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Cardiovascular Research 2002 55(3):626-632; doi:10.1016/S0008-6363(01)00505-3
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Copyright © 2002, European Society of Cardiology

Involvement of endogenous prostaglandins in ischemic preconditioning in pigs

Petra Gres, Rainer Schulz, Johanna Jansen, Christian Umschlag and Gerd Heusch*

Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Germany

gerd.heusch{at}uni-essen.de

* Corresponding author. Tel.: +49-201-723-4480; fax: +49-201-723-4521

Received 16 August 2001; accepted 20 September 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: In pigs, the infarct size (IS) reduction achieved by a strong preconditioning stimulus (IPs) of 10 min ischemia and 15 min reperfusion is greater than that by a weaker preconditioning stimulus (IPw) of 3 min ischemia and 15 min reperfusion. The cardioprotection achieved by IPw is completely abolished by blockade of bradykinin-B2-receptors. Since activation of bradykinin-B2-receptors subsequently activates cyclooxygenase, we now tested whether or not inhibition of cyclooxygenase with indomethacin interferes with IS reduction by IP. Methods and results: In 42 enflurane-anesthetized pigs, the LAD coronary artery was cannulated, and subendocardial blood flow (ENDO, microspheres, ml/min/g) and IS (%, TTC-staining) were determined. Following 90 min ischemia and 120 min reperfusion, IS averaged 25.5±3.8 (S.E.M.) (ENDO: 0.05±0.01). IS was reduced by IPw to 6.3±2.1 (ENDO: 0.07±0.01) and further reduced by IPs to 2.4±1.0 (ENDO: 0.06±0.01). Indomethacin (10 mg/kg i.v.) did not alter IS per se (20.9±5.4, ENDO: 0.06±0.02), but completely abolished the IS reduction by IPw (23.2±5.9, ENDO: 0.06±0.01). In contrast, indomethacin abolished the IS reduction by IPs in only two of seven pigs (16.1±7.4, ENDO: 0.05±0.01). Conclusion: Prostaglandins are involved in IP. However, with stronger IP stimuli other triggers/mediators can compensate for the lack of prostaglandins.

KEYWORDS Ischemia; Preconditioning; Prostaglandins; Reperfusion


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The reduction of infarct size by ischemic preconditioning (IP) is the most powerful endogenous cardioprotective phenomenon known so far, and it is present in all species tested so far [1,2], including humans [3]. Goto et al. [4] were the first to demonstrate the interaction of different triggers with variation of the preconditioning protocol. In their study, bradykinin was of major importance only during a weaker preconditioning stimulus, i.e., a single cycle of 5 min preconditioning ischemia and 5 min reperfusion, while during a strong preconditioning stimulus, i.e., four cycles of preconditioning ischemia/reperfusion, adenosine was of greater importance. Similarly, in pigs in which infarct size reduction by IP was less pronounced with a preconditioning stimulus of 3 min preconditioning ischemia and 15 min reperfusion than with a stronger preconditioning stimulus of 10 min preconditioning ischemia and 15 min reperfusion, bradykinin was of major importance only with the weaker preconditioning stimulus while adenosine [5] and opioids [6] were of greater importance with a stronger preconditioning stimulus.

Activation of bradykinin-B2-receptors subsequently activates cyclooxygenase [7,8]. Indeed, cyclooxygenase products are involved in the antiarrhythmic effect [9] and the preservation of endothelial function by ischemic preconditoning [10]. We therefore now tested in an established pig model of ischemic preconditioning whether or not inhibition of cyclooxygenase with indomethacin at this dose abolishes the infarct size reduction by ischemic preconditioning, and whether or not the loss of protection depends on the strength of the preconditioning stimulus and thus on the specific triggers involved in the cardioprotective effect.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The experimental protocols employed in this study were approved by the bioethical committee of the district of Düsseldorf, Germany, and they adhere to the guiding principles of the American Physiological Society.

2.1 Experimental preparation
Forty-two Göttinger minipigs (20–40 kg) of either sex were initially sedated using ketamine hydrochloride (1 g i.m.) and then anesthetized with thiopental (Trapanal, 500 mg i.v., Byk Gulden, Konstanz, Germany). Through a midline cervical incision, the trachea was intubated for connection to a respirator (Dräger, Lübeck, Germany). Anesthesia was then maintained using enflurane (1–1.5%) with an oxygen–nitrous oxide (40:60) mixture. Arterial blood gases were monitored frequently in the initial stages of the preparation until stable and then periodically throughout the study (Radiometer, Copenhagen, Denmark). Rectal temperature was monitored, and body temperature was kept between 37 and 38°C using heating pads. Pigs were instrumented for the measurement of left ventricular pressure and wall thickness [5,11]. After heparinization, the left anterior descending (LAD) coronary artery and vein were cannulated, and the artery was perfused from an extracorporeal circuit, including a roller pump. During ischemia, blood flow into the cannulated LAD coronary artery was reduced (see below) by reducing the speed of the roller pump; however, a residual blood flow of approximately 15–20% was always maintained.

2.2 Regional myocardial function and regional myocardial blood flow
Regional systolic wall thickening was determined using sonomicrometry, and regional myocardial blood flow was measured with radioactive microspheres [12].

2.3 Morphology
Up to six transverse myocardial slices from each heart were incubated in triphenyl tetrazolium chloride solution to identify necrotic tissue [5].

2.4 Experimental protocols
2.4.1 Group 1 (placebo, n = 8)
Following control measurements of systemic hemodynamics and regional myocardial function and blood flow, coronary inflow was reduced to achieve a 90% reduction in regional myocardial function. At 5 and 85 min ischemia, measurements were repeated, and thereafter the myocardium was reperfused for 2 h.

2.4.2 Group 2 (IP3, n = 7)
Following control measurements of systemic hemodynamics and regional myocardial function and blood flow, the myocardium was subjected to one cycle of 3 min preconditioning ischemia, with a 90% reduction in regional myocardial function, and 15 min reperfusion. During reperfusion, coronary arterial pressure was maintained at the level measured prior to ischemia by continuously adapting coronary inflow with the roller pump. Following reperfusion, coronary inflow was once again reduced to the same level as during the preconditioning ischemia. Thereafter, the protocol of group 2 was identical to that of group 1.

2.4.3 Group 3 (IP10, n = 7)
The protocol of group 3 was identical to that of group 2, except that the preconditioning ischemia was of 10 min duration.

2.4.4 Group 4 (Indo, n = 7)
Following control measurements of systemic hemodynamics and regional myocardial function and blood flow, cyclooxygenase was inhibited by intravenous infusion of 10 mg/kg indomethacin over 30 min. This dose regimen has previously been demonstrated to abolish the coronary vasodilation induced by intracoronary arachidonic acid [8]. After infusion of indomethacin all measurements were repeated before coronary inflow was reduced. Thereafter the protocol of group 4 was identical to that of group 1.

2.4.5 Group 5 (Indo+IP3, n = 6)
The protocol of group 5 was identical to that of group 2, except that the indomethacin administration (10 mg/kg i.v.) was started 30 min prior to the preconditioning ischemia.

2.4.6 Group 6 (Indo+IP10, n = 7)
The protocol of group 6 was identical to that of group 3, except that the indomethacin administration (10 mg/kg i.v.) was started 30 min prior to the preconditioning ischemia.

2.5 Data analysis and statistics
Data are reported as mean values±S.E.M. Statistical analysis for groups 1–6 comprised two-way analysis of variance (ANOVA) for repeated measures and Fisher's LSD tests when significant overall effects were detected. Infarct size and area at risk were analyzed by one-way ANOVA and Fisher's LSD tests. A p-value less than 0.05 was accepted as indicating a significant difference in mean values.

In groups 1–6, linear regression analyses between subendocardial blood flow at 5 min ischemia in the left ventricular area at risk and infarct size (expressed as percent of the area at risk) were performed. Regression lines were compared by analysis of covariance.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Hemodynamics
Heart rate was held constant by left atrial pacing. Systemic hemodynamics, regional myocardial function, and regional myocardial blood flow were not different between groups 1 to 6 at baseline (Table 1). Regional myocardial function of the posterior control wall remained stable throughout the experimental protocol in each group.


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  		Table 1 Systemic hemodynamics, regional myocardial function and flow

 
In groups 4 to 6 indomethacin increased LV peak pressure and mean coronary arterial pressure, whereas anterior systolic wall thickening was decreased. Indomethacin per se did not alter transmural myocardial blood flow.

3.2 Infarct size
The area at risk was comparable between groups 1 to 6 (Fig. 1). Following 90 min severe myocardial ischemia and 120 min reperfusion, infarct size averaged 25.5±3.8% (group 1, Fig. 1). IP by one cycle of 3 min ischemia and 15 min reperfusion reduced infarct size to 6.3±2.1% (group 2, p<0.05 vs. group 1). IP by one cycle of 10 min ischemia and 15 min reperfusion reduced infarct size further to 2.4±1.0% (group 3, Fig. 1). The relationship between infarct size and subendocardial blood flow was significantly shifted downwards with IP3 (group 2, Fig. 2) compared to the relationship obtained in the placebo group (group 1, Fig. 2). The relationship was further shifted downwards by IP10 (group 3, Fig. 2)


Figure 1
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  		Fig. 1 Area at risk (% of the left ventricle) and infarct size (% of the area at risk) in groups 1–6. Area at risk did not differ between groups. Infarct size was significantly reduced in hearts preconditioned by 3 min ischemia and 15 min reperfusion (group 2) and further reduced by 10 min preconditoning ischemia and 15 min reperfusion (group 3). Indomethacin did not alter infarct size per se (group 4), but completely abolished the infarct size reduction by 3 min ischemic preconditioning (group 5) and attenuated the infarct size reduction by 10 min ischemic preconditioning (group 6). *p<0.05 vs. group 1. #p<0.05 vs. group 2.

 

Figure 2
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  		Fig. 2 Relationships between infarct size and subendocardial blood flow in pigs undergoing 90 min ischemia without (group 1, filled circle, solid line) or with a cycle of 3 min preconditioning ischemia and 15 min reperfusion (group 2, open circle, dashed line) or a cycle of 10 min preconditioning ischemia and 15 min reperfusion (group 3, filled triangle, dashed and dotted line). The relationship between infarct size and subendocardial blood flow in group 2 was significantly shifted downwards compared to the relationship obtained in group 1 and shifted further downwards in group 3. *p<0.05 vs. group 1. #p<0.05 vs. groups 1 and 2.

 
In the presence of indomethacin, IS following 90 min sustained ischemia and 120 min reperfusion (group 4, Fig. 1) was 20.0±5.4%, and it did not differ from that in the placebo group (group 1). Indomethacin abolished the IS reduction by IP3; i.e., IS was 23.2±5.9% (group 5, Fig. 1). Indomethacin abolished the IS reduction by IP10 in only two out of seven pigs, and IS averaged 16.1±7.4% (group 6, Fig. 1). The relationships between infarct size and subendocardial blood flow in indomethacin-treated pigs without or with IP3 (groups 4 and 5) were superimposable with the relationship obtained with placebo (group 1, Fig. 3). The relationship between infarct size and subendocardial blood flow in indomethacin-treated pigs with IP10 (group 6), however, was significantly different from the relationships obtained with placebo (group 1) or IP10 (group 3, Fig. 4).


Figure 3
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  		Fig. 3 Relationships between infarct size and subendocardial blood flow in pigs undergoing 90 min ischemia without (group 1, filled circle, solid line) or with a cycle of 3 min preconditioning ischemia and 15 min reperfusion (group 2, open circle, dashed line). Indomethacin per se did not alter the relationship (group 4, open triangle, dashed and dotted line) but prevented the downward shift with preconditioning (group 5, filled square, dotted line). *p<0.05 vs. group 1.

 

Figure 4
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  		Fig. 4 Relationships between infarct size and subendocardial blood flow in pigs undergoing 90 min ischemia without (group 1, filled circle, solid line) or with a cycle of 10 min preconditioning ischemia and 15 min reperfusion (group 3, filled triangle, dashed line). Indomethacin per se did not alter the relationship (group 4, open triangle, dashed and dotted line) and did not interfere with the downward shift with preconditioning (group 6, open square). *p<0.05 vs. group 1.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The major finding of the present study is that prostaglandins are involved in the signal cascade of ischemic preconditioning in pigs, their involvement depending on the strength of the preconditioning stimulus. Whereas inhibition of cyclooxygenase with indomethacin (10 mg/kg) completely abolished the infarct size reduction achieved by a weaker preconditioning stimulus (IP3), it abolished infarct size reduction by a stronger preconditioning stimulus (IP10) in only two of seven pigs. Thus, with stronger preconditioning stimuli other triggers/mediators can compensate for the lack of prostaglandins.

4.1 Critique of methods
The strengths and limitations of the experimental model have been discussed in detail elsewhere [5].

Indomethacin increased left ventricular pressure and mean coronary arterial pressure. The latter finding is in accordance with studies in conscious dogs, in which a basal tonic release of prostaglandins – measured as the release of PGF1{alpha} – was reported, and blockade of such release with either indomethacin (5 mg/kg) or diclofenac (10 mg/kg) increased smooth muscle tone and subsequently coronary perfusion pressure [13].

4.2 Determinants of infarct size
As mentioned above, indomethacin increased left ventricular pressure but did not alter infarct size (groups 1 and 4). This finding is in agreement with results from previous experiments in which increases in left ventricular pressure at a constant heart rate and myocardial blood flow did not influence the extent of myocardial infarction [14].

Ischemic blood flow is another major determinant of infarct development [15], and therefore the relation of infarct size to subendocardial blood flow is a more sensitive endpoint than infarct size per se. Indeed, mean infarct size did not significantly differ between the three indomethacin-treated groups, although the blood flow-infarct size relationship revealed a complete loss of preconditoning's protection only in hearts with a weaker preconditioning stimulus (IP3), but a loss of protection in only two out of seven hearts with a stronger preconditioning stimulus (IP10).

4.3 Source and nature of prostaglandins
In the present study, prostaglandin release was not measured, and thus the nature of the prostaglandins involved in the infarct size reduction by a weak ischemic preconditioning stimulus could not be defined. In isolated rat cardiomyocytes, release of 6-ketoprostaglandin F1{alpha}, prostaglandin E2 and to a smaller amount PGF2{alpha} was measured, which was increased during hypoxia [16]. In isolated rabbit hearts [17], bradykinin induced a prostaglandin release, the most important cyclooxygenase-products being prostaglandin I2 (70%) and E2 (30%). Apart from isolated cardiomyocytes [16], vascular endothelial and smooth muscle cells [7] produce prostaglandins. The signal cascade involves G-proteins, inositoltriphosphate and diacylglycerol, and subsequently protein kinase C activation [7].

4.4 Comparison to other studies
In contrast to the present study, endogenous prostaglandins appear to be not involved in the infarct size reduction by ischemic preconditoning in rats and rabbits, since aspirin or indomethacin failed to block preconditioning's protection [18,19]. The failure of blockade of cyclooxygenase to attenuate infarct size reduction by ischemic preconditioning in rats might relate to the greater strength of the preconditioning stimulus with three cycles of 3 min ischemia and 15 min reperfusion [18], and thus the involvement of additional triggers. The failure of blockade of cyclooxygenase to attenuate ischemic preconditioning's protection in isolated rabbit hearts [19], however, is less likely be related to the strength of the preconditioning stimulus. In this model, with a single preconditioning episode of 5 min ischemia/reperfusion, bradykinin preferentially triggers the observed cardioprotection, which is blocked by the bradykinin-B2-receptor antagonist HOE140 [4].

One potential explanation for the lack of blockade of ischemic preconditioning's protection by either indomethacin alone [19] or the NO-synthase inhibitor L-NAME alone [20] is their cooperative action. Indeed, in isolated rabbit hearts, bradykinin infusion increases both nitric oxide (measured as an increase in cGMP) and prostaglandin (measured as 6-keto-PGF1{alpha}) release [17]. Pharmacological preconditioning with bradykinin reduced infarct size, which was, however, not affected by the blockade of cyclooxygenase with indomethacin alone nor the blockade of nitric oxide synthase with L-NAME alone. Unfortunately, combined blockade of both cyclooxygenase and nitric oxide synthase was not performed. A cooperative signal transduction has been previously demonstrated for protein kinase C and protein tyrosine kinases in rats and pigs (for review, see Ref. [21]).

An alternative, although purely speculative explanation relates to the concentration of the blocker used to inhibit cyclooxygenase; in this respect, aspirin at a dose of 1 mg/kg [19] failed to block the protective effect of ACE-inhibitors on myocardial stunning in anesthetized dogs [22], whereas indomethacin at a dose of 10 mg/kg completely abolished this protection [8].

4.5 Triggers/mediators of ischemic preconditioning
The signal cascade of IP in pigs involves several endogenous triggers such as adenosine [23], bradykinin [5], and opioids [6].

Bradykinin binds to B2-receptors which are coupled to phospholipase C via G-proteins. Activation of phospholipase C results in an increased formation of inositoltriphosphate and diacylglycerole and enhanced intracellular calcium levels and activation of protein kinase C, an established mediator of ischemic preconditioning [24,25]. Both, the enhanced intracellular calcium concentration by subsequent activation of phospholipase A2 and the activation of protein kinase C could potentially result in enhanced prostaglandin formation [7], supporting the idea of prostaglandins as an important mediator of preconditioning's protection.

In the present study, we cannot distinguish between prostaglandins of the E-type and the I-type. However, both pharmacological activation of the EP3-receptor by prostaglandin E1 [26] and synthetic analogues [27–29] and administration of the prostacyclin analogue iloprost [30,31] have been shown to reduce the damage by ischemia/reperfusion.

The interaction of triggers of IP is rather complex [4,5]. Bradykinin appears to be an important trigger with a weaker/more short-lasting IP stimulus, whereas adenosine [4,5] and/or opioids [6] gain more importance with stronger/longer stimuli. In pigs, the infarct size reduction achieved by 3 min preconditioning ischemia and 15 min reperfusion was completely abolished by blockade of bradykinin-B2-receptors, whereas the infarct size reduction by a stronger stimulus, i.e., 10 min ischemia and 15 min reperfusion, was almost unaffected by blockade of bradykinin-B2-receptors [5]. A similar pattern was found in the present study; whereas the protection by a weaker preconditioning stimulus was completely lost, indomethacin failed to affect infarct size reduction by a stronger preconditioning stimulus in five out of seven pigs. The loss of protection in two out of seven pigs, however, points to the fact that the interaction of different triggers/mediators in ischemic preconditioning is quite complex, and that interindividual variations exist; such interindividual variations were recently also demonstrated for the ischemia-induced phosphorylation of p38 MAP kinase in the same pig model [32].

In conclusion, prostaglandins are involved in ischemic preconditioning in pigs. However, with stronger preconditioning stimuli other triggers/mediators can compensate for the lack of prostaglandins. Whereas the present study clearly identifies the involvement of prostaglandins in ischemic preconditioning, their cellular and subcellular source as well as their exact location in the signal transduction cascade of ischemic preconditioning remain to be defined.

Time for primary review 21 days.


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

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