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European Journal of Heart Failure 2001 3(5):545-551; doi:10.1016/S1388-9842(01)00158-1
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© 2001 European Society of Cardiology

DOCA-salts induce heart failure in the guinea pig

Alberto Tiritilli*

Laboratoire de Physiologie et Pharmacologie Cardiovasculaire Centre Hospitalier 20, rue Armagis, Saint-Germain-en-Laye 78104, France


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Heart failure (HF) is a common clinical problem confronting physicians and is often the final manifestation of many cardiovascular disorders. Despite recent advances in the pharmacological management of HF, it remains a highly lethal and disabling disorder. A number of animal models have been developed to study both the pathophysiology of HF and new therapeutic approaches to this complex syndrome. Only through an improved understanding of the basic biology of the early stages of the syndrome can HF be prevented or at least anticipated. With this in view, we have developed an easily realisable and inexpensive model in the guinea pig, which presents numerous structural, metabolic and biochemical similarities compared with the human heart. Thirty guinea pigs, aged 5 weeks and weighing 300 g were used. After anaesthesia, left nephrectomy was performed. After 1 week the guinea pigs were divided into: (a) control group (n = 15), which received an injection of vehicle as well as tap water for 10 weeks; (b) DOCA-salts group (n = 15), where the animals were treated with an IM injection of 10 mg DOCA 5 days a week for 10 weeks and with drinking water containing 9 g/l–1 NaCl and 2 g/l–1 KCl. Our results demonstrate that the administration of DOCA-salts to guinea pigs for 10 weeks caused a significant increase in blood pressure (BP + 30%) associated with left ventricular hypertrophy (LVH), evaluated by LV weight (+37%), LV wall (+36%), by the ratio LV weight/Body weight (+23%) and by an increase in LV volume (+51%). Concerning HF, the latter was clinically evident through an increase in body weight, heart rate and dyspnoea. Indeed, guinea pigs presented pleural and/or pericardial effusion often associated with ascite. This model, which combines pressure and volume overload, results in a slow evolution towards HF. This allows a better understanding of the mechanisms in early LV remodelling which has the potential to develop into HF. Some recent studies have emphasised the value of using guinea pigs. The guinea pig heart muscle presents two major regulatory mechanisms of contractility that are closer to those found in humans, the isomyosin pattern which is predominantly V3 and the phenomenon of Ca2+-induced Ca2+-release from the sarcoplasmic reticulum. The DOCA-salts model in the guinea pig is an easy surgical procedure with high post-operative survival, which causes an increase in arterial BP, LVH associated with HF. This model is a useful tool for studying some of the basic mechanisms of cardiovascular diseases.

Key Words: DOCA-salts • Heart failure • Guinea pig

Received July 20, 2000; Revised October 27, 2000; Accepted December 4, 2000


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Heart failure (HF) is still one of the most common clinical problems and it is often the last manifestation of many cardiovascular disorders. The progress made in our understanding of the pathophysiology and treatment of cardiac failure would not be possible without a number of animal models of left ventricular hypertrophy (LVH) or cardiac failure. Thus, a number of animal models have been developed both to study the pathophysiology and the new therapeutic approaches to this complex syndrome. The animal species and the interventions used to create cardiac failure depend on the scientific question as well as on ethical factors and economic considerations. Furthermore, a good model must be accessible, inexpensive and reproducible. There are no perfect animal models that mimic human cardiac failure. Each model has advantages and specific limitations. Extrapolations from experimental to clinical HF require critical evaluation.

A comprehensive review of different experimental models of HF has already been published [1]. Moreover, several other recent reviews have been published in the same area [2–4]. In short, animals used for the study of HF should have chronic, stable disease produced by methods, which allow us to quantify damage and predictable disease severity. These models have involved the induction of pressure or volume overload by the creation of aortic or pulmonary artery stenosis or by the creation of aortic insufficiency arterio-venous shunt, but these methods are limited by the difficulties involved in quantifying the severity of the disease [1].

Coronary artery ligation or occlusion produces HF in experimental animals, with clear clinical relevance [5]. However, this technique includes total arrhythmias and collateral vessel growth that prevent or slow down the onset of HF. Cardiac failure may be induced by embolism with microspheres. After microembolization, the animals show an increase in pulmonary artery and left ventricular end-diastolic pressure, with an increase in noradrenaline levels but the renin–angiotensin–aldosterone system is not activated [6]. Cardiac failure obtained using cardiotoxic agents, such as adriamycin or catecholamines has been widely employed for experimental purposes, nevertheless the control of the extent of damage remains difficult to quantify. Another model of HF can be produced by repeated or single direct-current (DC) shocks across the left ventricle. The reduction of output and ejection fraction has been observed after 4 months and is accompanied by an increase in plasma noradrenaline without renin activity [7]. It has recently been suggested that a single DC shock, three to seven-times the threshold defibrillating current, administrated to the left ventricle can induce HF [8]. Chronic rapid ventricular pacing produces a predictable HF with neurohumoral and haemodynamic changes, which mimic the clinical pattern [9]. While these models are useful in evaluating different aspects of HF, many other observations of HF obtained from these models may not entirely mimic patterns of cardiac failure in man.

Deoxycorticosterone acetate (DOCA)-salt is a useful model in which a reliable increase in blood pressure (BP) followed by LVH is produced. This model, largely used with rats, has recently been adapted to the guinea pig [10]. Compared with the rat, guinea pig models appear highly relevant to the clinical situation given that the slow V3 myosin isoform predominates, the plateau of the action potential is long in both guinea pig and human and also because the dependence of contraction on calcium-induced–calcium-release from the guinea pig's sarcoplasmic reticulum resembles more closely that in man [11]. Attempts to induce cardiac failure in the guinea pig using the method of aortic stenosis have failed due to the fact that high sensitivity to anaesthesia and post-surgical mortality affected more than 50%. Moreover, LVH was moderate and no sign of HF was observed. Thus, the present study shows a simple procedure to induce hypertension, cardiac hypertrophy and HF in the guinea pig using the DOCA-salts method.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Preparation of animals and surgical procedure
Thirty guinea pigs (Elevage de la Peulve Thiron-Gardais, France), aged 5 weeks and weighing 280–300 g, were used. All animals fasted overnight before surgery. After anaesthesia (ketamine hydrochloride 160 mg/kg–1 IM), left nephrectomy was performed. In all animals, sulfadoxine+trimethoprine (62 mg and 12.5 mg, respectively) was injected subcutaneously. To prevent dehydration, 5 ml of glucose (10%) was injected by the same route. Animals were then kept in a unit at a temperature varying between 22 and 25°C, with a humidity level of 50–60% and a constant 12:12 h light/dark cycle. After 1 week the guinea pigs were divided into two groups: (a) control group (n=15), which received an injection of vehicle as well as tap water for 10 weeks; and (b) DOCA-salts group (n=15), where the animals were treated with an IM injection of 10 mg DOCA 5 days a week for 10 weeks and with drinking water containing NaCl 9 g/l–1 and KCl 2 g/l–1. The dose of DOCA (DOCA, Russel, Paris France) used was chosen after preliminary experiments to obtain equipotent effects on BP without significant side effects such as anorexia or trembling. All animals were fed ad libidum. The investigations conform with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

2.2. Hemodynamic study
The animals were weighed before the study. Hemodynamic studies were performed under anaesthesia (ketamine hydrochloride 160 mg/kg–1 IM) at the end of the treatment period. In preliminary experiments, we have shown that anaesthesia per se does not affect BP. The measurements were taken at the same time each day. The left carotid artery was exposed and cannulated with a stiff polyethylene catheter (internal and external diameter, 0.76 and 1.22 mm, respectively, Biotrol, Paris, France) and connected to a pressure transducer (Narco bio-system instrument, Houston, Texas). Systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) (in mmHg) were recorded using a Gould differentiator amplifier (Gould Inc Test and Measurement Group, Ohio, USA). Heart rate (bpm) was determined from the measurement of beat-to-beat intervals over 30 s. The cardiac workload was estimated using the product SBP (mmHg)xheart rate (bpm). After the hemodynamic parameters had been recorded, the animals were killed with an intra-arterial injection of 0.3 ml 10% KCl to cause cardiac arrest in diastole.

2.3. Assessment of cardiac hypertrophy
The thorax was rapidly opened, in the heart showing pericardial effusion, the liquid was extracted with a syringe and stored at 4°C until analysis and the heart then quickly removed. After pericardectomy, the heart, left ventricle (LV) and right ventricle (RV) were weighed. The atria were removed and weighed separately. The LV was opened sagitally (long axis) from the aortic valve to the apex. The equatorial circumference (C), as well as the length (L) between the aortic valve borders and the apex and thickness of the LV free wall in the middle region were measured using a Vernier calliper. The volume of the left ventricular chamber was calculated according to the formula:


Formula

adapted from Dodge et al. [12]. The septum was considered as part of the LV and weighed with it. Furthermore, prior to the removal and weighing of the lungs and livers, pleural effusion and/or ascite were taken and stored at 4°C for quantification of protein content.

2.4. Evaluation of degree of hypertrophy and cardiac failure
The degree of cardiac hypertrophy was estimated on the basis of left ventricular weight, (LV weight in mg) to body weight, (in g) ratio greater than 2.3 and of the thickness of the LV free wall >3.5 mm. Cardiac failure was evident when the animal showed clinical tachycardia and dyspnoea associated with pleural, pericardial effusion and/or ascite (protein content >30 g/l). Furthermore, the LV volume must be increased by at least 40%.

2.5. Statistical analysis
Statistical analysis was achieved using a polystat computer program (Cricket Software, Philadelphia, PA, USA). The experimental data given in the text are expressed as mean±S.E.M. Multiple comparisons were made using one-way analysis of variance (ANOVA) followed by a Scheffé F-test. The level of statistically significant difference was P<0.05.


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Hemodynamic study
Table 1 shows that 10 weeks of DOCA-salts treatment induced a significant increase in BP. In the DOCA-salts group, systolic, diastolic and mean blood pressure (mmHg) was higher than in the control group. In the control group, the SBP, DBP and MBP were 78±3, 50±2 and 59±2, respectively. In the DOCA-salts group, the SBP, DBP and MBP were 115±9, 70±6 and 85±7, respectively, (P<0.001). Heart rate (bpm) was 229±8 in control and 271±7 in the DOCA-salts group (P<0.001). Furthermore, the double product SBPxHR (mmHgxbpm) was significantly increased in the DOCA-salts group (P<0.001).


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  		Table 1 Arterial blood pressure and heart rate in control and DOCA-salts treated guinea pigs measured after 10 weeks

 
3.2. Assessment of cardiac hypertrophy
Our results are summarised in Tables 2 and 3. At the end of the experiments all animals in the control group were alive, whereas 5% of the animals in the DOCA-salts group died. The DOCA-salts treated animals developed a significant cardiac hypertrophy and HF. Heart weight was increased, we found 1.15±0.4 g in control and 1.78±0.9 g in the DOCA-salts group (P<0.001). Concerning the LV weight, we found 0.868±0.3 g in control and 1.379±0.7 g in the DOCA-salts group (P<0.001). The LV free wall thickness, another basic parameter necessary to assess the degree of LVH, was significantly higher in the DOCA-salts group compared to the control group (P<0.001). In the same way, the LV weight/body weight, which is one of the major indices allowing an assessment of the degree of LVH, increased significantly (P<0.001). Furthermore, cardiac workload was significantly increased in the DOCA-salts group (P<0.001).


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  		Table 2 Anatomical data for heart failure in control and DOCA-salts treated guinea pigs measured after 10 weeks

 


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  		Table 3 Anatomical data for right ventricle, lung and liver in control and DOCA-salts treated guinea pigs measured after 10 weeks

 
Regarding cardiac failure, the latter was clinically evident through an increase in body weight, we found 452±5 g in control and 561±32 in the DOCA-salts group (P<0.001). Moreover, the repercussions of cardiac failure were evident in the RV. Indeed, the RV weight was 270±0.1 mg in control and 350±0.1 mg in the DOCA-salts group (P<0.001). Similarly, the RV wall was hypertrophied, we found 0.51±0.01 mm in control and 0.89±0.02 mm in the DOCA-salts treated animals (P<0.001). Furthermore, the ratio RVW/BW (mg/g) was increased, and showed 0.59±0.5 in control and 0.62±0.9 in the DOCA-salts group (P<0.05). To the same extent, the ratio LVW/RVw (mg/mg) was significantly increased in the DOCA-salts group (P<0.05). Concerning lung and liver weight, both increased significantly in the DOCA-salts group (P<0.001).

As for the LV volume, the latter was dramatically higher in the DOCA-salts group, we found 1.07±0.7 ml in control and 2.20±0.6 ml in the DOCA-salts group (P<0.001). Tachycardia is one of the first clinical signs of HF, thus heart rate was increased by 15% in the DOCA-salts group (P<0.05). Furthermore, dyspnoea, another clinical sign of HF, was constantly present in animals in which we found pericardial, pleural effusion and/or ascite. Whereas, pericardial effusion was too difficult to quantify, concerning pleural and ascite effusion, we found 0.1±0.01 and 0.5±0.04 ml, respectively.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The DOCA-salts model of hypertension in rats is well documented [13,14]. However, available data concerning the DOCA-salts model in the guinea pig are scarce. The results of the present study indicate that the administration of DOCA-salts to guinea pigs for 10 weeks causes a significant rise in BP associated with LVH and cardiac failure. The method described in this study presents several advantages. As far as methodology is concerned, the DOCA-salts model was chosen for its rapid application and low surgical mortality rate. This model which combines pressure and volume overload, results in a slow evolution towards hypertension, LVH and HF. Also of interest was the predictability of the model leading to hypertension, LVH and cardiac failure, so that it was possible at each stage to correlate the results obtained, e.g. biochemistry to electrophysiology, and histological results to pharmacology. Apparently, the dose of DOCA 10 mg IM 5 days per week for 10 weeks appears to be the most suitable, since it led to a statistically significant rise in BP without an increase in mortality rate. The group treated with DOCA-salts showed a significant increase in BP, cardiac hypertrophy and HF. In the DOCA-salts group even though the SBP did not exceed 115 mmHg, it was sufficient to induce LVH. This points to the fact that hemodynamic and non-hemodynamic effects are involved in heart hypertrophy. LVH appears to be a greater risk factor able to induce cardiac failure. The present study allows an assessment of the effects of drugs with a beneficial influence in prevention or regression of cardiac hypertrophy. Heart failure remains a major clinical problem, the progression of a well-compensated hypertrophied heart to its decompensated stage is poorly understood. Our model, by its guaranteed slow evolution towards LVH and HF allows us not only to understand the transition from a reversible to an irreversible state of LVH, but also certain aspects of the development from compensated to decompensated HF and consequently to prevent cardiac failure.

Myocardial infarction after coronary artery ligation is a widely used model to induce HF in rats. Failure is associated with a LV dilatation, decreasing systolic function and increasing the filling pressure [15,16]. LV dysfunction and HF are associated with neurohumoral activation similar to that seen in patients with HF. Furthermore, angiotensin-converting enzyme activity in the LV is correlated inversely with LV function. Depressed cardiac function is associated with altered Ca2+ transients [17]. The density of L-type channels is depressed, moreover, it has been shown that SR-Ca2+-ATPase mRNA and protein levels decrease continuously according to the severity of congestive HF. In this model, besides an increased mortality rate and a moderate induction of HF, using the present technique for long-term pharmacological studies remains controversial. Despite the fact that rats are inexpensive, there are several limitations to using rat models given differences in myocardial function compared to the human heart.

The rat myocardium exhibits a very short action potential which normally lacks a plateau phase [18]. Calcium removal from the cytosol is predominated by the activity of the sarcoplasmic reticulum calcium pump, whereas Na+/Ca2+-exchanger activity is less relevant [18,19]. In the normal rat myocardium, alpha myosin heavy-chain isoform predominates and a shift toward the beta-myosin isoform occurs with hemodynamic load or hormonal changes. Moreover, heart rate is five times that of the human and the force-frequency relation is inverse [18].

Some recent studies have emphasized the value of using guinea pigs. The normal LV in the guinea pig is different from that observed in rats and/or rabbits. In the guinea pig, the slow V3 isomyosin is dominant. Moreover, the phenomenon of the Ca2+ autocatalitic release described by Fabiato is weak, as is seen in humans [11].

We know that the changes observed during cardiac hypertrophy are partly specific to the species studied [20,21]. Thus, when hypertrophy is induced in rats or rabbits, there is an adaptation or modification of the isoenzymes in the ventricular myosin, the rapid V1 isoform diminishes in response to the slow V3 isoform. This structural change in the sarcomere is currently considered as one of the major determinants for contractile efficiency [22,23].

It has recently been demonstrated that in the guinea pig, papillary muscle subjected to an aortic stenosis, there were severe alterations in both contraction and relaxation parameters. Normal guinea pig papillary muscle has a slower maximum shortening velocity (Vmax) than that in rats. Another consideration in the guinea pig is that in chronic cardiac overload the time leading to peak tension (TPT) is decreased rather than increased. The duration of TPT is one of the most important compensatory mechanisms providing the force with more time to develop, this mechanism is evident in rats and rabbits but not in the guinea pig. Thus, if a significant reduction in the speed of contraction was observed, relaxation was also impaired. If the load-dependency of relaxation is a mechanical property, which requires a functional sarcoplasmic reticulum, this suggests that the latter is impaired during cardiac hypertrophy and probably modified during cardiac failure [24].

Recent biochemical data from the guinea pig, have demonstrated no change in either the Ca2+- or Mg2+-activated myofibril ATP-ase or in the K+-, Ca2+- or Mg2+-activated myosin ATP-ase activity during chronic overload. This has been confirmed by a mechanical study using skinned fibers. The time for tension recovery, after a quick stretching of the muscle gives an idea of the turnover of the cross-bridges. In rats, this index of velocity is depressed in chronic overload, conversely, this time is almost unchanged in the guinea pig, however, sensitivity to calcium remain unaltered in both species. These data suggest that in the guinea pig there is no detectable adaptation in the changes in the sarcomere structure allowing us to explain the reduction in Vmax, and this suggests that the changes occur at the sarcolemma membrane level, as well as in the sarcoplasmic reticulum during cardiac overload [25]. In this study we have demonstrated that an IM injection of DOCA combined with unilateral nephrectomy and maintenance on NaCl 9 g/l–1 and KCl 2 g/l–1 for 10 weeks is an effective means of producing hypertension, LVH and HF in the guinea pig. Taken separately, all parameters evaluating the degree of hypertrophy, such as heart weight, LVw, LV wall thickness, as well as the LVw/Bw ratio, significantly increased in the DOCA-salts group. In the same way, the increase in the RVw as well as the ratio LVw/RVw in the DOCA-salts group demonstrated that the degree of hypertrophy was also manifest in this cavity. Moreover, this is the first proof (to our knowledge) that HF can be induced by this technique in the guinea pig.


   5. Conclusion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
In this study, the DOCA-salts model was applied to the guinea pig. Treatment with DOCA-salts may cause a significant increase in BP, one of the major determining factors in the development of LVH and HF. Cardiac failure in the guinea pig is of considerable interest in cardiovascular research due to its similarity to human cardiovascular disease. In fact, the guinea pig heart muscle is closer to that of man than that of the rat, in that it presents many major regulatory mechanisms of contractility, the isomyosin pattern is predominantly V3 and the Ca2+-induced–Ca2+-release is similar to that observed in humans. The DOCA-salts method in the guinea pig provides: (1) an easy surgical procedure, with high post-operative survival; (2) an increase in arterial BP associated with a significant increase in LVH and cardiac failure; (3) a useful method to study some of the basic mechanisms of cardiovascular diseases; and (4) the present model may be suitable to study the transition from cardiac hypertrophy to HF, allowing the identification of drugs able to prevent the development and progression of the disease. No model is perfect, but a good model is feasible, especially when it presents the advantages of being inexpensive and having a myocardial metabolism closely resembling that of the human. Consequently, we suggest the DOCA-salts model in the guinea pig rather than in the rat.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
* Tel.: +33-1-39-50-65-67; fax: +33-1-39-51-90-54. E-mail address: tiritillialb{at}aol.com (A. Tiritilli) Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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