Cardiovascular Research

Cardiovascular Research 1999 43(3):595-606; doi:10.1016/S0008-6363(99)00151-0
© 1999 by European Society of Cardiology

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Copyright © 1999, European Society of Cardiology

NO and cardiac diastolic function

Walter J Paulus^a,* and Ajay M Shah^b

^aCardiovascular Center, O.L.V. Ziekenhuis, Aalst, Belgium
^bDepartment of Cardiology, GKT School of Medicine, King’s College London, London, UK

^* Corresponding author. Tel.: +32-53-724-433

Received 13 January 1999; accepted 19 April 1999

KEYWORDS Clinical; Experimental; Heart; General physiology; Pathophysiology; Nitric oxide; Diastole; Endothelial function; Heart failure; Ventricular function

	1 Introduction

Top 1 Introduction 2 NO and myocardial... 3 NO and myocardial... 4 Conclusions References

 
Since the first report of a role for nitric oxide (NO) in modulating myocardial contractile function in 1991 [1], an enormous number of studies have been published in this field (recently reviewed in Refs. [2–4]). It is now recognised that, under physiological conditions, the major sources of NO that are important for contractile regulation are (1) endothelial-type nitric oxide synthase (eNOS) expressed in cardiac endothelial cells, and (2) eNOS expressed in cardiac myocytes themselves. In a variety of pathological situations, contractile function may also be influenced by inducible NOS (iNOS) expressed in several cell types, including infiltrating inflammatory cells, coronary microvascular and endocardial endothelial cells, coronary vascular smooth muscle, and cardiac myocytes. In contrast to the relatively well-defined, essentially species-independent primary action of NO in the vasculature (i.e., mediation of endothelium-dependent vasodilatation), in the heart multiple and sometimes contradictory actions of NO have been reported (Table 1). Some of these actions may be species-specific while others have not always been reproduced by independent laboratories despite the use of apparently similar experimental preparations and protocols. Apart from species and methodological differences, additional relevant factors that are likely to influence the response to NO include: the cellular source of NO, the amount released (or experimentally studied), prevailing redox balance and antioxidant status, the target tissue (e.g., atrial or ventricular tissue), interactions with neurohumoral and other stimuli, the presence of immune activation or disease, and the activation of distinct cGMP-dependent and -independent subcellular signal transduction pathways.

View this table: [in this window] [in a new window]   Table 1 Reported actions of NO on the heart. Due to constraints of space, only a limited number of original references have been cited. Many other original references may be found in the bibliography of Refs. [2–4]

 
Most studies that have investigated the effects of NO on contractile function have focused on the modulation of systolic function [3], and have attempted to classify NO as negatively or positively inotropic. However, in studies where a more complete analysis of mechanical performance has been undertaken, NO has been reported to exert significant effects on the relaxation phase of cardiac contraction, in some cases even in the absence of changes in systolic function. Indeed, the original observations on the effects of NO on basal contractile function in the setting of an isolated papillary muscle preparation with variable contraction modes, emphasized the unique action of NO to selectively induce an earlier onset of isometric relaxation without affecting the rate of isometric tension development [1]. Subsequent studies have reported similar relaxation-hastening effects of NO in several other preparations and species, including the human, and have also generally found an accompanying increase in diastolic myocardial distensibility.

In addition to these effects of NO on myocardial relaxation and diastolic function, it is now clear that NO can influence several other aspects of myocardial function (Table 1). The influence of NO on the responses to β-adrenergic stimulation is the subject of another review in this spotlight issue. Some of the other effects of NO are potentially relevant to basal contractile performance (i.e., in the absence of agonist prestimulation). A number of studies have reported that low (submicromolar) doses of NO may exert a small positive inotropic effect on basal contractile function, whereas a ‘relaxation-hastening’ effect of NO becomes apparent as the dose of NO is increased [5,6]. Experiments with NO donors suggest the potential for NO to modulate fundamental events of myocardial excitation–contraction coupling. Nitrosothiol agents have been shown to modulate sarcolemmal Ca²⁺ influx, independent of sarcoplasmic reticulum Ca²⁺ release or of cGMP, albeit at rather high (millimolar) doses [14]. Nitrosothiols and NO donors have also been reported to activate sarcoplasmic reticulum Ca²⁺ release [15]. Some investigations suggested that sarcoplasmic reticulum Ca²⁺ release channels may be inhibited by high doses of nitrosothiols [16]. It remains to be established whether endogenously released NO has similar effects on excitation–contraction coupling under physiological conditions. NO may also exert both chronotropic and dromotropic effects [3,10]. A series of studies by Hintze and colleagues have provided evidence for an effect of endothelium-derived NO to reversibly inhibit myocardial O₂ consumption (e.g. Ref. [9]). These authors suggested that the paracrine release of NO from coronary microvascular endothelial cells modulates myocardial O₂ consumption. It seems feasible that NO-dependent changes in energetics could also secondarily affect myocardial relaxation and diastolic function, although this possibility was not directly addressed.

Discussion of all of these areas is beyond the scope of the present article, but has been covered in detail elsewhere [2–4]. Some of these areas are also covered by other articles in this focused issue. In the present article, we focus on the effects of NO on myocardial relaxation and diastolic distensibility, both in experimental preparations and the human heart.

	2 NO and myocardial diastolic function in experimental preparations

Top 1 Introduction 2 NO and myocardial... 3 NO and myocardial... 4 Conclusions References

 
2.1 Papillary muscle studies
Much of the early work on the myocardial effects of NO was performed in isolated papillary muscle preparations [1,5]. Smith and colleagues [1] reported a characteristic pattern of changes in the ferret papillary muscle: an altered time course of isometric twitch, with an earlier onset of relaxation and a reduction in peak tension development, but little or no change in the maximum rate of tension development (dT/dt_max) (Fig. 1). These effects were observed with exogenous NO donors, endothelium-derived NO (released by substance P), a cGMP analogue, and with atrial natriuretic peptide (which raises myocardial cGMP via stimulation of particulate guanylyl cyclase). Such a pattern of effect — relatively selective for the relaxation phase of contraction — was quite unique for an ‘inotropic’ intervention (apart from atrial natriuretic peptide [17]), but resembled the immediate effects of a change in resting muscle length. Similar effects have been documented in cat and human papillary muscle following administration of NO donors (e.g. sodium nitroprusside) or the stimulation of endogenous NO release from endothelial or endocardial cells with stimuli such as substance P, 5-HT, ATP or aggregating platelets [5,18–21]. Recently, stimulation of β3-adrenoceptors in human ventricular muscle was also reported to induce an abbreviation of the isometric twitch and a decrease in peak tension via activation of eNOS [22].

View larger version (16K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Effect of NO or cGMP on myocardial relaxation. Left panel: isotonic contraction of isolated cardiac myocyte; middle panel: isometric contraction of isolated papillary muscle; right panel: auxotonic contraction of isolated ejecting heart. In each preparation, there is an earlier onset of relaxation with little or no effect on early systolic function. C=control trace prior to intervention; 8bcGMP=8-bromo-cGMP (50 µM); sub P=substance P (1 µM); SNP=sodium nitroprusside (10 µM).

 
2.2 Isolated heart studies
Similar effects of NO on LV relaxation have been documented in the isolated ejecting buffer-perfused guinea pig heart, studied at constant preload, afterload and heart rate. In this preparation, either sodium nitroprusside [23] or NO released from the coronary endothelium following stimulation with bradykinin or substance P [24], induced an earlier onset and faster rate of LV relaxation and a small reduction in peak LV pressure (LVP) without changing LV dP/dt_max (Fig. 1). These effects were independent of alterations in coronary flow, and could not be reproduced with the NO- and cGMP-independent vasodilator, nicardipine. The effects of sodium nitroprusside, substance P or bradykinin were inhibited by the NO scavenger haemoglobin. Identical effects were also observed in this preparation following acute exposure to an angiotensin converting enzyme (ACE) inhibitor, captopril [25]. This effect of captopril was inhibited either by a bradykinin B₂ receptor antagonist (HOE 140) or by haemoglobin, implying the involvement of a bradykinin and NO dependent mechanism [25]. Direct evidence for kinin-mediated release of NO from coronary microvessels, in response to several agents, such as ACE inhibitors, bradykinin, acetylcholine and ₂-adrenoceptor agonists, has been reported by Hintze and colleagues [26].

2.3 Isolated cardiac myocyte studies: altered myofilament responsiveness to Ca²⁺
An effect of NO and/or cGMP on twitch relaxation and diastolic properties has also been reported in isolated cardiac myocytes. In adult rat ventricular myocytes, 8-bromo-cGMP caused an earlier onset of isotonic twitch relaxation and an increase in diastolic cell length, without significantly altering either the amplitude of the Ca²⁺ transient or the diastolic Ca²⁺ level [27] (Fig. 1). Similar changes in isotonic twitch contraction and diastolic cell length were observed in rat cardiac myocytes following exposure to the NO donors, sodium nitroprusside or S-nitroso-N-acetyl-penicillamine (SNAP) [28,29]. The absence of changes in Ca²⁺ transient suggested that the subcellular mechanism of these effects was a reduction in myofilament responsiveness to Ca²⁺ [27]. The underlying mechanism for this remains to be clarified. It was previously reported that cGMP-dependent protein kinase (PKG) reduced myofilament Ca²⁺ sensitivity in skinned cardiac fibres by phosphorylating troponin I [30]. Consistent with such a mechanism, the effects of 8-bromo-cGMP in rat myocytes were blocked by a PKG inhibitor, KT5823, or by prior treatment with isoproterenol, which phosphorylates troponin I [27]. In contrast, Ito et al. [28] reported that the effects of sodium nitroprusside in rat myocytes were attributable to a fall in intracellular pH, secondary to inhibition of forward Na⁺–H⁺ exchange.

The NO- or cGMP-induced increase in myocyte diastolic length, in the absence of changes in diastolic Ca²⁺, has been suggested to be due to an acute reduction in active diastolic tone [27], and is analogous to the changes in LV diastolic pressure–volume relations observed in clinical studies (see below). The underlying mechanism of such an acute change in diastolic tone remains speculative, but could involve reduced force generation by low-intensity diastolic crossbridge cycling (secondary to reduced myofilament Ca²⁺ responsiveness), alterations in cytoskeletal protein properties or in contractile activity of myofibroblasts. An alternative mechanism is suggested by the finding that in isolated rabbit ventricular myocytes, exposure to lipopolysaccharide reduced cell volume through a NO and cGMP-mediated mechanism [31].

Alterations in myofilament responsiveness to Ca²⁺ contribute, at least in part, to the positive inotropic effects of endothelin-1 [32] and angiotensin II [33] in adult myocardium. A similar mechanism is thought to account in large part for the immediate increase in force that occurs following cardiac muscle stretch, i.e., the Frank–Starling response [34]. A recent report suggests that the delayed effects of muscle stretch may also involve stretch-induced autocrine release of angiotensin II and endothelin-1 [35]. Hence, it is feasible that multiple and often opposing paracrine signalling pathways (i.e., NO, angiotensin II, endothelin-1) as well as changes in muscle preload could interact via changes in myofilament responsiveness to Ca²⁺, and thereby affect myocardial relaxation and diastolic distensibility. Such interactions have not so far been studied in detail, and it is possible that interactions at other levels, e.g. changes in sarcolemmal Ca²⁺ influx, may also be involved. Recent studies do provide evidence for an interaction between the effects of NO and those of changes in muscle preload (i.e., stretch).

2.4 NO and the response to altered preload
In isolated ejecting guinea pig hearts, inhibition of endogenous NOS by N^G-monomethyl-L-arginine (L-NMMA) or by free haemoglobin significantly attenuated preload-induced increases in cardiac output, an effect that was independent of changes in coronary flow [36]. This effect of L-NMMA or haemoglobin was associated with a left- and upward shift of the (estimated) diastolic LV pressure–volume relation [36]. In anaesthetized dogs, L-NMMA increased diastolic myocardial stiffness and reduced preload-induced augmentation of cardiac output, while administration of L-arginine resulted in opposite effects [37]. These data suggest that endogenous NO facilitates the Frank–Starling response in the whole heart, probably by increasing diastolic distensibility. Furthermore, since the effects of L-NMMA were greater at higher preloads, it was suggested that the production/release of NO might be greater at higher LV end-diastolic volume [36]. Elegant studies by Pinsky et al. [38] have recently confirmed this. These investigators used a porphyrinic NO sensor in the beating rabbit heart to show that an increase or decrease in ventricular preload was followed by parallel changes in intramyocardial NO concentrations. They also showed that the source of NO appeared to be the cardiac endothelial cells. Thus, increased LV chamber stretch may increase the intra-cardiac release of NO, which in turn facilitates an increase in cardiac output by increasing diastolic LV distensibility and LV filling.

	3 NO and myocardial diastolic function in the normal human heart

Top 1 Introduction 2 NO and myocardial... 3 NO and myocardial... 4 Conclusions References

 
The direct effects of NO on diastolic LV function have been studied in the normal human heart, using brief (5 min), low-dose intracoronary infusions of sodium nitroprusside in patients with atypical chest pain and normal coronary arteries undergoing diagnostic cardiac catheterization [39]. A bicoronary infusion technique was employed, with adjustment of the dose of NO donor per coronary artery in accordance with coronary anatomy, in order to avoid inhomogeneous delivery to the LV myocardium. Bicoronary sodium nitroprusside infusion caused (1) an earlier onset of LV relaxation, (2) a concomitant reduction in peak and end-systolic LVP, without change in LV dP/dt_max (3) a fall in LV minimum and end-diastolic pressures (LVEDP), (4) an increase in LV end-diastolic volume, and (5) a down and rightward displacement of the LV diastolic pressure–volume relation (Fig. 2). The relaxation-hastening effects observed in the human heart were similar to the in vitro findings discussed above. The fall in LV minimum pressure and LVEDP at larger LV diastolic volumes and the down- and rightward displacement of individual diastolic LV pressure–volume plots are consistent with an NO-induced increase in LV diastolic distensibility.

View larger version (19K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Effect of bicoronary infusion of the NO donor, sodium nitroprusside (SNP), on the human heart. Left panel: changes in high-fidelity LV pressure; right panel: LV diastolic pressure–volume relation before and after SNP infusion. (Reproduced from Int J Cardiol 1995;50:225–231, with permission from Elsevier Science Ireland.)

 
A similar downward shift of the diastolic LV pressure–volume relation during intravenous (i.v.) administration of NO donors has previously been observed by several investigators, but was attributed to the effects of right ventricular unloading and biventricular interaction, secondary to venodilation [40–42]. Carroll et al. reported an i.v. nitroprusside-induced downward shift of the diastolic LV pressure–volume relation in patients with dilated cardiomyopathy who had elevated right atrial pressures [41]. Kingma et al. reported that the i.v. nitroglycerin-induced downward shift of the diastolic LV pressure–volume relation in heart failure patients was no longer apparent if LVP was expressed as transmural diastolic LVP by subtracting right ventricular from diastolic LVP [42]. However, the downward shift of the diastolic LV pressure–volume relation observed during bicoronary sodium nitroprusside infusion [39] could not be attributed to right ventricular unloading and biventricular interaction but instead appeared to result from a direct myocardial action of NO because: (1) the doses of sodium nitroprusside studied (2 to 4 µg/min) were too low to have significant vasodilator effects; (2) a right atrial infusion of the same dose of sodium nitroprusside failed to reproduce the observed changes in LV diastolic pressures; (3) the changes in LV diastolic pressure–volume relations persisted even after expression of filling pressures as transmural LV diastolic pressures by subtracting the right atrial from LV filling pressure; (4) the fall in LVEDP was accompanied by an increase in LV diastolic volumes and a slight fall in heart rate, both of which were incompatible with peripheral vasodilator effects of the NO donor. A similar increase in LV end-diastolic volume had previously also been observed during i.v. infusion of sodium nitroprusside in some patients with LV hypertrophy [43]. These data suggest that for control of LV diastolic volume, the myocardial effects of NO can override its venodilator effects during i.v. administration of NO donors.

The stimulation of endogenous NO release from coronary endothelium, by bicoronary infusion of the specific agonist substance P, produced similar effects on LV relaxation and diastolic function in subjects with normal cardiac function [44]. Bicoronary infusion of substance P caused an earlier onset of LV relaxation, a reduction in peak and end-systolic LVP, a fall in LVEDP at larger LV end-diastolic volume, and a downward displacement of the LV diastolic pressure–volume relation.

3.1 Autoregulatory, beat-to-beat modulation of cardiac function by NO?
The most relevant physiological stimuli for the release of NO by cardiac endothelial cells are likely to be physical forces, i.e., pulsatile flow-induced fluid shear stress and mechanical deformation (e.g. stretch) [45–47]. The localisation of eNOS to plasmalemmal caveolae [48] may be important for this mechanotransduction. Since these physical forces vary in a cyclical fashion during the cardiac cycle, it has been speculated that the release and action of NO may also be cyclical [4]. Over 25 years ago, it was reported that cGMP levels in frog myocardium vary during a single cardiac cycle, with a rise in levels coinciding with ventricular relaxation [49]. Now, Pinsky et al. have demonstrated with the use of a porphyrinic NO sensor that there is indeed a cyclical release of NO in the beating heart, with a brisk rise around the time of early diastolic filling [38]. Thus, bursts of NO are released at precisely the appropriate time for modulation of myocardial relaxation and diastolic tone. NO released early in diastole would also serve to maximise coronary perfusion.

Variations in the release of NO, perhaps even on a beat-to-beat basis, may serve to provide an acute autoregulatory feedback between LV workload and diastolic LV performance, thus optimising overall pump function. For example, during periods of increased LV workload (such as exercise), the accompanying increases in heart rate, preload, contractility, and coronary flow would lead to increased stimuli for the release of NO (i.e., increased flow pulsatility, greater mechanical forces on endothelial cells, and increased shear stresses). Augmented NO release would (1) hasten LV relaxation, thus prolonging the diastolic interval for LV filling and coronary perfusion, (2) increase LV distensibility, thus improving LV filling as well as subendocardial blood flow due to reduced diastolic wall stress.

3.2 NO and diastolic dysfunction
Diastolic LV dysfunction is characterised by delayed or incomplete LV relaxation and/or increased ventricular diastolic stiffness [50]. The former usually affects early diastole and may compromise early LV filling, while the latter may impair late (‘passive’) LV filling. An increased diastolic chamber stiffness may also compromise subendocardial blood flow, and may lead to pulmonary congestion and dyspnoea secondary to elevated LV filling pressures. Cardiac conditions characterised by diastolic LV dysfunction include pressure-overload LV hypertrophy, ischaemia–reperfusion, dilated cardiomyopathy (DCM), the cardiac allograft, and diabetic cardiomyopathy. Many of these conditions are also characterised by endothelial dysfunction. In view of the previously described effects of NO on LV diastolic function, it is possible that deficient NO production (or action) could contribute to diastolic dysfunction. In addition, augmentation of NO or cGMP could be a useful therapeutic strategy in these conditions.

In some situations, the excessive production of NO (e.g. with induction of iNOS) may also lead to diastolic dysfunction, usually in the context of peroxynitrite formation. The reaction between equimolar amounts of NO and superoxide leads to the formation of peroxynitrite, which may be deleterious via formation of hydroxyl-like species that can modify protein structure and function [51]. In general, diastolic dysfunction resulting from excessive NO and/or peroxynitrite formation will usually be accompanied by systolic dysfunction. We now consider the roles of NO in several conditions characterised by diastolic dysfunction.

3.3 Experimental hypoxia-reoxygenation
Myocardial reperfusion (or reoxygenation) following brief ischaemia (or hypoxia) results in profound, although usually transient, diastolic dysfunction. The underlying mechanisms are not fully understood but may involve alterations in myofilament responsiveness to Ca²⁺ as well as cytosolic Ca²⁺ overload. A decrease in NO availability could theoretically play a role. In adult rat cardiac myocytes, pretreatment with 8-bromo-cGMP fully prevented the markedly impaired relaxation otherwise seen upon reoxygenation following 10 min severe hypoxia [52]. Similarly, in the isolated rat heart, supplementation with sodium nitroprusside during brief hypoxia improved LV relaxation [53]. NO donors also inhibited reoxygenation-induced hypercontracture of isolated rat cardiac myocytes following severe prolonged hypoxia [54]. NO-dependent changes in cardiac substrate utilization, O₂ consumption and efficiency [9] could also affect the response to hypoxia-reoxygenation and the occurrence of diastolic dysfunction.

On the other hand excessive production of NO and peroxynitrite may also lead to diastolic dysfunction. Cardiac reoxygenation (or reperfusion) is associated with the generation of peroxynitrite [55], and it has been shown that this can profoundly inhibit respiration and contractility [56]. In experimental diabetic cardiomyopathy in rats, it was recently reported that myocardial iNOS expression accounted for a profound post-hypoxic diastolic LV dysfunction of isolated hearts, which could be abrogated by a selective iNOS inhibitor [57].

3.4 LV hypertrophy
In a guinea-pig model of compensated LVH with diastolic dysfunction (induced by aortic banding), MacCarthy and colleagues reported that the LV relaxant effect of agonists that stimulate NO release from coronary endothelium (bradykinin, substance P, ACE inhibitors) was blunted, independent of changes in coronary flow [58]. However, the LV relaxant effect of sodium nitroprusside was unaffected, suggesting that the responsiveness of hypertrophied myocardium to NO was unaltered but that endothelial dysfunction may contribute to the diastolic dysfunction. Consistent with this, the expression of eNOS in coronary microvascular endothelial cells of aged spontaneously hypertensive rats (SHR) was found to be reduced [59], whereas this was not the case in young SHR [60]. However, Ito and colleagues found that in a rat model of pressure-overload LV hypertrophy, the response of isolated cardiac myocytes to sodium nitroprusside was abolished, suggesting that hypertrophied myocardium was less responsive to NO [28]. The difference between these studies could relate to the different models studied (isolated hearts versus unloaded myocytes) or different severities of LV hypertrophy.

In patients with aortic stenosis and severe LV hypertrophy, intracoronary administration of nitroglycerin or of sodium nitroprusside resulted in a marked fall in LVEDP and in LV end-diastolic chamber stiffness [61], which was larger than the fall observed in normal subjects by a different group [39]. However, the NO-induced reduction in peak and end-systolic LVP was smaller than in normal controls [61]. These data suggested a higher susceptibility of hypertrophied myocardium to the distensibility-increasing effect but not the relaxation-hastening effect of NO. However, alternative explanations for the larger effect of NO on LVEDP could be: (1) that the hypertrophied LV was operating on a steeper portion of the diastolic LV pressure–volume relation, such that a similar downward displacement of the pressure–volume relation would result in a larger fall in LVEDP compared to a normal LV operating on the flat portion of the diastolic LV pressure–volume relation; and/or (2) that part of the fall in LVEDP was attributable to relief of latent subendocardial ischaemia. Clearly, further studies are required to confirm whether hypertrophied myocardium truly has a different sensitivity to the distensibility-increasing and relaxation-hastening effects of NO, whether the action of endothelium-derived NO is altered, and if so what the underlying mechanisms are.

3.5 The cardiac allograft
The excessive production of NO by iNOS is implicated in cardiac transplant rejection, both experimentally and in human patients (reviewed in Ref. [62]). It is likely that in this setting NO and peroxynitrite contribute to systolic and diastolic dysfunction via multiple mechanisms, including cardiodepression, Ca²⁺ overload, impaired energetics, inflammation and increased microvascular permeability. In a clinical study of transplant recipients studied in the first year after surgery, Lewis et al. [63] reported an association between the presence of iNOS mRNA in surveillance endomyocardial biopsies and systolic and diastolic LV dysfunction assessed by echocardiography.

A number of clinical studies have investigated the effects of NO on myocardial function in non-rejecting cardiac allografts. Transplant recipients had smaller reductions in peak systolic LVP and in LVEDP following bicoronary sodium nitroprusside than normal subjects, with a similar rise in LV end-diastolic volume [44,64]. Baseline diastolic LV dysfunction of the cardiac allograft (e.g., increased LVEDP and , the time constant of isovolumic LV relaxation) predicted a smaller relaxation-hastening effect of exogenous NO. This might possibly be due to increased ROS production in the transplanted hearts, which would inactivate NO as well as cause basal diastolic dysfunction.

Another possibility is an alteration of the β-adrenergic pathway in the cardiac allograft (possibly related to cardiac denervation), leading to reduced cAMP levels. In isolated papillary muscle, it has been reported that the relaxation-hastening effect of NO is greater at higher baseline cAMP levels [5]. In allograft recipients, the relaxation hastening effect of intracoronary NO could indeed be profoundly augmented following pretreatment with i.v. dobutamine (Fig. 3) [65]. In these patients, concurrent β-adrenergic stimulation and endothelial release of NO resulted in a dramatic decrease in peak and end-systolic LV pressure with a minimal or no reduction in LV dP/dt_max. In these studies, the decrease in peak and end-systolic LV pressure was not the consequence of a reduction in the rate of LV pressure development, but instead due to premature LV relaxation. Similarly, in allograft recipients with high iNOS mRNA expression in simultaneously procured endomyocardial biopsies, an i.v. dobutamine infusion elicited a larger relaxation-hastening effect and a larger reduction in peak and end-systolic LVP than in recipients with low iNOS gene expression [66]. This pattern of effects (which is similar to the relaxation-hastening effects of NO described earlier) differs from those reported in clinical studies that have found an interaction between NOS inhibition and β-adrenergic response [67], in that the latter was manifest as a significant change in LV dP/dt_max (i.e., in systolic function). The subcellular mechanism(s) underlying the interaction between the relaxation-hastening effects of NO and β-adrenergic stimulation remains to be defined, but obvious possibilities include a cumulative effect on myofilament responsiveness to Ca²⁺ or an enhancement of NO release by cAMP-dependent mechanisms.

View larger version (79K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 3 Effect of intracoronary substance P (SP-IC) in a cardiac transplant recipient before and during co-infusion of intravenous dobutamine (DOB-IV). The traces show the electrocardiogram (top panel), LV dP/dt, and LV pressure recorded via a Millar catheter. Before intravenous dobutamine (above), substance P induces a small fall in peak and end-systolic LV pressure without significant change in LV dP/dtmax. During co-infusion of dobutamine (below), substance P induces a substantial decrease in peak and end-systolic LV pressure, again with minor reduction in LV dP/dtmax.

 
3.6 Dilated cardiomyopathy and heart failure
There is considerable interest in the potential role of NO in the pathophysiology of cardiac dysfunction in heart failure. A widely proposed mechanism invokes excessive production of NO in the heart secondary to iNOS induction, which would then lead to cardiac depression in a similar manner to that proposed to occur in septic shock. This hypothesis is based mainly on studies reporting the presence of iNOS (mRNA, protein and/or Ca²⁺-independent NOS activity) in cardiac tissue of patients with DCM and/or ischaemic cardiomyopathy [68–71], as well as the presence of high levels of cytokines such as tumour necrosis factor- (TNF-) that are known to induce iNOS [70,72,73]. However, it should be emphasised that direct proof of this hypothesis (i.e., that induction of iNOS in the heart in vivo leads to cardiac depression in heart failure) is lacking. It has generally been assumed that a major cell type expressing iNOS in failing myocardium is the cardiac myocyte. Haywood et al. [69] and Habib et al. [70] reported immunocytochemical evidence for iNOS protein expression in cardiac myocytes of ischemic and non-ischemic failing hearts. However, Vejlstrup et al. [74] found that iNOS mRNA and protein were invariable located to vascular endothelial and smooth muscle cells in a study of explanted hearts from patients with end-stage DCM (n=8) or ischaemic cardiomyopathy (n=14). Some myocyte iNOS expression was found only in a minority of patients. In another study of 25 explanted failing human hearts (eight with DCM, 13 with ischaemic cardiomyopathy), cardiac iNOS activity correlated with the density of infiltrating macrophages but not with apparent iNOS expression in cardiac myocytes, regardless of heart failure aetiology [75]. Stein et al. [76] reported that iNOS was expressed only in two of 30 end-stage failing hearts (14 DCM, nine ischaemic and seven post-myocarditis). In an in vitro study of dedifferentiated human cardiac myocytes, it was suggested that expressed iNOS was non-functional [77], although the relevance of this finding to the situation in vivo may be questioned. Similar data have been reported in experimental animal studies. In canine pacing-induced heart failure in conscious dogs, the total cardiac production of NO_x was found to be reduced [9]. In heart failure-prone rats (SHHF), no evidence of iNOS activity was detected [78].

Direct evidence for a deleterious functional effect of iNOS on baseline LV function in human heart failure is also lacking. In DCM patients, intracoronary administration of L-NMMA had no significant effect on baseline LV contractile function (LV dP/dt_max) [67]. In this study, L-NMMA augmented the inotropic response to dobutamine, but whether this involved iNOS was not studied. Likewise, L-NMMA had no effect on baseline isometric force of left ventricular muscle strip preparations isolated from end-stage failing hearts with apparent high iNOS activity [71]. In this study too, L-NMMA was found to increase the inotropic response to β-adrenergic stimulation. However, the same was not found in a study of myocytes isolated from end-stage failing human myocardium [79]. In coronary microvessels and cardiac myocytes isolated from failing human hearts, Hintze’s group reported that the release of NO from microvessels was reduced and that there was no detectable NO produced by myocytes [26].

What happens to cardiac expression and activity of eNOS in heart failure is also not definitively established. Numerous clinical and experimental studies have reported that endothelium-mediated coronary vasodilatation (macrovascular and microvascular) is reduced in heart failure [80–83]. In pacing-induced heart failure in conscious dogs, this was associated with a decreased expression of eNOS [81]. However, some studies have suggested that the expression of eNOS is increased in end-stage human heart failure, although evidence of increased activity was not provided [76]. Fukuchi et al. [75] reported a variably increased eNOS only in subendocardial cardiac myocytes, which did not correlate with eNOS activity, and found that eNOS expression elsewhere in the heart (especially in coronary microvessels) was reduced. In some animal models, e.g. the SHHF rat, LV Ca²⁺-dependent NOS activity and eNOS protein expression is reportedly increased compared to SHR [78].

Both with respect to iNOS and eNOS, it must be borne in mind that the level of expression of mRNA or protein does not necessarily reflect functional activity, which may be impaired because of substrate (L-arginine) or co-factor (tetrahydrobiopterin) deficiency or may even be dysfunctional with production of superoxide [84,85]. Furthermore, the results of NOS activity assays performed in the presence of non-limiting concentrations of substrate and co-factors may not necessarily reflect the true activity of the enzyme in vivo. A final caveat is that the expression and activity of both NOS proteins may vary according to the stage of progression of cardiac dysfunction and heart failure.

Some recent studies have linked altered eNOS and iNOS expression/activity with changes in LV diastolic function in heart failure. In pacing-induced heart failure in conscious dogs, Recchia et al. [9] found a close inverse correlation between reduced basal cardiac production of NO and elevated LVEDP, suggesting that this might reflect loss of control by NO of LV relaxation and venous return. These authors also reported that the reduction in NO production was associated with a switch in myocardial substrate utilisation, from free fatty acids to glucose, and a decrease in cardiac efficiency. It is feasible that these metabolic changes may contribute to diastolic dysfunction.

In DCM patients, the relaxation-hastening effect of substance P was potentiated following pretreatment with dobutamine [65], as was found to be the case in transplant recipients. Again similar to the transplant patients, i.v. dobutamine induced a larger relaxation-hastening effect and a larger concomitant drop in end-systolic LVP in patients who had high expression of iNOS mRNA in simultaneously procured endomyocardial biopsies [86]. In an extension of these studies, parameters of LV function in DCM patients were correlated with the expression level of iNOS and eNOS mRNA (measured by competitive PCR) in simultaneously procured endomyocardial biopsies [87]. Good linear correlations were observed between LV stroke work and the level of eNOS or iNOS mRNA expression. Furthermore, in the same patients, intracoronary substance P infusion caused an increase in LV stroke work, which resulted from rightward displacement of the diastolic LV pressure–volume relation [88]. These data are consistent with the hypothesis that endothelium-derived NO increased LV distensibility and thereby LV preload-recruitable stroke work.

Taken together with the findings of Recchia et al. [9] in conscious dogs, there thus appears to be some evidence that intra-cardiac NO can in fact be beneficial for baseline LV function in heart failure, (1) by optimising diastolic function, especially in patients with reduced inotropic reserve who are dependent on the LV Frank–Starling response to maintain cardiac output, and (2) by its effects on myocardial metabolism and O₂ consumption. Deficiency of NO appears to correlate with diastolic dysfunction in heart failure. Further studies are required to confirm these data, to define the mechanisms responsible for the variations in iNOS and eNOS gene expression in individual patients, and to directly establish the relationship between NOS gene expression and functional activity in vivo.

3.7 Chronic effects of NO on normal and abnormal diastolic function?
Changes in diastolic LV function as a result of chronic effects of NO merit consideration. NO is known to have anti-mitogenic effects in the vasculature, and recent studies indicate that it can also inhibit myocardial hypertrophy and deleterious LV remodelling independent of effects on cardiac loading [13,89,90]. Thus, it is feasible that NO may also influence diastolic function by modifying LV structure and passive properties. Consistent with this, chronic blockade of NOS in rats treated for 8 weeks with oral L-NAME results in an upward shift of the diastolic LV pressure–volume relation and a significant reduction in LV unstressed volume despite the absence of an increase in LV mass [91]. The possible role of augmented NO release in mediating appropriate LV remodelling, e.g. the dilatation of the athlete’s heart, also merits investigation, since coronary endothelial eNOS expression and NO release are upregulated with chronic exercise [92].

	4 Conclusions

Top 1 Introduction 2 NO and myocardial... 3 NO and myocardial... 4 Conclusions References

 
NO released from the coronary endothelium influences several aspects of myocardial contractile function. Among these is a distinct effect on basal diastolic LV function, comprising a hastening of LV relaxation and an increase in LV distensibility. Variations in the release of NO in accordance with prevailing cardiac workload, signalled via preload, coronary flow, mechanical forces and heart rate, may provide an acute autoregulatory feedback that optimises diastolic LV performance and overall pump function–possibly even on a beat-to-beat basis. Deficient production of NO in conditions such as pressure-overload LV hypertrophy, the cardiac allograft, and heart failure contributes to diastolic dysfunction. Appropriate augmentation of NO may be beneficial in these conditions, especially for patients with heart failure and reduced inotropic reserve who are dependent on the LV Frank–Starling response to maintain cardiac output. In some settings, the excessive production of NO and/or peroxynitrite may also cause diastolic dysfunction, which however will usually be accompanied by systolic dysfunction.

Time for primary review 34 days.

	Acknowledgements

 
We are very grateful to all our colleagues and collaborators who have contributed to the studies discussed here. AMS is supported by the British Heart Foundation (RG/98008).

	References

Top 1 Introduction 2 NO and myocardial... 3 NO and myocardial... 4 Conclusions References

 

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