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G J Grover

Publications and source records attributed to G J Grover.

At least 55 records · Page 3Linked to original sources
PubMed1995

Protective effect of K(ATP) openers in ischemic rat hearts treated with a potassium cardioplegic solution.

ATP-sensitive potassium channel (KATP) openers directly protect ischemic myocardium, which may make them useful for treating patients undergoing cardiopulmonary bypass, but whether high-potassium-containing cardioplegic solutions would inhibit their protective effects is not clear. We determined whether additional protection greater than that provided by cardioplegia could be found for KATP openers. We studied the effect of 10 microM cromakalim or BMS-180448 pretreatment (10 min before cardioplegia) on severity of ischemia in isolated rat hearts given normothermic or cold St. Thomas' cardioplegic solution (16 mM K+). After cardioplegic arrest, the hearts were subjected to 30-min (normothermic) or 150-min (hypothermic) global ischemia, each followed by 30-min reperfusion. The cardioplegic solutions significantly protected the hearts, as measured by increased time to onset of contracture, enhanced recovery of function, and reduced lactate dehydrogenase (LDH) release. Cromakalim and BMS-180448 both further significantly increased time to contracture in both normothermic and hypothermic arrested hearts; this was accompanied by enhanced recovery of reperfusion contractile function and reduced cumulative LDH release. This additional protective effect of the K ATP openers was abolished by glyburide. Because administration of the K ATP openers only with the cardioplegic solution (1 min before global ischemia) was not efficacious, >1-min pretreatment apparently is necessary. K ATP openers provide additional protection to that afforded by cold or normothermic potassium cardioplegia in rat heart, although the timing of treatment may be crucial.

Adenosine Triphosphate↗
PubMed1995

Inhibition of nitric oxide synthesis does not affect ischemic preconditioning in isolated perfused rat hearts.

Endothelium-derived nitric oxide (NO) has recently been reported to be a mediator of ischemic preconditioning in dog hearts. The aim of the present study was to determine the role of NO in ischemic preconditioning in isolated perfused rat hearts. Rat hearts were perfused at either constant pressure (80 mmHg) or constant flow. After aerobic perfusion (37 degrees C) for 10 min, hearts were treated with N omega-nitro-L-arginine methyl ester (L-NAME; 30 microM), which is an inhibitor of NO synthase, or vehicle. Ten minutes later, the hearts were preconditioned (4 episodes of 5 min of global ischemia and 5 min of reperfusion) or perfused normally before a 30-min global ischemic period. All hearts were reperfused for 30 min. Coronary flow or perfusion pressure plus heart rate and contractile function were measured continuously. Hearts perfused at constant pressure and treated with 30 microM L-NAME, a concentration that effectively inhibits endogenous NO synthesis, exhibited decreased coronary flow after 10 min, and flow remained decreased throughout the experiment. Ischemic preconditioning before 30 min of global ischemia resulted in a doubling of contractile function and a reduction of lactate dehydrogenase release at the end of the 30-min reperfusion period compared with nonpreconditioned hearts. The protective effect of preconditioning was not different in L-NAME-treated hearts. In addition, inhibition of NO synthase had no effect on the severity of ischemia in nonpreconditioned hearts. Similar results were obtained in preconditioned hearts that were perfused at constant flow, indicating that the flow reductions caused by L-NAME did not influence the results.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1995

Protective effect of the serotonin receptor antagonist cinanserin in two canine models of pacing-induced myocardial ischemia.

Previous studies have indicated that structurally dissimilar serotonin2 (5HT2) antagonists can protect globally ischemic/reperfused reperfused rat hearts. We therefore determined if the 5HT2 antagonist cinanserin can protect the ischemic myocardium in two models of pacing-induced ischemia in anesthetized dogs. In one model, dogs were subjected to repeated 5-min episodes of pacing superimposed upon left anterior descending coronary artery stenosis such that an ST segment elevation of 10-11 mV was obtained and upon cessation of pacing, a return of ST segment elevation to baseline. In vehicle-treated animals, this ST segment elevation to baseline. In vehicle-treated animals, this ST segment elevation was constant for all pacing-induced ischemic episodes. After infusion of 20 micrograms/kg/min cinanserin (intracoronary, i.c.), ST segment elevation was significantly reduced during pacing-induced ischemia at all times measured postdrug. In the second model, animals were subjected to pacing-induced ischemia for 15 min such that segmental shortening was reduced to zero. Upon cessation of pacing-induced ischemia, recovery of shortening was assessed. In vehicle-treated dogs, function recovered to only 40% of baseline at 3 h into recovery. Pretreatment with 5 micrograms/kg/min cinanserin i.c. significantly improved recovery of postischemic function. In both protocols, cinanserin had no effect on ischemic regional blood flow or peripheral hemodynamics. Thus, cinanserin appears to exert profound protective effects in two models of effort-induced ischemia.

Analysis of Variance↗
PubMed1995

Does ischemic preconditioning in the human involve protein kinase C and the ATP-dependent K+ channel? Studies of contractile function after simulated ischemia in an atrial in vitro model.

Protein kinase C (PKC) and the ATP-dependent K+ channel (KATP channel) have been implicated in the mechanism of ischemic preconditioning in animal models. This study investigated the role of KATP channels and PKC in preconditioning in human myocardium and whether KATP channels are activated via a PKC-dependent pathway. Right atrial trabeculae were superfused with Tyrode's solution and paced at 1 Hz. After stabilization, muscles underwent one of nine different protocols, followed by simulated ischemia (SI) consisting of 90 minutes of hypoxic substrate-free superfusion paced at 3 Hz and then by 120 minutes of reperfusion. Preconditioning consisted of 3 minutes of SI and 7 minutes of reperfusion. The experimental end point was recovery of contractile function after SI, presented here as percentage recovery (%Rec) of baseline function. %Rec was significantly improved by preconditioning by the KATP channel opener cromakalim (CK), and by the PKC activator 1,2-dioctanoyl-sn-glycerol (DOG) compared with nonpreconditioned controls when these treatments were given before the SI insult (control group, 29.5 +/- 3.6%; preconditioned group, 63.5 +/- 5.4%, CK-treated group, 52.9 +/- 3.1%; and DOG-treated group, 48.0 +/- 3.5%; P < .01). The effects of CK could be blocked by the KATP channel blocker glibenclamide (%Rec, 17.8 +/- 3.5%). Preconditioning could be blocked by the PKC antagonist chelerythrine (%Rec, 24.1 +/- 5.0%) and the KATP blocker glibenclamide (%Rec, 24.8 +/- 3.1%). The effects of DOG could also be blocked by glibenclamide (%Rec, 23.1 +/- 2.3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1995

Endogenous catecholamines are not necessary for ischaemic preconditioning in the isolated perfused rat heart.

OBJECTIVE: The mechanism of the protective effect of ischaemic preconditioning in the myocardium is not yet known. The aim of this study was to test the hypothesis that endogenous myocardial catecholamines may be mediators of preconditioning. METHODS: To test whether endogenous catecholamines are involved in preconditioning, experiments were performed in hearts from rats which had been catecholamine depleted with either reserpine or 6-hydroxydopamine. Experiments were also done to determine if noradrenaline can mimic preconditioning. RESULTS: Catecholamine depletion with either reserpine or 6-hydroxydopamine had no effect on preischaemic coronary flow or cardiac function. Ischaemic preconditioning (four episodes of 5 min global ischaemia and 5 min reperfusion) resulted in a significant increase in postischaemic cardiac function and a 50% decrease in lactate dehydrogenase (LDH) release following 30 min ischaemia and 30 min reperfusion compared with non-preconditioned hearts. Reserpine pretreatment did not affect the response to ischaemia or to preconditioning, although LDH release tended to be greater than in normal hearts, especially in the non-preconditioned group. Although 6-hydroxydopamine significantly increased postischaemic cardiac function in the preconditioned group, no other index of ischaemic damage (for example, LDH release, left ventricular end diastolic pressure) was affected. Further studies showed that 10 nmol.min-1 noradrenaline did not affect the severity of ischaemia, indicating that it does not mimic preconditioning. CONCLUSIONS: Endogenous catecholamines are not necessary for ischaemic preconditioning in isolated rat hearts and play little or no role in the functional responses to ischaemia.

Animals↗
PubMed1995

Glyburide-reversible cardioprotective effect of BMS-180448 is independent of action potential shortening.

OBJECTIVE: We determine if action potential duration (APD) shortening and cardioprotection are separable phenomena in ATP-sensitive potassium channel (KATP) openers which protect ischemic myocardium via a glyburide-reversible mechanism. METHODS: We determined the effect of the weakly vasodilating KATP opener, BMS-180448, and the less cardiac-selective cromakalim, on APD in normal, hypoxic or ischemic guinea pig papillary muscles or isolated hearts and compared their APD effects with their cardioprotective activity in isolated guinea pig hearts. RESULTS: In isolated ischemic guinea pig hearts, cromakalim and BMS-180448 had similar cardioprotective potencies (EC25 of 3.2 and 3.3 microM, respectively, for increasing time to the onset of contracture). At 10 microM, BMS-180448 produced no APD shortening, yet was equally protective at this concentration compared to cromakalim, which produced profound APD shortening under either hypoxic or ischemic conditions. The cardioprotective effects of both compounds at 10 microM were abolished by 0.3 microM glyburide. CONCLUSIONS: APD shortening is not correlated with cardioprotective activity for BMS-180448 and cromakalim while their cardioprotective effects are abolished by glyburide. These results suggest the possibility of reduced proarrhythmic activity in some KATP openers and that their cardioprotective activity is not associated with sarcolemmal KATP opening.

Action Potentials↗
PubMed1994

The effect of alpha 2-adrenoceptor antagonists in isolated globally ischemic rat hearts.

The alpha 2-adrenoceptor antagonist, yohimbine, has been reported to protect hypoxic myocardium. Yohimbine has several other activities, including 5-HT receptor antagonism, at the concentrations at which protection was found. Therefore we designed a study to determine if yohimbine was protecting ischemic myocardium via antagonism of alpha 2-adrenoceptors. In isolated globally ischemic rat hearts, the effects of two structurally distinct classes of alpha 2-adrenoceptor antagonists, the indole alkaloids (yohimbine and rauwolscine) and the imidazolines (idozoxan and tolazoline) were investigated. Pretreatment with yohimbine (1-10 microM) caused a concentration-dependent increase in reperfusion left ventricular developed pressure and a reduction in end diastolic pressure and lactate dehydrogenase release. The structurally similar compound rauwolscine (10 microM) also protected the ischemic myocardium. In contrast, idozoxan (0.3-10 microM) or tolazoline (10 microM) had no protective effects. The cardioprotective effects of yohimbine were partially reversed by 30 microM 5-HT. These results indicate that the mechanism for the cardioprotective activity of yohimbine may involve 5-HT receptor antagonistic activity.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1994

Characterization of rabbit myocardial phospholipase A2 activity using endogenous phospholipid substrates.

We have developed an assay for studying myocardial phospholipase A2 activity by measuring accumulation of lysophospholipids resulting from hydrolysis of the endogenous choline glycerophospholipid pool. This assay was used to characterize phospholipase A2 activity in rabbit myocardium. Lyophilized rabbit myocardium was incubated at 37 degrees C in Tris-HCl buffer containing either ethylene glycol bis(beta-aminoethyl ether) N,N'-tetraacetic acid (EGTA)/EDTA or calcium, and palmitoyl-lysophosphatidylcholine (P-LPC), oleoyl-LPC, stearoyl-LPC, and 16:0-lysoplasmenylcholine were measured using a recently developed HPLC method. The identity of the individual species was confirmed by ion-spray LC-MS-MS. In the presence of EGTA/EDTA, incubation for up to 30 min caused a linear increase in all lysophospholipids. The main increases were found in P-LPC and 16:0-lysoplasmenylcholine, which increased by 37 +/- 3 (mean +/- SE, N = 8) and 48 +/- 3 nmol/g dry wt x min, respectively. The apparent phospholipase A2 activity was found to be calcium, temperature, and pH sensitive. The pH optimum was between 6.5 and 8.0, and incubation at room temperature and 45 degrees C decreased the activity by 80 and 40%, respectively. Studies of the metabolism of the formed lysophospholipids showed a substantial metabolism of the lysophospholipids that accounted for about 40% of the total phospholipase A2 activity. This method offers a novel approach to study phospholipase A2 activities by measuring accumulation of products resulting from hydrolysis of endogenous phospholipid pools.

Animals↗
PubMed1994

Role of endothelin receptor subtype B (ET-B) in myocardial ischemia.

Previous work indicated that endothelin (ET) may be involved in the pathogenesis of myocardial ischemia, although the relative importance of the ET receptor subtypes is presently not clear. The purpose of this study was to determine the role of myocardial ET-B receptors in mediating ischemic/reperfusion damage in isolated rat hearts. Saturation binding analyses were conducted with [125I]ET-1 and [125I]IRL-1620 to assess changes in ET-A and ET-B receptor binding. Total ET receptor density (Bmax) was greater in atrial versus ventricular tissue. ET-A Bmax was 8 to 10-fold greater than ET-B Bmax. In ischemic and ischemic/reperfused atrial tissue neither the equilibrium dissociation constant (Kd) nor Bmax for ET-B receptors was changed. The ET-B receptor Kd in ischemic or ischemic/reperfused ventricular tissue was also unchanged. In ischemic ventricular tissue there was a trend towards an increased ET-B Bmax, which was accentuated after ischemia/reperfusion. No changes were found in ET-A Bmax or Kd in ischemic ventricular or atrial tissue. The physiological importance of this receptor subtype in ischemic myocardium was determined using the selective ET-B agonist, sarafotoxin S6c. In non-ischemic tissue no effect on coronary flow or function were observed with sarafotoxin S6c. Furthermore, no changes were seen in ischemic time to contracture or any of the reperfusion indexes of myocardial damage. The sarafotoxin S6c utilized was active as it inhibited [125I]ET-3 binding to ET-B receptors (Ki = 0.1 nM). Thus, the pro-ischemic effect of ET-1 seems to be mediated by ET-A receptors. ET-B receptors do not appear to play a role in the pathogenesis of myocardial ischemia.

Animals↗
PubMed1994

Effect of potassium on the action of the KATP modulators cromakalim, pinacidil, or glibenclamide on arrhythmias in isolated perfused rat heart subjected to regional ischaemia.

OBJECTIVE: The ATP sensitive potassium channel openers cromakalim (n = 10) and pinacidil (n = 10), and a blocker of this channel, glibenclamide (n = 10), were studied in isolated perfused rat hearts subjected to regional ischaemia at varying concentrations (2 to 8 mM) of external potassium ([K+]o). METHODS: Hearts were isolated and perfused on a Langendorff apparatus. Vehicle (0.1% DMSO), cromakalim (10 microM), pinacidil (10 microM), or glibenclamide (10 microM) were given 10 min before ischaemia. The left coronary artery was then occluded for 15 min and reperfused for 5 min. RESULTS: No agent caused more than a 10% change in heart rate. Both cromakalim and pinacidil increased (30%), and glibenclamide decreased (30%) coronary flow at 4 and 6 mM [K+]o. In the vehicle group, increases in [K+]o produced concentration dependent reductions in arrhythmia scores by decreasing ventricular fibrillation. No concentration dependent effects of [K+]o on ischaemic ventricular tachycardia was observed. Under ischaemic conditions, potassium channel openers and glibenclamide more markedly reduced ischaemic ventricular tachycardia and fibrillation relative to the effects of increased [K+]o. CONCLUSIONS: Ischaemic ventricular fibrillation was inversely related to changes in [K+]o, whereas effects on ventricular tachycardia were all-or-none. Neither potassium channel openers nor glibenclamide elicited significant proarrhythmic activity despite variations in [K+]o. These data suggest that both potassium channel openers and glibenclamide display potential antiarrhythmic activity through their ability to abolish two distinct arrhythmogenic mechanisms during ischaemia. It is also suggested that the underlying mechanisms of ventricular tachycardia and fibrillation are coupled during ischaemia in the rat.

Animals↗
PubMed1994

Thromboxane receptor antagonist BMS-180291, but not aspirin, reduces the severity of pacing-induced ischemia in dogs.

We determined the effect of thromboxane A2 (TXA2) prostaglandin endoperoxide (TP) receptor antagonism, using BMS-180291 or aspirin, on the severity of pacing-induced ischemia in anesthetized dogs. Thromboxane receptor antagonists may not only have antithrombotic activity, but may also have direct cardioprotective effects, unlike aspirin. Left anterior descending coronary artery (LAD) stenosis was adjusted so that a significant (10-12 mV) ST segment elevation was observed only when superimposed on atrial pacing. Each heart was subjected to 5-min episodes of pacing-induced ischemia 10, 40, and 70 min after initiation of BMS-180291 (1 mg/kg + 1 mg/kg/h) or vehicle. In the vehicle group, ST segment elevation was reproducible at all pacing-induced ischemia episodes, whereas BMS-180291 significantly reduced it by 30% at the later ischemia episodes. This reduction in ST segment increase was not accompanied by alterations in regional myocardial blood flow (RMBF) nor in hemodynamic status. Aspirin in the same model [10 mg/kg intravenously (i.v.) given 10 min before pacing-induced ischemia] did not significantly reduce ST segment elevation, indicating a lack of protective effect in this model. Thromboxane receptor blockade appears to protect myocardium subjected to pacing-induced ischemia, an effect not produced by aspirin.

Angina Pectoris↗
PubMed1994

Myocardial salvage efficacy of the thromboxane receptor antagonist ifetroban in ferrets and dogs.

The effects of the thromboxane A2 (TXA2)/prostaglandin endoperoxide (TP) receptor antagonist ifetroban (BMS-180291) on infarct size (IS) resulting from coronary occlusion/reperfusion was determined in anesthetized dogs and ferrets. In dogs, ifetroban (1 + 1 mg/kg/h, intravenously, i.v.) or vehicle administration was initiated 10 min before left circumflex coronary artery (LCX) occlusion. In ferrets, the left anterior descending coronary artery (LAD) was occluded; after 75 min, a continuous infusion of ifetroban (0.3 + 0.3 mg/kg/h i.v.) or vehicle was started. After 90-min ischemia in both species, the LCX or LAD occlusion was released; reperfusion was continued for 5 h, at which time IS was determined. Regional myocardial blood flow (RMBF) before and during occlusion and during reperfusion were measured with radioactive microspheres. Ifetroban significantly decreased the extent of infarction to 39 +/- 5% of the area at risk (AAR) from 64 +/- 5% in dogs and to 15 +/- 2% of the left ventricle as compared with a control of 22 +/- 2% in ferrets. The protective effect of ifetroban in both species occurred with no increase in collateral BF or treatment-related alterations in peripheral hemodynamic status. Ifetroban, at the doses that reduced IS in ferrets, inhibited 99% of platelet TP receptors throughout the experiment, as measured by inhibition of the ex vivo platelet shape change response to U-46,619, a TP receptor agonist. Thus, doses of ifetroban causing profound TP receptor blockade also salvaged jeopardized myocardium in dogs and ferrets without changing collateral BF or peripheral hemodynamics.

Animals↗
PubMed1994

Pyruvate increases threshold for preconditioning in globally ischemic rat hearts.

Isolated rat hearts can be protected by preconditioning, although this has not been found when they are perfused with pyruvate. We addressed the question of whether pyruvate could increase the threshold for preconditioning in isolated rat hearts and whether this could be overcome with increased durations of ischemia. A protocol of four periods of 5 min of ischemic preconditioning (4 x 5 min) protected hearts (improved recovery of function, reduced lactate dehydrogenase release) not perfused with pyruvate from a subsequent 30-min period of global ischemia, but did not protect pyruvate-perfused hearts. Pilot studies indicated that hearts perfused in the presence of pyruvate must be ischemic for approximately 40% longer to produce equivalent ischemic damage in nonpyruvate-treated hearts. Thus the preconditioning period of 5 min was increased by approximately 40% to 7 min to produce equivalent degrees of preconditioning. Hearts preconditioned with the 4 x 7 min protocol with pyruvate were significantly protected against a subsequent severe global ischemia (enhanced recovery of function, reduced lactate dehydrogenase release). High-energy phosphates were measured at the end of the preconditioning protocol (before final global ischemia) to determine whether there was a correlation between cardioprotection and high-energy phosphate levels. There was no correlation between ATP, ADP, or AMP levels and the efficacy of preconditioning. However, an increase in creatine phosphate was associated with cardioprotection, although the importance of this in mediating preconditioning is doubtful. Thus the ability to precondition rat hearts is somewhat dependent on their energy source, but this appears to be due to changes in the severity of the ischemic preconditioning event.

Animals↗
PubMed1994

Protective effects of ATP-sensitive potassium-channel openers in experimental myocardial ischemia.

Adenosine triphosphate (ATP)-sensitive potassium channels (KATP) exist in cardiac tissue and a potential role in the pathogenesis of myocardial ischemia was hypothesized early after their discovery. Studies in in vitro models of myocardial ischemia and reperfusion have indicated that KATP openers, as a class, exert protective effects. This has been assessed by determination of recovery of contractile function, inhibition of contracture, or inhibition of necrosis. This protective effect appears to be exerted directly on the myocardium and is not dependent on peripheral or coronary dilator activities. These protective effects are uniformly abolished by blockers of KATP. The protective effects of KATP openers are accompanied by a conservation of myocardial energy during ischemia, and this occurs despite a relative lack of cardiodepressant effects. In vivo studies have shown more variable results with some investigators showing efficacy and others not showing efficacy. The lack of efficacy for some investigators may be related to the potent vasodilator activity of the KATP openers used. Efficacy for KATP openers has been shown in canine models of infarction and stunned myocardium. KATP blockers also appear to abolish the protective effects of KATP openers in these models. Future work on KATP openers is focused on the determination of the molecular mechanism of action for the cardioprotective effects of these agents, development of tissue selectivity, and the importance of action potential shortening in mediating cardioprotection.

Action Potentials↗
PubMed1994

The cardioprotective and electrophysiological effects of cromakalim are attenuated by meclofenamate through a cyclooxygenase-independent mechanism.

Recent published studies indicate that the cyclooxygenase inhibitor meclofenamate can abolish preconditioning. Unpublished preliminary data from this laboratory suggest that meclofenamate may be blocking cardiac ATP-sensitive potassium channels (KATP channels), which may also mediate preconditioning. The purpose of the present study was to determine whether meclofenamate is a cardiac KATP channel blocker and it can abolish the anti-ischemic activity of the KATP channel opener cromakalim. This concept was tested initially in an isolated rat heart model of 25 min of ischemia and 30 min of reperfusion. Meclofenamate, in a concentration (5 microM) that did not cause proischemic effects alone, abolished the protective effect of cromakalim, as measured by recovery of contractile function, lactate dehydrogenase release and contracture formation. The preischemic coronary dilating activity of cromakalim was not attenuated by meclofenamate. The cyclooxygenase inhibitors indomethacin and SQ 29,109 had no effect on the cardioprotection afforded by cromakalim. Concentration-response curves for the ability of cromakalim to increase time to contracture during ischemia in rat hearts were generated alone or in the presence of 5 or 10 microM meclofenamate. Cromakalim increased the time to contracture with an EC25 of approximately 3 microM. Meclofenamate appeared to block this effect in a manner that was not surmountable by 100 microM cromakalim. Studies in guinea pig hearts showed that meclofenamate had no effect on action potential duration or effective refractory period when given alone. Meclofenamate attenuated the action potential duration shortening effects of cromakalim in this model. Thus, meclofenamate blocked the cardioprotective effects of cromakalim and this effect was not related to cyclooxygenase inhibition. Meclofenamate appears to be a cardiac KATP channel blocker.

Animals↗
PubMed1994

The cardioprotective effects of R 75231 and lidoflazine are not caused by adenosine A1 receptor activation.

The goal of this study was to determine the cardioprotective profile for the nucleoside transport inhibitor 2-(aminocarboxyl)-N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4- fluorophenyl)pentyl]-1-piperazinylacetamide trihydrochloride-2,5 hydrate (R 75231) in isolated rat hearts and whether its protective effects are caused by adenosine A1 activation. R 75231 increased time to contracture during global ischemia in a concentration-dependent manner (EC25 = 2.6 microM) that was comparable to the structurally related compound lidoflazine (EC25 = 1.2 microM). R 75231 caused only modest improvements in reperfusion contractile function, whereas it profoundly reduced LDH release. The cardioprotective effects of R 75231 were accompanied by preischemic negative inotropy with modest bradycardic effects. Adenosine also increased time to contracture, although it was not very potent (EC25 > 300 microM), and this effect was accompanied by significant preischemic bradycardia without measurable negative inotropic activity. Both the preischemia bradycardia and increase in ischemic time to contracture with adenosine were abolished completely by the A1 blocker 8-cyclopentyl-1,3-dipropylxanthine. The adenosine-induced increase in time to contracture was reversed partially by glybenclamide. Neither the pre- nor postischemic effects of R 75231 were abolished by 8-cyclopentyl-1,3-dipropylxanthine or glybenclamide, except for the preischemic bradycardia. Similar results were observed for lidoflazine. Thus, the cardioprotective effects of R 75231 are not mediated by adenosine A1 receptor activation and, thus, probably are not caused by its activity as a nucleoside transport inhibitor. It may be acting as a calcium antagonist in this model.

Animals↗