B. Preckel

Inotropic Effects of Glyceryl Trinitrate and Spontaneous NO Donors in the Dog Heart

BACKGROUNDnIn vitro, NO has a biphasic effect on myocardial inotropy. To determine the inotropic effect of NO in vivo, we investigated the activity of glyceryl trinitrate (GTN) and the NO donors S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and sodium-(2)-1-(N,N-diethyl-amino)-diazen-1-ium-1,2-diolat+ ++ (DEA/NO) in dogs.nnnMETHODS AND RESULTSnEight anesthetized open-chest dogs were instrumented for measurement of left ventricular and aortic pressures (tip manometers) and coronary flow (ultrasonic flow probes). Regional myocardial function was assessed by sonomicrometry as systolic wall thickening (sWT), mean systolic thickening velocity (Vs), and regional myocardial stroke work index (RSW). GTN, SNAP, and DEA/NO were infused into the left anterior descending coronary artery (LAD) to achieve defined coronary plasma concentrations of GTN, SNAP (both 10 to 100 micromol/L), and DEA/NO (2 to 20 micromol/L). All drugs increased LAD flow and myocardial contractile function in the LAD-dependent myocardium within the first 120 seconds. The greatest inotropic effect was noted after infusion of DEA/NO (20 micromol/L), which increased sWT by 9.7+/-3.1% from 28.5+/-2.2%, Vs by 10.3+/-3.4% from 9.1+/-1.1 mm/s, and RSW by 7.1+/-2.1% from 200.0+/-22.1 mm Hg x mm (P<.05). At the same time, systemic hemodynamics remained unchanged. Prevention of the flow response to GTN by external narrowing of the LAD did not influence the inotropic effect of GTN.nnnCONCLUSIONSnOrganic nitrates and NO donors evoke a small but constant positive inotropic effect in vivo that is not caused by coronary vasodilation.

Thiopentone does not block ischemic preconditioning in the isolated rat heart

PurposeIschemic preconditioning protects the heart against subsequent prolonged ischemia by opening of adenosine triphosphate-sensitive potassium (KATP) channels. Thiopentone blocks KATP channels in isolated cells. Therefore, we investigated the effects of thiopentone on ischemic preconditioning.MethodsIsolated rat hearts (n = 56) were subjected to 30 min of global no-flow ischemia, followed by 60 min of reperfusion. Thirteen hearts underwent the protocol without intervention (control, CON) and in 11 hearts (preconditioning, PC), ischemic preconditioning was elicited by two five-minute periods of ischemia. In three additional groups, hearts received 1 (Thio 1,n = 11), 10(Thio 10,n = 11) or 100 μg·mL−1 (Thio 100,n = 10) thiopentone for five minutes before preconditioning. Left ventricular (LV) developed pressure and creatine kinase (CK) release were measured as variables of myocardial performance and cellular injury, respectively.ResultsRecovery of LV developed pressure was improved by ischemic preconditioning (after 60 min of reperfusion, mean ± SD: PC, 40 ± 19% of baseline) compared with the control group (5 ± 6%,P < 0.0l) and this improvement of myocardial function was not altered by administration of thiopentone (Thio 1, 37 ± 15%; Thio 10, 36 ± 16%; Thio 100, 38 ± 16%,P=0.87–0.99 vs PC). Total CK release over 60 min of reperfusion was reduced by preconditioning (PC, 202 ± 82 U·g−1 dry weight) compared with controls (CON, 383 ± 147 U·g−1,P < 0.0l) and this reduction was not affected by thiopentone (Thio 1, 213 ± 69 U·g−1; Thio 10, 211 ± 98U·g−1; Thio 100, 258 ± 128 U·g−1,P=0.62–1.0vs PC).ConclusionThese results indicate that thiopentone does not block the cardioprotective effects of ischemic preconditioning in an isolated rat heart preparation.RésuméObjectifLe préconditionnement ischémique protège le cœur contre l’ischémie ultérieure prolongée en ouvrant les canaux potassiques sensibles à l’adénosine triphosphate (KATP). Or, le thiopental bloque les canaux KATP dans des cellules isolées. Nous avons donc recherché les effets du thiopental sur le préconditionnement ischémique.MéthodeDes cœurs de rats isolés (n = 56) ont été soumis à 30 min d’ischémie globale à débit nul, puis de 60 min, à une reperfusion. Treize cœurs ont subi le protocole sans intervention (témoin, TEM) et dans onze cœurs (groupe de préconditionnement, PC) le préconditionnement ischémique a été amorcé par deux périodes de cinq minutes d’ischémie. Dans trois groupes additionnels, les cœurs ont reçu 1 (Thio 1, n = 11), 10 (Thio 10, n = 11) ou 100 μg·mL−1 (Thio 100, n = 10) de thiopental pendant cinq minutes avant le préconditionnement. La pression du ventricule gauche (VG) développée et la libération de créatine kinase (CK) ont été mesurées en qualité de variables de la performance myocardique et de la lésion cellulaire, respectivement.RésultatsLa récupération de la pression du VG développée a été améliorée par le préconditionnement ischémique (après 60 min de reperfusion, la moyenne ± l’écart type : PC, 40 ± 19 % de la mesure de base) comparée au groupe témoin (5 ± 6 %, P < 0,01). Cette amélioration de la fonction myocardique n’a pas été modifiée par l’administration de thiopental (Thio 1, 37 ± 15 %; Thio 10, 36 ± 16 %; Thio 100, 38 ± 16%, P = 0,87 - 0,99 vs PC). La libération totale de CK après 60 min de reperfusion a été réduite par le préconditionnement (PC, 202 ± 82 U·g−1 de poids anhydre) comparé au témoin (TEM, 383 ± 147 U·g−1, P < 0,01) et cette réduction n’a pas été affectée par le thiopental (Thio 1, 213 ± 69 U·g−1; Thio 10, 211 ± 98 U·g−1; Thio 100, 258 ± 128 U·g−1, P = 0,62– 1,0 vs PC).ConclusionCes résultats indiquent que le thiopental ne bloque pas les effets cardioprotecteurs du préconditionnement ischémique dans une préparation de cœur de rat isolé.

Spatial heterogeneity of energy turnover in the heart

Abstract. Local myocardial blood flow varies substantially in spite of a rather homogeneous morphology. To further elucidate this paradox, the spatial heterogeneity of tricarboxylic acid cycle turnover (JTCA, µmol min–1 g–1) and coronary flow was assessed at a high spatial resolution (6×6×6xa0mm3) in the open chest dog. Local flow differed more than 2.5-fold between individual samples in each heart (n=7). Out of 1500 myocardial samples, 1/10 received less than 60% and another 1/10 more than 138% of the normalized mean. In low- and high-flow samples, pyruvate uptake and metabolism were analyzed by 13C NMR spectroscopy. Following [3-13C]pyruvate infusion (2xa0mM, 12xa0min), glutamate [4-13C]/[3-13C] was significantly greater in low-flow (2.21±0.75, 40 samples) than in high-flow (1.64±0.49, 39 samples) areas. This suggests that there are major differences in JTCA. Glutamate, citrate and lactate content positively correlated with flow. Anaplerotic pathways contributed a fraction similar to JTCA in low- and high-flow areas, as demonstrated by isotopomer analysis after 60xa0min of [3-13C]pyruvate application. Mathematical model analysis of NMR data and relevant pool sizes revealed that JTCA and thus myocardial oxygen consumption (

Effect of dantrolene in an in vivo and in vitro model of myocardial reperfusion injury

{rm M}dot V{rm O}_{rm 2}

Does local coronary flow control metabolic flux rates? A 13C-NMR study.

n) in high-flow areas exceed values in low-flow areas at least threefold. Thus low and high metabolic states normally coexist within the well perfused heart, suggesting that there is considerable spatial heterogeneity of cardiac energy generation and work.

Effects of enflurane, isoflurane, sevoflurane and desflurane on reperfusion injury after regional myocardial ischaemia in the rabbit heart in vivo.

Abstract. We investigated whether a combination of ischaemic late preconditioning (LPC) and ischaemic early preconditioning (EPC) induces additive myocardial protection in vivo, and the role of ATP-sensitive K (KATP) channels in ischaemic LPC and in LPC+EPC. Sixty rabbits were divided into seven groups. Anaesthetized animals were subjected to 30xa0min of coronary artery occlusion and 120xa0min of reperfusion (I/R). Controls (CON, n=9) were not preconditioned. LPC (n=10) was induced in conscious rabbits by a 5-min period of myocardial ischaemia 24xa0h before I/R. The KATP channel blocker 5-hydroxydecanoate (5-HD, 5xa0mg/kg) was given 10xa0min before I/R with (LPC+5-HD, n=9) or without LPC (5-HD, n=8). EPC (n=8) was induced by a 5-min period of myocardial ischaemia 10xa0min before I/R. Animals received LPC and EPC without (LPC+EPC, n=8) or with 5-HD (LPC+EPC+5-HD, n=8). LPC reduced infarct size (IS, triphenyltetrazolium staining) from 57±11% (MW±SD, CON) of the area at risk to 31±19% (LPC, P=0.004). 5-HD did not affect IS (5-HD: 60±12%, P=0.002 versus LPC), but abolished the cardioprotective effects of LPC (LPC+5-HD: 62±18%, P=0.001 versus LPC). EPC reduced IS to 18±8%. Additional LPC led to a further reduction to 8±4% (LPC+EPC, n=8; P=0.005 versus EPC; P=0.004 versus LPC). 5-HD abolished this additional cardioprotective effect of LPC+EPC (LPC+EPC+5-HD, n=8; 46±11%, P≤0.001 versus LPC+EPC). We conclude that the combination of ischaemic LPC and EPC induces additive cardioprotection. KATP channel opening mediates the cardioprotective effects of ischaemic LPC and LPC+EPC.

Effects of halothane, enflurane, isoflurane, sevoflurane and desflurane on myocardial reperfusion injury in the isolated rat heart.

Background: In skeletal muscle, dantrolene reduces free cytosolic calcium by inhibiting calcium release from the sarcoplasmic reticulum. A similar effect in ischemic‐reperfused heart cells would protect myocardial tissue against reperfusion injury. We tested the hypothesis that dantrolene infusion during reperfusion protects the heart against reperfusion injury.

One MAC of sevoflurane provides protection against reperfusion injury in the rat heart in vivo

Abstract The aim of the present study was to investigate whether the non-peptide angiotensin II type 1 (AT1) receptor antagonist irbesartan (SR 47436, BMS 186295, 2-n-butyl-3[2‘-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one) has myocardial protective effects during regional myocardial ischemia/reperfusion in vivo. Eighteen anesthetized open-chest dogs were instrumented for measurement of left ventricular and aortic pressure (tip manometer and pressure transducer, respectively), and coronary flow (ultrasonic flowprobes). Regional myocardial function was assessed by Doppler displacement transducers as systolic wall thickening (sWT) in the antero-apical and the postero-basal wall. The animals underwent 1 h of left anterior descending coronary artery (LAD) occlusion and subsequent reperfusion for 3 hours. Irbesartan (10 mg kg−1, n=9) or the vehicle (KOH, control, n=9) was injected intravenously 30 min before LAD occlusion. Regional myocardial blood flow (RMBF) was measured after irbesartan injection and at 30 min LAD occlusion using colored microspheres. Infarct size was determined by triphenyltetrazolium chloride staining after 3 h of reperfusion. There was no recovery of sWT in the LAD perfused area in both groups at the end of the experiments (systolic bulging, −15.1±6.1% of baseline (irbesartan) vs. −12.3±3.0% (control), mean±SEM). Irbesartan led to an increase in RMBF in normal myocardium (2.47±0.40 vs. 1.35±0.28 ml min−1 g−1, P<0.05), and also to an increase in collateral blood flow to the ischemic area (0.27±0.04 vs. 0.17±0.02 ml min−1 g−1, P=<0.05). Infarct size (percent of area at risk) was 24.8±3.2% in the treatment group compared with 26.9±4.8% in the control group (P=0.72). These results indicate that a blockade of angiotensin II AT1 receptors with irbesartan before coronary artery occlusion led to an increase in RMBF, but did not result in a significant reduction of myocardial infarct size.