Preconditioning In Rabbits Research Articles

Time Course of Desflurane-induced Preconditioning in Rabbits

The authors tested the hypothesis that volatile anesthetic-induced preconditioning (APC) follows a similar time pattern as that described for ischemic preconditioning and that delayed APC is mediated by nitric oxide. A prospective randomized vehicle-controlled study. A university research laboratory. New Zealand white rabbits (n = 75). Rabbits were instrumented for the measurement of systemic hemodynamics and subjected to a 30-minute coronary artery occlusion (CAO) and 3 hours of reperfusion. Desflurane (1.0 minimum alveolar concentration) was administered for 30 minutes and was discontinued 0.5 hours, 2 hours, 3 hours, 12 hours, 24 hours, 48 hours, 72 hours, and 96 hours before CAO, respectively. In 2 separate experimental groups, the nitric oxide synthase inhibitor N-omega-nitro-L-arginine (L-NA) was administered 72 hours after the administration of 0.0 or 1.0 minimum alveolar concentration of desflurane. The infarct size was determined gravimetrically. Data are mean +/- standard deviation. Desflurane significantly (p < 0.05) reduced the infarct size compared with the control (63% +/- 12%, n = 7) when administered 0.5 hours (35% +/- 5%, n = 7), 2 hours (35% +/- 9%, n = 7), 24 hours (31% +/- 8%, n = 7), 48 hours (30% +/- 11%, n = 6), and 72 hours (39% +/- 5%, n = 6) before CAO. However, when desflurane was administered 3 hours (53% +/- 9%, n = 7), 12 hours (71% +/- 6%, n = 7), or 96 hours (66% +/- 5%, n = 7) before CAO, the myocardial infarct size was not reduced. The second window (72 hours) of preconditioning was abolished by the NOS inhibitor L-NA (52% +/- 16%, n = 7). L-NA alone had no effect on infarct size (64% +/- 11%, n = 7). Desflurane induces a first (0.5-2 hours) and second window of preconditioning (24-72 hours) in the rabbit model of acute myocardial infarction. The second window of APC is mediated by nitric oxide.

Acute administration of vitamin C abrogates protection from ischemic preconditioning in rabbits

Vitamin C is considered to be an antioxidant agent that is broadly used. Free radicals are involved in the protective mechanism of preconditioning (PC), but some antioxidant compounds abolish this benefit. The aim of the present study was to evaluate the effect of vitamin C on the protective effect of PC with respect to infarct size and oxidative stress in anesthetized rabbits. Male rabbits were randomly divided into six groups and subjected to 30 min of myocardial ischemia and 3 h of reperfusion with the following interventions per group: (1) Control (no intervention), (2) Vit C 150 group (i.v. vitamin C at a total dose of 150 mg/kg for 75 min, starting 40 min before the onset of long ischemia and lasting up to the 5th min of reperfusion), (3) Vit C 300 group (i.v. vitamin C at a total dose of 300 mg/kg as previously described), (4) PC group (two cycles of 5 min ischemia and 10 min reperfusion), (5) combined PC-Vit C 150 group and (6) combined PC-Vit C 300 group. Blood samples were taken at different time points for malondialdehyde (MDA) assessment as a lipid peroxidation marker and for superoxide dismutase (SOD) activity. At the end of the experiment the infarct size was determined. Vitamin C, at both doses, did not reduce the infarct size (35.5 ± 4.1%, 38.3 ± 7.0% vs. 44.9 ± 3.3% in the control group) and diminished the protection afforded by PC (32.0 ± 2.7%, 43.8 ± 3.3% vs. 15.7 ± 2.9% in the PC group, P < 0.05). At reperfusion there was an elevation of circulating MDA levels in the control and PC groups while in both vitamin C groups the levels were decreased. SOD activity was enhanced in the PC group compared to the controls; vitamin C did not change SOD activity during ischemia–reperfusion. Vitamin C abrogates the beneficial effect of ischemic PC on infarct size and elicits antioxidant properties during ischemia–reperfusion.

Myocardial injury and its prevention in the perioperative setting

Myocardial injury and its prevention in the perioperative setting

Sevoflurane confers additional cardioprotection after ischemic late preconditioning in rabbits.

Sevoflurane exerts cardioprotective effects that mimic the early ischemic preconditioning phenomenon (EPC) by activating adenosine triphosphate-sensitive potassium (KATP) channels. Ischemic late preconditioning (LPC) is an important cardioprotective mechanism in patients with coronary artery disease. The authors investigated whether the combination of LPC and sevoflurane-induced preconditioning results in enhanced cardioprotection and whether opening of KATP channels plays a role in this new setting. Seventy-three rabbits were instrumented with a coronary artery occluder. After recovery for 10 days, they were subjected to 30 min of coronary artery occlusion and 120 min of reperfusion (I/R). Controls (n = 14) were not preconditioned. LPC was induced in conscious animals by a 5-min period of coronary artery occlusion 24 h before I/R (LPC, n = 15). Additional EPC was induced by a 5-min period of myocardial ischemia 10 min before I/R (LPC+EPC, n = 9). Animals of the sevoflurane (SEVO) groups inhaled 1 minimum alveolar concentration of sevoflurane for 5 min at 10 min before I/R with (LPC+SEVO, n = 10) or without (SEVO, n = 15) additional LPC. The KATP channel blocker 5-hydroxydecanoate (5-HD, 5 mg/kg) was given intravenously 10 min before sevoflurane administration (LPC+SEVO+5-HD, n = 10). Infarct size of the area at risk (triphenyltetrazolium staining) was reduced from 45 +/- 16% (mean+/-SD, control) to 27 +/- 11% by LPC (P < 0.001) and to 27 +/- 17% by sevoflurane (P = 0.001). Additional sevoflurane administration after LPC led to a further infarct size reduction to 14 +/- 8% (LPC+SEVO, P = 0.003 vs. LPC; P = 0.032 vs. SEVO), similar to the combination of LPC and EPC (12 +/- 8%; P = 0.55 vs. LPC+SEVO). Cardioprotection induced by LPC+SEVO was abolished by 5-HD (LPC+SEVO+5-HD, 41 +/- 19%, P = 0.001 vs. LPC+SEVO). Sevoflurane administration confers additional cardioprotection after LPC by opening of KATP channels.

Evidence for a ceiling of cardioprotection with a nitric oxide donor-induced delayed preconditioning in rabbits.

Although extensive attention has been devoted to the window of preconditioning, only few studies investigated the efficacy of preconditioning against ischemia with increasing durations. To date, a "ceiling of protection" has been demonstrated to occur with early preconditioning but nothing is known about delayed preconditioning. Accordingly, the efficacy of a nitric oxide (NO)-donor-induced delayed preconditioning was tested against ischemic insults of increasing duration. Accordingly, 65 rabbits received a 75-min intravenous infusion of either saline (control group), or an NO-donor (S-nitroso-N-acetylpenicillamine) at 3 microg/kg/min (SNAP-3 group) or 30 microg/kg/min (SNAP-30 group). Twenty-four hours later, rabbits randomly underwent either a 15-, 20-, or a 30-min coronary artery occlusion (CAO). Infarct size was assessed after 72-h reperfusion (triphenyltetrazolium chloride staining, percentage of the area at risk). After 15-min CAO, both SNAP-3 and SNAP-30 reduced infarct size compared with control (10 +/- 3, 5 +/- 1 versus 29 +/- 8%, respectively; p < 0.05). After 20-min CAO, significant cardioprotection was only observed with SNAP-30 (29 +/- 4, 21 +/- 6 versus 36 +/- 2% for SNAP-3, SNAP-30 versus control, respectively). After 30-min CAO, both SNAP-3 and SNAP-30 failed to reduce infarct size (48 +/- 2, 50 +/- 5 versus 50 +/- 4% for SNAP-3, SNAP-30 versus control, respectively). In conclusion, this study demonstrates a dose-related ceiling of protection with delayed preconditioning induced by an NO donor. It supports that delayed preconditioning might exert its maximal beneficial effect with early reperfusion and this finding supports the necessary use of different durations of ischemia when investigating cardioprotective strategies.

Mechanism of Isoflurane-Induced Preconditioning in Rabbits: A Role for Reactive Oxygen Species

Mechanism of Isoflurane-Induced Preconditioning in Rabbits: A Role for Reactive Oxygen Species

Effects of neutral endopeptidase 24.11 inhibition on myocardial infarct size and ischemic preconditioning in rabbits.

This study was designed to determine whether inhibition of neutral endopeptidase 24.11 (NEP) reduces infarct size and enhances protection afforded by ischemic preconditioning (PC) by elevation of the tissue bradykinin (BK) level in the heart in situ. In experiments to determine a dose of thiorphan (Thio) that inhibits NEP activity in the rabbit, infusion of Thio at a rate of 15 micro g/kg per min was found to be NEP-selective, since it increased the extent and duration of hypotension after BK injection (50 ng/kg and 100 ng/kg, i.v.) but did not inhibit pressor response to angiotensin I (100 ng/kg and 500 ng/kg, i.v.). Infusion of Thio at a rate of 25 micro g/kg per min blunted pressor response to angiotensin I by 30%, suggesting this dose partially inhibits angiotensin-converting enzyme activity. In the second series of experiments, myocardial infarction was induced by 30-min coronary occlusion and 3-h reperfusion in rabbits. In untreated controls, infarct size as a percentage of area at risk (%IS/AR) was 50.1+/-4.1%, and infusion of Thio at 15 micro g/kg per min and 25 micro g/kg per min failed to limit infarct size (54.3+/-4.0% and 50.1+/-2.8%, respectively). However, these doses of Thio significantly reduced %IS/AR when combined with PC with 2-min ischemia to 25.7+/-3.3% and 19.7+/-3.1%, respectively, although this submaximal PC protocol alone did not achieve significant cardioprotection (%IS/AR=35.6+/-4.0%). This effect of Thio on PC was abolished by pretreatment with icatibant (2 micro g/kg), a BK B(2) receptor blocker. The results of the present study suggest that NEP inhibition does not increase anti-infarct tolerance of the myocardium but significantly enhances cardioprotection of PC via a B(2) receptor-mediated mechanism.

Reperfusion duration paradox with late myocardial preconditioning in rabbits

In this study, pharmacological late preconditioning was induced in 53 rabbits with an adenosine A 1 receptor agonist (2-chloro- N 6-cyclopentyladenosine, CCPA, 100 μg/kg), or a NO-donor ( S-nitroso- N-acetyl-penicillamine, SNAP, 2.5 μg/kg/min; 75 min) vs. saline as control. Later, after 24 h, rabbits underwent a 30-min coronary occlusion and subsequent reperfusion. After 3 h of coronary artery reperfusion, infarct size was reduced with CCPA (43±4%) and SNAP (27±4%) vs. saline (56±4%). However, after 72 h of coronary artery reperfusion, infarct sizes were similar in all groups, demonstrating an only transient effect of late preconditioning against myocardial infarction. Combined administration of CCPA and SNAP failed to induce sustained cardioprotection.

Delayed or second window preconditioning induced by adenosine A1 receptor activation is independent of early generation of nitric oxide or late induction of inducible nitric oxide synthase.

Transient adenosine A1 receptor (A1R) activation induces a second window or delayed preconditioning against myocardial infarction 24-72 h later. Early generation of nitric oxide and delayed induction of nitric oxide synthase have been implicated in mediating delayed cardioprotection after ischemic preconditioning in rabbits. Recent evidence indicates that some of the regulatory roles of adenosine in cardiac tissue may be mediated by A1R-induced generation of nitric oxide. This study examined the role of nitric oxide in the mediation of A1R-induced delayed preconditioning against infarction. Pharmacologic preconditioning of rabbits with the selective A1R agonist 2-chloro-N6-cyclopentyladenosine 100 microg/kg (CCPA) significantly reduced myocardial infarct size compared with control animals, after 30 min regional ischemia and 2 h reperfusion in vivo 24 h later (27.3+/-4.7 vs. 46.0+/-3.7%, respectively; p = 0.001). Nonselective inhibition of nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (10 mg/kg) before administration of CCPA did not affect this infarct limitation at 24 h. Selective inhibition of inducible nitric oxide synthase before the prolonged ischemic insult on day 2, with two structurally independent inducible nitric oxide synthase inhibitors, L-N(6)-(1-iminoethyl)-lysine (10 mg/kg) or aminoguanidine (300 mg/kg), did not abrogate the reduction in infarction observed by pharmacologic preconditioning with CCPA 24 h earlier. These results suggest that the second window or delayed protection against myocardial infarction observed 24 h after pharmacologic preconditioning with an adenosine A1 agonist occurs independently of either early generation of nitric oxide or subacute induction of inducible nitric oxide synthase.

No Confirmation for a Causal Role of Volume-regulated Chloride Channels in Ischemic Preconditioning in Rabbits

Volume-regulated chloride channels have recently been proposed to be end-effectors in ischemic preconditioning. The present study attempted to confirm this hypothesis by looking both at cardioprotection and channel activity. In isolated rabbit cardiomyocytes, hypo-osmotic stress (167 mosm/l) induced a current with a magnitude of 2–5 pA/pF at 60 mV. That current could be blocked by the selective chloride channel blockers 5-nitro–2–(3-phenylpropylamino) benzoic acid (NPPB) or indanyloxyacetic acid 94 (IAA-94), but only at 100 μM and 1 m M respectively. Lower concentrations were not effective. Because the channel-blocking concentrations were toxic in isolated perfused rabbit hearts, as evidenced by cessation of cardiac contraction and massive infarction, neither agent could be tested against preconditioning's anti-infarct effect. NPPB and IAA-94 at 1 μM and 10 μM, respectively (the doses used in a previous report), did not affect coronary flow, heart rate and developed pressure, and also did not prevent the infarct size reduction of ischemic preconditioning with 5 min global ischemia/10 min reperfusion preceding 30 min of regional ischemia and 120 min of reperfusion [11.4(±3.6) and (11.1(±3.7)% infarction of risk area, respectively]. The volume-regulated chloride and organic osmolyte channel blocker 4,4-diisothiocyanostilbene-2,2-disulfonic acid (DIDS) at 100 μM blocked the hypo-osmotically induced current in myocytes, but again could not be used, since it induced total cessation of cardiac contraction and reduced infarct size in non-preconditioned hearts. Our data do not confirm a prior study on a causal role for volume-regulated chloride channels in the protection of ischemic preconditioning. This hypothesis remains to be adequately tested.

Dilazep dihydrochloride prolongs the infarct size-limiting effect of ischemic preconditioning in rabbits.

Recent studies have indicated the key role of adenosine receptor activation as a trigger for ischemic preconditioning (PC). Hence, the augmentation of endogenous adenosine may potentiate the cardioprotective effects of PC. In this study. we aimed to test the hypothesis that dilazep dihydrochloride, an adenosine transport inhibitor, potentiates the PC effect. Protocol 1: Infarcts were produced in open-chest anesthetized rabbits by 30-min occlusion of a coronary artery and 2 days' reperfusion. PC was elicited by a preceding 5-min occlusion and either 5, 40, or 120 min of reperfusion. PC with the 5-min reperfusion markedly limited the infarct size after the 30-min ischemia (infarct size to area at risk (IS): 10%+/-3% vs 41%+/-3%, P < 0.05). PC was not protective when the reperfusion periods were 40 or 120 min (IS: 47%+/-5% and 44%+/-3%. P = not significant (NS) vs control, respectively). However, concomitant treatment with dilazep (0.2mg/kg) preserved the PC effect in the 40-min reperfusion group (18%+/-5%, P < 0.05 vs control) but not in the 120-min reperfusion group (43%+/-4%, P = NS vs control). Protocol 2: Infarct was produced in a similar rabbit model by either a 45- or 50-min occlusion of a coronary artery and 2 days of reperfusion. PC was elicited by a preceding 5-min occlusion and a 5-min reperfusion. PC was protective in the 45-min occlusion group (30%+/-7% vs 67%+/-3%, P < 0.05) but not in the 50-min occlusion group (74%+/-4% vs 79%+/-5%, P = NS). Treatment with dilazep (0.2mg/kg) failed to retrieve protection in this preconditioned group (77%+/-6%, P = NS vs 50-min occlusion group without PC). Thus, dilazep prolonged the infarct size-limiting effect of PC, but failed to retrieve protection in the group with a longer sustained ischemia.

Exogenous Nitric Oxide Can Trigger a Preconditioned State Through a Free Radical Mechanism, But Endogenous Nitric Oxide Is Not a Trigger of Classical Ischemic Preconditioning

Nitric oxide (NO) has been reported to play an important role in the late phase of ischemic preconditioning (PC) in the rabbit heart. However, the role of NO in the early phase of ischemic PC (««classical PC»») is controversial. Accordingly, the present study was designed to determine whether NO contributes to the cardioprotective effect of classical PC in rabbits. Isolated hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.2±3.3% of the risk zone. PC with 5 min of global ischemia and 10 min of reperfusion reduced infarct size to 10.2±2.4% (P<0.05). Perfusion with 2 μ m S-nitroso-N-acetylpenicillamine (SNAP), a NO donor, in lieu of ischemia mimicked PC (4.4±1.9% infarction, P<0.01 v control). To determine whether this protection was dependent on either protein kinase C (PKC) as has previously been demonstrated for classical PC or free radicals known to be produced during exogenous NO administration, chelerythrine (5 μ m), a PKC inhibitor, or N-(2-mercaptopropionyl)-glycine (300 μ m), a free radical scavenger, was administered with or shortly after SNAP. Neither drug had any independent effect on infarct size, and each blocked SNAP's cardioprotection (31.0±5.1 and 25.7±5.2% infarction, resp.). Nω-nitro- L -arginine methyl ester (L -NAME, 100 μ m), a NO synthase inhibitor, failed to block the cardioprotection from the above ischemic PC protocol (9.5±2.8% infarction,P <0.05 v control). L -NAME alone had no effect on infarct size (30.6±2.7%). These results suggest that the beneficial effect of exogenous NO production during SNAP pretreatment is mediated by a protein kinase C-dependent pathway via MPG-sensitive oxidants. However, we were unable to show any contribution of endogenous NO to classical PC's protection in isolated rabbit hearts.

Bifunctional role of protein tyrosine kinases in late preconditioning against myocardial stunning in conscious rabbits.

Although protein tyrosine kinases (PTKs) have been implicated in late preconditioning (PC) against infarction, their role in late PC against stunning is unknown. Furthermore, it is unknown whether PTK signaling is necessary only to trigger late PC on day 1 or also to mediate it on day 2. Thus, conscious rabbits underwent a sequence of six 4-minute coronary occlusion/4-minute reperfusion cycles for 3 consecutive days (days 1, 2, and 3). In the control group (group I, n=7), the recovery of systolic wall thickening after the 6 occlusion/reperfusion cycles was markedly improved on days 2 and 3 compared with day 1, indicating the development of late PC against stunning. Administration of the PTK inhibitor lavendustin-A (LD-A, 1 mg/kg IV) before the first occlusion on day 1 (group II, n=7) completely prevented the late PC effect against stunning on day 2. Late PC against stunning was also abrogated when LD-A was given before the first occlusion on day 2 (group III, n=7); however, in these rabbits, the late PC effect became apparent on day 3, indicating that LD-A itself did not have any delayed deleterious actions on myocardial stunning. In group V (n=5), the sequence of 6 occlusion/reperfusion cycles resulted in a robust increase in the activity of inducible NO synthase (iNOS [assessed as Ca(2+)-independent L-citrulline formation]) and nitrite+nitrate (NO(x)) tissue levels 24 hours later (on day 2), with no concomitant change in Ca(2+)-dependent NO synthase (endothelial NO synthase and/or neuronal NO synthase) activity. Similar results were obtained on day 3 (group VIII, n=6), indicating sustained upregulation of iNOS. Administration of LD-A either on day 1 (group VI, n=5) or on day 2 (group VII, n=6) abrogated the increase in iNOS activity and NO(x) levels on day 2. LD-A had no effect on iNOS activity or NO(x) levels in the absence of PC (group X, n=5). This study demonstrates that in conscious rabbits, PTK activity is necessary not only to trigger late PC against stunning on day 1 but also to mediate the protection on day 2. This investigation also provides the first direct evidence that cardiac iNOS activity is upregulated during the late phase of ischemic PC in rabbits. Furthermore, the data indicate that PTK signaling is essential for the augmentation of iNOS activity and that PTKs modulate this enzyme at two distinct levels: at an early stage on day 1 and at a late stage on day 2. This bifunctional role of PTKs in late PC has broad implications for the signaling mechanisms that underlie the response of the heart to ischemic stress and, possibly, other stresses.

ATP-sensitive potassium (KATP) channel is involved in the second window of ischemic preconditioning in rabbit

ATP-sensitive potassium (KATP) channel is involved in the second window of ischemic preconditioning in rabbit

KATP channels are common mediators of ischemic and calcium preconditioning in rabbits.

Calcium preconditioning (CPC), like ischemic preconditioning (IPC), reduces myocardial infarct size in dogs and rats. ATP-sensitive potassium (KATP) channels induce cardioprotection of IPC in these animals. To determine whether KATP channels mediate both IPC and CPC, pentobarbital sodium-anesthetized rabbits received 30 min of coronary artery occlusion followed by 180 min of reperfusion. IPC was elicited by 5 min of occlusion and 10 min of reperfusion, and CPC was elicited by two cycles of 5 min of calcium infusion with an interval period of 15 min. Infarct size expressed as a percentage of the area at risk was 38 +/- 3% (mean +/- SE) in controls. IPC, CPC, and pretreatment with a KATP channel opener, cromakalim, all reduced infarct size to 13 +/- 2, 17 +/- 2, and 12 +/- 3%, respectively (P < 0.01 vs. controls). Glibenclamide, a KATP channel blocker administered 45 min (but not 20 min) before sustained ischemia, attenuated the effects of IPC and CPC (31 +/- 4 and 41 +/- 6%, respectively). Thus KATP channel activation appears to contribute to these two types of cardioprotection in rabbits.

Does protein kinase C play a role in ischemic preconditioning in rat hearts?

Protein kinase C (PKC) has been implicated in the cardioprotective effects of ischemic preconditioning in rabbits, but whether it plays a role in rats is unknown. We tested this preconditioning PKC theory by assessing whether the inhibition of PKC with calphostin C, a potent and specific inhibitor of PKC, can block the preconditioning effects in this model. Four groups of rats were studied: 1) control + vehicle, 2) control + calphostin C, 3) preconditioning + vehicle, and 4) preconditioning + calphostin C. All rats underwent 90 min of coronary occlusion followed by 4 h of reperfusion; in addition, preconditioned rats underwent three 3-min episodes of ischemia and 5 min of reperfusion before the 90 min of ischemia. Two injections of vehicle or calphostin C (0.1 mg/kg) were administered in intravenous boluses 29 min and 3 min before the 90-min coronary occlusion, i.e., one dose was given 5 min before preconditioning, and another dose was given between preconditioning and the sustained 90 min of ischemia in preconditioned rats. After 4 h of reperfusion, the area at risk (AR) was delineated by dye injection and area of necrosis was assessed by triphenyltetrazolium chloride staining. The electrocardiogram was recorded for the incidence of ventricular tachycardia (VT) and ventricular fibrillation. AR was similar in all four groups. In the nonpreconditioned control rats receiving vehicle, myocardial infarct size expressed as a percentage of the AR averaged 45.7 +/- 1.7%. Pretreatment with calphostin C had no effect on infarct size (48.9 +/- 3.4%) in nonpreconditioned control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of anesthesia and K+ ATP channel blockade on interstitial adenosine accumulation in ischemic rabbit myocardium.

Glibenclamide, a K+ ATP channel antagonist, blocks the anti-infarct effect of ischemic preconditioning in rabbits, but only when the latter are anesthetized with ketamine-xylazine. Furthermore, the protection triggered by pinacidil, a K+ ATP channel opener, can be aborted by treatment with the adenosine antagonist 8-(P-sulfophenyl)theophylline. This study tests whether either the anesthetic regimen or glibenclamide affects infarct size by modulating interstitial adenosine levels. Interstitial adenosine and total purine concentrations were assessed in open-chest rabbits by the microdialysis technique. Dialysis fibers were inserted into myocardium served by a coronary artery branch surrounded by a snare. All animals sustained a 30-min coronary occlusion and then 120-min reperfusion. Rabbits were anesthetized with either sodium pentobarbital or a ketamine-xylazine mixture. Half of the latter animals also received glibenclamide. The control levels of adenosine in the dialysate were comparable in the three groups, as were those of total purines, and the infusion of glibenclamide caused no change. Ischemia led to 10- to 20-fold increases in interstitial adenosine and 10- to 40-fold rises in total purine concentrations. These increases were equivalent in all groups. Further-more, infarct size as a percentage of the myocardium at risk was also comparable in the three groups. Neither the anesthetic agent nor glibenclamide appears to modulate interstitial adenosine release from ischemic tissue.

Alpha-adrenoceptor stimulation with exogenous norepinephrine or release of endogenous catecholamines mimics ischemic preconditioning.

Brief episodes of ischemia induced by proximal coronary artery occlusion can precondition the myocardium. Whether other stressful stimuli have the potential to protect the myocardium from subsequent ischemia remains controversial. To study the hypothesis that transient alpha-adrenoceptor stimulation mimics preconditioning, for 5 minutes we administered 0.25 micrograms.kg-1.min-1 norepinephrine or saline 10 minutes before a 30-minute coronary occlusion and 4 hours of reperfusion in an in vivo rabbit model. The area of necrosis (AN) and area of risk (AR) were measured. We found that norepinephrine pretreatment caused a reduction in infarct size when compared with controls (AN/AR, 0.17 +/- 0.04 versus 0.31 +/- 0.04; P < .02). Ischemic preconditioning also reduced infarct size (AN/AR, 0.22 +/- 0.03). The protection observed with norepinephrine treatment was entirely eliminated by pretreatment with alpha-adrenergic blockade using prazosin (AN/AR, 0.42 +/- 0.06). Tyramine, an agent that causes release of endogenous catecholamines, was administered (1.5 mg/kg i.v.) 10 minutes before coronary occlusion in another group of rabbits. Tyramine pretreatment resulted in a smaller infarct size than in untreated controls (AN/AR, 0.16 +/- 0.04 versus 0.41 +/- 0.07; P < .01). Both norepinephrine and tyramine caused an increase in systemic arterial pressure during infusion; tyramine also increased heart rate. In rabbits pretreated with prazosin, heart rate and systemic pressure during the norepinephrine infusion were similar to baseline values. During coronary occlusion, the degree of ischemia was similar in all groups. Exposure of the heart to either transient exogenous norepinephrine or endogenous release of norepinephrine and/or other catecholamines by tyramine can mimic the effects of ischemic preconditioning in rabbits.

Acadesine potentiates the cardioprotective effects of ischemic preconditioning in rabbits

Acadesine potentiates the cardioprotective effects of ischemic preconditioning in rabbits