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Cardiovascular Research 1998 38(1):133-139; doi:10.1016/S0008-6363(97)00297-6
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Sodium nitroprusside enhances in vivo left ventricular function in β-adrenergically stimulated rabbit hearts

Peter A De Muldera, Stefan G De Herta,*, Roeland J Van Kerckhovenb, Hugo F Adriaensena and Thierry C Gillebertc

aDepartment of Anesthesiology, University of Antwerp, Antwerp, Belgium
bDepartment of Experimental Surgery, University of Antwerp, Antwerp, Belgium
cDepartment of Cardiology, University of Antwerp, Antwerp, Belgium

* Corresponding author. Department of Anesthesiology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Edegem, Belgium. Tel.: +32 (3) 821-3042; Fax: +32 (3) 825-0594; E-mail: sdehert@uia.ac.be

Received 17 July 1997; accepted 28 October 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Sodium nitroprusside (SNP) is an activator of soluble guanylate cyclase, which depresses myocardial contractility. These exclusively negative inotropic effects of SNP were recently challenged by in vitro data. In isolated rat ventricular myocytes, a moderate increase of cGMP improved the contractile response at baseline and in isoprenaline-stimulated conditions. The present study evaluated in vivo the inotropic effects of SNP at baseline and during administration of low dose dobutamine. Methods: Anesthetized open-chest rabbits (n=18) were instrumented with micromanometers, ultrasound crystals and atrial pacing wires. Measurements were obtained during caval occlusion with ventilation suspended at end-expiration. Systolic function was assessed with dP/dtmax and the slope Ees of the end-systolic pressure–volume relation. Diastolic function was assessed with the time constant {tau} and the stiffness constant Kc of the diastolic pressure–volume relation. SNP (0.02, 0.08, 0.32 µg·kg–1·min–1) was administered at baseline and during low dose dobutamine. Results: At baseline, SNP reduced dP/dtmax from 3750±88 to 3470±88 mmHg/s (mean±s.e.m.) and Ees from 148±16 to 103±13 mmHg/ml (P<0.01). During dobutamine infusion, SNP increased dP/dtmax from 4340±125 to 4681±230 mmHg/s and Ees from 148±19 to 190±30 mmHg/ml (P<0.01). Effects of SNP on dP/dtmax and Ees were different at baseline and during dobutamine (interaction P<0.01). SNP did not alter Kc at baseline nor during dobutamine. Conclusions: SNP enhances in vivo systolic function in β-adrenergically stimulated rabbits.

KEYWORDS Rabbit; Sodium nitroprusside; Dobutamine; Systolic; Diastolic; Ventricular function


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Sodium nitroprusside (SNP) is a widely used nitrovasodilator and an activator of soluble guanylate cyclase [1, 2]. In isolated ferret papillary muscles, SNP induced an earlier onset of isometric twitch relaxation and a slight reduction in peak force. These effects were associated with elevation of cyclic 3',5'-guanosine monophosphate (cGMP) content [3]. In isolated cardiac myocytes, administration of the cGMP analog 8-bromo-cGMP reduced twitch amplitude and time to peak shortening. The observed negative inotropic effect was attributed to a decreased affinity of the cross-bridges for Ca2+ [4]. In addition, elevation of intracellular cGMP through SNP was shown to inhibit cyclic 3',5'-adenosine monophosphate (cAMP)-stimulated L-type Ca2+ current [5]. Negative inotropic effects of cGMP regulating agents were confirmed in selected patient populations during infusion of SNP and during infusion of substance P [6–8].

The idea that stimulation of cGMP would solely depress contractility, was recently challenged by in vitro data. In guinea pig ventricular myocytes, cGMP was found to stimulate the L-type Ca2+ current in the presence of isoprenaline or cAMP [9]. In isolated rat ventricular myocytes, a moderate increase of cGMP improved the contractile response by increasing cAMP and activating cAMP-dependent protein kinase [10].

In order to study the inotropic response to SNP in the in vivo situation, effects of SNP were evaluated in healthy rabbits at baseline and during administration of low-dose dobutamine.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Subjects
The experimental procedures were approved by the Local Committee For Ethics of the University of Antwerp, and conformed with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1985). The population comprised 18 male New Zealand White rabbits (mean body weight 3.3 kg, range 2.7–3.9 kg) supplied by the State Center for Small Animal Breeding (Merelbeke, Belgium).

2.2 Experimental preparation
Anesthetic regimen and surgical technique resulted in a preparation characterized by limited adrenergic stimulation and by cardiovascular and biochemical stability for a duration exceeding the duration of the present protocol [11]. Animals were anesthetized by intramuscular administration of a combination of ketamine hydrochloride (25 mg/kg, i.m.) and xylazine hydrochloride (15 mg/kg, i.m.). Tracheostomy was performed and mechanical ventilation was started. Anesthesia was maintained with i.v. administration of propofol 0.6 mg·kg–1·min–1, fentanyl 0.5 µg·kg–1·min–1 and vecuronium bromide 0.3 mg·kg–1·h–1. Fluid infusion rate was set at 1 ml/min throughout to compensate for the vasodilating effects of the anesthetics, evaporation and surgical fluid loss [11]. During the test period, left ventricular (LV) end-diastolic pressure was kept constant at 7–8 mmHg with small boluses (2 ml) of a solution of modified gelatins (Geloplasma®, Pasteur Mérieux MSD, Belgium; MW 23 000–35 000 Da in Ringer's solution without Ca2+) to ensure similar LV preload conditions. Bilateral cervical vagotomy was performed at the level of the cricoid cartilage. After midline sternotomy, the heart was exposed and a ribbon was positioned around the inferior caval vein. The pericardium was widely excised and removed. Epicardial pacing wires were sutured to the right atrial appendage and the heart was paced at a rate of 260±4 (mean±s.e.m.) beats/min (bpm). The midventricular diameter of the left ventricle was measured with an ultrasonic length gauge, composed of two 5 MHz epicardial crystals with a diameter of 2 mm facing each other. A small arrowshaped crystal was inserted through the anterior epicardium, angulated at 30° and positioned in the subendocardium facing the anterior epicardial crystal in order to measure anterior wall thickness. The gauges were connected to a sonomicrometer amplifier (Triton Electronics System 6, Triton Technology Inc., San Diego, CA, USA) that was calibrated with time signals of known duration. A high fidelity manometer (Dräger, Best, The Netherlands) was inserted through the apex into the LV cavity and secured with a purse-string suture. The manometer was calibrated against a high-fidelity pressure gauge (DPI 601, Druck Limited, Leicester, UK) and zeroed after stabilization for 30 min in a water bath at body temperature. The zero value was checked at the completion of the experimental protocol.

2.3 Experimental protocol
All recordings were obtained at fixed heart rate, with respiration suspended at end-expiration and consisted of consecutive heart beats before and during occlusion of the inferior caval vein (ICV) (Fig. 1). An estimate of systolic and diastolic LV performance was provided by a series of pressure–volume (P–V) loops of consecutive cardiac cycles during occlusion of the ICV. The occlusion is performed by pulling the ribbon around the caval vein. This allowed calculation of the ventricular elastance Ees (mmHg/ml), slope of the end-systolic P–V relation, and the ventricular stiffness constant Kc (mmHg/ml) of the end-diastolic P–V relation. Representative examples of an occlusion of the ICV are shown in Fig. 2.


Figure 1
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  		Fig. 1 Time course of the experimental protocol. After hemodynamic stabilization, control recordings were obtained at baseline. During 10-min periods, sodium nitroprusside (SNP) was administered intravenously at different, incremental doses (0.02, 0.08 and 0.32 µg·kg–1·min–1). After each 10-min period, SNP recordings were obtained. After completion of the recording at the highest dose, SNP was discontinued and recovery was allowed for 30 min. Then dobutamine was titrated in order to reach a steady-state increase of dP/dtmax by 10%. After a stabilization period of 30 min, control recordings were obtained under dobutamine. Then administration of incremental doses of SNP 0.02, 0.08 and 0.32 µg·kg–1·min–1 during 10-min periods was repeated under dobutamine. After each 10-min period, SNP recordings were obtained.

 

Figure 2
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  		Fig. 2 Pressure–volume loops. At baseline (left), sodium nitroprusside (SNP) induced a downward shift of the systolic pressure–volume relation. The end-diastolic volumes and diastolic function remained unaltered. Under dobutamine (right), SNP induced an upward shift of the systolic pressure–volume relation. The diastolic volumes were larger at any pressure, indicating increased left ventricular distensibility. Effects of SNP on both systolic and diastolic function were different from baseline.

 
After hemodynamic stabilization, control recordings were obtained at baseline (Fig. 1). SNP was administered intravenously at different, incremental doses (0.02, 0.08 and 0.32 µg·kg–1·min–1). Recordings under SNP administration were obtained after 10 min at each dose. After completion of the recording at 0.32 µg·kg–1·min–1, SNP was discontinued. When hemodynamic parameters had returned to control values, an additional recovery period of 30 min was included before the second part of the experimental protocol was started.

Then dobutamine was titrated in order to reach a steady-state increase of dP/dtmax by 10%. Infusion rates of dobutamine ranged from 1.0 to 2.5 µg·kg–1·min–1. After a stabilization period of 30 min under dobutamine, control recordings were obtained. Then administration of incremental doses of SNP 0.02, 0.08 and 0.32 µg·kg–1·min–1 was repeated (n=14). Recordings under SNP administration were obtained after 10 min at each dose. In separate sham experiments (n=4), saline was administered instead of dobutamine.

2.4 Data analysis
LV pressure (P), electrocardiogram (limb lead II), LV external diameter and LV wall thickness were recorded. Signals were digitally converted on line with a sampling rate of 500 Hz (Codas, Data-Q). The first derivative of the LV pressure signal was obtained with an analog differentiating circuit with fc=200 Hz. Internal diameter was calculated as external diameter minus 2 times wall thickness. The LV internal diameter is directly related to LV volume and this relationship improves when the linear dimension is cubed [12]. Volume therefore was calculated as the cube of the internal diameter. Five consecutive cardiac cycles before caval vein occlusion were averaged for each individual measurement. End-diastole was defined as the trough in the LVP waveform after atrial systole. If this was not readily apparent, end-diastole was timed as the right lower corner of the P–V loop. End-systole was defined as the left upper corner of the P–V loop. The onset of LVP fall was measured as time from end-diastole to dP/dtmin. LV relaxation was assessed with dP/dtmin and with the time constant {tau}. {tau} was calculated according to the logarithmic method of Weiss, which assumes that LV pressure fall follows a mono-exponential course and can be described with the formula Pt=P0 e–time/{tau}+P{infty}, where Pt is pressure at time t, P0 is pressure at dP/dtmin, P{infty} is the asymptote pressure [13]. Diastolic and systolic function were evaluated using end-diastolic and end-systolic pressure–volume relationships obtained during caval vein occlusion. Diastolic LV function was described by fitting a three-constant exponential equation allowing LVP to decay to a natural asymptote: P=AxeKcxV+P0, where P and V represent end-diastolic pressure and volume, Kc the LV stiffness constant, A an empirical constant and P0 the pressure-axis intercept. Systolic LV function was fitted by linear least squares analysis to: P=Ees (V–V0), where P is end-systolic pressure, Ees is the slope of the end-systolic pressure–volume relationship, V is end-systolic volume and V0=the volume-axis intercept. Effective arterial elastance (Ea) represents arterial mechanical properties, and therefore gives an estimate of afterload. Ea was calculated as the ratio of end-systolic LV pressure/stroke volume under steady state hemodynamic conditions (Ea=Pes/SV). LV–arterial coupling was described as the ratio of Ees/Ea, which allows assessment of systolic function corrected for possible changes in afterload [14].

2.5 Statistics
Data are presented as means±s.e.m. A two factor analysis of variance for repeated measurements (Jandel Scientific, Erkrath, Germany) was performed comparing effects of incremental doses of SNP at baseline and during dobutamine. Interaction analysis compared effects of SNP at baseline to effects of SNP under dobutamine.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
For all experimental conditions, data are shown in Table 1 and Fig. 3.


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  		Table 1 Effects of SNP in open-chest rabbits before and after β-stimulation with low dobutamine (n=14)

 

Figure 3
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  		Fig. 3 Graphs displaying dose–response curves of sodium nitroprusside (SNP) at baseline ({circ}) and during dobutamine infusion ({diamondsuit}). Effects of SNP are shown for dP/dtmax (A), Ees (slope of the end-systolic pressure–volume relation) (B), Ees/Ea (Ea is arterial elastance) (C) and stroke volume (D). Data are means±s.e.m. (n=14). {dagger}P<0.01 dobutamine control vs. baseline control; {ddagger}P<0.05 dobutamine control vs. baseline control; *P<0.01 SNP vs. control condition. Interaction analysis revealed that effects of SNP under dobutamine infusion were different from effects of SNP at baseline for each parameter and is indicated by the displayed P-values.

 
3.1 Effects of SNP at baseline
LV end-diastolic pressure was kept constant and volume did not change. Peak LVP decreased. End-systolic volume and stroke volume were not significantly altered. SNP decreased LV contractile function as manifested by a decrease in dP/dtmax and Ees (Fig. 3A,B). Effective arterial elastance (Ea) was reduced with SNP. The observed decrease in peak LVP could, therefore, be attributed to a combined decrease in ventricular contractile function and arterial elastance. The decrease in Ea was more pronounced than the decrease in Ees as was apparent from the decrease in Ees/Ea ratio (Fig. 3C). Time interval from end-diastole to dP/dtmin slightly increased, dP/dtmin decreased and {tau} remained unchanged. The stiffness constant Kc also remained unaltered. End-diastolic LV volume at matched end-diastolic LV pressure was not altered (Fig. 2, left).

3.2 Effects of dobutamine
End-diastolic volume increased and end-systolic volume remained unchanged, hence stroke volume increased (Fig. 3D). Peak LVP and dP/dtmax increased (P<0.01) (Fig. 3A). The increase in Ees was less pronounced: from 135±19 at baseline to 151±20 mmHg/ml under dobutamine (P=0.029) (Fig. 3B). The Ees/Ea ratio and time to dP/dtmin remained unaltered but rate of LVP fall accelerated (Fig. 3C). The stiffness constant Kc remained unaffected. At matched end-diastolic pressure, the end-diastolic volume was increased, indicating enhanced diastolic distensibility.

3.3 Effects of SNP under dobutamine
LV contractile function improved as evidenced by the increase in dP/dtmax, Ees, and stroke volume (Fig. 3A,B,D). The ratio Ees/Ea increased, due to the increase in Ees and the decrease in Ea (Fig. 3C). Onset of LVP fall and LVP fall were accelerated. The stiffness constant Kc remained unaltered. At matched end-diastolic pressure, the end-diastolic volume was further increased indicating further enhancement of diastolic distensibility. The answer of diastolic distensibility to SNP was different under dobutamine than at baseline (Fig. 2, right). Under dobutamine, effects of SNP on dP/dtmax, Ees, and Ees/Ea ratio were different from baseline (P<0.01).

In a control group (n=4), dobutamine was replaced by saline. These animals developed an identical response to SNP in the two consecutive dose–response protocols. These observations demonstrated that different effects under dobutamine were not caused by time-dependent changes in LV function throughout the experiments.


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The original finding of the present study is that in vivo, the dose-dependent negative inotropic effect of SNP was turned into a positive inotropic effect in the presence of low-dose dobutamine. Interaction between SNP and β-adrenergic agents was observed in vitro, but its relevance for in vivo cardiac physiology remained to be established. In the present study, the positive inotropic effect of SNP under dobutamine was characterized by an increased rate of pressure development, a decreased duration of contraction and an accelerated LV pressure fall. The hemodynamic pattern of these changes with SNP was similar to what is observed with administration of drugs increasing intracellular cAMP [15]. This similarity suggested a possible effect of SNP (which elevates intracellular cGMP) on cAMP-dependent regulation of myocardial function.

The possible underlying mechanisms of this interaction remain to be established. Electrophysiological observations in mammalian ventricular myocytes described the potentiation of the β-adrenergic effect on L-type Ca2+-current by low-dose cGMP [9, 16, 17]. In isolated ventricular myocytes, a small increase of cGMP caused a positive inotropic response in both basal and isoprenaline-stimulated conditions [10]. This positive inotropic effect was attributed to a cGMP-dependent inhibition of the type III cAMP phosphodiesterase. This inhibition resulted in an elevation of intracellular cAMP and, therefore, in additional stimulation of cAMP-dependent protein kinase, causing the positive inotropic effect. Further increase of cGMP however, will predominantly stimulate cGMP-dependent protein kinase, resulting in a decreased contractility [10, 17].

Regulation of myocardial function by cGMP- and cAMP-mediated mechanisms might, therefore, be critically dependent on the experimental conditions. Interaction between cGMP- and cAMP-mediated inotropic mechanisms depends on species specific and age related properties, the origin of the cardiac myocyte (atrial versus ventricular), the presence of the endocardial endothelium, and the metabolic and/or (patho)physiological condition of the preparation [18–21]. Doses and source of NO (endogenous or exogenous) also seem to be of particular importance. Positive inotropic actions or stimulation of L-type Ca2+-current have only been observed when very low doses of exogenous NO-donors or other cGMP-regulating agents were administered. Negative inotropic effects were reported with higher doses of exogenous NO-donors or by stimulation of endogenous NO synthesis (NOS). These data suggest that the balance from positive to negative actions may be very subtle. These possible differences in experimental findings should be kept in mind when reports on effects of nitrovasodilators are compared.

The effects of SNP on diastolic LV function were affected by dobutamine as well. The stiffness constant Kc did not change, so that compliance was not altered. At baseline, there was a small increase in distensibility, with a larger volume at matched end-diastolic pressure, in some, but not in all, animals (Fig. 3, left). Distensibility was enhanced by dobutamine and further enhanced by concomitant administration of SNP (Fig. 3, right). Effects of SNP on distensibility, therefore, were more important under dobutamine administration.

Several methodological issues deserve attention. Changes in autonomic baseline tone can influence contractility. All animals of the present study were vagotomized, minimizing parasympathetic activity. In addition, the anesthetic regimen and surgical technique were previously shown to result in a preparation characterized by limited adrenergic stimulation and by cardiovascular and biochemical stability for a duration exceeding the duration of the present protocol [11]. It is therefore not likely that variations in autonomic baseline tone have influenced the present observations. In the present setting of the intact ejecting heart of a rabbit, coronary circulation was not quantitatively evaluated.

Throughout the experiments, LV end-diastolic pressure was kept constant. Effects of SNP were evaluated not only on ventricular function, but also on arterial elastance. In the presence of a constant preload (LV end-diastolic pressure), the ratio of Ees over Ea (Ees/Ea) allowed assessment of changes in contractility with SNP corrected for its effects on afterload, evaluated with Ea. From this observation, it appeared that the improved ventricular function was not only due to the vasodilatory effects of SNP, but also to its positive inotropic actions.

In summary, the present study demonstrated that, in β-adrenergically unstimulated rabbits, low doses of SNP produced a dose-dependent negative inotropic effect, which was reverted into a positive inotropic effect during β-receptor stimulation with low-dose dobutamine. These data demonstrate the interaction between cGMP and cAMP dependent inotropic mechanisms in vivo.

Time for primary review 27 days.


   Acknowledgements
 
This research was supported by grants from the Fonds voor Wetenschappelijk Onderzoek (FWO) Krediet aan Navorsers S 2/5, 1995, Onderzoekskrediet G. 0.343.97, 1997–2000, and from the University of Antwerp (Onderzoeksraad Kleine Projecten 1994 and 1995). P.A.D. was supported by a Research Fellowship from the Department of Medicine, University of Antwerp. S.G.D. was supported by an Investigator's Grant from the FWO.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 

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