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M Karmazyn

Publications and source records attributed to M Karmazyn.

At least 55 records · Page 3Linked to original sources
PubMed1997

Prostaglandins attenuate cardiac contractile dysfunction produced by free radical generation but not by hydrogen peroxide.

The aim of this study was to examine and compare the potential influence of cyclooxygenase or lipoxygenase derived metabolites of arachidonic acid on myocardial injury produced either by a free radical generating system consisting of purine plus xanthine oxidase or that produced by hydrogen peroxide. A free radical generating system consisting of purine (2.3 mM) and xanthine oxidase (10 U/L) as well as hydrogen peroxide (75 microM) produced significant functional changes in the absence of either significant deficits in high energy phosphates or ultrastructural damage. Prostaglandin F2 alpha (30 nM) significantly attenuated both the negative inotropic effect of purine plus xanthine oxidase as well as the ability of the free radical generator to elevate diastolic pressure. An identical concentration of prostaglandin 12 (prostacyclin) significantly reduced diastolic pressure elevation only and had no effect on contractile depression. The salutary effects of the two PGs occurred in the absence of any inhibitory influence on superoxide anion generation produced by the purine and xanthine oxidase reaction. None of prostaglandins modulated the response to hydrogen peroxide. In addition, neither prostaglandin E2 nor leukotrienes exerted any effect on changes produced by either type of oxidative stress. A 5 fold elevation in the concentrations of free radical generators or hydrogen peroxide produced extensive injury as characterized by a virtual total loss in contractility, 400% elevation in diastolic pressure, ultrastructural damage and significant depletions in high energy phosphate content. None of these effects were modulated by eicosanoid treatment. Our results therefore demonstrate a selective ability of both prostaglandin F2 alpha and to a lesser extent prostacyclin, to attenuate dysfunction produced by purine plus xanthine oxidase but not hydrogen peroxide. It is possible that these eicosanoids may represent endogenous protective factors under conditions of enhanced oxidative stress associated with superoxide anion generation.

Animals↗
PubMed1996

Modulation of endothelin-1 effects on rat hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP.

Endothelin-1 (ET-1) has been demonstrated to produce numerous cardiac effects and increased production of the peptide has been shown in cardiac disease states. Although the cardiac effects of ET-1 have been examined extensively on its own, few studies have reported potential cross-talk between ET-1 with other endothelium-derived factors. We examined whether nitric oxide (NO) can modulate the effects of ET-1 on isolated rat hearts or ventricular myocytes. At 0.05 nM, ET-1 produced no effects on either systolic or diastolic function although a two-fold increase in left ventricular end-diastolic pressure (LVEDP) was observed in hearts pretreated with 10 microM of the NO synthase inhibitor L-NAME. Higher concentrations of ET-1 (0.5 and 5 nM) produced a direct elevation in LVEDP which was enhanced by L-NAME and totally blocked by the NO donor S-nitrosoacetylpenicillamine (SNAP, 10 microM) although responses to 5 nM ET-1 were highly variable with no significant differences between treatment groups. SNAP totally prevented ventricular fibrillation produced by either 0.05 or 0.5 nM ET-1 whereas the pro-fibrillatory actions of 5 nM ET-1 were unaffected. In cardiac myocytes, SNAP significantly attenuated the elevation in intracellular Ca2+ produced by ET-1 (5 nM). The positive inotropic actions of ET-1 on either hearts or myocytes were unaffected by any treatment. The protective effect of SNAP against ET-1 in both isolated hearts (reduction in LVEDP and incidence of fibrillation) as well as ventricular myocytes (attenuation of the elevation in intracellular Ca2+) was mimicked by 8-bromo-cyclic GMP (50 microM). Our study suggests that NO protects against the cardiotoxic effects of ET-1, possibly via inhibition of intracellular Ca2+ elevations, a property shared by cGMP, the likely mediator of the biological effects of NO.

Animals↗
PubMed1996

Transient ischemia in the presence of an adenosine deaminase plus a nucleoside transport inhibitor confers protection against contractile depression produced by hydrogen peroxide. Possible role of glycogen.

We previously reported that adenosine A1 receptor activation protects against the cardiodepressant effects of hydrogen peroxide in isolated rat hearts. The present study examined whether a transient ischemic period of 5 min duration, which preconditions the heart against ischemic and reperfusion-induced dysfunction, can bestow protection against 30-min exposure to hydrogen peroxide in isolated rat hearts. Transient ischemia on its own failed to alter the cardiac response to hydrogen peroxide. However, when transient ischemia was carried out in the presence of the nucleoside transport inhibitor S-(4-Nitrobenzyl)-6-thioguanosine and the adenosine deaminase inhibitor erythro-9-(2-Hydroxy-3-nonyl)adenine, a significant attenuation of the hydrogen peroxide-induced loss in contractility was evident and this was associated with significant preservation of tissue glycogen content. The protective effect of the transient ischemia/drug combination on both functional changes and glycogen levels was abolished by the adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine as well as by glibenclamide, a blocker of the ATP-sensitive potassium channel (KATP). To further assess the role of glycogen in the protection against hydrogen peroxide, we compared the effects of the adenosine A1 agonist N6-cyclopentyl adenosine (CPA) and insulin. While both treatments protected against hydrogen peroxide the effect of insulin was superior to any other treatment. Moreover, while all protective modalities preserved glycogen stores after hydrogen peroxide treatment, the protection afforded by insulin was also associated with significantly elevated glycogen levels prior to hydrogen peroxide administration. No protection by either CPA or insulin was evident in the absence of exogenous glucose. Taken together, our results demonstrate that a brief period of ischemia with concomitant administration of agents which increase interstitial adenosine levels protects against hydrogen peroxide toxicity. The effect is mediated by activation of adenosine A1 receptors and is linked to KATP stimulation. Moreover, our results are strongly suggestive of an important role of glycogen preservation in bestowing protective effects against hydrogen peroxide cardiotoxicity.

Adenosine Deaminase↗
PubMed1996

Improved cardiac function after prolonged hypothermic ischemia with the Na+/H+ exchange inhibitor HOE 694.

BACKGROUND: Na+/H+ exchange represents an important mechanism for pH regulation in the cardiac cell that, however, may paradoxically mediate tissue damage in the reperfused myocardium. We investigated whether inhibition of the exchanger can protect the heart against damage after prolonged hypothermic storage with the use of the selective inhibitor 3-methylsulfonyl-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 694). METHODS: After equilibration, isolated rabbit hearts were arrested with a 3 minute infusion of modified St. Thomas' cardioplegic solution and subsequently maintained in ischemic arrest at 4 degrees C for 12 hours before reperfusion at 37 degrees C for 60 minutes. Left ventricular function and creatine kinase release were measured at intervals throughout reperfusion. High-energy phosphate and adenine nucleotide content were determined in hearts before cardioplegia, at the end of the 12-hour storage period, and at the end of reperfusion. HOE 694 (1 mumol/L) was administered either with cardioplegia and throughout reperfusion (study 1) or selectively with either cardioplegia or reperfusion only (study 2). RESULTS: In study 1, systolic function in untreated hearts recovered to less than 40% of preischemic values and was associated with a greater than 1,000% percent sustained elevation in left ventricular end-diastolic pressure. In contrast, systolic recovery in HOE 694-treated hearts was significantly accelerated and improved to approximately 80%, whereas left ventricular end-diastolic pressure increased to only 300% of baseline. Significant protection also occurred in those hearts in which HOE 694 was administered only at reperfusion while the drug was less effective if given only during cardioplegia. Creatine kinase release was not significantly affected except in study 2, where it was significantly lower after 60 minutes of reperfusion in hearts where HOE 694 was added at the time of reperfusion. Tissue metabolite content was not affected by drug treatment. CONCLUSIONS: This study shows a marked protective effect of the Na+/H+ exchange inhibitor HOE 694 in rabbit hearts subjected to 12 hours of hypothermic ischemia and strongly suggests that antiport inhibitors could play an effective role in myocardial preservation.

Animals↗
PubMed1996

Inhibition of beta- but not alpha 1-mediated adrenergic responses in isolated hearts and cardiomyocytes by nitric oxide and 8-bromo cyclic GMP.

OBJECTIVES: The study was carried out to assess the effect of nitric oxide (NO) generation or inhibition of NO synthase on the cardiac response to beta- and alpha 1-adrenergic agonists. In addition, we determined the effects of the cell-permable analogue of cGMP, 8-bromo-cGMP (8Br-cGMP). METHODS: Experiments were done in electrically-paced isolated perfused rat hearts as well as in ventricular myocytes. Hearts were exposed to either the beta-adrenoceptor agonist, isoproterenol (0.1 microM), or the alpha 1-adrenoceptor agonist, phenylephrine (2 microM in the presence of equimolar concentrations of propranolol), either with each drug alone or in the presence of the NO donors S-nitrosoacetylpenicillamine (SNAP, 10 microM) and 3-morpholino-sydnonimine (SIN-1, 10 microM), the NO synthase inhibitor L-NAME (10 microM) or 8Br-cGMP (50 microM). These concentrations of SNAP and 8Br-cGMP increase tissue cGMP levels approximately 3-fold after 15 min treatment. Myocardial contractility was assessed by determining left ventricular pressure with a fluid-filled balloon inserted into the left ventricle. Similar experiments were performed in myocytes in which cell shortening and intracellular calcium transients were determined although concentrations of isoproterenol and phenylephrine in myocytes were higher (1 and 5 microM, respectively) than those used in isolated hearts in order to achieve optimum responses. RESULTS: In isolated hearts isoproterenol increased developed pressure by about 50%, which was totally prevented by SNAP and SIN-1 and unaffected by L-NAME. 8Br-cGMP, however, did not significantly diminish the positive inotropic effect of isoproterenol. Phenylephrine increased developed pressure of isolated hearts by about 30%, but this was totally unaffected by either SNAP, SIN-1 or 8Br-cGMP. In myocytes, isoproterenol significantly increased the calcium transient by more than 50% and cell shortening by about 70%. Both effects were significantly attenuated by SNAP, SIN-1 and 8Br-cGMP but unaffected by L-NAME. Phenylephrine significantly increased cell shortening and the calcium transient, but these responses were unaffected either by SNAP or 8Br-cGMP. CONCLUSION: The present study demonstrate that NO as well as guanylate cyclase inhibitors and, to a lesser extent, 8Br-cGMP attenuate beta-receptor-mediated cardiac responses and supports the concept that NO serves as an endogenous regulator of beta-mediated effects of catecholamines in the heart. In addition, our findings suggest that the antiadrenergic effects of NO are restricted to these receptors but likely do not involve alpha 1-mediated effects.

Adrenergic alpha-Agonists↗
PubMed1996

The sodium-hydrogen exchange system in the heart: its role in ischemic and reperfusion injury and therapeutic implications.

OBJECTIVES: To review evidence supporting a role for sodium-hydrogen exchange (Na/H exchange) in mediating myocardial ischemic and reperfusion injury, and to outline clinical implications in terms of the development of novel cardioprotection strategies. DATA SOURCES: Various sources were used including MEDLINE and Reference Update. Only articles written in the English language were used. DATA EXTRACTION: A wide range of publications dealing with cardiac injury and particularly studies involving intracellular pH regulation and Na/H exchange activity. The vast majority of papers cited were published since 1986, with a large percentage appearing within the past five years. DATA SYNTHESIS: Na/H exchange is a major mechanism for restoration of intracellular pH after ischemia, although its activation during both ischemia and reperfusion has been shown to be involved in a paradoxical induction of cell injury. This likely reflects the fact that activation of the exchanger is closely coupled to sodium influx and, as a consequence, to elevation in intracellular calcium concentrations through sodium-calcium exchange. In addition to intracellular acidosis, other factors can stimulate the exchanger, including various autocrine and paracrine factors such as endothelin-1 and activation of alpha 1 adrenergic receptors, both of which likely act through signal transduction processes including activation of protein kinase C. Although at least 5 Na/H exchange isoforms have been identified, it appears that subtype 1, termed NHE-1, is the predominant isoform in the mammalian myocardium. Effective pharmacological inhibitors of Na/H exchange, including those that are NHE-1 specific, have been developed. These have been extensively demonstrated to protect the ischemic and reperfused myocardium, as shown by improved systolic and diastolic function, preservation of cellular ultrastructure and reduced incidence of arrhythmias. Moreover, the salutary effects of these agents have been demonstrated by a variety of experimental models and animal species, suggesting that the role of Na/H exchange in mediating injury is not species-specific. CONCLUSION: Na/H exchange is an important target for pharmacological intervention in attenuation of ischemia- and reperfusion-induced cardiac injury. Coupled with the low potential for toxicity by the agents, Na/H exchange inhibition could emerge as an effective therapeutic strategy in cardiac disorders, particularly involving conditions associated with ischemia and reperfusion.

Animals↗
PubMed1995

Sodium-hydrogen exchange inhibitors improve postischemic recovery of function in the perfused rabbit heart.

OBJECTIVE: The aim was to examine the effects of the Na+/H+ exchange inhibitors amiloride and methylisobutyl amiloride (MIA) in buffer perfused rabbit hearts subjected to one hour of normothermic ischaemia (37 degrees C) followed by reperfusion. METHODS: Experiments were carried out in five groups of Langendorff perfused rabbit hearts: (1) control, (2) amiloride, and (3) MIA (agents in both the preischaemic and reperfusion perfusate), (4) amiloride-R and (5) MIA-R (agents added at reperfusion only). Functional evaluation included serial measurement of resting tension, force, rates of ventricular force development and relaxation, and coronary perfusion pressure. Samples of coronary effluent were obtained for creatine kinase assay and hearts were freeze clamped for metabolite assays. RESULTS: Reperfusion resulted in a marked increase in resting tension in group (1) which was statistically significant compared to groups (2) and (3). Groups (2) and (3) also showed significantly improved recovery of ventricular force, rate of force development, and rate of ventricular relaxation. Addition of either agent only during reperfusion failed to produce a significant beneficial effect. There were no significant differences among the groups with respect to postreperfusion creatine kinase release or end reperfusion metabolite levels. CONCLUSION: This study shows for the first time that both of the Na+/H+ exchange inhibitors amiloride and MIA produce improved recovery of ventricular function in rabbit hearts subjected to ischaemia and reperfusion, although the beneficial effect was not obtained with drug administration at the time of reperfusion only.

Amiloride↗
PubMed1994

Adenosine-sensitive alpha 1-adrenoceptor effects on reperfused ischaemic hearts: comparison with phorbol ester.

1. We have examined the effects of the alpha 1-adrenoceptor agonists, phenylephrine or methoxamine, on contractility in rat and rabbit isolated hearts as well as their effects on postischaemic ventricular recovery. We compared these effects to those of 12-phorbol 13-myristate acetate (PMA), a direct activator of protein kinase C (PKC). 2. The positive inotropic effect of alpha 1-receptor agonists was significantly attenuated in the presence of the Na/H exchange inhibitor, methylisobutyl amiloride (MIA, 1 microM), whereas the positive inotropic effect of PMA was unaffected. 3. Reperfusion of rat hearts subjected to either 30 or 60 min of zero-flow ischaemia, resulted in recovery of contractility to 91 +/- 2% and 57 +/- 7% of the preischaemic values, respectively which was unaffected by phenylephrine. In contrast, PMA at a concentration (10 pM) devoid of direct depressant effects, significantly decreased recovery following 60 min of ischaemia to 31 +/- 4% of pre-ischaemic value (P < 0.05 from control); an effect which was completely prevented by the PKC inhibitor, bisindolylmaleimide. A similar inhibitory effect of PMA and lack of effect of phenylephrine were seen in reperfused rabbit hearts. 4. As alpha 1-receptor activation has been shown previously to stimulate cardiac adenosine production, we assessed whether blockade of adenosine A1 receptors with the specific antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 0.5 microM) would unmask the actions of phenylephrine in hearts subjected to 30 min ischaemia and reperfusion. In the presence of DPCPX, phenylephrine reduced recovery to 44 +/- 9% compared to 82 +/- 10% recovery in the absence of phenylephrine (P < 0.05). Identical results were observed in rabbit hearts treated with DPCPX in which recovery was reduced from 57.1 +/- 11.2% to 17.8 +/- 6.8% by phenylephrine (P < 0.05). Another A1 receptor antagonist, (+/-)-N6-endonorbornan-2-yl-9-methyladenine (N-0861, 0.5 microM) produced virtually identical results to those observed with DPCPX. 5. MIA failed to modulate the inhibition of postischaemic recovery by phenylephrine. Bisindolylmaleimide, on the other hand, partially prevented the effects of phenylephrine on postischaemic contractile dysfunction. The inhibitory effect of either PMA or phenylephrine on postischaemic recovery of both rat and rabbit hearts was generally dissociated from alterations in energy metabolism, although in the case of rat hearts, inhibition by phenylephrine was associated with diminished high energy phosphate content. 6. Our results demonstrate that both alpha 1-receptor activation as well as direct activation of PKC with phorbol ester can attenuate post-ischaemic ventricular recovery. Moreover, our results strongly suggest that endogenous adenosine protects the heart against the deleterious effects of alpha 1-receptor activation during ischaemia and reperfusion.

Adenosine↗
PubMed1994

Role of Na(+)-H+ exchange in mediating effects of endothelin-1 on normal and ischemic/reperfused hearts.

Endothelin (ET) has been shown to be elevated under conditions of cardiac pathology and to produce diverse cardiac effects, including coronary constriction and a positive inotropic influence. We characterized the concentration- and time-dependent effects of the most potent of the ET isoforms, ET-1 (0.4, 2, and 4 nmol/L), on myocardial contractility and coronary resistance and assessed its effects on the ischemic and reperfused heart. Because ET-1 has been shown to activate the Na(+)-H+ exchanger in cardiac myocytes, we determined the contribution of the antiport by examining the effects of ET-1 in the presence of the Na(+)-H+ exchange inhibitor methylisobutyl amiloride (MIA). At all three concentrations, ET-1 produced an initial positive inotropic effect that was reversed with continued perfusion, the degree of the reversal being dependent on ET-1 concentration. With 0.4 nmol/L, contractility returned to pre-ET-1 values, whereas after 75 minutes of perfusion with 4 nmol/L ET-1, contractility was depressed by 75%. At all concentrations, ET-1 produced a coronary-constricting effect, whereas an elevation in resting tension was observed only with 4 nmol/L ET-1. MIA significantly prevented the positive inotropic effect of ET-1 but had no effect on loss in function or elevation in resting tension produced by 4 nmol/L ET-1. Furthermore, MIA partially, but not significantly, attenuated the constricting effects of all ET-1 concentrations. In the ischemic heart, 0.4 nmol/L ET-1 appeared to delay the loss in contractility produced by cessation of flow, although the effect was not significant. Higher concentrations of ET-1 were without effect on ischemia-induced contractile depression, although their presence produced a marked elevation in resting tension during ischemia that was attenuated by MIA. Recovery in contractility was reduced by all concentrations of ET-1, although the effects of the lowest concentration were associated primarily with defective relaxation. The depressant effects of ET-1 either in normal or ischemic/reperfused hearts were irreversible. The inhibitory effects of ET-1 on contractile recovery were associated with diminished tissue glycogen and elevated lactate levels. High-energy phosphates after reperfusion were depressed in hearts treated with 4 nmol/L ET-1. The attenuation in contractile recovery and alterations in metabolite content were prevented by MIA. These results provide evidence that ET-1 produces complex effects on heart function that are likely mediated via different mechanisms and demonstrate its ability to aggravate ischemic and reperfusion injury through a mechanism possibly involving Na(+)-H+ exchange activation.

Animals↗
PubMed1993

Protective effects of the potent Na/H exchange inhibitor methylisobutyl amiloride against post-ischemic contractile dysfunction in rat and guinea-pig hearts.

We studied the effects of the potent Na/H exchange inhibitor methylisobutyl amiloride (MIA, 1 microM) on post-ischemic ventricular recovery and energy metabolic status in spontaneously contracting, isolated rat and guinea-pig hearts subjected to 45 min zero-flow ischemia followed by reperfusion. For both species, MIA was added either 15 min prior to ischemia and was present throughout reperfusion or was added at the time of reperfusion only. In control rat hearts, force recovery after 30 min of reperfusion was 25.6 +/- 6.0% of the pre-ischemic value whereas in hearts pre-treated with MIA recovery was enhanced to 55.4 +/- 9% (P < 0.05). Elevation of resting tension during the first 20 min of reperfusion was also significantly reduced by MIA pre-treatment. When MIA was added at the time of reperfusion only, recovery was generally lower than that seen with MIA pre-treatment although significantly higher values were seen through much of the reperfusion period. In rat hearts, MIA reduced the time required for return to sustained contractile recovery particularly in those hearts where the drug was added prior to ischemia (control, 11.4 +/- 2.7 min; MIA, 2.6 +/- 0.5 min, P < 0.05). Similar effects of MIA pre-treatment were seen in guinea-pig hearts in terms of contractile recovery, time to recovery and reduction in resting tension although MIA addition at the time of reperfusion was without beneficial effect either on the magnitude of contractile recovery or time required for restoration of function. In guinea-pig hearts, recovery of function was accompanied by substantial bradycardia. However, maintenance of ventricular rate through electrical pacing exerted no significant influence on the protective effects of MIA pre-treatment. There was no effect of MIA on energy metabolites in reperfused rat hearts or paced guinea-pig hearts, although in spontaneously contracting guinea-pig hearts improved recovery of function was associated with significantly higher levels of high energy phosphates. No effects of tissue metabolites were seen in ischemic non-reperfused hearts irrespective of treatment. The protective effects of MIA were not related to diminished release of creatine kinase during reperfusion. Our results demonstrate marked protective effects of MIA, on the reperfused rat and guinea-pig myocardium. These studies also demonstrate, for the first time, that the effects of amiloride analogues are not species specific and further support the concept that Na/H exchange inhibition may represent an effective therapeutic approach for the protection of reperfused cardiac tissue.

Adenine Nucleotides↗
PubMed1993

Calcium dependent positive inotropic effects of low phorbol ester concentrations in isolated rat hearts.

OBJECTIVE: The aim was to examine the cardiac effects of phorbol esters over a wide concentration range and to determine if the effects are related to Ca2+ availability. METHODS: Studies were carried out using isolated rat hearts exposed for 60 min either to phorbol 12-myristate 13-acetate (PMA, 10(-11) to 10(-6) M) or phorbol 12,13-dibutyrate (PDBu, 10(-12) to 10(-7) M) in the presence of either 1.25 or 2.50 mM CaCl2. Experiments were also done to assess the effect of BAY K8644, a Ca2+ agonist, on phorbol ester effects. After treatment, hearts were freeze clamped for later analysis of energy products. RESULTS: At the lowest concentrations studied, both PMA and PDBu produced positive inotropic effects, whereas higher concentrations resulted in a loss of contractile force in hearts perfused with 1.25 mM CaCl2. Doubling the CaCl2 concentration or the presence of BAY K8644 had little effect on the negative inotropic influence of either phorbol ester but reversed the positive inotropic effect to a negative inotropic one. Neither treatment had any effect on the coronary constricting effects of phorbol esters. Increases in resting tension and reductions in high energy phosphate content were evident only with the highest phorbol ester concentrations and were unaffected either by changes in CaCl2 concentrations or the presence of BAY K8644. CONCLUSIONS: At picomolar and nanomolar concentrations phorbol esters produce positive inotropic actions which are probably mediated by enhanced Ca2+ influx. Although higher concentrations produce negative inotropic effects, these are not influenced by [Ca2+]o nor are they related to disturbances in energy metabolism except at the highest concentrations. We conclude that phorbol esters produce complex concentration dependent cardiac effects which are not mediated by a single mechanism of action.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Effect of prostaglandins I2 (prostacyclin) and F2 alpha on function, energy metabolism, and calcium uptake in ischaemic/reperfused hearts.

OBJECTIVE: The aim was to examine the effect on cardiac function, energy metabolism, and calcium uptake of either prostaglandin I2 (PGI2, prostacyclin) or prostaglandin F2 alpha (both 28.6 nM) on the response of isolated rat hearts to 25 min of total global ischaemia with or without 30 min reperfusion. METHODS: Rat hearts were perfused by the Langendorff method and function assessed by left ventricular pressure. Energy metabolites were measured using enzymatic techniques and 45Ca2+ uptake determined by radioisotopic analysis. RESULTS: Although there was no effect of either prostaglandin on contractile depression during ischaemia, both compounds accelerated the onset of and increased the magnitude of ischaemic contracture. High energy phosphate content at the end of the ischaemic period was not affected by prostaglandin treatment; however, tissue lactate levels were increased by PGI2 as was tissue calcium content. Under control conditions mean recovery of left ventricular developed pressure ranged from 66% to 83%. In the presence of PGI2 and PGF2 alpha, recovery of developed pressure was reduced to 20% and 38% of preischaemic values, respectively. The reduced recovery in developed pressure was accompanied by an approximately threefold increase in diastolic pressure (p < 0.05). The depression of functional recovery in reperfused hearts treated with prostaglandins was associated with various disturbances of cellular metabolism including depressed ATP and creatine phosphate content and increased tissue lactate and calcium following 30 min of reperfusion. A significant correlation was found between the changes in developed pressure and diastolic pressure during reperfusion and the reduction in ATP and creatine phosphate repletion. The deficit in recovery of ventricular function also correlated significantly with increased lactate and calcium accumulation in the reperfused heart. CONCLUSIONS: Low concentrations of PGI2 and PGF2 alpha can depress contractile recovery of the globally ischaemic heart through a mechanism associated with altered cellular energy metabolism and increased calcium accumulation.

Adenosine Triphosphate↗
PubMed1993

Role of Na+/H+ exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox.

Na+/H+ exchange, an electroneutral cotransport system, is activated by reperfusion of the ischaemic heart. While activation can restore intracellular pH following an acid load, the concomitant increase in intracellular Na+ can also aggravate existing derangements of ionic homeostasis, particularly with respect to calcium overload, and result in exacerbation and acceleration of tissue injury, a phenomenon which has been termed the pH paradox. In addition, Na+/H+ exchange has been shown to participate in the activation of both platelets and neutrophils, factors widely acknowledged to participate in ischaemic and reperfusion injury. All studies thus far reported (summarised in the table) have shown desirable and beneficial effects of Na+/H+ exchange inhibitors on various cellular processes which contribute to myocardial reperfusion injury. These multiple effects of Na+/H+ exchange inhibitors are unique and unmatched by any other group of pharmacological agents. They offer the hope of superior tissue protection and salvage, with limited potential for toxicity, following reperfusion protocols. We propose, therefore, that activation of the Na+/H+ exchanger mediates reperfusion injury and that suppression of the exchanger will be of superior benefit in reduction of such injury during restoration of flow. The rapid development of new and highly specific Na+/H+ exchange inhibitors offers substantial promise for the use of these agents as adjunct therapy in numerous reperfusion protocols.

Animals↗