(Circulation. 1996;93:1223-1229.)
© 1996 American Heart Association, Inc.
Articles |
Myocardial Contractile Response to Nitric Oxide and cGMP
From the Department of Physiology and Medicine, University of Antwerp, and the Cardiovascular Center (W.J.P.), O.L.V. Ziekenhuis, Aalst, Belgium.
Correspondence to Stanislas U. Sys, MD, PhD, Department of Physiology and Medicine, University of Antwerp (RUCA), Groenenborgerlaan 171, B-2020 Antwerp, Belgium.
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Abstract |
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Background Cardiac endothelium releases a number of factors that may modulate performance of underlying cardiac muscle. Nitric oxide (NO), which accounts for the biological activity of the vascular endothelium-derived relaxing factor and relaxes vascular smooth muscle by elevating intracellular cGMP, may be involved in this cardiac modulation.
Methods and Results We examined the myocardial contractile effects of the NO-releasing nitrovasodilators sodium nitroprusside (SNP), 3-morpholino-sydnonimine (SIN-1), and S-nitroso-N-acetyl-penicillamine (SNAP); of a cGMP analogue, 8-bromo-cGMP; and of the cGMP-phosphodiesterase inhibitor zaprinast in isolated cat papillary muscle. Modulation of these effects by endocardial endothelium (EE) and by cholinergic and adrenergic stimulation was also investigated. Concentration-response curves with addition of NO-releasing nitrovasodilators (SNP, SIN-1, SNAP) and 8-bromo-cGMP resulted in a biphasic inotropic response. Although administration of low concentrations induced a positive inotropic effect, higher concentrations induced a negative inotropic effect. Both NO-induced positive and negative inotropic effects were attenuated by methylene blue, suggesting a role for cGMP. The response to high concentrations of 8-bromo-cGMP was shifted to the right in muscles with damaged EE, whereas cholinergic stimulation shifted the curve leftward. Zaprinast caused a monophasic concentration-dependent positive inotropic effect; damaging the EE shifted the terminal portion of the curve upward. Concomitant cholinergic or adrenergic stimulation modified the response to zaprinast into a negative inotropic response.
Conclusions NO and cGMP induced a concentration-dependent biphasic contractile response. The myocardial contractile effects of NO and cGMP were modulated by the status of EE and by concomitant cholinergic or adrenergic stimulation.
Key Words: nitric oxide • myocardium • contractility • endothelium • endocardium
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Introduction |
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It has been increasingly recognized that the cardiac endothelium, both vascular and endocardial, regulates performance of underlying cardiac muscle, probably by release of certain factors.1 2 3 4 5 The mediators whose release from the EE has been demonstrated to date are NO,6 prostaglandin I2 and E2,7 endothelin,8 and other as yet unidentified factors.9
NO, which accounts for the biological activity of the vascular endothelium-derived relaxing factor, relaxes vascular smooth muscle by elevating intracellular cGMP.10 By analogy, NO may be involved in the endothelial modulation of myocardial performance through cGMP regulation11 in the myocyte. The role of NO in modulating cardiac contractility has been examined in different cardiac preparations and in humans. Administration of exogenous NO in vitro has generally been reported to cause a small negative inotropic effect with early induction of relaxation,2 12 13 14 although administration of physiological concentrations of NO was not associated with an acute negative inotropic effect.15 Paulus et al16 demonstrated, during intracoronary infusion of the NO donor SNP, a decrease in LV peak systolic pressure, an LV relaxation–hastening effect, and an increase in diastolic LV distensibility. Administration of inhibitors of NO synthase in experimental animals and in humans has also been associated with cardiac depression.17 18 19 20 21 The response to cGMP as well as the underlying mechanism is therefore multifaceted.22
It was believed that cGMP opposed the effects of cAMP (the "yin-yang" hypothesis)23 and thereby regulated cardiac contractility. The evidence for cGMP-mediated negative inotropic effect in the heart came mainly from experiments with acetylcholine, which increases intracellular cGMP concentration.24 25 26 27 28 29 This hypothesis has subsequently been challenged by the demonstration of a dissociation of cGMP concentrations and contractile state, since low concentrations of acetylcholine induced a negative inotropic effect even in the absence of any change in cGMP concentration.26 27 30 31 32 33 Increases in cGMP by other agents also did not correlate with changes in contractility.27 33 34 35 Administration of exogenous cGMP or its analogues has had variable effects on contractility: it has been reported to produce a negative inotropic effect in different cardiac preparations,30 35 36 37 38 39 40 41 42 which was not observed by others.43 Therefore, the precise role and importance of cGMP-mediated regulation of cardiac function have remained unclear.30 44 45 46
To explore the role of NO and cGMP in the modulation of myocardial contractile performance, this report examines the effects of the NO-liberating nitrovasodilators SNP, SIN-1, and SNAP; of a cGMP analogue, 8-bromo-cGMP; and of the cGMP-phosphodiesterase inhibitor zaprinast on isolated papillary muscles.
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Methods |
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Muscle Preparations
Muscle preparation, treatment, and experimental apparatus have been described in detail.1 Briefly, beating hearts were excised from anesthetized cats (sodium pentobarbitone 40 mg/kg IP); papillary muscles were isolated from the right ventricle and mounted vertically in a 50-mL organ bath containing Krebs-Ringer solution (composition in mmol/L: NaCl 118, KCl 4.7, MgSO4·7H2O 1.2, KH2PO4 1.1, NaHCO3 24, CaCl2·2H2O 1.25, glucose 4.5) at 29°C bubbled with a gas mixture of 95% oxygen/5% carbon dioxide. The tendinous end of the muscle was attached to an electromagnetic length-tension transducer. The muscle was stimulated electrically at 0.2 Hz by rectangular pulses of 5-ms duration and a voltage of
10% above threshold. The muscle was stabilized initially at 29°C
for 2 to 3 hours and then at 35°C for at least 1 hour at
Lmax.
Experimental Protocol
Myocardial performance was derived from
preloaded
isotonic and isometric twitches at 35°C and at Lmax.
After the control twitches were obtained, SNP (10 µmol/L) or SIN-1
(10 µmol/L) was added to the bath containing the papillary muscle
with intact EE and after the EE was damaged (see below). Muscle
twitches were recorded after a stable response was obtained,
usually after 10 to 15 minutes. Experiments were also performed with
SNP (10 µmol/L) or SIN-1 (10 µmol/L) in the presence of MB (50
µmol/L), an inhibitor of guanylate cyclase,
both before and after the EE was damaged. In a group of muscles with
intact EE, cumulative concentration responses were obtained for
SNAP (0.01 to 300 µmol/L). Cumulative concentration-response
curves were also obtained for the effects of the addition of
8-bromo-cGMP (1 µmol/L to 1 mmol/L), a poorly
hydrolyzable, lipophilic cGMP analogue, on isolated papillary muscles
both before and after the EE was damaged. The effects of
8-bromo-cGMP were recorded at 5 to 7 minutes after drug
administration. A cumulative concentration-response curve for
8-bromo-cGMP was also obtained in the presence of 1 µmol/L
acetylcholine, which has been well documented to increase intracellular
cGMP concentration in
cardiomyocytes.24 25 26 27 28 29
Experiments with acetylcholine were performed in the presence of the
cholinesterase inhibitor physostigmine (0.01 µmol/L). To
further evaluate the effect of an increase in basal intracellular cGMP
concentration in myocardium in the absence of exogenous
cGMP administration, additional experiments were performed using
zaprinast (M&B 22948), a selective inhibitor of cGMP
phosphodiesterase (PDE V). Cumulative concentration-response curves
were obtained with administration of zaprinast (1 nmol/L to 30
µmol/L) in muscles with both intact and damaged EE. To examine the
interaction of adrenergic and cholinergic stimulation with an increase
in intracellular cGMP secondary to zaprinast, zaprinast (1 µmol/L)
was also added to muscles with intact EE in the presence of a
ß-agonist (isoproterenol, 0.3 µmol/L) or acetylcholine (0.01
µmol/L).
The EE was selectively damaged by immersion of the mounted and stabilized muscles for 1 second in 0.5% Triton X-100 dissolved in preoxygenated Krebs-Ringer solution. This was followed by a rapid and abundant wash with the control Krebs-Ringer solution. This method induces endocardial damage with no damage to underlying myocardium.1
Parameters measured included AT and +dT/dt. Isometric twitch duration was assessed by tHR. Results are presented for isometric twitches only, since isotonic twitches showed similar results. Muscle cross-sectional area was calculated by dividing the lightly blotted wet weight of the muscle at the end of the experiment by its length at Lmax, assuming a cylindrical shape and a specific gravity of 1.0. Tension measurements were normalized by muscle cross-sectional area and length measurements by Lmax.
All the chemicals were obtained from a commercial catalogue (Sigma). SIN-1 was kindly provided by Therabel (Belgium). Zaprinast (M&B 22948) was kindly provided by Prof H. Bult, Department of Cardiovascular Pharmacology, University of Antwerp. The animal care and investigations conformed to institutional guidelines and to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication 85-23, revised 1985).
Statistical Methods
All the data are expressed as
mean±SEM. Values before and after
addition of SNP or SIN-1 were statistically compared by
paired-sample t test. Percent changes with addition of
SNP or SIN-1 in different conditions (±EE, without and with MB) were
compared by Kruskal-Wallis ANOVA, followed by a Dunn-type multiple
comparison test. Values obtained at different concentrations of SNP,
SIN-1, SNAP, 8-bromo-cGMP, or zaprinast for
concentration-response curves were compared with control values by
a randomized block ANOVA followed by a Dunnett-type multiple
comparison test. Statistical significance was considered at
P<.05.
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Results |
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TopAbstractIntroductionMethodsResults Discussion References |
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Effects of SNP and SIN-1
The administration of the NO-releasing nitrovasodilators SNP (10 µmol/L) or SIN-1 (10 µmol/L) to isolated papillary muscle with intact EE produced a negative inotropic effect (Figs 1
and
2), manifest as a reduction in AT and a shortening
of the twitch duration as suggested by tHR, with no change in +dT/dt,
as previously reported.2 47 The negative inotropic
effect
of SNP or SIN-1 in the intact EE papillary muscle was attenuated in the
presence of MB, an inhibitor of guanylate
cyclase, suggesting that it was mediated by cGMP (Figs 1 and
2).
Addition of MB alone had no significant inotropic effect.
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P<.05 vs +EE;
P<.05 vs without MB.
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When the EE
of the papillary muscle was selectively damaged, the
addition of SNP (10 µmol/L) or SIN-1 (10 µmol/L) produced a
positive inotropic effect (Figs 1
and 2)
appearing in 7 to 10 minutes
and lasting for at least 15 to 20 minutes. The positive inotropic
response to SNP or SIN-1 was apparent as an increase in AT (percent
change versus baseline: SNP, +8.9±1.9%; SIN-1,
+8.3±1.9%; both,
P<.05) and +dT/dt (SNP, +9.9±2.0%; SIN-1,
+10.3±3.2%; both, P<.05) with no change in twitch
duration. The presence of MB in the bath significantly diminished the
positive inotropic response to the nitrovasodilators
(P<.05), suggesting that this response was also mediated by
cGMP (Figs 1 and 2).
Effects of SNAP
Administration of SNAP, one of the most
stable NO-donor
substances, to a group of papillary muscles with intact EE was
associated with a concentration-dependent biphasic response for AT
(Fig 3). Whereas lower concentrations (0.01 to 10
µmol/L) caused a positive inotropic effect, higher concentrations
caused a negative inotropic response (% baseline: SNAP, 300 µmol/L;
AT, -12.0±3.2). The response on twitch duration was also
dependent on the concentration of SNAP administered (Fig 3). At
lower
concentrations (up to 1 µmol/L), there was no change in twitch
duration, whereas higher concentrations of SNAP caused a
concentration-dependent abbreviation of twitch duration (%
baseline: SNAP, 300 µmol/L; tHR, -5.8±0.9).
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Effects of 8-Bromo-cGMP
To further evaluate and clarify the
regulation of cGMP in
the myocardium and the role of EE, we used
8-bromo-cGMP, a lipophilic and poorly hydrolyzable analogue of
cGMP. Cumulative administration of 8-bromo-cGMP to the
isolated papillary muscle in the presence of either intact or damaged
EE revealed a biphasic response in contractility (Fig 4). In
papillary muscles with intact EE, an increase in
AT was observed with 8-bromo-cGMP concentrations from 1 to 30
µmol/L with no change in twitch duration (Fig 4,
representative twitches in inset). Further increase in
concentration of 8-bromo-cGMP above 30 µmol/L, however, caused a
concentration-dependent reduction in AT with a shortening of twitch
duration (tHR at 1 mmol/L 8-bromo-cGMP, -2.3±1.6%
versus baseline).
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When the EE was selectively damaged, the terminal
portion of the
concentration-response curve of 8-bromo-cGMP was shifted to the
right (Fig 4). Up to a 10-fold higher concentration (0.3
mmol/L) of
8-bromo-cGMP resulted in a positive inotropic response as
manifested by an increase in AT followed by a reduction in AT at 1
mmol/L 8-bromo-cGMP. Conversely, in the presence of acetylcholine
(1 µmol/L), the concentration-response curve of 8-bromo-cGMP
was shifted leftward (Fig 4). Addition of acetylcholine itself
had a
positive inotropic effect (1 µmol/L: AT, +12.5±3.4,
P<.05) with no change in twitch duration (tHR,
+0.6±1.0).
Effects of Zaprinast
Zaprinast, between 1 nmol/L and 30
µmol/L, caused a
concentration-dependent positive inotropic effect with no change in
twitch duration (30 µmol/L: AT, +9.7±2.2; tHR,
+1.6±1.6) (Fig 5). Damaging the EE shifted the
terminal portion
of the concentration-response curve upward, similar to the shift of
the concentration-response curve observed with 8-bromo-cGMP. In
the presence of isoproterenol (0.3 µmol/L), zaprinast (1 µmol/L)
induced a negative inotropic effect (AT, -21.1±6.2) (Fig
5).
Isoproterenol itself caused an increase in AT (+57.2±15.0)
associated
with a decrease in tHR (-6.3±1.8). A similar negative inotropic
effect (AT, -14.6±8.5) was observed by addition of zaprinast (10
µmol/L) in the presence of acetylcholine (0.01 µmol/L) (Fig
5),
which by itself had no significant effect (AT, -1.1±1.8).
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Discussion |
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TopAbstractIntroductionMethodsResults Discussion References |
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The results of the present study demonstrate a bidirectional myocardial response for myocardial contractility to three different NO-liberating vasodilators: SNP, SIN-1, and SNAP. The direction of the response was determined by the concentration of the NO donor used, by the integrity of the EE, and by the presence of cholinergic or adrenergic stimulation. The responses to SNP and SIN-1 were both attenuated by MB, suggesting that the observed responses may be a manifestation of cGMP regulating myocyte contractile response. SNP-induced negative inotropic effect in isolated papillary muscle has previously been shown to be associated with increased cGMP.2 However, a cGMP-mediated myocardial positive inotropic response produced by the addition of SNP has not been reported previously.2 47 Addition of the cGMP analogue 8-bromo-cGMP to isolated papillary muscles produced a concentration-dependent biphasic response in terms of myocardial contractility. The concentration-response curve of 8-bromo-cGMP could be shifted in opposite directions by damage to the EE or by prior cholinergic stimulation, respectively. Increasing intracellular cGMP concentration by inhibiting degradation of cGMP by zaprinast, a cGMP phosphodiesterase inhibitor, caused a concentration-dependent positive inotropic effect, with no negative inotropic effect observed even at high concentrations. However, in the presence of concomitant adrenergic or cholinergic stimulation, zaprinast induced a negative inotropic effect.
The observation of a concentration-dependent biphasic inotropic
response to SNAP and 8-bromo-cGMP, previously unreported, is of
considerable interest. These results suggest a novel role for NO and
cGMP in the regulation of myocardial performance. A
cGMP-induced positive inotropic response was also recently reported,
although unexplained, with low-dose intravenous
administration of zaprinast, an inhibitor of the
low-Km cGMP phosphodiesterase (PDE V), in
both anesthetized and conscious rats.48 49 The
observation of a concentration-dependent positive inotropic effect
with zaprinast in the present experiments is in agreement with
these reports. Present results are also consistent with
previous reports of negative inotropic effects of cGMP in isolated
papillary muscle preparations, since they invariably used high
concentrations (
100 µmol/L) of cGMP or its
analogues.30 37 38 39 40 41 42
Although a positive inotropic effect
with cGMP analogues was observed by some
investigators,30 43 this aspect of cGMP-mediated
regulation of cardiac contractility has subsequently
been ignored. Linden and Brooker30 quoted a personal
communication from A. Fabiato, who reported a biphasic contractile
effect with application of cGMP to single cardiac cells from which
sarcolemma had been stripped. cGMP 1 µmol/L enhanced developed
tension, whereas higher levels (100 µmol/L) had a depressant
contractile effect (observations still valid; A. Fabiato, MD, personal
communication, 1994). The authors suggested that this biphasic effect
of cGMP, which was inhibitory only when cGMP was elevated
to nonphysiologically high levels, was
mediated by direct action on contractile proteins and that lower levels
of cGMP (<1 µmol/L) enhance rather than depress
contractility. The results of the present study
support these conclusions, since elevation in intracellular cGMP, even
at high concentrations of zaprinast, did not cause a negative inotropic
effect, whereas administration of high concentrations (possibly
nonphysiological) of SNAP and 8-bromo-cGMP
did.
The mechanism of this dual response to cGMP in the myocardium cannot be ascertained from the present experiments. In isolated guinea pig ventricular myocytes, relatively low concentrations of cGMP (0.1 to 10 µmol/L) had a stimulatory effect on cAMP-elevated L-type ICa,50 which would lead to an increase in Ca2+ availability. Higher concentrations of cGMP, 8-bromo-cGMP, or cGMP-PK either had no effect or reduced ICa. It was suggested that this stimulation of cAMP-elevated ICa by low concentrations of cGMP was due to participation of cGMP-inhibitable cAMP-phosphodiesterase, whose presence in the heart has been well documented.51 52 The higher concentrations of cGMP have been reported to inhibit cAMP-elevated ICa via cGMP-PK in mammalian myocytes.53 Intracellular perfusion of cGMP-PK fragment caused a similar inhibition of ICa.54 In addition to its direct effects on Ca2+ channels, cGMP-PK may also decrease the Ca2+ sensitivity of the myofilaments through phosphorylation of the inhibitory subunits of troponin.55 In isolated cardiac myocytes, administration of relatively high concentrations of 8-bromo-cGMP (50 µmol/L) was associated with a negative inotropic effect that was mediated by cGMP-PK–induced decreased Ca2+ sensitivity of the myofilaments.42 The other possible mechanism underlying NO-cGMP–mediated positive inotropic effect may involve cADPR, a recently described intracellular second messenger. cADPR stimulates release of Ca2+ from intracellular stores through the ryanodine receptor in sea urchin eggs.56 57 cADPR has been shown to increase the open probability of cardiac ryanodine-sensitive Ca2+ channels.58 Thus, cADPR can trigger the release of Ca2+ from the sarcoplasmic reticulum in cardiac cells. In sea urchin eggs, cGMP-induced Ca2+ transient was mediated through ryanodine receptors by stimulation of cADP-ribosyl cyclase.59 These mechanisms still need to be examined specifically in cardiomyocytes with respect to NO-cGMP–mediated effects.
Administration of nitrovasodilators in various myocardial preparations has generally been associated with reductions in twitch amplitude and duration.2 15 41 42 This may be due to relatively large increases in cGMP levels produced by these agents in those preparations or utilization of high concentrations of the agent itself. An NO synthase inhibitor–induced cardiac depression in animals without associated change in arterial pressure, heart rate,17 18 coronary flow, and oxygen supply-demand ratio17 and regional myocardial tissue perfusion19 may be explained in part by a significant reduction in myocardial cGMP. Recently, two separate groups reported an unexplained NO synthase–induced myocardial depression.20 21 Inhibition of NO synthesis worsened myocardial stunning independent of effects on blood flow in conscious dogs.20 In human volunteers, inhibition of basal NO release with infusion of NG-monomethyl-L-arginine was associated with declines in cardiac output and stroke volume.21 The authors suggested that some basal release of NO is required to preserve cardiac function in vivo. Recently, an NO-mediated biphasic response of stimulated ICa was reported in frog ventricular myocytes with administration of increasing concentrations of SIN-1.60 All the responses to SIN-1 were inhibited by MB and LY83583, another inhibitor of guanylate cyclase. The authors suggested that the stimulatory effect of NO donors on ICa resulted from an inhibition of the cGMP-inhibitable cAMP-phosphodiesterase, whereas the inhibitory response was due to activation of the cGMP-stimulated cAMP-phosphodiesterase, both linked to the activation of guanylate cyclase. A similar stimulatory and inhibitory effect of SIN-1 on ICa was also reported by another group,61 but both the effects were said to be mediated by cGMP-PK.
Thus, it seems that the concentration-dependent biphasic response of contractility observed with SNAP and 8-bromo-cGMP may explain the apparently contradictory results reported with administration of exogenous cGMP analogues, NO donors, and NO synthase inhibitors in different models. According to the present study, the response to an increase in intracellular cGMP depends on cholinergic or adrenergic stimulation and on the state of EE. The change in direction of response to zaprinast from positively to negatively inotropic in the presence of ß-adrenergic stimulation is in accordance with the "yin-yang" hypothesis. It may be suggested that the "myofilament-desensitizing factor" reportedly released from cultured EE cells9 may have contributed to the negative inotropic effect observed with NO donors in muscles with intact EE. The loss of this factor by damage to the EE may then underlie the positive inotropic effect in muscles with damaged EE. Similarly, damaging the EE would also remove other endothelial mediators like prostaglandins and endothelin. However, since both prostaglandins62 and endothelin63 are positive inotropes in similar conditions, their absence does not explain the positive inotropic effects of NO donors in muscles with damaged EE. Another hypothesis that may be formulated from the observations in the present study would suggest regulation of intracellular cGMP concentration in the cardiomyocyte by the overlying EE. The results suggest that in the presence of an intact EE, nitrovasodilators or exogenous NO causes a further elevation in already high baseline myocardial cGMP levels, leading to a negative inotropic response. This is supported by the observation that a prior increase in intracellular cGMP with acetylcholine shifted the 8-bromo-cGMP response curve to the left with no positive inotropic effect even at low concentrations of 8-bromo-cGMP. Also, the positive inotropic effect of zaprinast (1 µmol/L) in control conditions was changed to a negative inotropic effect in the presence of acetylcholine, suggesting an increase in basal cGMP level by cholinergic stimulation. In hamster papillary muscle, cholinergic stimulation, in addition to its role in the negative force-frequency relation, may also be responsible for the positive inotropic effect of NO synthase inhibition14 through induction of a similar leftward shift of the cGMP response curve.
The role of a regulation of myocardial contractility by myocyte cGMP depending on cholinergic and adrenergic stimulation and on integrity of the EE in vivo is an exciting potential area of investigation, which may shed new light on the effects of NO on LV contractile performance in humans and on the therapeutic role of nitrovasodilators in patient management.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from the National Fund for Scientific Research (NFWO) and Levenslijn-VTM, Belgium. We also wish to acknowledge the Belgian Program on Interuniversity Poles of Attraction, initiated by the Belgian State, Prime Minister's Office, Science Policy Programming.
Received May 25, 1995; revision received October 12, 1995; accepted October 15, 1995.
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B. Stein, T. Eschenhagen, J. Rudiger, H. Scholz, U. Forstermann, and I. Gath Increased expression of constitutive nitric oxide synthase III, but not inducible nitric oxide synthase II, in human heart failure J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1179 - 1186. [Abstract] [Full Text] [PDF]
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J. Bartunek, S. Dempsey, E. O. Weinberg, N. Ito, M. Tajima, S. Rohrbach, and B. H. Lorell Chronic L-arginine treatment increases cardiac cyclic guanosine 5'-monophosphate in rats with aortic stenosis: effects on left ventricular mass and beta-adrenergic contractile reserve J. Am. Coll. Cardiol., August 1, 1998; 32(2): 528 - 535. [Abstract] [Full Text] [PDF]
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N. Suto, A. Mikuniya, T. Okubo, H. Hanada, N. Shinozaki, and K. Okumura Nitric oxide modulates cardiac contractility and oxygen consumption without changing contractile efficiency Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H41 - H49. [Abstract] [Full Text] [PDF]
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S. U Sys, G. W De Keulenaer, and D. L Brutsaert Physiopharmacological evaluation of myocardial performance: how to study modulation by cardiac endothelium and related humoral factors? Cardiovasc Res, July 1, 1998; 39(1): 136 - 147. [Full Text] [PDF]
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 I. S. Ali, M. Gandhi, B. A. Finegan, A. Koshal, and A. S. Clanachan Cardioprotection by Activation of NO/cGMP Pathway After Cardioplegic Arrest and 8-Hour Storage Ann. Thorac. Surg., May 1, 1998; 65(5): 1303 - 1309. [Abstract] [Full Text] [PDF]
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D. L. Brutsaert, P. Fransen, L. J. Andries, G. W. De Keulenaer, and S. U. Sys Cardiac endothelium and myocardial function Cardiovasc Res, May 1, 1998; 38(2): 281 - 290. [Abstract] [Full Text] [PDF]
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P. A De Mulder, S. G De Hert, R. J Van Kerckhoven, H. F Adriaensen, and T. C Gillebert Sodium nitroprusside enhances in vivo left ventricular function in {beta}-adrenergically stimulated rabbit hearts Cardiovasc Res, April 1, 1998; 38(1): 133 - 139. [Abstract] [Full Text] [PDF]
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R. E Klabunde, J. Tse, and H. R Weiss Guanylyl cyclase inhibition reduces contractility and decreases cGMP and cAMP in isolated rat hearts Cardiovasc Res, March 1, 1998; 37(3): 676 - 683. [Abstract] [Full Text] [PDF]
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L. J. Andries, D. L. Brutsaert, and S. U. Sys Nonuniformity of Endothelial Constitutive Nitric Oxide Synthase Distribution in Cardiac Endothelium Circ. Res., February 9, 1998; 82(2): 195 - 203. [Abstract] [Full Text] [PDF]
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 P. C. Kouretas, A. K. Myers, Y. D. Kim, P. A. Cahill, J. L. Myers, Y.-N. Wang, J. V. Sitzmann, R. B. Wallace, and R. L. Hannan Heparin And Nonanticoagulant Heparin Preserve Regional Myocardial Contractility After Ischemia-Reperfusion Injury: Role Of Nitric Oxide J. Thorac. Cardiovasc. Surg., February 1, 1998; 115(2): 440 - 449. [Abstract] [Full Text] [PDF]
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L. Fei, A. D. Baron, D. P. Henry, and D. P. Zipes Intrapericardial Delivery of L-Arginine Reduces the Increased Severity of Ventricular Arrhythmias During Sympathetic Stimulation in Dogs With Acute Coronary Occlusion : Nitric Oxide Modulates Sympathetic Effects on Ventricular Electrophysiological Properties Circulation, December 2, 1997; 96(11): 4044 - 4049. [Abstract] [Full Text]
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H. Hu Nipavan Chiamvimonvat Toshio Yamagishi Eduardo Direct Inhibition of Expressed Cardiac L-Type Ca2+ Channels by S-Nitrosothiol Nitric Oxide Donors Circ. Res., November 19, 1997; 81(5): 742 - 752. [Abstract] [Full Text]
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W. J. Paulus, S. Kastner, P. Pujadas, A. M. Shah, H. Drexler, and M. Vanderheyden Left Ventricular Contractile Effects of Inducible Nitric Oxide Synthase in the Human Allograft Circulation, November 18, 1997; 96(10): 3436 - 3442. [Abstract] [Full Text]
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K. Yamamoto, J. C. Burnett Jr., and M. M. Redfield Effect of endogenous natriuretic peptide system on ventricular and coronary function in failing heart Am J Physiol Heart Circ Physiol, November 1, 1997; 273(5): H2406 - H2414. [Abstract] [Full Text] [PDF]
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M. Kelm, S. Schafer, R. Dahmann, B. Dolu, S. Perings, U. K.M Decking, J. Schrader, and B. E Strauer Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation Cardiovasc Res, November 1, 1997; 36(2): 184 - 194. [Abstract] [Full Text] [PDF]
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B. Preckel, G. Kojda, W. Schlack, D. Ebel, K. Kottenberg, E. Noack, V. Thamer, E. Noack, and V. Thämer Inotropic Effects of Glyceryl Trinitrate and Spontaneous NO Donors in the Dog Heart Circulation, October 21, 1997; 96(8): 2675 - 2682. [Abstract] [Full Text]
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P. Beaulieu, R. Cardinal, P. Page, F. Francoeur, J. Tremblay, and C. Lambert Positive chronotropic and inotropic effects of C-type natriuretic peptide in dogs Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1933 - H1940. [Abstract] [Full Text] [PDF]
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 N. Abi-Gerges, T. Eschenhagen, L. Hove-Madsen, R. Fischmeister, and P.-F. Mery Methylene Blue Is a Muscarinic Antagonist in Cardiac Myocytes Mol. Pharmacol., September 1, 1997; 52(3): 482 - 490. [Abstract] [Full Text]
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B. D. Prendergast, B M. Sci, V. F. Sagach, and A. M. Shah Basal Release of Nitric Oxide Augments the Frank-Starling Response in the Isolated Heart Circulation, August 19, 1997; 96(4): 1320 - 1329. [Abstract] [Full Text]
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M. Flesch, H. Kilter, B. Cremers, O. Lenz, M. Südkamp, F. Kuhn-Regnier, and M. Böhm J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1340 - 1349. [Abstract] [Full Text]
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A. J. Sherman, C. A. Davis III, F. J. Klocke, K. R. Harris, G. Srinivasan, A. S. Yaacoub, D. A. Quinn, K. A. Ahlin, and J. J. Jang Blockade of Nitric Oxide Synthesis Reduces Myocardial Oxygen Consumption In Vivo Circulation, March 4, 1997; 95(5): 1328 - 1334. [Abstract] [Full Text]
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J. Bartunek, A. M. Shah, M. Vanderheyden, and W. J. Paulus Dobutamine Enhances Cardiodepressant Effects of Receptor-Mediated Coronary Endothelial Stimulation Circulation, January 7, 1997; 95(1): 90 - 96. [Abstract] [Full Text]
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R. A. Kelly, J.-L. Balligand, and T. W. Smith Nitric Oxide and Cardiac Function Circ. Res., September 1, 1996; 79(3): 363 - 380. [Full Text]
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R. R. Lamberts, M. H. P. van Rijen, P. Sipkema, P. Fransen, S. U. Sys, and N. Westerhof Increased coronary perfusion augments cardiac contractility in the rat through stretch-activated ion channels Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1334 - H1340. [Abstract] [Full Text] [PDF]
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J. Layland, J.-M. Li, and A. M Shah Role of cyclic GMP-dependent protein kinase in the contractile response to exogenous nitric oxide in rat cardiac myocytes J. Physiol., April 15, 2002; 540(2): 457 - 467. [Abstract] [Full Text] [PDF]
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H.-J. Cheng, Z.-S. Zhang, K. Onishi, T. Ukai, D. C. Sane, and C.-P. Cheng Upregulation of Functional {beta}3-Adrenergic Receptor in the Failing Canine Myocardium Circ. Res., September 28, 2001; 89(7): 599 - 606. [Abstract] [Full Text] [PDF]
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G. U. Ahmmed, Y. Xu, P. Hong Dong, Z. Zhang, J. Eiserich, and N. Chiamvimonvat Nitric Oxide Modulates Cardiac Na+ Channel via Protein Kinase A and Protein Kinase G Circ. Res., November 23, 2001; 89(11): 1005 - 1013. [Abstract] [Full Text] [PDF]
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F. Brunner, P. Andrew, G. Wolkart, R. Zechner, and B. Mayer Myocardial Contractile Function and Heart Rate in Mice With Myocyte-Specific Overexpression of Endothelial Nitric Oxide Synthase Circulation, December 18, 2001; 104(25): 3097 - 3102. [Abstract] [Full Text] [PDF]
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