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Eur J Cardiothorac Surg 2001;19:500-506
© 2001 Elsevier Science NL

Comparison of histopathologic effects of carnitine and ascorbic acid on reperfusion injury

Haci Akar^a, Atilla Saraç^a, Cüneyt Konuralp^b, Levent Yildiz^c, Ferat Kolbakir^a

^a Ondokuz Mayis University, Faculty of Medicine, Department of Cardiovascular Surgery, Samsun, Turkey
^b Siyami Ersek Thoracic and Cardiovascular Surgery Center, Department of Cardiovascular Surgery, Istanbul, Turkey
^c Ondokuz Mayis University, Faculty of Medicine, Department of Pathology, Samsun, Turkey

Received 12 December 2000; received in revised form 6 February 2001; accepted 7 February 2001.

Corresponding author. Aye Çavus Sokak, No. 7/6, Huri Apartments, Suadiye, 81070, Istanbul, Turkey. Tel.:/fax: +90-216-363-3642
e-mail: ckonuralp{at}usa.net

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Objective: Reperfusion injury can be seen after acute arterial occlusion, acute myocardial infarctus and during open heart surgery and vascular surgery. Protective effects of ascorbic acid and carnitine on reperfusion damage were tested and compared using histopathologic examination on ischemia model in the rabbit hind limb. Methods: Four groups (each containing ten animals) were used. In group I (G1), only anesthesia was administered and a biopsy was taken from the soleus muscle after 6 h. In group II (G2), group III (G3), and group IV (G4), after induction of anesthesia, arterial blood circulation of right posterior extremity was blocked by a tourniquet proximally. After four hours of ischemia, just before releasing of tourniquet, physiologic saline solution, sodium ascorbate (Redoxan) and L-carnitine (Carnitine) were administered intravenously to G2, G3 and G4, respectively. Following 2 h of reperfusion, biopsies were taken from soleus muscles. All of the biopsy slides were observed under the light microscope from the aspect of six different histopathologic criteria (loss of striation, nuclear centralisation, formation of ring and/or splitting, changing on diameters of muscle fibers, necrosis and minimal fibrosis) of ischemic muscle. Results: Ischemic change criteria were seen less frequency in both vitamin C and carnitine groups compared to the control and placebo groups. However, this protective effect was statistically significant only for the aspect of segmental necrosis, centralization of nuclei and diameter change parameters in G3 and in G4. When G3 and G4 were compared, the differences on protective effects were significant only from the aspect of fibrosis (P<0.001) and changing on diameter of the fibers (P<0.001). Conclusions: Both sodium ascorbate and carnitine are effective on reducing the reperfusion injury in skeletal muscle. But when we compared these two agents to each other, we found that carnitine seems a little more protective on our experimental model.

Key Words: Reperfusion • Ischemia • Carnitine • Ascorbic acid • Muscle

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Skeletal muscle ischemia is a common sequel of acute arterial occlusion. Restoration of blood flow, i.e. reperfusion, can sometimes cause more necrosis of muscle than ischemia itself. The clinical picture is characteristic with edema of affected extremity, metabolic acidosis and macroscopic myoglobunuria. In some cases, acute renal and respiratory failure, cardiac dysfunction and even death can occur as a result of systemic toxic effects of reperfusion products known as myonephropathic-metabolic syndrome [1,2]. In vascular surgery practice, because of the potential for metabolic complications and risks involved, the prognosis is extremely serious, not only for the salvage of the extremity but also for the survival of the patient. Reported mortality and limb loss rates change from 30 to 80% and from 30 to 50% respectively [2,3].

The mechanism of reperfusion injury is the same on skeletal muscle and myocardium [4,5]. However, the results of reperfusion injury are different. The main reasons of different results are: (1) its higher oxygen requirement makes heart muscle more vulnerable to hypoxia than skeletal muscle. (2) Activities of the some key-point enzymes (e.g. LDH) for energy metabolism are different in the myocardium and striatal muscle. (3) Higher volume of the skeletal muscle mass cause to release more toxic substances which means more systemic complications [2]. Recovery of normal mechanical functions of the heart after ischemia is related to the kinds of energy resource used during reperfusion.

1.1. Primary histopathologic reactions of the muscle fibre to ischemia
Microscopically, there is a great variety of morphologic changes of the muscle fibers, ranging from slight to moderate degenerative changes to actual necrosis [3].

1. Loss of striation (loss of cytoplasmic myofilaments): Cross striations are features exclusively found in the myofibrils. The chief reason for cross striation seeming to extend from one side of a fibre to the other is that the myofibrils are close together and their cross striations are approximately, but not perfectly, in register with one another. Loss of cross striations is a good indicator reflecting myofilament damage after ischemia.
   
2. Nuclear centralization (dislocation of sarcolemmal nuclei): Normally, the multiple nuclei are small, in spindle shape and located just beneath the plasma membrane (sarcolemma) of the myocyte. Transverse sections of muscle also demonstrate the subsarcolemmal position of the nucleus in most fibers. In degenerative states, this nuclei are found centrally in the cytoplasm and are markedly enlarged.
   
3. Formation of ring and/or splitting: Ring fibers are muscle fibers in which the peripheral myofilaments have become reoriented to run circumferentially (on transverse sections). Fiber splitting is the presence of what appear to be clefts (i.e. damage) in a single large fibre.
   
4. Changing of diameters: Generally fibers diameter are increased with ischemic stress.
   
5. Segmental necrosis: Destruction of only a portion of a myocyte (which could be followed by myophagocytosis as macrophages infiltrate the region) can be seen in early phase. This is ischemic or coagulative necrosis. Coagulative necrosis is characterized by conversion of the muscle cells to acidophilic ghost cells. And loss of nucleus. Also, myofibre may sustain transverse fractures often through the Z lines. Multiple fracture lines may induce so-called "shredding" of the fibre.
   
6. Minimal fibrosis: Fibrosis is a chronic tissue response that follows necrosis. However, there are some precedent reactions that mark fibrosis. After the cell death, collagen fibers are usually observed around the necrotic cell islands and form a fibrohistiocytic tissue reaction (early fibrosis). So it can be called a fibrohistiocytic reaction rather than true fibrosis.
   

Other characteristics (non-specific) of myophatic injury include vacuolation, alterations in structural proteins or organelles, and accumulation of intracytoplasmic deposits.

Necrosis is, of course, the most important parameter but occurrence of only one of these parameters is also accepted as the existence of injury [3]. Cessation of blood flow to the muscle tissue causes biochemical derangements that result in changes in myocyte morphology. If ischemia is allowed to continue beyond 30–40 min, metabolic and morphological changes begin to occur rapidly.

The restoration of blood flow after a period of tissue ischemia has been shown to cause cellular injury that was not present during circulatory interruption. The generation of oxygen free radicals has been clearly established as a fundamental process is the development of reperfusion injury in the myocardium and skeletal muscle. These compounds are injurious to proteins, sugars and nucleic acids. Ischemia also reduces intracellular levels of naturally occurring antioxidants, which further compounds the propensity for free radical formation during reperfusion.

Muscle cells are constantly exposed to small quantities of oxygen free radicals as a result of mitochondrial electron transport, prostaglandin synthesis, catecholamine oxidation, and activated neutrophils. Normally, free radicals are degraded safely by a variety of naturally occurring antioxidant systems. Metabolic changes that occur during ischemia greatly enhance the production of free radicals at the time of reperfusion, when an ample supply of oxygen becomes available. An ischemia induced decrease in antioxidant activity further exacerbates cell injury.

A lot of methods and drugs have been suggested to decrease or to avoid reperfusion injury including -tocopherol (vitamin E), inhibitors of lipid peroxydase [6], mannitol [7], catalase, superoxide dismutase, allopurinol [8], inhibitors of tromboxane-A₂ [9], EPC-K1 (a phosphate diester of alpha-tocopherol and ascorbic acid) [10], and a period of controlled, slow reperfusion [11] are some of them.

Some of these agents are also used in open heart surgery as additives for cardioplegic solutions to prevent or decrease reperfusion injury and to extend ischemia tolerance after cross clamping.

Ascorbic acid and carnitine have been considered the most famous ones of these substances. Because, they are endogen, cheap and can be found easily in the market.

Because of its reductan effect, ascorbic acid, also called vitamin C, is a strong antioxidant agent and has ability of reacting with superoxide anion and hydroxyl ion of oxygen-derived free radicals.

Carnitine is the essential factor for the transport of long-chain fatty acids (acyl CoA) from the cytoplasm to within the mitochondrion where the beta-oxidation process takes place. Carnitine also can increase the oxidation of glucose during the reperfusion phase by performing transportation of long-chain fatty acids to the mitochondrial matrix for beta-oxidation.

In this experimental study; the effects of carnitine and ascorbic acid on reperfusion injury on the skeletal muscle were studied and were tried to find if one of them is more protective than the other from the aspect of histopathologic changes.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
The study was performed at the Experimental Animal Research Laboratory on female rabbits between the dates of March 20, 2000–April 10, 2000 with permission of the Ethic Committee of our institution (all rabbits received humane care in compliance with the European Convention on Animal Care).

A warm ischemia/reperfusion (I/R) model was created on New Zealand type female rabbits on the basis of the method described earlier by Hardy et al. [12]. Forty rabbits weighing between 2.5–3.3 kg (mean: 3.1 kg) were divided into four randomized groups. At the room temperature (20°C) anesthesia was administered by intramuscular (IM) injection of kethamine hydrochlorur (Ketalar) of 30 mg/kg and xylosine hydrochlorur (Rompun) of 2 mg/kg to the left anterior foot. Ten milligrams of IM kethamine was repeated at every 30–45 min for maintenance. In group I (G1, n=10) only anesthesia was applied and a biopsy was taken from right soleus muscle after six hours from induction of anesthesia. Following induction of anesthesia; in group II (G2, n=10), group III (G3, n=10) and group IV (G4, n=10) ischemia was induced to the right posterior extremities of animals by blocking right femoral arterial blood flow proximally using a tourniquet to the groin area (cessation of blood flow was verified by Doppler ultrasound). After 4 h of ischemia, 1.5 ml physiological saline, 50 mg/kg (total 1.5 ml) L-ascorbic acid sodium (Redoxon amp 500 mg/5 cc, Roche) and 100 mg/kg (total 1.5 ml) L-Carnitine (Carnitine amp. 1 g/5 cc, Santa Farma) were given intravenously from the left femoral vein to G2, G3 and G4, respectively and tourniquet was released. Following 2 h of reperfusion, an excisional biopsy (about 3x1 cm size) was taken from the right soleus muscle in each rabbit.

2.1. Histopathologic analysis
Muscle specimens were excised and cut into slices along the longitudinal axis. Tissue was fixed in 10% formalin neutralized with phosphate buffers (monobasic and dibasic sodium phosphate) for 24 h. Overnight schedule was done for tissue processing using an automatic tissue processor [13]. Tissues were embedded in paraffin wax, and 5 µm-thick sections were stained with Hematoxylen-Eosine (HE) in routine fashion. Slides were examined by a light microscope (Nicon Nippon Kogako K.K., Model: Optiphot-2, Serial number: 141874, Tokyo, Japan; 200 and 400 magnifications).

Six different histopathologic criteria of ischemic muscle tissue (loss of striation, nuclear centralization, formation of ring and/or splitting, changing on diameters of muscle fibers, necrosis and minimal fibrosis) were investigated (Figs. 1 and 2) . The borders of the longitudinal axis of the specimen were followed through preparats. For every specimen, a picture was taken from any slice that shows normal histologic muscle morphology. Then, this picture was compared with the other images that show some abnormality.

View larger version (123K): [in this window] [in a new window]   Fig. 1. Segmental necrosis of muscle fibers (x400 HE).

View larger version (130K): [in this window] [in a new window]   Fig. 2. Centralization of nuclei in muscle fibers (x200 HE).

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
All animals have completed the study and there was no any mortality. Data about ischemic changes in the soleus muscles are shown in Tables 1–4. The symbol ‘+’ refers to the existence of investigated parameter (in any of examining preparats) while ‘-’ to the absence. Because, the specimens were taken in very early phase of injury, visible changes on cytoskeletal structure were limited. Thus, a grading score could not be used and any minor change from normal structure from the aspect of our histopathologic criteria was considered ‘positive’.

Statistical analysis of these results are summarized on Table 5. Loss of striation and splitting/ring formation showed no significant differences for any group when control group was excluded. Changes on diameters were insignificant for G1–G4 (P<0.3) and significant for the others. From the aspect of necrosis, the differences were insignificant in comparison for G3–G4 (P<0.4), and significant for all other comparisons. Results for centralization of nuclei also revealed insignificant differences for G3–G4 (P<0.5), and significant for others resembling to those of necrosis. G2–G4 (P<0.08) and G2–G3 (P<0.9) showed insignificant, and significant for all other comparisons from the aspect of minimal fibrosis. When compared G3 and G4, carnitine group shows better protection on minimal fibrosis (P<0.03) and diameter change (P<0.03).

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

Striation loss, splitting and ring formation are minor and initial changes. Necrosis, centralization and diameter change reflect more serious and advanced injury. Therefore, it seems these agents prevent the tissue from serious damage. However, it is difficult to explain why there is no any protection for fibrosis. Probably related to the small number of subjects.

Ischemic injury is not limited to the damage that occurs during the period of hypoperfusion. Additional injury develops during the initial period of reperfusion, as highly active oxygen metabolites such as the superoxide and hydroxyl radicals accumulate and compound the cellular insult.

Restoration of blood flow to the extremity exposed to ischemia can cause the reperfusion injury by leading to formation of oxygen-derived free radicals resulting in more muscle necrosis than ischemia itself. Sometimes reperfusion injury leads to life-threatening metabolic abnormalities and high mortality and morbidity rates [1]. During ischemia, muscle cells cannot keep their membrane integrity and this causes releasing of calcium, phospholipid A₂ and formation of polyunsaturated fatty acids and fatty acid radicals. If the oxygenation is re-established at that stage of ischemia, fatty acid radicals react with oxygen and perform the lipid peroxidation reaction. This reaction increases the membrane permeability and also stimulates chemotaxis of leukocytes, which can release oxygen-derived free radicals and proteolytic enzymes when activated. As a result, ischemic cell injury is worsened by reperfusion.

Severe hypoperfusion of a limb, if left untreated, inevitably progress to tissue infarction and irreversible cell death. However, there is no sharp demarcation between reversible injury and irreversible injury that ultimately causes cell death. Instead, there is a continuum of biochemical and morphological reactions to injury.

For skeletal muscle, histologic chances can be observed after only 4 h of warm ischemia and irreversible infarction may develop within 6 h [14]. At 2 h [5] minimal ultrastructural damage occurs, followed by complete regeneration of intramuscular phosphogens and glycogen on reperfusion, with complete normalization of lipid oxidation products.

The initial ischemia in striated muscle results in rhabdomyolysis and during the reperfusion phase is further complicated by free radical induced ischemia leading to an additional superimposed necrosis. With reflow or reperfusion into a region of hypoxic or ischemic skeletal muscle, paradoxical results, consisting of a marked increase of ischemic damage, may be observed.

A number of experimental studies have shown that obstruction of blood flow of skeletal muscle for from 30 min to several hours may result in edema formation after release of the occlusion. Korthuis et al. [15] and Harris et al. [5] showed that prolonged ischemia followed by reperfusion produces morphological alterations in skeletal muscle similar to those seen after reperfusion of ischemic myocardium, intestine, brain, and kidney. Korthuis et al. showed that the role of oxygen derived free radicals in the genesis of increased vascular permeability could prevent the production of active oxygen species when the patient is subjected to pretreatment with specific oxygen radical scavengers. Again, these investigators pointed out that most of the damage to skeletal muscle occurred, not only during the ischemic period, but also after reoxygenation has been restored.

Harris et al. [5] emphasize the prolonged glycolytic activity of skeletal muscle during global ischemia and document the increased production of oxygen free radical-mediated lipid oxidation products in irreversibly injured muscle.

Chemically, Carnitine is beta-hydroxy-gamma-trimethylaminobutyric acid. It is a naturally occurring compound in the body and its distribution in the myocardium and in muscular tissue amounts to 95% of total carnitine [16].

Reduced levels of Carnitine have been observed in skeletal muscle during exercise (and also in the ischemic myocardium) whether acute or chronic. The administration of L-Carnitine restores normal levels of the substance and has been shown to be capable of improving the mitochondrial function of ischemic cells, thus reducing the tissue damage produced by the ischemia [17].

The mechanism by which carnitine exerts its action in ischemic metabolism lies in its ability to react with the acyl CoA, which has accumulated as a result of slowing down of beta-oxidation to form acyl carnitine, which, in turn, is capable of carrying acyl groups out of the anoxic cell [18].

Ascorbic acid is a natural antioxidant agent and directly inhibits superoxide production in the stoplasm. It also catalyzes synthesis of -tocopherol (vitamin E) and Carnitine.

Studies that support a positive role of carnitine in ameliorating the (I/R)-induced damage of human skeletal muscle are limited. Most of the in vivo studies about carnitine have been conducted on heart muscle [19–21].

There are more studies for ascorbic acid on skeletal muscle in the literature. Sadiç et al. [22] have created an I/R model on the lower extremities of dogs and found out that intravenous administration of high doses (75 mg/kg) of vitamin C (before reperfusion) was reduced the reperfusion injury. Similarly, Lagerwall et al. [23] showed that treatment with ascorbate had an immediate, positive effect on the recovery of high energy phosphates and pH on striated muscle at the time of reflow. The results provide in vivo evidence for a salvaging effect of ascorbate on ischemia-reperfusion injury in skeletal muscle, probably owing to its antioxidant function and other ancillary effects, mainly its provision of additional buffer capacity.

In another experimental I/R study [24], high doses of ascorbic acid were given to the animals during 4 h of ischemia and 1 h of reperfusion. Histopathological analysis of anterior tibial muscle revealed reduction in reperfusion injury.

While in some of the studies mentioned above are concluded that carnitine and vitamin C premedications were very effective in reducing reperfusion injury of skeletal muscle and myocardium, in the others [25], that effectivity couldn't be demonstrated. We didn't find any study doing comparison for both agents at the same time. We used both agents at the same protocol (on striatal muscle). And used histopathologic criteria to test their protective effects rather than clinical observations. Our study showed that both sodium ascorbate and carnitine were effective in reducing the reperfusion injury when compared to the placebo and control group. Differences were insignificant for sodium ascorbate and significant for carnitine statistically. Compared to each other, carnitine was superior to sodium ascorbate but the difference was significant statistically only from the aspect of fibrosis (which is interesting) and changes of diameters of muscle fibers.

In consideration of all studies done until now, including our study, we conclude that it is still wisely to use carnitine in acute arterial occlusion and major and minor vascular surgery cases or to pretreat patient by this agent. Also, ascorbic acid can be added to obtain additive effect. In order to encourage to use these agents in acute myocardial infarctus, interventional cardiology and open heart surgery, a similar study needs to be performed in heart muscle.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Akar, H. Articles by Kolbakir, F. Search for Related Content PubMed PubMed Citation Articles by Akar, H. Articles by Kolbakir, F. Related Collections Extracorporeal circulation Myocardial protection