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K Przyklenk

Publications and source records attributed to K Przyklenk.

At least 19 recordsLinked to original sources
PubMed2001

No loss in the in vivo efficacy of ischemic preconditioning in middle-aged and old rabbits.

OBJECTIVES: We tested the hypothesis that cardioprotection with ischemic preconditioning (PC) is lost in the aging, or senescent, heart. BACKGROUND: Although infarct size reduction with PC has been documented in virtually all models, a purported exception to this paradigm is the aging heart, the population in which cardioprotection is most relevant. However, no previous studies have assessed the concept of an age-associated loss in the efficacy of PC in an in vivo model of acute myocardial infarction in which definitive hallmarks of cardiovascular aging were demonstrated and a reduction of infarct size, the "gold standard" of PC, served as the primary end point. METHODS: Using the in vivo rabbit model, three cohorts of animals were studied: adult (4 to 6 months old), middle-aged ( approximately 2 years old) and old ( approximately 4 years old) rabbits. Within each cohort we assessed: 1) infarct size (measured by tetrazolium staining and expressed as percent myocardium at risk) in control and PC groups; and 2) morphologic and functional hallmarks of cardiovascular aging (progressive myocyte hypertrophy, increased myocardial fibrosis and attenuated responsiveness to beta-adrenergic stimulation). RESULTS: In adult animals, infarct size was significantly smaller in the PC group than in the control group (29 +/- 4% vs. 57 +/- 2%; p < 0.01). Although middle-aged and old rabbits exhibited all three archetypal indexes of cardiovascular aging, a comparable (approximately 50%) reduction in infarct size with PC was evident in both cohorts. CONCLUSIONS: These data provide the first in vivo evidence that infarct size reduction with PC is not precluded by increased cardiovascular age, per se.

Aging↗
PubMed2001

Detection of myocardial viability based on measurement of sodium content: A (23)Na-NMR study.

MRI of total sodium (Na) content may allow assessment of myocardial viability, but information on Na content in normal myocardium, necrotic/scar tissue, and stunned or hibernating myocardium is lacking. Thus, the aims of the study were to: 1) quantify the temporal changes in myocardial Na content post-myocardial infarction (MI) in a rat model (Protocol 1); 2) compare Na in normally perfused, hibernating, and stunned canine myocardium (Protocol 2); and 3) determine whether, in buffer-perfused rat hearts, infarct scar can be differentiated from intact myocardium by (23)Na-MRI (Protocol 3). In Protocol 1, rats were subjected to LAD ligation. Infarct/scar tissue was excised at control and 1, 3, 7, 28, 56, and 128 days post-MI (N = 6-8 each), Na content was determined by (23)Na-NMR spectroscopy (MRS) and ion chromatography. Na content was persistently increased at all time points post-MI averaging 306*-160*% of control values (*P < 0.0083 vs. control). In Protocol 2, (23)Na-MRS of control (baseline), stunned and hibernating samples revealed no difference in Na. In Protocol 3, (23)Na-MRI revealed a mean increase in signal intensity, to 142 +/- 6% of control values, in scar tissue. A threshold of 2 standard deviations of the image intensity allowed determination of infarct size, correlating with histologically determined infarct size (r = 0.91, P < 0.0001).

Animals↗
PubMed2001

p38 MAPK activity is not increased early during sustained coronary artery occlusion in preconditioned versus control rabbit heart.

Our aim was to test the hypothesis that cardioprotection achieved with ischemic preconditioning (PC) involves increased activity of p38 mitogen-activated protein kinase (MAPK) early during sustained coronary artery occlusion. Using the isolated buffer-perfused rabbit heart model of regional ischemia, we quantified p38 MAPK activity (pmol/min/mg protein: by biochemical assay) at 5 and 10 min into coronary occlusion in hearts that first received PC ischemia or no intervention (controls), and in non-ischemic shams. Control hearts exhibited significant increases in p38 MAPK activity, averaging 883+/-142 and 1135+/-179 at 5 and 10 min of occlusion, v 144+/-49 in shams (P<0.05 and P<0.01). p38 MAPK activity was not, however, augmented with PC; rather, at 5 min into occlusion, activity was attenuated, averaging 432+/-72 (P=N.S. v sham). This early, modest reduction in p38 MAPK activity may be physiologically relevant: in additional hearts subjected to 30 min of sustained coronary occlusion and 2 h of reperfusion, infarct size (by tetrazolium staining: expressed as a % of the risk region) was 54+/-5% in hearts treated with SB 203580 (confirmed in our study to inhibit p38 MAPK activity at 5 min into occlusion) v 70+/-5% in vehicle controls (P<0.05). Thus, cardioprotection achieved with ischemic preconditioning in rabbit heart does not involve augmentation of p38 MAPK activity early during sustained coronary occlusion.

Animals↗
PubMed2001

Naloxone blocks transferred preconditioning in isolated rabbit hearts.

We have shown that the cardioprotective benefits of ischemic preconditioning (PC) can be transferred from PC to virgin acceptor hearts via coronary effluent transfusion, implicating the presence of hormonal preconditioning factor(s). Using isolated buffer-perfused rabbit hearts, our aims were to: (1) determine whether the protective factor(s) could be concentrated and recovered by reverse phase chromatography and (2) whether opioid receptor activation contributes to this transferred cardioprotection. Material released into the coronary effluent during PC ischemia/reperfusion or normoxic perfusion was concentrated by reverse phase chromatography. In phase one, hearts received no intervention (controls), PC ischemia, concentrate generated from normoxic hearts (normoxic acceptors) or concentrate from PC hearts (PC acceptors). All hearts underwent 40 min of global ischemia, and area of necrosis (AN) was delineated by tetrazolium staining. In phase two, three additional groups of hearts (control, PC and PC acceptors) received the opioid antagonist naloxone (2 microM) throughout the intervention phase. Treatment with normoxic concentrate had no effect on infarct size: (AN: normoxic acceptors 39+/-8%; control 42+/-8%). In contrast, treatment with PC concentrate evoked cardioprotection equivalent to that afforded by conventional PC (AN 19+/-5% and 21+/-6% respectively P<0.05 v control). Naloxone had no effect on infarct size in controls, and did not inhibit preconditioning. However, naloxone abrogated the protection achieved by transfer of PC concentrate (AN: 44+/-7%). These results indicate that PC concentrate evokes a cardioprotective effect via a mechanism requiring an intact opioid receptor system.

Animals↗
PubMed2001

Sildenafil citrate (Viagra) does not exacerbate myocardial ischemia in canine models of coronary artery stenosis.

OBJECTIVES: Our aim was to determine whether sildenafil citrate (Viagra) unfavorably alters coronary perfusion in canine models of coronary artery stenosis. BACKGROUND: Concern has been raised that sildenafil may exacerbate ischemia in patients with coronary artery disease. However, the effects of sildenafil on coronary perfusion are largely unexplored. METHODS: Using anesthetized dogs, a micromanometer constrictor was applied to either an intact coronary artery (model of stable hypoperfusion: Protocol 1) or a site of arterial injury (model of recurrent platelet-mediated thrombosis: Protocol 2). After monitoring coronary flow for 1 h, dogs received two escalating, clinically relevant doses of sildenafil or placebo. Perfusion was assessed during the initial hour pretreatment, for 1 h following dose 1 and 1 h following dose 2 by measuring the area of the flow-time profile, normalized to baseline flow x 60 min. Interaction between sildenafil and adenosine-mediated inhibition of platelet aggregation was evaluated by in vitro platelet aggregometry (Protocol 3). RESULTS: In Protocol 1, flow-time area was maintained at 50% to 60% of baseline in both placebo- and sildenafil-treated groups. In Protocol 2, controls exhibited an expected modest, temporal adenosine-mediated improvement in flow-time area (from 40 +/- 5% to 61 +/- 7%; p < .05) while in contrast, perfusion in sildenafil-treated dogs remained unchanged (37 +/- 6% vs. 33% to 35% before vs. after treatment). In vitro aggregometry confirmed that sildenafil rendered platelets refractory to the inhibitory effects of adenosine receptor stimulation. CONCLUSIONS: Sildenafil did not exacerbate ischemia in canine models of coronary stenosis. However, in the setting of recurrent thrombosis, sildenafil-treated dogs were apparently unresponsive to the platelet inhibitory effects of endogenous adenosine.

Adenosine↗
PubMed2001

Pharmacologic treatment of the stunned myocardium: the concepts and the challenges.

During the past two decades (i.e., since 1980), in excess of 1000 published papers have focused on the phenomenon of the 'stunned myocardium', with many of these studies seeking to identify mechanisms-based treatment strategies to attenuate post-ischemic contractile dysfunction. Early investigations focused largely on abrogating the deleterious effects of oxygen-derived free radicals and unfavorable alterations in calcium homeostasis, both considered to contribute significantly to the pathogenesis of the stunned myocardium. More recently, favorable results have also been obtained using a somewhat different paradigm: that is, attempting to capitalize on endogenous cardioprotective mediators, most notably adenosine, nitric oxide, and the ATP-sensitive potassium channel. Now that potential therapeutic candidates have been identified in the experimental laboratory, the as-yet unmet challenge is to translate this information into the design of effective pharmacologic therapies to treat myocardial stunning in the clinical arena.

Animals↗
PubMed2000

Brief antecedent ischemia enhances recombinant tissue plasminogen activator-induced coronary thrombolysis by adenosine-mediated mechanism.

BACKGROUND: Clinical studies have implicated preinfarct angina (brief antecedent ischemia/reperfusion [I/R]) as a predictor of more rapid thrombolysis and lower rates of reocclusion. However, the effects of antecedent ischemia on the efficacy of thrombolysis have not been rigorously assessed. Using a canine model of coronary thrombosis, we aimed to (1) reproduce these clinical findings and (2) determine whether release of adenosine (a potent inhibitor of platelet aggregation via stimulation of platelet A(2) receptors) during brief I/R contributes to this improved patency. METHODS AND RESULTS: To address our first objective, we compared the time required to achieve lysis with recombinant tissue plasminogen activator and patency during the first 2 hours after lysis in dogs in which 1-hour thrombotic occlusion was preceded by brief I/R (10-minute coronary occlusion/10-minute reperfusion) versus 20-minute uninterrupted perfusion (controls). Time to lysis was accelerated in the I/R group versus the control group (11+/-1 versus 35+/-6 minutes, P=0.004). In addition, the duration of subsequent reocclusion was reduced (17+/-12 versus 30+/-11 minutes), and the area of the flow-time profile (normalized to baseline flow x 120 minutes) was increased (64+/-12% versus 35+/-7%, P=0.04) in the I/R cohort. The protocol was then repeated, but all dogs were pretreated with the adenosine A(2)/A(1) antagonist CGS 15943 (CGS, 1.5 mg/kg). Time to lysis (38 versus 39 minutes) and subsequent patency were comparable in the CGS+control group versus the CGS+I/R group. CONCLUSIONS: Brief antecedent I/R enhances the efficacy of coronary thrombolysis in this canine model, which is due, at least in part, to an adenosine-mediated mechanism.

Adenosine↗
PubMed2000

Monophosphoryl lipid A: a novel nitric oxide-mediated therapy to attenuate platelet thrombosis?

Nitric oxide (NO) is a potent inhibitor of platelet aggregation. However, the benefits of NO-based therapies can be confounded by concomitant hypotension. Monophosphoryl lipid A (MLA) is a nontoxic derivative of endotoxin that purportedly increases nitric oxide synthase (NOS) activity and, presumably, NO production, yet has a hemodynamically benign profile. Thus our aims were to determine whether (a) MLA attenuates in vivo platelet aggregation in damaged and stenotic canine coronary arteries by a NO-mediated mechanism but without reductions in arterial pressure; and (b) the platelet inhibitory effects are manifest in vitro. To address the first aim, anesthetized dogs underwent coronary injury + stenosis, resulting in cyclic variations in coronary blood flow (CFVs) caused by the formation/dislodgement of platelet-rich thrombi. In protocol I, dogs received MLA (100 microg/kg + 40 microg/kg/h) or vehicle beginning 15 min before stenosis. Protocol II was identical, except the NOS inhibitor aminoguanidine was coadministered with MLA/vehicle. Coronary patency was assessed throughout the initial 3 h after injury + stenosis. Infusion of MLA did not result in hypotension. However, in protocol I, the median nadir of the CFVs was higher (2.1 vs. 0.8 ml/min; p < 0.05), median duration of total thrombotic occlusion tended to be reduced (0 vs. 10.4 min; p = 0.1), and mean flow-time area, expressed as a percentage of baseline flow, was increased (53 +/- 9% vs. 33 +/- 3%; p < 0.05) in MLA-treated versus vehicle-treated dogs. In contrast, in protocol II, vessel patency was comparable in both groups. Finally, whole blood impedance aggregometry (protocol HI) revealed a significant reduction in the in vitro platelet aggregation in blood samples receiving exogenous MLA, which was blocked by coadministration of exogenous aminoguanidine. Thus MLA attenuates platelet-mediated thrombosis in both damaged and stenotic canine coronary arteries and in vitro, possibly by an NO-mediated mechanism, but without concomitant hypotension.

Adjuvants, Immunologic↗
PubMed2000

"Preconditioning at a distance" in the isolated rabbit heart.

OBJECTIVE: Brief myocardial ischemia evokes a cardioprotective response, referred to as "ischemic preconditioning" (IP), that limits injury caused by a subsequent prolonged ischemic insult. The myocardial IP effect can be induced by ischemia of "distant" cardiac and noncardiac tissue, implicating the involvement of an as-yet-unidentified humoral trigger. If a preconditioning hormone exists, the authors hypothesize that the IP effect should be transferable, via administration of coronary effluent, from a preconditioned donor heart to a virgin non-preconditioned acceptor heart. METHODS: Isolated buffer-perfused rabbit hearts were assigned to one of four treatment groups in a donor/acceptor sequence. Donor hearts underwent either three IP cycles or a matched period of uninterrupted perfusion (control donors). Coronary perfusate collected from IP and control donor hearts was reoxygenated and transfused to virgin acceptor hearts. All hearts then underwent 30 minutes of global ischemia followed by 30 minutes of reperfusion. Left ventricular developed pressure (LVDP) (the authors' index of cardioprotection) was monitored throughout the protocol by a left ventricular (LV) balloon. RESULTS: In donor controls, LVDP assessed at 30 minutes post-reflow was restored to only 49 +/- 5% of baseline values. Recovery of LV function was significantly enhanced in both IP donor hearts (69 +/- 4%*) and IP acceptor hearts (70 +/- 6%*) vs donor controls (*p < 0.05), while, in acceptor controls, intermediate values of LVDP (62 +/- 7%) were obtained. CONCLUSION: The IP effect can be transferred between rabbit hearts, suggesting the presence of a humoral trigger signal for distant preconditioning. Isolating this hormone may have therapeutic and diagnostic implications in the management of acute myocardial ischemia.

Animals↗
PubMed1999

Brief myocardial ischemia attenuates platelet thrombosis in remote, damaged, and stenotic carotid arteries.

BACKGROUND: Brief antecedent periods of coronary artery occlusion improve subsequent vessel patency in damaged and stenotic coronary arteries via release of adenosine from ischemic/reperfused myocardium and resultant adenosine receptor stimulation. However, the site of receptor stimulation-circulating blood-borne elements (ie, platelets) versus vessel-wall components of the culprit artery-remains unclear. If platelet adenosine receptors are involved, then the benefits of brief coronary occlusion (1) should be manifested systemically and improve patency at a remote site and (2) should be inhibited by an antagonist of adenosine A(2) receptors, whereas, in contrast, (3) brief vascular occlusion not associated with appreciable adenosine release should be ineffective in improving vessel patency. METHODS AND RESULTS: In Protocol 1, anesthetized rabbits received 5 minutes of transient coronary occlusion, 5 minutes of transient bilateral carotid occlusion (purported to cause negligible adenosine release from the brain), or no intervention. All rabbits then underwent injury plus stenosis of the left carotid artery, resulting in repeated cyclic variations in carotid blood flow (CFVs). Carotid patency during the initial 2 hours after stenosis (assessed by quantifying the nadir of the CFVs and area of the flow-time profile) was significantly enhanced with antecedent coronary-but not carotid-occlusion versus controls. In Protocol 2, improvement in carotid patency after brief coronary occlusion was corroborated in anesthetized dogs. However, the benefits of brief coronary occlusion were abrogated by the A(2)/A(1) antagonist CGS 15943. CONCLUSIONS: Brief antecedent coronary artery occlusion enhanced vessel patency in remote, damaged, and stenotic carotid arteries, largely due to adenosine receptor stimulation on circulating elements.

Adenosine↗
PubMed1999

Cellular mechanisms of infarct size reduction with ischemic preconditioning. Role of calcium?

Brief episodes of ischemia protect or "precondition" the heart and reduce infarct size caused by a subsequent sustained ischemic insult. Despite a decade of intensive investigation, the cellular mechanism(s) responsible for this paradoxical protection remain poorly understood. In this review, we focus on the emerging concept that alterations in intracellular calcium homeostasis may participate in either triggering and/or mediating infarct size reduction with preconditioning.

Animals↗
PubMed1999

Preconditioning-induced cardioprotection and release of the second messenger inositol (1,4,5)-trisphosphate are both abolished by neomycin in rabbit heart.

The mechanisms responsible for infarct size reduction with preconditioning remain controversial. Our aim was to determine whether release of the second messenger inositol (1,4,5)-triphosphate (Ins(1,4,5)P3) during the preconditioning stimulus may play a role. To test this concept, Langendorff-perfused rabbit hearts underwent sham perfusion, 5 min of coronary artery occlusion (CO), or 5 min of CO + infusion of neomycin, an agent which inhibits formation of Ins(1,4,5)P3. Direct quantitation (by competitive binding assay) revealed a 2-fold increase in Ins(1,4,5)P3 content with brief ischemia vs shams (0.69 +/- 0.14 vs 0.34 +/- 0.05 pmol/mg tissue; p < .05) that was blocked by neomycin (0.15 +/- 0.04 pmol/mg). Infarct size (by tetrazolium staining) was assessed in additional hearts that underwent 30 min of sustained CO and 2 h of reperfusion. As expected, two 5-min episodes of preconditioning ischemia reduced infarct size versus controls (30 +/- 6% versus 63 +/- 3% of the myocardium at risk; p < .01). In contrast, infarct size was comparable (54-56% of the risk region) in neomycin-treated control and preconditioned hearts. These results demonstrate that myocardial Ins(1,4,5)P3 content is increased in response to brief preconditioning ischemia and are consistent with the concept that Ins(1,4,5)P3 may be a potential mediator of infarct size reduction with preconditioning in isolated rabbit heart.

Animals↗
PubMed1999

Rabbit heart can be "preconditioned" via transfer of coronary effluent.

Brief myocardial ischemia not only evokes a local cardioprotective or "preconditioning" effect but also can render remote myocardium resistant to sustained ischemia. We propose the following hypotheses: remote protection is initiated by a humoral trigger; brief ischemia-reperfusion will result in release of the humoral trigger (possibly adenosine and/or norepinephrine) into the coronary effluent; and transfer of this effluent to a virgin acceptor heart will elicit cardioprotection. To test these concepts, effluent was collected during normal perfusion from donor-control hearts and during preconditioning ischemia-reperfusion from donor-preconditioned (PC) hearts. After reoxygenation occurred and aliquots for measurement of adenosine and norepinephrine content were harvested, effluent was transfused to acceptor-control and acceptor-PC hearts. All hearts then underwent 40 min of global ischemia and 60 min of reperfusion, and infarct size was delineated by tetrazolium staining. Mean infarct size was smaller in both donor- and acceptor-PC groups (9% of left ventricle) than in donor- and acceptor-control groups (36% and 34%; P < 0.01). Protection in acceptor-PC hearts could not, however, be attributed to adenosine or norepinephrine. Thus preconditioning-induced cardioprotection can be transferred between rabbit hearts by transfusion of coronary effluent. Although adenosine and norepinephrine are apparently not responsible, these results suggest that remote protection is initiated by a humoral mechanism.

Adenosine↗
PubMed1999

Pharmacological manipulation of Ins(1,4,5)P3 signaling mimics preconditioning in rabbit heart.

Recent evidence revealed biphasic alterations in myocardial concentrations of the second messenger inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] with ischemic preconditioning (PC), i.e., increase during brief PC ischemia and decrease early during sustained test occlusion. Our aim was to determine whether an agonist and an antagonist of Ins(1,4,5)P(3) signaling (D-myo-inositol-1,4,5-trisphosphate hexasodium salt [D-myo-Ins(1,4, 5)P3] and 2-aminoethoxydiphenyl borate (2-APB), respectively), given such that they mimic this biphasic profile, would mimic infarct size reduction with PC. To test this concept, isolated, buffer-perfused rabbit hearts received no intervention (control), ischemic PC, D-myo-Ins(1,4,5)P3, D-myo-Ins(1,4,5)P(3) + PC, 2-APB, or 2-APB + PC. All hearts then underwent 30-min coronary occlusion and 2 h reflow, and infarct size was delineated by tetrazolium staining. In addition, the effects of D-myo-Ins(1,4,5)P3 and 2-APB on Ins(1,4,5)P3 signaling were evaluated in isolated fura 2-loaded rat cardiomyocytes. Mean infarct size was reduced with PC and in all D-myo-Ins(1,4,5)P3- and 2-APB-treated groups versus control (59 and 42-55%, respectively, vs. 80% of myocardium at risk, P < 0.05). Thus pharmacological manipulation of Ins(1,4,5)P3 signaling mimics the cardioprotection achieved with ischemic PC in rabbit heart.

Animals↗
PubMed1998

Prospective temporal analysis of the onset of preinfarction angina versus outcome: an ancillary study in TIMI-9B.

BACKGROUND: The timing of onset of angina before myocardial infarction in relation to outcome is unknown. METHODS AND RESULTS: We prospectively determined the importance of the time of onset of preinfarction angina in relation to 30-day outcomes in the TIMI-9B study from standardized forms. Of the 3002 patients entered into the study, 425 reported angina before their myocardial infarction. Patients with angina onset within 24 hours of infarction had a lower 30-day cardiac event rate (mortality, recurrent myocardial infarction, heart failure, or shock) at 4% than those with onset of angina >24 hours (17%; P=.030). A history of any angina alone was not associated with reduced event rate. Peak creatine kinase levels tended to be lower in the group with angina within 24 hours. These benefits were not due to higher rates of use of antianginal medicines or aspirin and were not a consequence of differences in baseline characteristics or disease states (hypertension, hypercholesterolemia) among subgroups. CONCLUSIONS: These temporal observations are consistent with the concept of preconditioning by preinfarction angina but do not rule out other mechanisms.

Aged↗