Yasushi Abiko

Propofol Improves Functional and Metabolic Recovery in Ischemic Reperfused Isolated Rat Hearts

Propofol attenuates mechanical dysfunction, metabolic derangement, and lipid peroxidation by exogenous administration of H2 O2 in the Langendorff rat heart.In this study, we examined the effects of propofol on mechanical and metabolic changes, as well as on lipid peroxidation induced by ischemia-reperfusion, in isolated, working rat hearts. Rat hearts (in control-modified Krebs-Henseleit bicarbonate buffer) were treated with two doses (25 micro M and 50 micro M) of propofol in an intralipid vehicle. In the first protocol, propofol was administered during the preischemic and reperfusion period, whereas in the second, it was only administered during the reperfusion period. Ischemia (15 min) decreased peak aortic pressure (PAOP), heart rate (HR), rate-pressure product (RPP), coronary flow (CF), and tissue concentrations of adenosine triphosphate (ATP) and creatine phosphate. After postischemic reperfusion (20 min), the CF and tissue concentration of ATP recovered incompletely; however, PAOP, HR, and RPP did not. Ischemia-reperfusion also increased the tissue concentration of malondialdehyde (MDA). In both protocols, both doses of propofol enhanced recovery of PAOP, HR, RPP, CF, and tissue concentration of ATP during reperfusion, and inhibited the tissue accumulation of MDA. These results indicate that propofol improves recovery of mechanical function and the energy state in ischemic reperfused isolated rat hearts, and the mechanism may involve the reduction of lipid peroxidation during postischemic reperfusion. Implications: We evaluated the possible cardioprotective effects of propofol in isolated, working rat hearts subjected to 15-min ischemia, followed by 20-min reperfusion. We observed that propofol attenuated mechanical dysfunction, metabolic derangement, and lipid peroxidation during reperfusion. This latter finding seems to be one mechanism for cardioprotective effects of propofol. (Anesth Analg 1998;86:252-8)

INVOLVEMENT OF NITRIC OXIDE IN SPINALLY MEDIATED CAPSAICIN- AND GLUTAMATE-INDUCED BEHAVIOURAL RESPONSES IN THE MOUSE *

The intrathecal (i.t.) injection of capsaicin (0.1 nmol/mouse) through a lumbar puncture elicited scratching, biting and licking responses. Pretreatment with the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (320 nmol), by i.t. injection, resulted in a significant inhibition of the behavioural response produced by i.t. capsaicin (0.1 nmol/mouse). Similar behavioural responses were induced by i.t. injections of NMDA (0.4 nmol), kainate (0.05 nmol) or AMPA (0.05 nmol), which were all inhibited by co-administration of L-NAME (20-80 nmol). L-Arginine (600 mg/kg, i.p.) but not D-arginine (600 mg/kg, i.p.) reversed the inhibitory effect of L-NAME on capsaicin-, NMDA-, kainate- and AMPA-induced behavioural response. Scratching, biting and licking responses induced by tachykinin receptor agonists, substance P, [Sar9,Met(O2)11]substance P, neurokinin A and neurokinin B were not affected by co-administration of L-NAME (40 and 80 nmol). These results suggest that spinal nitric oxide may play a significant role in mechanisms of the behavioural response to capsaicin, probably through the release of glutamate, but not tachykinins.

Effects of diltiazem and propranolol on irreversibility of ischemic cardiac function and metabolism in the isolated perfused rat heart.

Ischemia was induced by lowering the after-load pressure of the perfused working rat heart, and continued until the heart was reperfused by raising the after-load. After ischemia, the following changes were observed: decreases in the pressure-rate product (peak aortic pressure × heart rate) and coronary flow; depletion of adenosine triphosphate and creatine phosphate; and accumulation of lactate. When the heart was exposed to ischemia for more than 20 min, reperfusion of the ischemic heart could not restore the pressure-rate product and the tissue adenosine triphosphate completely, suggesting that irreversible ischemic damage occurred. Diltiazem (2.41 × 10−6, 1.21 × 10−5, and 2.41 × 10−5 M) or propranolol (1.69 × 10−5 and 3.38 × 10−5 M) was provided for the heart 5 min before the onset of ischemia. In the presence of diltiazem or propranolol, the levels of adenosine triphosphate and creatine phosphate were preserved even after 20 min of ischemia. Reperfusion with the normal perfusate after 20 min of ischemia with the buffer containing diltiazem or propranolol recovered the pressure-rate product that had been decreased by ischemia, depending on the concentration of diltiazem or propanolol provided. These results indicate that diltiazem, as well as propranolol, delays the onset of irreversible ischemic damage of the heart, suggesting their protective effects on the ischemic myocardium.

Rebound recovery of myocardial creatine phosphate with reperfusion after ischemia

It has been accepted that both mechanical function and tissue level of creatine phosphate (CP) of the heart decrease after interruption of myocardial perfusion (ischemia of the heart). A strange but interesting fact is that the myocardial CP level, that has been decreased by ischemia, recovers to a level higher than that of the preischemic level after reperfusion of the ischemic myocardium (rebound recovery or overshoot phenomenon1-6), even when mechanical function of the heart does not recover completely; i.e., although the CP store is refilled as energy conservation, the mechanical function of the reperfused heart does not recover. The mechanism of this phenomenon, however, remains obscure. We therefore reexamined the phenomenon, and found a plausible and reasonable interpretation-the rebound recovery of the CP level is due to the decrease of mechanical function of the heart during reperfusion after ischemia. Hearts removed from male Sprague-Dawley rats weighing 300 to 350 gm were perfused by the working heart technique with Krebs-Henseleit bicarbonate buffer containing 11 mmol/L glucose.7 Ischemia was induced by lowering the afterload pressure from 60 to 0 mm Hg.6 Under these conditions of ischemia, coronary flow was not exactly 0 ml/min but was less than 0.2 ml/min (ischemic perfusion). In some experiments, the buffer containing high concentration of KC1 (20 mmol/L), propranolol (10 mg/L), or diltiazem (10 mg/L), or that was being cooled at loo or 20” C was used as a perfusion solution for a period of ischemic perfusion in order to protect the heart against ischemic injury. After 20 minutes of ischemia, hearts were reperfused by again raising the afterload pressure to 60 mm Hg. Ischemia produced the heart arrest with a marked decrease in the tissue levels of CP and adenosine

Exogenous lysophosphatidylcholine increases non-selective cation current in guinea-pig ventricular myocytes.

Whole cell, patch-clamp studies were performed to examine the effect of lysophosphatidylcholine (LPC) on the membrane current in guinea-pig ventricular myocytes. The addition of 10 μM LPC to the external solution induced a membrane current which had a reversal potential of 0 mV. When Na+, the main cation in the external solution, was replaced by either K+, N-methyl-D-glucamine (NMG) or 90 mM Ca2+, LPC induced a current with the reversal potential near 0 mV, indicating that the current passed through a Ca2+-permeable non-selective cation channel. The order of the cationic permeability calculated from the reversal potential of the current was Cs+ > K+ > NMG > Na+ > Ca2+. Cl- did not pass through the LPC-induced channel. The LPC-induced current was not blocked by Gd3+ in the external solution, nor by the absence of Ca2+ in the pipette solution. In conclusion, LPC induces a Ca2+-permeable non-selective cation channel in guinea-pig ventricular myocytes.

Influences of pravastatin and simvastatin, HMG-CoA reductase inhibitors, on myocardial stunning in dogs.

Summary: We examined the effects of pravastatin and simvastatin, HMG-CoA reductase inhibitors, on stunned myocardium in vivo. Pravastatin and simvastatin were given orally 2 mg/kg for 3 weeks. After 3 weeks of administration, pentobarbital-anesthetized dogs were subjected to 15-min left anterior descending (LAD) coronary artery occlusion followed by 2-h reperfusion. Myocairdial segment function was determined by sonomicrometry. The tissue energy and carbohydrate metabolites were determined in the 2-h-reperfused hearts. Administration of pravastatin and simvastatin for 3 weeks decreased serum cholesterol level and blood pressure (BP). Simvastatin resulted in a worsening of segment shortening in the reperfused myocardium as compared with control and pravastatin groups. The level of ATP in the simvastatin group was significantly lower as compared with that in the control group. The other metabolite levels were not significantly altered by either pravastatin or simvastatin. These results suggest that simvastatin enhances stunning of the myocardium in association with ATP reduction after reperfusion subsequent to ischemia

Effects of antiischemic drugs on veratridine-induced hypercontracture in rat cardiac myocytes

The effects of different groups of substances (beta-adrenoceptor antagonists, Ca2+ channel blockers and vasodilators) which are known to have antiischemic properties were studied on veratridine-induced hypercontracture. Veratridine increases Na+ influx by slowing the inactivation process of the Na+ channel, thereby inducing a continuously increased Na+ entry in depolarized cells. Veratridine (6.3 x 10(-6) M) produced a change in cell shape from rod-shape to round, resulting from hypercontracture of cells. Before treatment with veratridine the proportion of rod-shaped cells was 70% and fell to 0% 5 min after the treatment with veratridine. dl-Propranolol, d-propranolol, l-penbutolol, d-penbutolol, nisoldipine, and dilazep all inhibited veratridine-induced hypercontracture dose dependently. In contrast, acebutolol, atenolol, timolol, nifedipine, diltiazem, and nitroglycerin did not inhibit the rounding of cells. Concomitantly with the rounding of cells, the [Ca2+]i was increased by veratridine. dl-Propranolol, d-propranolol and dilazep prevented the increase of [Ca2+]i induced by veratridine, whereas timolol and nitroglycerin did not. These results show that dl-propranolol, d-propranolol, l-penbutolol, d-penbutolol, nisoldipine, and dilazep possess Na+ channel blocking actions on the veratridine-modified Na+ channel, thereby preventing excessive Na+ influx and secondary Ca2+ overload.

Ranolazine Attenuates Palmitoyl-l-carnitine-induced Mechanical and Metabolic Derangement in the Isolated, Perfused Rat Heart

The effect of ranolazine, a novel anti‐ischaemic drug that stimulates the activity of pyruvate dehydrogenase, on palmitoyl‐l‐carnitine‐induced mechanical dysfunction and metabolic derangement in isolated perfused rat hearts has been studied and compared with the effect of dichloroacetate, an activator of pyruvate dehydrogenase. Rat hearts paced electrically were perfused aerobically at constant flow by the Langendorff technique. Palmitoyl‐l‐carnitine (4 μm) increased left ventricular end‐diastolic pressure and reduced left ventricular developed pressure (i.e. induced mechanical dysfunction); it also reduced tissue levels of adenosine triphosphate and increased tissue levels of adenosine monophosphate (i.e. induced metabolic derangement). These functional and metabolic alterations induced by palmitoyl‐l‐carnitine were attenuated by ranolazine (5, 10, and 20 μm) in a concentration‐dependent manner. In contrast, dichloroacetate (1 and 10 mm) did not attenuate palmitoyl‐l‐carnitine‐induced mechanical and metabolic derangement. In the normal (palmitoyl‐l‐carnitine‐untreated) heart, however, ranolazine did not modify mechanical function and energy metabolism.

Increase of myocardial pH by l- and d-propranolol during ischemia of the heart in dogs

Myocardial pH was measured continuously with a micro pH electrode inserted into the left ventricular wall in dogs. Anterior descending coronary flow was reduced to about 1/3 of the original flow by partial occlusion of the coronary artery. Myocardial pH decreased from 7.50--7.60 to 7.06--7.24 after partial occlusion. Drugs were injected intravenously during ischemia of the heart caused by partial occlusion. l-Propranolol (1 mg/kg) reduced heart rate and increased the pH from 7.06 +/- 0.04 to 7.48 +/- 0.04 (P less than 0.01). d-Propranolol (1 mg/kg) reduced heart non-significantly and increased the pH from 7.24 +/- 0.05 TO 7.56 +/- 0.05 significantly (P less than 0.05). In other studies, the effect of l- and d-propranolol on both heart rate and metabolic responses to isoproterenol (500 micrograms/kg i.p.) was studied. Isoproterenol increased heart rate and also elevated the blood levels of glucose and lactate. l-Propranolol inhibited these responses to isoproterenol. d-Propranolol did not inhibit the heart rate response but inhibited the blood lactate response to isoproterenol significantly. The blood glucose response to isoproterenol was inhibited by d-propranolol non-significantly. The action of both l- and d-propranolol on ischemic myocardial pH may be related to their action on cardiac metabolism as well as to their local anesthetic action.

Positive inotropic and negative chronotropic effects of (−)-cis-diltiazem in rat isolated atria

1 The cardiovascular effects of (−)‐cis‐diltiazem, an optical isomer of diltiazem, were studied in the isolated atrium and aortic strip. (−)‐cis‐Diltiazem (30 μm or more) increased the developed tension of the rat left atrium, while (+)‐cis‐diltiazem (1 μm or more) decreased it. 2 (−)‐cis‐Diltiazem (1 to 100 μm) decreased the rate of spontaneous beating in the right atrium as did (+)‐cis‐diltiazem. 3 The potency of the positive inotropic action of (−)‐cis‐diltiazem was almost the same as that of ouabain in the rat left atrium, but in the guinea‐pig left atrium it was considerably weaker than that of ouabain. 4 In both endothelium‐intact and endothelium‐denuded aortic strips, (−)‐cis‐diltiazem relaxed the Ca2+‐induced contraction. In the endothelium‐intact rat aortic strip depolarized by 15 mm KCl, Bay K 8644, a calcium channel agonist, increased the contractile force, whereas (−)‐cis‐diltiazem did not. 5 These results indicate that (−)‐cis‐diltiazem has a positive inotropic action in isolated atria in rats and guinea‐pigs, but the mode of positive inotropic action of (−)‐cis‐diltiazem is different from that of ouabain or Bay K 8644.