Biomedical subjects

R D Lasley

Publications and source records attributed to R D Lasley.

At least 37 records · Page 2Linked to original sources

PubMed1998

Myocardial preconditioning produced by ischemia, hypoxia, and a KATP channel opener: effects on interstitial adenosine in dogs.

Previous research has demonstrated that a transient increase in interstitial adenosine and subsequent activation of ATP-sensitive K+ (KATP) channels are involved in triggering ischemic preconditioning (PC), however, the role of adenosine in mediating the cardioprotection of hypoxic PC and that produced by KATP channel openers is less clear. Thus, the aim of the present study was to determine the role of adenosine in mediating the cardioprotective effects of PC produced by 5 min of ischemia, hypoxia, or by a 5-min intracoronary (i.c.) infusion of the KATP channel opener bimakalim (1 microgram/min). A single microdialysis probe was implanted into the midwall of the ischemic area for sampling of interstitial fluid adenosine and its breakdown products during the PC stimulus, prolonged occlusion (60 min) and during the first 30 min of the reperfusion (3 h) period. Ischemic, hypoxic and bimakalim pretreatment significantly reduced infarct size, 5.3 +/- 1.5; 8.9 +/- 2.5; 11.4 +/- 3.2, respectively, as compared to control: 27.3 +/- 6.5. Both ischemic and hypoxic PC produced similar and significant increases (0.56 +/- 0.13 mumol/l to 1.12 +/- 0.12 mumol/l and 1.32 mumol, control, ischemic and hypoxic PC, respectively) in dialysate adenosine concentration which persisted during the brief 10-min reperfusion period following PC. However, i.c. bimakalim resulted in a significant decrease in dialysate adenosine (0.56 +/- 0.13 mumol/l to 0.22 +/- 0.04 mumol/l) which persisted during the 10-min drug-free period. All three PC protocols resulted in similar decreases in dialysate adenosine, inosine and uric acid concentrations throughout the prolonged ischemic period as compared to control animals. In conclusion (1): PC produced by ischemia or hypoxia results in an increase in interstitial adenosine prior to a prolonged occlusion period; (2) the KATP channel agonist, bimakalim, significantly decreased interstitial adenosine prior to a prolonged occlusion period; (3) ischemic PC, hypoxic PC, and bimakalim pretreatment produced a similar reduction in interstitial adenosine and its breakdown products during the prolonged ischemic period. These results suggest that an increase in interstitial adenosine may be necessary for the initiation of the protective effect of ischemic and hypoxic PC but an increase in adenosine is not necessary for the cardioprotective effect of a direct opener of the KATP channel.

Adenine Nucleotides↗

PubMed1998

Adenosine attenuates in vivo myocardial stunning with minimal effects on cardiac energetics.

Adenosine has been shown to modulate myocardial intermediary metabolism. The purpose of this study was to determine whether adenosine-mediated attenuation of in vivo myocardial stunning is associated with improved myocardial phosphorylation potential. Adult, open chest pigs were subjected to 10 minutes of regional myocardial ischemia and 90 minutes reperfusion. Regional ventricular function was assessed by measuring systolic wall thickening. Myocardial phosphorylation potential was estimated from the tissue (CrP/CrxPi) ratio determined in rapid-frozen tissue biopsy samples from normal and stunned myocardium. Control pigs were compared to animals treated prior to ischemia with intracoronary adenosine (50 micrograms/kg/min). Postischemic regional systolic wall thickening in adenosine treated pigs was significantly improved (40 +/- 3% of preischemic values) compared to control untreated pigs (26 +/- 3%). Myocardial stunning was associated with decreased ATP levels, but neither the total creatine pool (CrP + Cr) nor the (CrP/CrxPi) ratio was reduced. Adenosine pretreatment was associated with decreased Pi and Cr contents resulting in improved postischemic (CrP/CrxPi) ratio in the stunned bed compared to controls, but this effect occurred only after postischemic function had attained maximal improvement. These results suggest that adenosine attenuation of in vivo myocardial stunning is independent of elevated myocardial phosphorylation potential.

Adenosine↗

PubMed1998

Pyruvate augments calcium transients and cell shortening in rat ventricular myocytes.

Pyruvate has been shown to be a metabolic inotrope in the myocardium. In millimolar concentrations, it has been shown to increase both myocardial phosphorylation potential and the cytosolic [NAD+]-to-[NADH] ratio. To determine if changes in these parameters can alter intracellular Ca2+ concentration ([Ca2+]i) and hence contractile function, Ca2+ transients and cell shortening (CS) were measured in isolated rat ventricular myocytes superfused with a physiological N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer (11 mmol/l glucose) with and without additional pyruvate, L-lactate, acetate, or isoproterenol. The addition of 5 mmol/l pyruvate resulted in a 33% increase in CS and a 39% increase in systolic [Ca2+]i. These pyruvate effects were 70% of those observed with 100 nmol/l isoproterenol. The mitochondrial monocarboxylate transport inhibitor alpha-cyano-4-hydroxycinnamate (250 mumol/l) strongly inhibited pyruvate inotropy, suggesting a substantial obligatory coupling between pyruvate inotropism and its oxidation by the mitochondria. A possible role of the cytosolic [NAD+]-to-[NADH] ratio was assessed by comparing the effects of 20 mmol/l L-lactate to those of equimolar pyruvate. In contrast to 20 mmol/l pyruvate, excess L-lactate failed to appreciably increase CS or systolic [Ca2+]i. The findings imply that, at levels substantially above 5 mmol/l, a portion of pyruvate inotropism might be due to extreme cytosolic [NAD+]-to-[NADH] ratios. This study is the first evidence that augmented [Ca2+]i transients are most likely the mechanism of cardiac pyruvate inotropism.

Animals↗

PubMed1998

Dose-dependent effects of adenosine on interstitial fluid adenosine and postischemic function in the isolated rat heart.

Exogenous adenosine produces numerous beneficial effects in ischemic myocardium, but pharmacological doses of adenosine are required to exert these effects. This is thought to be due to the rapid metabolism of adenosine by coronary endothelium, although there is no direct evidence supporting this hypothesis in the ischemic/reperfused heart. The purpose of this study was to determine the relationship between vascular and interstitial fluid (ISF) adenosine levels during adenosine-induced cardioprotection. Isolated perfused rat hearts were submitted to 30-min global normothermic ischemia and 30- min reperfusion. Left ventricular developed pressure (LVDP) was measured with a fluid-filled latex balloon, and ISF adenosine was estimated with cardiac microdialysis. Control hearts were compared with hearts treated with increasing doses of adenosine (1, 10 and 100 microM) for 10 min immediately preceding ischemia. Adenosine produced dose-dependent increases in coronary effluent adenosine levels, but only 10 and 100 microM adenosine increased dialysate adenosine concentrations. All adenosine doses increased coronary flow to the same extent, but only the two higher doses decreased spontaneous heart rate. Control and 1 microM adenosine-treated hearts recovered 60 +/- 3% and 46 +/- 7% of preischemic LVDP, respectively, whereas 10 and 100 microM adenosine improved recovery to 80 +/- 5% and 90 +/- 4% of preischemic LVDP, respectively, after 30-min reperfusion. Because ISF bathes the cardiac myocytes, these results are consistent with the hypothesis that adenosine protects the ischemic rat heart via the activation of cardiac myocyte adenosine receptors.

Adenosine↗

PubMed1997

Safety, tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during coronary artery bypass surgery.

Myocardial stunning after heart surgery is associated with increased morbidity and mortality in patients with severe multivessel disease and reduced myocardial function. The purpose of this study was to evaluate the safety, tolerance, and efficacy of adenosine as a cardioprotective agent when added to blood cardioplegia in patients undergoing coronary artery bypass surgery. Sixty-one patients were randomized to standard cold-blood cardioplegia, or cold-blood cardioplegia containing 1 of 5 adenosine doses (100 microM, 500 microM, 1 mM, 2 mM, and 2 mM with a preischemic infusion of 140 microg/kg/min of adenosine). Invasive and noninvasive measurements of ventricular performance and rhythm were obtained preoperatively, prebypass, and then at 1, 2, 4, 8, 16, and 24 hours postbypass. Use of inotropic agents and vasoactive drugs pastoperatively was recorded; blood samples were collected for measurement of nucleoside levels. High-dose adenosine treatment was associated with a 249-fold increase in the plasma adenosine concentration and a 69-fold increase in the combined levels of adenosine, inosine, and hypoxanthine (p <0.05). Increasing doses of the adenosine additive were also associated with lower requirements of dopamine (p = 0.003) and nitroglycerine (p = 0.001). The 24-hour average doses for dopamine and nitroglycerine in the placebo group were 28-fold and 2.6-fold greater than their respective high-dose adenosine treatment cohorts. Finally, the placebo- and 100 microM-adenosine group was associated with a lower ejection fraction when compared to patients receiving the intermediate dose or high-dose treatment. These findings are consistent with the hypothesis that adenosine is effective in attenuating myocardial stunning in humans.

Adenosine↗

PubMed1997

Effects of protein kinase C inhibitors in in situ and isolated ischemic rabbit myocardium.

We tested the effects of the protein kinase C (PKC) inhibitors bisindolylmaleimide (1 microM) and chelerythrine (2 microM) on myocardial ischemia-reperfusion injury in in situ and isolated perfused rabbit hearts. In non-ischemic isolated hearts, bisindolylmaleimide (1 microM) and chelerythrine (2 microM) blocked sn-1,2-dioctanoylglycerol (DOG)-induced coronary vasoconstriction by approximately 80%. Intact hearts were subjected to 45 min coronary artery occlusion and 2 h reperfusion. Infarct size, determined by triphenyltetrazolium chloride (TTC)-staining and expressed as percentage of risk area, was reduced approximately 50% by both bisindolylmaleimide (0.05 mg/kg, i.v.) and chelerythrine (0.1 mg/kg, i.v.) compared to vehicle treated controls. In contrast, a higher dose of chelerythrine (3.8 mg/kg, i.v.) did not significantly reduce infarct size. Isolated hearts were subjected to 45 min of global normothermic (37 degrees C) ischemia and 60 min reperfusion. Control hearts exhibited 45+/-2% recovery of pre-ischemic left ventricular developed pressure (LVDP) compared to bisindolylmaleimide- (73+/-7%) and chelerythrine-treated hearts (70+/-11%). Bisindolylmaleimide and cherythrine reduced infarct size from a control value of 24+/-4 to 8+/-2 and 9+/-3%, respectively. Preconditioning isolated hearts with 5 min ischemia and 10 min reperfusion prior to prolonged ischemia reduced infarct size to 10.4+/-2.3%, an effect which was blocked by chelerythrine (22.5+/-4.2% infarct size). These results suggest that although PKC may play a role in ischemic preconditioning, PKC inhibitors can be cardioprotective during prolonged ischemia.

Alkaloids↗

PubMed1997

Infarct size reduction with the nucleoside transport inhibitor R-75231 in swine.

Adenosine (Ado) has been reported to be cardioprotective in several models of myocardial ischemia. The nucleoside transport inhibitor R-75231 (R-75) has been reported to enhance local Ado concentrations and postischemic recovery of function, but little is known regarding its effects on myocardial infarct size. The purpose of the present study was to determine the effects of R-75 on infarct size and to measure myocardial regional Ado concentrations. Studies were conducted in pentobarbital-anesthetized swine undergoing 60 min of coronary artery occlusion and 2 h of reperfusion. Control pigs (n = 8) were compared with those receiving R-75 (0.1 mg/kg i.v.) 15 min before either occlusion (Pre R-75, n = 8) or reperfusion (Rep R-75, n = 8). Interstitial fluid (ISF) Ado, coronary venous Ado, and infarct size (% of the region at risk) were measured. In the Pre R-75 group, ISF Ado concentrations were significantly increased before and during ischemia, reaching a peak value of 71.8 +/- 8.6 microM (vs. 16.8 +/- 0.8 microM in control). ISF inosine and hypoxanthine concentrations were significantly reduced during ischemia in Pre R-75 animals. Infarct size was smaller in Pre R-75 compared with control (21.6 +/- 1.9 vs. 38.4 +/- 2.6%, P < 0.05). The Rep R-75 group had significantly elevated coronary venous Ado concentrations but no increases in ISF Ado or reduction in infarct size (33.5 +/- 3.5%). These data indicate that R-75 increases myocardial Ado and reduces infarct size when administered before coronary occlusion. The R-75-induced reduction in infarct size appears to be related to the augmentation of ISF Ado before ischemia rather than to increased plasma Ado during reperfusion.

Adenosine↗

PubMed1997

Ryanodine receptor dysfunction in porcine stunned myocardium.

We investigated the effects of myocardial stunning on the function of the two main Ca2+ transport proteins of the sarcoplasmic reticulum (SR), the Ca(2+)-adenosinetriphosphatase and the Ca(2+)-release channel or ryanodine receptor. Regional myocardial stunning was induced in open-chest pigs (n = 6) by a 10-min occlusion of the left anterior descending coronary artery (LAD) and 2 h reperfusion. SR vesicles isolated from the LAD-perfused region (stunned) and the normal left circumflex coronary artery (LC)-perfused region were used to assess the oxalate-supported 45Ca2+ uptake, [3H]ryanodine binding, and single-channel recordings of ryanodine-sensitive Ca(2+)-release channels in planar lipid bilayers. Myocardial stunning decreased LAD systolic wall thickening to 20% of preischemic values. The rate of SR 45Ca2+ uptake in the stunned LAD bed was reduced by 37% compared with that of the normal LC bed (P < 0.05). Stunning was also associated with a 38% reduction in the maximal density of high-affinity [3H]ryanodine binding sites (P < 0.05 vs. normal LC) but had no effect on the dissociation constant. The open probability of ryanodine-sensitive Ca(2+)-release channels determined by single channel recordings in planar lipid bilayers was 26 +/- 2% for control SR (n = 33 channels from 3 animals) and 14 +/- 2% for stunned SR (n = 21 channels; P < 0.05). This depressed activity of SR function observed in postischemic myocardium could be one of the mechanisms underlying myocardial stunning.

Animals↗

PubMed1996

Adenosine reduces postbypass transfusion requirements in humans after heart surgery.

OBJECTIVE: The objective of this study was to determine the effect, if any, of adenosine blood cardioplegia on blood component usage after heart surgery. SUMMARY BACKGROUND DATA: The most common cause of nonsurgical postcardiopulmonary bypass bleeding is platelet dysfunction. For this reason, pharmacologic agents are under investigation in an effort to reduce the need for transfusion in this setting. METHODS: A posthoc analysis of blood product usage was performed in data obtained from a Phase I, single center, open label, randomized study performed in 63 patients. The trial was designed to test the safety and tolerance of adenosine when added to blood cardioplegia in increasing doses to enhance myocardial protection. The database provided information regarding the effect of adenosine cardioplegia on venous plasma adenosine concentrations, the amount of platelets, fresh frozen plasma and packed erythrocytes used, and the association between the adenosine dose and postoperative thoracic drainage. RESULTS: The postoperative thoracic drainage at 6 hours, 24 hours, and at the time of chest tube removal in the high-dose adenosine cardioplegia group was 68%, 76%, and 75% of the placebo and low-dose adenosine cardioplegia group (p < 0.05). The highest dose of adenosine studied increased baseline adenosine venous plasma levels 360-fold, from 0.17 +/- 0.09 mumol/L to 42.30 +/- 11.20 mumol/L (p < 0.05). This marked increase was associated with a 68%, 56%, and 58% reduction in platelet, fresh frozen plasma, and packed erythrocyte usage, respectively (p < 0.05). CONCLUSIONS: In addition to enhancing the heart's tolerance to ischemia, adenosine-supplemented cardioplegic solution also may reduce bleeding after cardiopulmonary bypass.

Adenosine↗

PubMed1995

Protective effects of adenosine in the reversibly injured heart.

BACKGROUND: There is substantial evidence that the nucleoside adenosine reduces postischemic ventricular dysfunction (ie, myocardial stunning). Studies performed in our laboratory have attempted to address the mechanism of adenosine-mediated protection of the reversibly injured heart. METHODS: Experiments were performed in isolated perfused rat and rabbit hearts and in in situ canine and porcine preparations. The role of adenosine A1 receptors was assessed by using adenosine A1 receptor agonists and antagonists, and by measuring interstitial fluid purine levels with the cardiac microdialysis technique. RESULTS: In isolated perfused hearts, treatment immediately before ischemia with adenosine and adenosine A1 receptor analogues significantly improved postischemic ventricular function, effects that were blocked by a selective adenosine A1 receptor antagonist. In in situ canine and porcine preparations, pretreatment with adenosine and an adenosine deaminase inhibitor increased preischemic interstitial fluid adenosine levels and attenuated regional myocardial stunning. Adenosine treatment was also associated with improved myocardial phosphorylation potential in isolated guinea pig hearts and in the in situ porcine preparation. CONCLUSIONS: These results suggest that adenosine-induced attenuation of myocardial stunning is mediated via adenosine A1 receptor activation and enhancement of postischemic myocardial phosphorylation potential.

Adenosine↗

PubMed1995

Different effects of an adenosine A1 analogue and ischemic preconditioning in isolated rabbit hearts.

BACKGROUND: Ischemic preconditioning reduces infarct size, but its effects on postischemic function are variable. Adenosine, which is thought to play a role in ischemic preconditioning, reduces both infarct size and postischemic dysfunction. The purpose of this study was to compare the cardioprotective effects of ischemic preconditioning and an adenosine A1 receptor agonist on recovery of function and infarct size in isolated rabbit hearts. METHODS: Krebs buffer-perfused hearts (at least 7 per group) were subjected to 60 minutes of global ischemia (37 degrees C) and 60 minutes of reperfusion. Ventricular function was assessed by measuring left ventricular developed pressure, and infarct size (percentage of the left ventricle) was determined by tetrazolium staining. RESULTS: Control hearts exhibited 34% +/- 6% infarct size and 56% +/- 4% recovery of preischemic left ventricular developed pressure. Ischemic preconditioning reduced infarct size to 13% +/- 1% but had no effect on recovery of function (65% +/- 5%). Hearts treated with the adenosine A1 agonist R-phenylisopropyladenosine for 5 minutes immediately before ischemia exhibited both reduced infarct size (10% +/- 2%) and enhanced postischemic recovery of left ventricular developed pressure (86% +/- 3%). Termination of the R-phenylisopropyladenosine treatment before ischemia eliminated its beneficial effects. The adenosine A1 receptor antagonist DPCPX blocked both of the effects of R-phenylisopropyladenosine but did not block ischemic preconditioning. CONCLUSIONS: These results demonstrate fundamental differences between the cardioprotective effects of adenosine A1 receptor activation and ischemic preconditioning.

Animals↗

PubMed1995

Salutary effects of exogenous adenosine administration on in vivo myocardial stunning.

Augmentation of endogenous adenosine levels is associated with decreased myocardial ischemic-reperfusion injury. The purpose of this study was to determine whether exogenous adenosine administered before ischemia could attenuate postischemic myocardial dysfunction. Regional myocardial stunning was induced by 15 minutes of coronary artery occlusion and 90 minutes of reperfusion in an open-chest canine preparation. Regional ventricular function was assessed by measurement of systolic wall thickening. Control untreated hearts were compared with two groups of hearts treated immediately before ischemia with intracoronary adenosine (5 micrograms/kg per minute and 50 micrograms/kg per minute). A fourth group of hearts was treated for the first 30 minutes of reperfusion with adenosine (50 micrograms/kg per minute). Preischemic adenosine administration increased coronary flow sixfold to sevenfold without altering regional function, mean arterial pressure, or left ventricular end-diastolic pressure. Both adenosine pre-treatments attenuated stunning compared with results in control animals (14.7% +/- 5.1% and 21.6% +/- 7.3% of preischemic systolic wall thickness versus -14.0% +/- 10%). Adenosine treatment during reperfusion transiently increased function in parallel with increased coronary blood flow, but after termination of the infusion regional function was not different from that in control stunned hearts (-5.0% +/- 13.1% of preischemic systemic wall thickness). These results indicate that adenosine pretreatment is associated with attenuation of stunning, an effect that can be produced at doses that do not alter systemic hemodynamics.

Adenosine↗

PubMed1995

Myocardial stunning: a therapeutic conundrum.

Dobutamine and pyruvate are two inotropic agents with different mechanisms of action. Although both agents alter postischemic myocardial dysfunction, their potential metabolic effects in the setting of in vivo myocardial stunning have not been addressed. In this study, the effects of dobutamine and pyruvate on systolic wall thickening, myocardial phosphorylation potential index, interstitial fluid adenosine level, and myocardial oxygen consumption in in vivo stunned porcine myocardium were assessed. Stunning was induced with a 10-minute occlusion of the left anterior descending coronary artery. After 30 minutes of reperfusion, pigs were treated with either intravenous dobutamine (10 micrograms/kg per minute) or intracoronary pyruvate (1 ml/min, 150 mmol/L solution, pH 7.4). Infusion of both agents resulted in a marked improvement in regional systolic wall thickening. The dobutamine effect, however, produced a marked increase in myocardial oxygen consumption and was associated with an increase in interstitial adenosine caused by myocardial de-energization, because the myocardial phosphorylation potential index ratio decreased from 0.17 +/- 0.02 to 0.09 +/- 0.02 (p < 0.05). In contrast, pyruvate enhanced myocardial energy status, because the myocardial phosphorylation potential index ratio increased from 0.20 +/- 0.03 to 0.55 +/- 0.08 (p < 0.01). These experimental findings suggest that under certain circumstances the use of beta-receptor agonists to treat myocardial stunning may be suboptimal, if not undesirable. Further investigation is warranted to determine the optimum therapy for the stunned heart.

Adenosine↗

PubMed1995

Preconditioning and its potential role in myocardial protection during cardiac surgery.

Myocardial preconditioning is the phenomenon whereby a brief stress to the heart (e.g., ischemia, hypoxia, etc.) prior to a prolonged period of ischemia renders the heart more resistant to ischemic injury. The cardioprotective effects of preconditioning include reduced infarct size and reduced ventricular arrhythmias. Preconditioning also is associated with beneficial metabolic effects during the prolonged ischemia, effects that also are observed during intermittent cardioplegia. However, there are conflicting reports about the effects of preconditioning on postischemic ventricular function. Although adenosine is thought to be the endogenous mediator of ischemic preconditioning, there are some important differences between adenosine and ischemic preconditioning mediated cardioprotection.

Adenosine↗

PubMed1995

Effects of ischemic and adenosine preconditioning on interstitial fluid adenosine and myocardial infarct size.

The accumulation of adenosine during a brief coronary occlusion has been proposed to mediate the infarct size-limiting effect of ischemic preconditioning. The purpose of this study was to compare the effects of ischemic preconditioning and a transient adenosine infusion on myocardial interstitial fluid (ISF) adenosine levels and infarct size. Microdialysis fibers (10.0 mm length) were placed in the left ventricular myocardium of pentobarbital sodium-anesthetized rabbits to estimate ISF adenosine. Ischemic preconditioning was induced by 5 min of coronary artery occlusion and 10 min of reperfusion before 45 min of occlusion. Adenosine preconditioning was induced with 5 min of intravenous adenosine infusion (140 micrograms.kg-1.min-1) followed by a 10-min washout before the prolonged occlusion. Myocardial infarct size was determined by triphenyltetrazolium chloride staining after 3 h of reperfusion. Five minutes of ischemia and 5 min of adenosine infusion produced comparable increases in dialysate adenosine levels (from 0.19 +/- 0.02 to 0.69 +/0- 0.11 and 0.28 +/- 0.10 to 0.71 +/- 0.18 microM, respectively) that decreased to baseline before the prolonged ischemia; however, ischemic-preconditioned hearts exhibited elevated dialysate adenosine levels for the first 5 min of reperfusion. Ischemic-preconditioned hearts exhibited significantly reduced dialysate adenosine concentrations for the first 20 min of the prolonged occlusion (P < 0.05 vs. control), and infarct size was reduced from 41 +/- 6 to 10 +/- 4% of risk area. Adenosine preconditioning had no effect on dialysate adenosine levels during prolonged ischemia but did reduce infarct size to 25 +/- 5% of risk area. These results indicate that a transient increase in ISF adenosine can reduce myocardial infarct size, but adenosine alone does not fully replicate the protective effects of ischemic preconditioning.

Adenosine↗

PubMed1994

Metabolically based treatment of stunned myocardium.

Reversible myocardial ischemia is associated with a rapid decrease in contractility and prolonged postischemic ventricular dysfunction, due in part to altered intracellular calcium handling and/or contractile protein dysfunction. The maintenance of intracellular calcium homeostasis and force development by the contractile apparatus are dependent upon the free energy derived from ATP hydrolysis. This energy of hydrolysis is determined by the myocardial phosphorylation potential, an estimate of which can be made from the ratio (CrP)/(Cr) x (P(i)). Results from in vitro and in vivo studies suggest that pyruvate enhances contractility in both normal and stunned myocardium by enhancing myocardial phosphorylation potential. In regionally stunned porcine myocardium, pyruvate infusion increased recovery of regional ventricular function from 33% +/- 4% of preischemic systolic wall thickening to 81% +/- 4% and increased the (CrP)/(Cr) x (P(i)) ratio fivefold from 0.21 +/- 0.04 to 1.05 +/- 0.08. Thus, metabolic substrates that enhance myocardial energetics and ventricular function may be effective agents for attenuating postischemic ventricular function.

Animals↗

PubMed1994

Adenosine attenuates phorbol ester-induced negative inotropic and vasoconstrictive effects in rat hearts.

Phorbol esters reduce cardiac contractility and produce coronary vasoconstriction presumably by stimulating protein kinase C (PKC). We tested whether adenosine altered the response to phorbol 12-myristate 13-acetate (PMA) in isolated rat hearts. Hearts, perfused at constant flow and constant heart rate, were exposed to PMA (10 nM) for 30 min and then allowed 30 min of recovery. PMA reduced left ventricular developed pressure (LVDP) from 81 +/- 2 to 49 +/- 3 and 40 +/- 2 mmHg (51 +/- 3% of baseline LVDP) after 30 min infusion and 30 min recovery, respectively. PMA also increased coronary perfusion pressure to 224 +/- 13% of baseline after 60 min. The PKC inhibitor bisindolylmaleimide (0.5 microM) blocked the PMA-induced negative inotropy and vasoconstriction. Adenosine (100 microM) and the A1-agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 0.1 microM) significantly attenuated the negative inotropic effect of PMA as LVDP was maintained at 81 +/- 4% and 99 +/- 7% of baseline, whereas CGS-21680, an A2-agonist, had no beneficial effect on function (54 +/- 4% of baseline). Adenosine and CGS-21680 (0.1 microM), but not CCPA, significantly attenuated PMA-induced coronary vasoconstriction. These results suggest that adenosine receptor activation may modulate myocardial PKC activity or attenuate the effects of increased PKC activity.

Adenosine↗

PubMed1994

The role of adenosine in extended myocardial preservation with the University of Wisconsin solution.

The purpose of this study was to determine the role that adenosine plays in enhanced myocardial preservation during cold storage with the University of Wisconsin solution. Hearts from adult rabbits were flushed with University of Wisconsin solution with or without adenosine and stored at 4 degrees C for 24 hours. Interstitial fluid purine levels during the period of cold storage were estimated with cardiac microdialysis probes. In a second series of experiments hearts were flushed with University of Wisconsin solution with or without adenosine or St. Thomas' Hospital cardioplegic solution and stored for 18 hours (4 degrees C). Functional recovery was assessed by reperfusing the hearts on a Langendorff apparatus (100 cm H2O) for 45 minutes with Krebs-Henseleit buffer. During cold storage dialysate adenosine concentrations in hearts flushed with University of Wisconsin solution were 20- to 40-fold greater than adenosine levels in hearts flushed without adenosine. After 45 minutes of reperfusion hearts preserved with University of Wisconsin solution exhibited a rate-pressure product of 11,098 +/- 576 mm Hg/min, significantly greater than that for hearts flushed with University of Wisconsin solution minus adenosine (8106 +/- 780 mm Hg/min) and St. Thomas' Hospital solution (7317 +/- 768 mm Hg/min). These results suggest that adenosine plays a major role in enhanced myocardial preservation with the University of Wisconsin solution, possibly by maintaining elevated interstitial fluid adenosine levels during the period of cold storage.

Adenosine↗