET, while both PGE2 and PGI2 inhibit ET production as well as secretion.73 However, further experiments specifically designed to discern alterations in the role of the individual COX end-products after MI are required to further investigate their role in the regulation of coronary vascular tone in health and disease.

Conclusions

In conclusion, perturbations in coronary resistance vessel tone regulation in the post-MI remodelled remote myocardium appear to be principally the result of a loss of NO bioavailability in conjunction with an increased ROS production. Together with structural changes in the coronary vascular tree and the increase in extravascular compressive forces acting on the microcirculation, these alterations in resistance vessel tone contribute to the observed decreases in coronary flow reserve and myocardial oxygen supply. Interestingly, several studies have demonstrated a reduced influence of a number of vasoconstrictors, including PDE5 and ET, which serve to blunt the abnormalities in myocardial oxygen balance in remodelled myocardium after MI.

Funding

The present study was supported by Grants from the Netherlands Heart Foundation (2000T042 to D.M. 2000T038 to D.J.D.).

Conflict of interest: none declared.

References

1
Narula
J
Haider
N
Arbustini
E
Chandrashekhar
Y
Mechanisms of disease: apoptosis in heart failure—seeing hope in death
Nat Clin Pract Cardiovasc Med
 , 
2006
, vol. 
3
 (pg. 
681
-
688
)
2
van der Velden
J
Merkus
D
Klarenbeek
BR
James
AT
Boontje
NM
Dekkers
DH
Stienen
GJ
Lamers
JM
Duncker
DJ
Alterations in myofilament function contribute to left ventricular dysfunction in pigs early after myocardial infarction
Circ Res
 , 
2004
, vol. 
95
 (pg. 
e85
-
e95
)
3
Spinale
FG
Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function
Physiol Rev
 , 
2007
, vol. 
87
 (pg. 
1285
-
1342
)
4
van Veldhuisen
DJ
van den Heuvel
AF
Blanksma
PK
Crijns
HJ
Ischemia and left ventricular dysfunction: a reciprocal relation?
J Cardiovasc Pharmacol
 , 
1998
, vol. 
32
 
Suppl 1
(pg. 
S46
-
S51
)
5
van den Heuvel
AF
Bax
JJ
Blanksma
PK
Vaalburg
W
Crijns
HJ
van Veldhuisen
DJ
Abnormalities in myocardial contractility, metabolism and perfusion reserve in non-stenotic coronary segments in heart failure patients
Cardiovasc Res
 , 
2002
, vol. 
55
 (pg. 
97
-
103
)
6
van den Heuvel
AF
Blanksma
PK
Siebelink
HM
van Wijk
LM
Boomsma
F
Vaalburg
W
Crijns
HJ
van Veldhuisen
DJ
Impairment of myocardial blood flow reserve in patients with asymptomatic left ventricular dysfunction: effects of ACE-inhibition with perindopril
Int J Cardiovasc Imag
 , 
2001
, vol. 
17
 (pg. 
353
-
359
)
7
Haitsma
DB
Bac
D
Raja
N
Boomsma
F
Verdouw
PD
Duncker
DJ
Minimal impairment of myocardial blood flow responses to exercise in the remodeled left ventricle early after myocardial infarction, despite significant hemodynamic and neurohumoral alterations
Cardiovasc Res
 , 
2001
, vol. 
52
 (pg. 
471
-
428
)
8
Merkus
D
Houweling
B
van den Meiracker
AH
Boomsma
F
Duncker
DJ
Contribution of endothelin to coronary vasomotor tone is abolished after myocardial infarction
Am J Physiol Heart Circ Physiol
 , 
2005
, vol. 
288
 (pg. 
H871
-
H880
)
9
Hoffman
JI
Spaan
JA
Pressure-flow relations in coronary circulation
Physiol Rev
 , 
1990
, vol. 
70
 (pg. 
331
-
390
)
10
Laughlin
MH
Davis
MJ
Secher
NH
van Lieshout
JJ
Arce-Esquivel
AA
Simmons
GH
Bender
SB
Padilla
J
Bache
RJ
Merkus
D
Duncker
DJ
Peripheral circulation
Compr Physiol
 , 
2012
, vol. 
2
 (pg. 
321
-
447
)
11
Duncker
DJ
Ishibashi
Y
Bache
RJ
Effect of treadmill exercise on transmural distribution of blood flow in hypertrophied left ventricle
Am J Physiol
 , 
1998
, vol. 
275
 (pg. 
H1274
-
H1282
)
12
Merkus
D
Kajiya
F
Vink
H
Vergroesen
I
Dankelman
J
Goto
M
Spaan
JA
Prolonged diastolic time fraction protects myocardial perfusion when coronary blood flow is reduced
Circulation
 , 
1999
, vol. 
100
 (pg. 
75
-
81
)
13
Remmelink
M
Sjauw
KD
Yong
ZY
Haeck
JD
Vis
MM
Koch
KT
Tijssen
JG
de Winter
RJ
Henriques
JP
Piek
JJ
Baan
J
Jr.
Coronary microcirculatory dysfunction is associated with left ventricular dysfunction during follow-up after STEMI
Netherlands Heart J
 , 
2013
, vol. 
21
 (pg. 
238
-
244
)
14
Zhao
H
Chen
H
Li
H
Li
D
Wang
S
Han
Y
Remodeling of small intramyocardial coronary arteries distal to total occlusions after myocardial infarction in pigs
Coron Artery Dis
 , 
2013
, vol. 
24
 (pg. 
493
-
500
)
15
Zhang
J
Wilke
N
Wang
Y
Zhang
Y
Wang
C
Eijgelshoven
MH
Cho
YK
Murakami
Y
Ugurbil
K
Bache
RJ
From
AH
Functional and bioenergetic consequences of postinfarction left ventricular remodeling in a new porcine model. MRI and 31 P-MRS study
Circulation
 , 
1996
, vol. 
94
 (pg. 
1089
-
1100
)
16
Helmer
GA
McKirnan
MD
Shabetai
R
Boss
GR
Ross
JJ
Hammond
HK
Regional deficits of myocardial blood flow and function in left ventricular pacing-induced heart failure
Circulation
 , 
1996
, vol. 
94
 (pg. 
2260
-
2267
)
17
Spinale
FG
Hendrick
DA
Crawford
FA
Smith
AC
Hamada
Y
Carabello
BA
Chronic supraventricular tachycardia causes ventricular dysfunction and subendocardial injury in swine
Am J Physiol
 , 
1990
, vol. 
259
 (pg. 
H218
-
H229
)
18
van der Velden
J
Merkus
D
de Beer
V
Hamdani
N
Linke
WA
Boontje
NM
Stienen
GJ
Duncker
DJ
Transmural heterogeneity of myofilament function and sarcomeric protein phosphorylation in remodeled myocardium of pigs with a recent myocardial infarction
Front Physiol
 , 
2011
, vol. 
2
 pg. 
83
 
19
Duncker
DJ
de Beer
VJ
Merkus
D
Alterations in vasomotor control of coronary resistance vessels in remodelled myocardium of swine with a recent myocardial infarction
Med Biol Eng Comput
 , 
2008
, vol. 
46
 (pg. 
485
-
497
)
20
Jankowski
V
Tolle
M
Vanholder
R
Schonfelder
G
van der Giet
M
Henning
L
Schluter
H
Paul
M
Zidek
W
Jankowski
J
Uridine adenosine tetraphosphate: a novel endothelium-derived vasoconstrictive factor
Nat Med
 , 
2005
, vol. 
11
 (pg. 
223
-
227
)
21
Berges
A
Van Nassauw
L
Timmermans
JP
Vrints
C
Time-dependent expression pattern of nitric oxide and superoxide after myocardial infarction in rats
Pharmacol Res
 , 
2007
, vol. 
55
 (pg. 
72
-
79
)
22
Boontje
NM
Merkus
D
Zaremba
R
Versteilen
A
de Waard
MC
Mearini
G
de Beer
VJ
Carrier
L
Walker
LA
Niessen
HW
Dobrev
D
Stienen
GJ
Duncker
DJ
van der Velden
J
Enhanced myofilament responsiveness upon beta-adrenergic stimulation in post-infarct remodeled myocardium
J Mol Cell Cardiol
 , 
2011
, vol. 
50
 (pg. 
487
-
499
)
23
Berges
A
Van Nassauw
L
Timmermans
JP
Vrints
C
Role of nitric oxide during coronary endothelial dysfunction after myocardial infarction
Eur J Pharmacol
 , 
2005
, vol. 
516
 (pg. 
60
-
70
)
24
Taverne
YJ
de Beer
VJ
Hoogteijling
BA
Juni
RP
Moens
AL
Duncker
DJ
Merkus
D
Nitroso-redox balance in control of coronary vasomotor tone
J Appl Physiol
 , 
2012
, vol. 
112
 (pg. 
1644
-
1652
)
25
Touyz
RM
Schiffrin
EL
Reactive oxygen species in vascular biology: implications in hypertension
Histochem Cell Biol
 , 
2004
, vol. 
122
 (pg. 
339
-
352
)
26
Taverne
YJ
Bogers
AJ
Duncker
DJ
Merkus
D
Reactive oxygen species and the cardiovascular system
Oxidative Med Cell Longevity
 , 
2013
, vol. 
2013
 pg. 
862423
 
27
Gutterman
DD
Miura
H
Liu
Y
Redox modulation of vascular tone: focus of potassium channel mechanisms of dilation
Arterioscler Thromb Vasc Biol
 , 
2005
, vol. 
25
 (pg. 
671
-
678
)
28
Liu
Y
Gutterman
DD
Oxidative stress and potassium channel function
Clin Exp Pharmacol Physiol
 , 
2002
, vol. 
29
 (pg. 
305
-
311
)
29
Grover
AK
Samson
SE
Fomin
VP
Werstiuk
ES
Effects of peroxide and superoxide on coronary artery: ANG II response and sarcoplasmic reticulum Ca2+ pump
Am J Physiol
 , 
1995
, vol. 
269
 (pg. 
C546
-
C553
)
30
Walia
M
Samson
SE
Schmidt
T
Best
K
Kwan
CY
Grover
AK
Effects of peroxynitrite on pig coronary artery smooth muscle
Cell Calcium
 , 
2003
, vol. 
34
 (pg. 
69
-
74
)
31
Forstermann
U
Nitric oxide and oxidative stress in vascular disease
Pflugers Arch
 , 
2010
, vol. 
459
 (pg. 
923
-
939
)
32
Karlsson
K
Marklund
SL
Extracellular superoxide dismutase in the vascular system of mammals
Biochem J
 , 
1988
, vol. 
255
 (pg. 
223
-
228
)
33
Landmesser
U
Merten
R
Spiekermann
S
Buttner
K
Drexler
H
Hornig
B
Vascular extracellular superoxide dismutase activity in patients with coronary artery disease: relation to endothelium-dependent vasodilation
Circulation
 , 
2000
, vol. 
101
 (pg. 
2264
-
2270
)
34
Matoba
T
Shimokawa
H
Kubota
H
Morikawa
K
Fujiki
T
Kunihiro
I
Mukai
Y
Hirakawa
Y
Takeshita
A
Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries
Biochem Biophys Res Commun
 , 
2002
, vol. 
290
 (pg. 
909
-
913
)
35
Rogers
PA
Dick
GM
Knudson
JD
Focardi
M
Bratz
IN
Swafford
AN
Jr.
Saitoh
S
Tune
JD
Chilian
WM
H2O2-induced redox-sensitive coronary vasodilation is mediated by 4-aminopyridine-sensitive K+ channels
Am J Physiol Heart Circ Physiol
 , 
2006
, vol. 
291
 (pg. 
H2473
-
H2482
)
36
Saitoh
S
Zhang
C
Tune
JD
Potter
B
Kiyooka
T
Rogers
PA
Knudson
JD
Dick
GM
Swafford
A
Chilian
WM
Hydrogen peroxide: a feed-forward dilator that couples myocardial metabolism to coronary blood flow
Arterioscler Thromb Vasc Biol
 , 
2006
, vol. 
26
 (pg. 
2614
-
2621
)
37
Yada
T
Shimokawa
H
Hiramatsu
O
Shinozaki
Y
Mori
H
Goto
M
Ogasawara
Y
Kajiya
F
Important role of endogenous hydrogen peroxide in pacing-induced metabolic coronary vasodilation in dogs in vivo
J Am Coll Cardiol
 , 
2007
, vol. 
50
 (pg. 
1272
-
1278
)
38
Chen
Y
Hou
M
Li
Y
Traverse
JH
Zhang
P
Salvemini
D
Fukai
T
Bache
RJ
Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart
Am J Physiol Heart Circ Physiol
 , 
2005
, vol. 
288
 (pg. 
H133
-
H141
)
39
Beckman
JS
Koppenol
WH
Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly
Am J Physiol
 , 
1996
, vol. 
271
 (pg. 
C1424
-
C1437
)
40
Cathcart
MK
Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis
Arterioscler Thromb Vasc Biol
 , 
2004
, vol. 
24
 (pg. 
23
-
28
)
41
Munzel
T
Daiber
A
Ullrich
V
Mulsch
A
Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase
Arterioscler Thromb Vasc Biol
 , 
2005
, vol. 
25
 (pg. 
1551
-
1557
)
42
Vasquez-Vivar
J
Kalyanaraman
B
Martasek
P
Hogg
N
Masters
BS
Karoui
H
Tordo
P
Pritchard
KA
Jr.
Superoxide generation by endothelial nitric oxide synthase: the influence of cofactors
Proc Natl Acad Sci USA
 , 
1998
, vol. 
95
 (pg. 
9220
-
9225
)
43
de Beer
VJ
Taverne
YJ
Kuster
DW
Najafi
A
Duncker
DJ
Merkus
D
Prostanoids suppress the coronary vasoconstrictor influence of endothelin after myocardial infarction
Am J Physiol Heart Circul Physiol
 , 
2011
, vol. 
301
 (pg. 
H1080
-
H1089
)
44
Merkus
D
Visser
M
Houweling
B
Zhou
Z
Nelson
J
Duncker
DJ
Phosphodiesterase 5 inhibition-induced coronary vasodilation is reduced after myocardial infarction
Am J Physiol. Heart Circulatory Physiology
 , 
2013
, vol. 
304
 (pg. 
H1370
-
H1381
)
45
Haitsma
DB
Merkus
D
Vermeulen
J
Verdouw
PD
Duncker
DJ
Nitric oxide production is maintained in exercising swine with chronic left ventricular dysfunction
Am J Physiol
 , 
2002
, vol. 
282
 (pg. 
H2198
-
H2209
)
46
Treasure
CB
Vita
JA
Cox
DA
Fish
RD
Gordon
JB
Mudge
GH
Colucci
WS
Sutton
MG
Selwyn
AP
Alexander
RW
Ganz
P
Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy
Circulation
 , 
1990
, vol. 
81
 (pg. 
772
-
779
)
47
Recchia
FA
McConnell
PI
Bernstein
RD
Vogel
TR
Xu
X
Hintze
TH
Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog
Circ Res
 , 
1998
, vol. 
83
 (pg. 
969
-
979
)
48
Wang
J
Seyedi
N
Xu
XB
Wolin
MS
Hintze
TH
Defective endothelium-mediated control of coronary circulation in conscious dogs after heart failure
Am J Physiol
 , 
1994
, vol. 
266
 (pg. 
H670
-
H680
)
49
Feil
R
Lohmann
SM
de Jonge
H
Walter
U
Hofmann
F
Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice
Circ Res
 , 
2003
, vol. 
93
 (pg. 
907
-
916
)
50
Rybalkin
SD
Yan
C
Bornfeldt
KE
Beavo
JA
Cyclic GMP phosphodiesterases and regulation of smooth muscle function
Circ Res
 , 
2003
, vol. 
93
 (pg. 
280
-
291
)
51
Corbin
JD
Francis
SH
Cyclic GMP phosphodiesterase-5: target of sildenafil
J Biol Chem
 , 
1999
, vol. 
274
 (pg. 
13729
-
13732
)
52
Wallis
RM
Corbin
JD
Francis
SH
Ellis
P
Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro
Am J Cardiol
 , 
1999
, vol. 
83
 (pg. 
3C
-
12C
)
53
Senzaki
H
Smith
CJ
Juang
GJ
Isoda
T
Mayer
SP
Ohler
A
Paolocci
N
Tomaselli
GF
Hare
JM
Kass
DA
Cardiac phosphodiesterase 5 (cGMP-specific) modulates beta-adrenergic signaling in vivo and is down-regulated in heart failure
FASEB J
 , 
2001
, vol. 
15
 (pg. 
1718
-
1726
)
54
Gebska
MA
Stevenson
BK
Hemnes
AR
Bivalacqua
TJ
Haile
A
Hesketh
GG
Murray
CI
Zaiman
AL
Halushka
MK
Krongkaew
N
Strong
TD
Cooke
CA
El-Haddad
H
Tuder
RM
Berkowitz
DE
Champion
HC
Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity
Cardiovasc Res
 , 
2011
, vol. 
90
 (pg. 
353
-
363
)
55
Halcox
JP
Nour
KR
Zalos
G
Mincemoyer
RA
Waclawiw
M
Rivera
CE
Willie
G
Ellahham
S
Quyyumi
AA
The effect of sildenafil on human vascular function, platelet activation, and myocardial ischemia
J Am Coll Cardiol
 , 
2002
, vol. 
40
 (pg. 
1232
-
1240
)
56
Adachi
H
Nishino
M
Coronary artery diameter increase induced by a phosphodiesterase 5 inhibitor, E4021, in conscious pigs
Jpn J Pharmacol
 , 
1998
, vol. 
77
 (pg. 
99
-
102
)
57
Herrmann
HC
Chang
G
Klugherz
BD
Mahoney
PD
Hemodynamic effects of sildenafil in men with severe coronary artery disease
N Engl J Med
 , 
2000
, vol. 
342
 (pg. 
1622
-
1626
)
58
Tawakol
A
Aziz
K
Migrino
R
Watkowska
J
Zusman
R
Alpert
NM
Fischman
AJ
Gewirtz
H
Effects of sildenafil on myocardial blood flow in humans with ischemic heart disease
Coron Artery Dis
 , 
2005
, vol. 
16
 (pg. 
443
-
449
)
59
Weinsaft
JW
Hickey
K
Bokhari
S
Shahzad
A
Bedding
A
Costigan
TM
Warner
MR
Emmick
JT
Bergmann
SR
Effects of tadalafil on myocardial blood flow in patients with coronary artery disease
Coron Artery Dis
 , 
2006
, vol. 
17
 (pg. 
493
-
499
)
60
Merkus
D
Sorop
O
Houweling
B
Boomsma
F
van den Meiracker
AH
Duncker
DJ
NO and prostanoids blunt endothelin-mediated coronary vasoconstrictor influence in exercising swine
Am J Physiol Heart Circ Physiol
 , 
2006
, vol. 
291
 (pg. 
H2075
-
H2081
)
61
Boulanger
C
Luscher
TF
Release of endothelin from the porcine aorta. Inhibition by endothelium-derived nitric oxide
J Clin Invest
 , 
1990
, vol. 
85
 (pg. 
587
-
590
)
62
Kelly
LK
Wedgwood
S
Steinhorn
RH
Black
SM
Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase
Am J Physiol Lung Cell Mol Physiol
 , 
2004
, vol. 
286
 (pg. 
L984
-
L991
)
63
Razandi
M
Pedram
A
Rubin
T
Levin
ER
PGE2 and PGI2 inhibit ET-1 secretion from endothelial cells by stimulating particulate guanylate cyclase
Am J Physiol
 , 
1996
, vol. 
270
 (pg. 
H1342
-
9
)
64
Wiley
KE
Davenport
AP
Physiological antagonism of endothelin-1 in human conductance and resistance coronary artery
Br J Pharmacol
 , 
2001
, vol. 
133
 (pg. 
568
-
574
)
65
Wiley
KE
Davenport
AP
Nitric oxide-mediated modulation of the endothelin-1 signalling pathway in the human cardiovascular system
Br J Pharmacol
 , 
2001
, vol. 
132
 (pg. 
213
-
220
)
66
Vane
JR
Bakhle
YS
Botting
RM
Cyclooxygenases 1 and 2
Annu Rev Pharmacol Toxicol
 , 
1998
, vol. 
38
 (pg. 
97
-
120
)
67
Zidar
N
Dolenc-Strazar
Z
Jeruc
J
Jerse
M
Balazic
J
Gartner
U
Jermol
U
Zupanc
T
Stajer
D
Expression of cyclooxygenase-1 and cyclooxygenase-2 in the normal human heart and in myocardial infarction
Cardiovasc Pathol
 , 
2007
, vol. 
16
 (pg. 
300
-
304
)
68
Duffy
SJ
Castle
SF
Harper
RW
Meredith
IT
Contribution of vasodilator prostanoids and nitric oxide to resting flow, metabolic vasodilation, and flow-mediated dilation in human coronary circulation
Circulation
 , 
1999
, vol. 
100
 (pg. 
1951
-
1957
)
69
Edlund
A
Sollevi
A
Wennmalm
A
The role of adenosine and prostacyclin in coronary flow regulation in healthy man
Acta Physiol Scand
 , 
1989
, vol. 
135
 (pg. 
39
-
46
)
70
Friedman
PL
Brown
EJ
Jr.
Gunther
S
Alexander
RW
Barry
WH
Mudge
GH
Jr.
Grossman
W
Coronary vasoconstrictor effect of indomethacin in patients with coronary-artery disease
N Engl J Med
 , 
1981
, vol. 
305
 (pg. 
1171
-
1175
)
71
Pacold
I
Hwang
MH
Lawless
CE
Diamond
P
Scanlon
PJ
Loeb
HS
Effects of indomethacin on coronary hemodynamics, myocardial metabolism and anginal threshold in coronary artery disease
Am J Cardiol
 , 
1986
, vol. 
57
 (pg. 
912
-
915
)
72
Lubrano
V
Baldi
S
Ferrannini
E
L'Abbate
A
Natali
A
Role of thromboxane A(2) receptor on the effects of oxidized LDL on microvascular endothelium nitric oxide, endothelin-1, and IL-6 production
Microcirculation
 , 
2008
, vol. 
15
 (pg. 
543
-
553
)
73
Prins
B
Hu
R
Nazario
B
Pedram
A
Frank
H
Weber
M
Levin
E
Prostaglandin E2 and prostacyclin inhibit the production and secretion of endothelin from cultured endothelial cells
J. Biol. Chem.
 , 
1994
, vol. 
269
 (pg. 
11938
-
11944
)