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Am J Physiol Heart Circ Physiol 286: H979-H984, 2004. First published October 2, 2003; doi:10.1152/ajpheart.00536.2002
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Contractile reserve but not tension is reduced in monocrotaline-induced right ventricular hypertrophy

J. Pieter Versluis, Johannes W. Heslinga, Pieter Sipkema, and Nico Westerhof

Laboratory for Physiology, Institute for Cardiovascular Research, Vrije University Medical Center, 1081 BT Amsterdam, The Netherlands

Submitted 27 June 2002 ; accepted in final form 16 September 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The objective of this study was to evaluate the role of right ventricular hypertrophy on developed tension (Fdev) and contractile reserve of rat papillary muscle by using a model of monocrotaline (Mct)-induced pulmonary hypertension. Calcium handling and the influence of bicarbonate () were also addressed with the use of two different buffers ( and HEPES). Wistar rats were injected with either Mct (40 mg/kg sc) or vehicle control (Con). Isometrically contracting right ventricular papillary muscles were studied at 80% of the length of maximal developed force. Contractile reserve (1 – Fdev/Fmax) was calculated from Fdev and maximal tension (Fmax). Calcium recirculation was determined with postextrasystolic potentiation. Both groups of muscles were superfused with either (Con-B and Mct-B, both n = 6) or HEPES (Con-H and Mct-H, both n = 6) buffer. With hypertrophy, contractions were slower but Fdev was not changed. However, Fmax was decreased (P < 0.05). With , Fmax decreased from 23.8 ± 6.5 mN·mm–2 in Con-B, to 13.7 ± 3.3 mN·mm–2 in Mct-B. With HEPES, it decreased from 16.3 ± 3.5 mN·mm–2 (n = 6, Con-H) to 8.3 ± 1.6 mN·mm–2 (Mct-H). Contractile reserve during hypertrophy was therefore also decreased (P < 0.05). With , it decreased from 0.73 ± 0.03 (Con-B) to 0.55 ± 0.04 (Mct-B). With HEPES, it decreased (P < 0.001) from 0.64 ± 0.07 (Con-H) to 0.19 ± 0.06 (Mct-H). The recirculation fraction decreased (P < 0.05) from 0.59 ± 0.04 in Con-B to 0.44 ± 0.04 in Mct-B. We conclude that contractile reserve and recirculation fraction are impaired during hypertrophy, with a stronger effect under HEPES than superfusion.

calcium; intracellular ions; sarcoplasmic reticulum function; 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid

CARDIAC HYPERTROPHY is an adaptive process to pressure overload in the left or right ventricle (14). Hypertrophy develops gradually over weeks and may finally lead to heart failure (35). Many studies (2, 25, 33) in papillary muscle have been performed to evaluate the changes in muscle properties caused by pressure overload.

There is a debate in the literature (15, 33, 35) whether or not developed tension (Fdev) decreases with hypertrophy. There are also conflicting results concerning the maximal tension (Fmax) at saturating Ca2+ concentration. Although at the cellular level Fmax may decrease significantly during hypertrophy (12), this has not been found in isolated muscles (33). In spontaneous hypertensive rats, pH regulation via the Na+-independent Cl–/bicarbonate () exchanger is impaired (9), which could also have a profound effect on calcium sensitivity and Fmax during hypertrophy (18, 24).

In many studies, monocrotaline (Mct) is used as a model for right ventricular hypertrophy. Mct is injected in the interscapular region (39) and then converted in the liver to Mct-pyrrole. This reactive product causes injury of the lung vasculature leading to pulmonary hypertension and subsequently to right ventricular hypertrophy (for review, see Ref. 5). The main advantages of this model are the ease of creating hypertrophy and the survival of animals until the day of experiment. However, the implications of this model for the contractility of isolated cardiac muscle have not been established.

We evaluated the role of hypertrophy on Fdev, twitch characteristics, and Fmax and potentiation in the rat papillary muscle with the use of the Mct model of right ventricular hypertrophy. We also studied the effect of hypertrophy on calcium handling by calculating the fraction of calcium recirculating to the sarcoplasmic reticulum (SR). To study the possible role of pH regulation, we used both the and HEPES buffer because it was shown that changing the buffer from HEPES to affects cytosolic pH (pHi) in cardiac muscle (7, 21, 23). We also mimicked the HEPES buffer by using the exchanger blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), preventing from entering the cell, and thus establishing the importance of ions.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals. All animals were treated in accordance with the "Guiding Principles in the Care and Use of Laboratory Animals," as approved by the Council of the American Physiological Society and under the regulations of the Institutional Animal Care and Use Committee.

Male Wistar rats (Harlan; Zeist, The Netherlands), weighing 170–190 g, were injected subcutaneously with either a single dose (29) of Mct (40 mg/kg in saline) or vehicle (Con).

Papillary muscle preparation. Three weeks after Mct injection, the hearts were rapidly removed under ether anesthesia and transferred to ice-cold Tyrode solution. The hearts were transferred to a Langendorff setup and a papillary muscle was dissected as described before (38). The muscle was placed in a muscle bath and suspended between a Perspex plate and a force transducer (model AE801, Mikro-Elekronikk; Horten, Norway). Muscles were superfused continuously and kept at 27°C. Muscle diameters were measured in two perpendicular directions and the muscle crosssectional area (CSA) was calculated assuming an elliptical shape. The muscle was stimulated with two platinum wire electrodes attached to a Grass stimulator (model SD9) at 0.2 Hz. Muscle length was then set at 80% of Lmax with the use of a micrometer; Lmax being the length at which developed force was maximal. Isometric force was measured and divided by the CSA to give isometric tension.

Morphometry. A group of 10 animals was divided into a Con (n = 5) and Mct (n = 5) subgroup to evaluate the existence of hypertrophy morphometrically (first group). The papillary muscles were fixed in 4% formalin, at 80% of Lmax, for 15 min and then stored at 4°C until further analysis. The muscles were embedded in paraffin and cut to 4-µm-thick cross-sectional slices. These preparations were stained with hematoxylin and eosin. The myocyte CSA was evaluated with a video micrometer system attached to a Leica microscope (DMRB; Wetzlar, Germany) with the use of NIH Image software version 1.61. An average of 50 myocytes per muscle was taken.

Hypertrophy and buffer composition. A second group of 24 animals was used to study the effect of hypertrophy and the modulating role of buffer composition on twitch characteristics and calcium handling. The animals received either an injection with Mct (n = 12) or vehicle (n = 12). At the time of experiment, both groups were divided in two subgroups. The first subgroup was superfused with buffer (Con-B and Mct-B, both n = 6). Another subgroup was superfused with HEPES buffer (Con-H and Mct-H, both n = 6).

The buffer contained (in mM) 128.3 NaCl, 4.7 KCl, 1.1 MgCl2, 0.42 NaH2PO4, 1.0 CaCl2, 11.1 glucose, and 20.2 NaHCO3. This solution was equilibrated by being gassed continuously with 95% O2-5% CO2 (pH 7.4). The HEPES buffer contained (in mM) 139.9 NaCl, 5.0 KCl, 1.8 MgCl2, 1.8 NaH2PO4, 1.0 CaCl2, 11.1 glucose, and 5.0 HEPES. This solution was set to pH 7.4 with the use of 5 M NaOH and gassed continuously with 100% O2.

The dry weights of the right ventricle (RV) and the left ventricle (LV) plus interventricular septum (LV + S) were measured in several of the control (n = 7) and Mct-treated (n = 7) animals to establish the existence of hypertrophy. The muscle CSA and body weight were established. In addition, lung wet weight was measured as an indication of lung edema.

Hypertrophy and DIDS. An additional group of Mct-treated animals (n = 5) was used to study the effects of buffer changes or application of DIDS to muscles. These muscles were superfused with either an HEPES or buffer modified from Aiello et al. (1). The (HEPES) solution consisted of (in mM) 133 NaCl, 5 KCl, 0.8 MgCl2, 0.42 NaH2PO4, 1.0 CaCl2, 11.1 glucose, and 10 HEPES; pH adjusted to 7.4 with 5 M NaOH. The solution contained (in mM) 118 NaCl, 5 KCl, 0.8 MgCl2, 0.42 NaH2PO4, 15 ChCl, 1.0 CaCl2, 11.1 glucose, 10 HEPES, and 20 NaHCO3, pH adjusted to 7.4 with 5 M NaOH after gassing with 95% O2-5% CO2. ChCl was added to achieve the same concentration of Cl– in both buffers. In two muscles, superfusion was started with and after postrest potentiation changed to HEPES. In three muscles, the superfusion was started in HEPES and later changed to . In one of those muscles, the buffer was changed to HEPES again, whereas in the two others, DIDS (0.6 mM) was added to the buffer to block the exchange and mimic an situation.

Twitch characteristics and recirculation fraction. Passive tension (Fpas) was measured, and Fdev was calculated as total tension minus passive tension. Muscles were used only if their Fdev/Fpas ratio was >15 during steady-state contractions. The steady-state contractions were used to analyze twitch characteristics by fitting the tension curve to the model of Nwasokwa (28). From this model, the time to peak contraction (tp) and time to half relaxation (t1/2) can be calculated in an objective manner as well as the positive and negative rate of contraction. We have earlier validated this model in our papillary muscle preparation (37). The r2 of all fitted twitches was >0.99.

To evaluate calcium handling, postextrasystolic potentiation (PESP) was performed (Fig. 1). The Grass stimulator was triggered by a personal computer that allowed a predetermined pacing protocol. When the muscle contractions had reached steady state (at 0.2 Hz), one single extrasystole was given 250 ms after a previous twitch (33). This led to a potentiation of the following beats (F1, F2, etc.). The amplitude of the potentiated beats returned exponentially to the steady state. Wohlfart and Noble (41) described the decay of the potentiation after a single extrasystole as

(1)
where Fn represents peak tension of the nth contraction after potentiation and Fn+1 that of the subsequent beat. Wohlfart and Noble (41) called the slope of the linear regression (D) of Fn+1 on Fn the decay constant. This slope, D, has been interpreted to reflect the fraction of Ca2+ recirculating to the SR.



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  		Fig. 1. Schematic drawing to illustrate the pacing protocol for postextrasystolic potentiation (PESP). Stimulation at steady state was at 0.2 Hz. Steady-state developed tension (Fdev) was normalized to maximal tension (Fmax). One extra stimulus (ES) was given after 250 ms. The amount of potentiation ({Delta}F) was determined on the first potentiated beat (F1). The tension of the following beats (F2 and F3) was decaying toward steady state. When tension reached steady state again, Fmax was determined with the use of postfrequency potentiation (PFP), where the muscle was stimulated with a high frequency (HF; 3.3 Hz) for 20 beats.

 

Potentiation and contractile reserve. From the PESP, the potentiation ({Delta}F) was determined and relative potentiation was calculated ({Delta}F/Fdev). Contractile reserve was defined as 1 – Fdev/Fmax. To determine Fmax, a postfrequency potentiation protocol was used, in which 20 stimuli with 303-ms intervals (3.3 Hz) were given, followed by a return to stimulation at 0.2 Hz. The first potentiated beat after this stimulation protocol equals Fmax and this value is comparable to tension produced with an optimal calcium concentration (33) at the length studied (80% Lmax).

Statistics. All values are given as means ± SE. Con and Mct values were compared with the use of an unpaired Student's t-test with Welch's correction for unequal variances if necessary. Steady-state contractions were fitted to the model of Nwasokwa (28) to evaluate twitch characteristics. Tension produced in potentiated beats of each muscle was plotted against that of its preceding beat. The slope of this regression line was then calculated using the least-squares method. These slopes (recirculation fractions) were averaged for all muscles within a group. The average circulation fractions were tested with one-way ANOVA, followed by Tukey's post hoc test. Comparisons for the effects of buffer and hypertrophy were made with a two-way ANOVA. A value of P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Hypertrophy. Three weeks after Mct injection, the CSA of the myocytes was increased (P < 0.001) from 159 ± 9 µm2 in control to 353 ± 10 µm2 in hypertrophied muscles (first group). Table 1 shows some more global characteristics (second group). The body weight of the Mct-treated animals was lower than in the Con group. The RV/(LV+S) ratio was significantly increased showing hypertrophy of the RV. This was also evident from the increase of the papillary muscle CSA. An increase in the lung-to-body weight ratio was also observed, indicating lung edema, which is associated with vascular damage in the lungs due to Mct.


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  		Table 1. Physiological parameters indicating RV hypertrophy in Mct-treated animals

 

Twitch characteristics and recirculation fraction. Table 2 shows the results for tp and t1/2. Both tp and t1/2 of hypertrophied muscles were higher (P < 0.001 and P < 0.05, respectively) than in control muscle. The contraction was faster in HEPES than in (P < 0.05), whereas relaxation was unaffected by the buffer composition. No differences were found between the rates of contraction and relaxation.


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  		Table 2. Effect of hypertrophy and buffer composition on twitch characteristics measured in papillary muscles

 

Potentiation ({Delta}F) of hypertrophied muscles in HEPES-buffered solution (Mct-H) was so low (0.06 ± 0.03, not significantly different from zero) that the recirculation fraction could not be calculated in these muscles. The average of the recirculation fraction is shown in Fig. 2. Because of the nondetectable recirculation fraction in one group, one-way ANOVA was performed on the remaining three groups. The recirculation fraction decreased from 0.59 ± 0.04 in Con-B to 0.44 ± 0.04 in Mct-B muscles (P < 0.05). The recirculation fraction of the control group (Con-H) in HEPES buffer was 0.67 ± 0.03, which was not different from the control group in (P > 0.05).



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  		Fig. 2. The effect of and HEPES on the recirculation fraction of control and hypertrophied muscles. In the monocrotaline (Mct) muscles treated with HEPES (MCT-H) group, potentiation was absent and a reliable recirculation fraction could not be calculated. ND, not detected. **P < 0.01, *P < 0.05 as evaluated with one-way ANOVA.

 

Figure 3 shows that changing the buffer from HEPES to in hypertrophied muscle caused a recovery of the potentiation. Moreover, the addition of the anion blocker DIDS (n = 2) to the superfusate blunted the potentiation again. In three other hypertrophied muscles a change from to HEPES also diminished the potentiation.



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  		Fig. 3. Example of the effect of buffer changes and addition of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) on PESP in a single hypertrophied papillary muscle. Under each condition, one ES was given after 250 ms, resulting in potentiation under superfusion only.

 

Potentiation and contractile reserve. Relative potentiation ({Delta}F/Fdev) as obtained with PESP is given in Fig. 4. The {Delta}F/Fdev decreased (P < 0.01) from 0.53 ± 0.09 in CON to 0.23 ± 0.13 in Mct muscles. In muscles, {Delta}F/Fdev was 0.57 ± 0.07, whereas in HEPES it was significantly lower (0.19 ± 0.03; P < 0.001).



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  		Fig. 4. The overall effect of hypertrophy (left) and buffer composition (right) on potentiation relative to developed tension ({Delta}F/Fdev). Because there was no interaction between hypertrophy and buffer composition, the groups in the left panel contain both muscle groups superfused with and HEPES. The groups in the right panel contain both Con and Mct muscles. **P < 0.01 vs. Con; {dagger}{dagger}{dagger}P < 0.001 vs. , as evaluated with two-way ANOVA.

 

Table 2 shows that both Fpas and Fdev were unaltered in hypertrophied muscles at 80% of Lmax. The composition of the buffer did not affect this because there were no significant differences in these parameters between and HEPES. However, the Fmax of Mct muscles was significantly decreased compared with Con. In Fig. 5, the effect of buffer composition and hypertrophy on the contractile reserve (1 – Fdev/Fmax) is shown. Under superfusion, there was a significant decrease (P < 0.05) of contractile reserve with hypertrophy from 0.73 ± 0.03 (Con-B) to 0.55 ± 0.04 (Mct-B). Under HEPES superfusion, this decrease (P < 0.001) was also seen: from 0.64 ± 0.07 (Con-H) to 0.19 ± 0.06 (Mct-H). The Mct-H group differed also significantly (P < 0.001) from both Con-B and Mct-B. Thus hypertrophied muscles are closer to Fmax. This effect was strongest in HEPES-buffered solution. Because there was no significant difference in Fdev, the decrease in contractile reserve during hypertrophy is due to the significant decrease of Fmax with hypertrophy (Table 2).



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  		Fig. 5. Contractile reserve (1 – Fdev/Fmax) of both control (Con) and hypertrophied (Mct) papillary muscles with or HEPES-buffered superfusion. The overall effects of both buffer (***P < 0.001) and hypertrophy (***P < 0.001) were significant. Because there was also a significant interaction between both effects (*P < 0.05), individual P values were calculated. The difference between Con-H and Mct-H was also significant (***P < 0.001).

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Twitch characteristics and recirculation fraction. The time for developing severe hypertrophy (and heart failure) after injection of Mct strongly depends on the dose in relation to the age of the animals used (39). In pilot experiments (n = 5), we have established that Mct-pyrrole had no direct effect on the papillary muscles. All of the injected animals in our study survived until the day of the experiment and showed no signs of failure (29), but hypertrophy was clearly present (Table 1). Furthermore, this can be seen in the increase in time to peak tension, which was earlier reported in hypertrophied rat (8) and cat (10) papillary muscles. This increase can be explained by the shift that was found from V1 to V3 myosin isoenzymes in Mct-treated rats (17), i.e., a slower but more economical contraction. The increase we found in t1/2 was also reported in rats (8) but not in cats (10). This slower relaxation might be due to altered calcium handling in hypertrophied cardiac muscle (8).

The decrease in recirculation fraction, a measure of SR contribution to the calcium handling (41), is qualitatively in line with what has been reported on papillary muscles after both pulmonary artery and aorta constriction (33). We found a stronger decrease with hypertrophy than these authors, which could result from the shorter muscle length we used because this factor influences the recirculation fraction (30).

In rats with left ventricular hypertrophy, the density of L-type calcium channels is not altered (31), whereas the total number of channels is increased. If we assume cardiomyocytes to be cylindrically shaped, the volume of the myocyte will increase more than the membrane area. Thus, with similar density of L-type calcium channels, more calcium transport over the cell membrane is taking place as found by Lee et al. (22), but the calcium concentration increase by transport over the sarcolemma is expected to be insufficient to compensate for the increase in cell volume. Calcium transients in Mct-treated rat hearts are increased early in hypertrophy (19, 20, 26). In addition, Studer at al. (36) showed that the amounts of Na+/Ca2+ exchanger mRNA and protein are increased in hypertrophy whereas the activity of this exchanger is increased as well.

Gómez et al. (13) showed that more calcium influx is needed in hypertrophied myocytes to trigger the ryanodine receptors to release calcium from the SR. There are also indications that the density of the ryanodine receptors is decreased in hypertrophy (27). SR Ca2+ ATPase expression is downregulated in hypertrophied hearts (for review, see Ref. 3). In addition, the network density of the SR was decreased during severe Mct-induced hypertrophy in rat hearts (19). These results suggest reduced calcium handling by the SR, i.e., the muscles become more dependent on extracellular calcium, which is in line with our finding of decreased recirculation fraction.

Potentiation and contractile reserve. In rat papillary muscle (33), a slight increase in Fdev has been reported, whereas in hypertrophied cat (35) and ferret (15) muscles a decrease was shown. The small changes are furthermore dependent on the external calcium concentration (15) and the length (35) at which the muscle was studied. We have studied a single length (80% Lmax), which is representative for the length of the muscle in the systolic phase (6). In addition, we used an external calcium concentration, which was close to the physiological concentration. Under these conditions, Fdev is not changed in hypertrophy but Fmax is strongly affected resulting in a reduction in contractile reserve.

We determined Fmax by using postfrequency potentiation (32). A short period of high-frequency pacing produces a tension, which is the same as that at a saturating external calcium concentration (3 mM) in normal and hypertrophied muscles (33). The smaller Fmax with hypertrophy was also shown in ferret muscle (16) and in single, isolated skinned cardiomyocytes from the rat (12). In severe hypertrophy (similar to the present degree of hypertrophy) not only Fmax is lower but calcium sensitivity is also impaired (12). Because Fdev was unaffected by hypertrophy, the muscles operate closer to the Fmax possible, i.e., contractile reserve (Fig. 5) is lower.

Changing the buffer from HEPES to has been shown to affect pHi in control cardiac muscle (7, 21, 23). A significantly higher pHi was found 30 min after changing the buffer from HEPES to , indicating that pHi is lower in HEPES-buffered solution (7). A decrease in pHi affects calcium uptake and release from the SR (11). It also diminishes calcium binding to troponin C (4). Moreover, Fmax is diminished as measured in skinned muscle fibers (34). We found no differences in Fdev and Fmax between HEPES and -buffered solution in control muscles. This is in agreement with earlier work on the rat (1) and cat (40). In a recent study (9) in spontaneously hypertensive rats, it was reported that the Na+-independent Cl–/ exchanger is overexpressed, leading to acidification in the absence of . In hypertrophied hearts from rats exposed to aorta constriction, acidification lowered the calcium sensitivity and the Fmax (18, 24), as well as the amount of calcium in the SR (18). Therefore, the contraction is less efficient in hypertrophy, thereby limiting function, especially under conditions of a high workload where acidification may occur.

The smaller potentiation, with HEPES in hypertrophy, could be mimicked by using the anion blocker DIDS that prevents ions to enter the cell via the exchanger. Aiello et al. (1) showed that DIDS brings membrane potential and action potential close to the situation under (HEPES) superfusate. Thus influx is involved in regulation of contractility during hypertrophy more than in control.

In conclusion, with the present experiments we have established the implications of the Mct model for several aspects of contractility. We have shown that Mct leads to significant hypertrophy of the right ventricular papillary muscle. The Fmax is depressed, whereas contraction and relaxation are also impaired but Fdev is not. The recirculation fraction of calcium to the SR is lower, indicating an increase in the relative importance of calcium transport via the sarcolemma.

Contractile reserve of hypertrophied muscles is decreased and is lowest in hypertrophied muscles with HEPES superfusion, where also extrasystolic potentiation is strongly depressed. Blockade of the exchanger under superfusion could mimic this decrease in potentiation. Thus pHi regulation via ions becomes more important during hypertrophy for maintaining calcium handling. Thus the Mct model can be used to investigate the effects of hypertrophy at a cellular level.

The data show that Fdev in Mct-induced hypertrophy is still compensated for, but contractile reserve is diminished. This suggests that hypertrophy is adaptive with respect to developed tension but is maladaptive with respect to contractile reserve and potentiation.


   ACKNOWLEDGMENTS
 
We thank P. J. van Diest and H. Ketelaars from the Department of Pathology of the Vrije Universiteit University Medical Center for work on the histological preparations.

GRANTS

This work was supported by the Netherlands Heart Foundation Grant 94-069 and National Heart, Lung, and Blood Institute Grant HL-44399-01.


   FOOTNOTES
 

Address for reprint requests and other correspondence: P. Sipkema, Laboratory for Physiology, Institute for Cardiovascular Research, Vrije Univ. Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands (E-mail: p.sipkema{at}vumc.nl).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 METHODS
 RESULTS
 DISCUSSION
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