Hiroyuki Arimura

Reduction of the Slow Inward Current of Isolated Rat Ventricular Cells by Thiamylal and Halothane

The barbiturates and halothane exert a negative inotropic effect on the myocardium. A reduction in the slow inward current, carried mainly by calcium ions, is an important factor for the underlying mechanism because the calcium current during the action potential provides the calcium ions for accompanying contraction, supplies Ca ions to the sarcoplasmic reticulum for subsequent contractions, and induces Ca release from the store site. It has been suggested that reduction in the slow inward current caused by anesthetics is indicated by depression of the slow action potential of the partially depolarized myocardium. In order to assess directly the effect of anesthetics on the slow inward current, we carried out voltage clamp experiments with single isolated rat ventricular cells obtained by an enzymatic dissociation method. Thiamylal (10‐4 mol·1‐1) and halothane (1%) decreased the slow inward current to 60 ± 5% (mean ± s. d., n = 8) and to 65 ± 10% (mean ± s. d., n = 8) of the control value, respectively, without changing the configuration of the current‐voltage curve. The results provide further evidence for anesthetic reduction of the slow inward current of the myocardium, and suggest that the negative inotropic effect is at least partly due to the reduction in that current.

Action of enflurane on cholinergic transmission in identified Aplysia neurones.

1 Effects of enflurane on the cholinergic transmission in Aplysia neurones were studied by current and voltage clamp methods. Acetylcholine (ACh) evoked three types of postsynaptic responses on different identified neurones: (1) a depolarizing response due to an increase in Na and K conductances (D‐response), (2) a fast hyperpolarizing response due to an increase in Cl conductance (Cl‐response), and (3) a slow hyperpolarizing response due to an increase in K conductance (K‐response). 2 Enflurane altered neither the action potential nor the membrane resistance of the neurones but depressed the three ACh‐induced responses, non‐competitively, in a dose‐dependent manner. The K‐response was less suppressed than the other two. 3 Blockade of the closed state of ion channel was suggested by a reduction in the first ACh response evoked 1 min after administration of enflurane. 4 The anaesthetic facilitated the decay of the neurally evoked e.p.s.c. and i.p.s.c. in suggesting a reduction in the mean open time of the postsynaptic ion channel. 5 It is concluded that enflurane depresses excitatory and inhibitory cholinergic transmission by reducing the postsynaptic currents.

Modifications by halothane of responses to acute hypoxia in systemic vascular capacitance, resistance, and sympathetic nerve activity in dogs

To examine the effects of halothane on segmental vascular responses to hypoxia, we used cardiopulmonary bypass with venous outflow divided into three compartments (splanchnic, coronary, and “other”) in dogs anesthetized with pentobarbital sodium. The reservoir volume changes represented the inverted changes in systemic blood volume (SBV). In addition, sympathetic efferent nerve activity (SENA) was simultaneously recorded from the ventral ansa subclavian nerve. Experiments were done in two groups: severe hypoxia (Po2 of 19 mm Hg) and moderate hypoxia (Po2 of 50 mm Hg). Hypoxia provoked a significant decrease in SBV of 22.3 ± 3.1 mL/kg and 10.5 ± 1.6 mL/kg during severe and moderate hypoxia, respectively. Two percent end-tidal halothane attenuated the decrease in SBV to 10.3 ± 1.3 mL/kg during severe hypoxia, and 1% halothane attenuated the decrease to 3.7 ± 1.4 mL/kg during moderate hypoxia. Subsequent chemoreceptor denervation in the presence of 1% halothane completely abolished the moderate hypoxia-induced decrease in SBV. In the presence of halothane, vascular resistance during hypoxia was significantly less than that during control conditions. Sympathetic efferent nerve activity increased significantly during severe and moderate hypoxia by about 180% and 55%, respectively. During severe hypoxia, halothane did not cause any change in the response of SENA, whereas during moderate hypoxia, halothane tended to decrease SENA, but not significantly, and subsequent chemoreceptor denervation completely abolished the increase in SENA. Coronary resistance showed a hypoxia-induced reduction that was not influenced by halothane. These results suggest that acute hypoxia causes a decrease in SBV dependent on the severity of hypoxia. Halothane attenuates the responses to moderate hypoxia in both resistance and capacitance vessels but does not completely abolish the decrease in vascular capacitance. During severe hypoxia, halothane (1% and 2%) does not depress the hypoxia-induced increase in sympathetic discharge, and the suppression of the vascular response by halothane is probably due to its peripheral (vascular) actions.

Effects of augmenting cardiac contractility, preload, and heart rate on cardiac output during enflurane anesthesia.

Changes in cardiac output in response to augmenting cardiac contractility, preload, and heart rate during enflurane anesthesia were examined in 12 open-chested dogs. Cardiac contractility was assessed by the slope of the end-systolic pressure-volume relation (Emax). Dobutamine (3, 6, and 9 μg·kg−1 ·min−1) was administered to augment cardiac contractility. Autologous blood (5.0 and 10 mL/kg) was infused to increase preload. Atrial pacing was used to increase the heart rate by about 30%. Cardiac output decreased from 96 ± 4 (0% enflurane) (mean ± SE) to 73 ± 5 (1.7% enflurane) and to 46 ± 7mL·kg−1·min−1 (3.4% enflurane), concomitantly with decreases in Emax from 6.0 ± 1.2 (0% enflurane) to 4.5 ± 1.2 (1.7% enflurane) and to 2.5 ± 0.5 mm μg/mL (3.4% enflurane). Dobutamine (3, 6, and 9 μg·kg−1· min−1) increased Emax, from 69% ± 7% (compared to 0% enflurane with no dobutamine) to 139% ± 15%, 167% ± 25%, and 183% ± 35% at 1.7% enflurane, and from 43% ± 8% to 78% ± 7%, 137% ± 20%, and 157% ± 22% at 3.4% enflurane, respectively. The decreases in cardiac output by 1.7% and 3.4% enflurane were reversed by the intravenous administration of 3 μg·kg−1·min−1 of dobutamine. Cardiac output was significantly increased by administration of 10 mL/kg of autologous blood at 1.7% enflurane, but did not significantly increase at 3.4% enflurane. Increasing the heart rate did not significantly increase cardiac output at 1.7% and 3.4% enflurane. The results of this study suggest that increasing cardiac contractility is the most effective therapeutic means of reversing circulatory depression during enflurane anesthesia.

Lack of effects of d-tubocurarine and pancuronium on the slow action potential of the guinea pig papillary muscle

Inotropic effects of non-depolarizing muscle relaxants were examined with guinea pig ventricular papillary muscle depolarized to -47 mV in high K Ba-Tyrode solution. Field stimulation of 0.1 Hz elicited the slow action potential, a measure of the calcium current. The amplitude, the duration at 0 mV level and dVldt of the action potential were monitored together with the contractile tension. Amelizol (3 mg.ml-1 d-tubocurarine (d-tc) and 5 mg.ml-1 chlorobutanol) depressed the four functions in a dose-dependent manner, while crystalline d-tc did not. Chlorobutanol (the antimicrobial preservative) had the same effects as Amelizol. Neither Mioblock (2 mg.ml-1 pancuronium and unpublished preservative) nor crystalline pancuronium altered the functions. These findings suggest that the negative inotropic effect of Amelizol is not due to d-tc but to chlorobutanol, which may exert its effect by depressing the calcium current. The lack of change in the slow action potential seen with pancuronium may indicate no direct effect on the calcium current, thereby further suggesting absent direct bela-adrenomimetic action of this agent.RésuméLes effets inotropes des relaxants musculaires non dépolarisants ont été éludiés avec des muscles papillaires ventriculaires de cobayes dépolarisés à-47 mV dans un bain de solution à haute concentration de potassium barium-Tyrode. Un champ de stimulation de 0.1 Hz a provoqué un potentiel d’action lent représentant une mesure du courant calcique. L’amplitude ainsi que la durée du potentiel d’action ’ 0 mV et le dVldt ont été étudiées en même temps que la force contractile. L’amelizol (3 mg-ml-d-tubocurarine (d-tc) et 5 mg-ml chlorobutanol) a provoqué une dépression des paramètres dépendamment de la dose administrée alors que la d-tc crystalline n’a provoqueé aucun changement. Le chlorobutanol (le préservatif bactériostatique) a eu les mêmes effets que I’amelizol. Ni le mioblock (2 mg-ml-pancuronium et préservatif non publié) ni le pancuronium crystalline n’ont altéré les paramètres. Ces résultats suggèrent que les effets inotropes négatifs de I’amelizol ne sont pas dûs à la d-tc mais au chlorobutanol qui excerce ses effets en déprimant les courants calciques. L’absence de changement dans le potential d’action lent observé avec le pancuronium peut indiquer qu’il n’a aucun effet direct sur les courants calciques suggérant ainsi l’absence d’effet direct bêeta-adrinomimeétique de cet agent.

Effects of prostaglandin E1 on left ventricular performance in dogs; Comparisons with trinitroglycerin and adenosine triphosphate

To examine the cardiovascular response to prostaglandin E1 infusion, we observed hemodynamic changes including left ventricular diameter (an ultrasonic crystal pair) during PGE1-induced hypotension in anesthetized open-chest dogs. Left ventricular contractility was assessed primarily by measuring the slope of the left ventricular end-systolic pressure-diameter relation (ESPDR) determined by combining end-systolic points from a vena caval occlusion. The cardiovascular effects of induced hypotension by infusions of trinitroglycerin and adenosine triphosphate were also examined at the equivalent magnitude of hypotension. Approximately 25% reduction of systemic blood pressure was produced by the three agents. PGE1 significantly increased cardiac output from 1200±132 to 1439±162 ml·min−1 (mean±SE,P<0.05), stroke volume from 9.1±1.1 to 10.0±1.0 ml (P<0.05), and %-diameter shortening from 10.4±0.8 to 14.4±0.8% (P<0.01), but the slope of ESPDR was unchanged. Similar changes were also observed during adenosine triphosphate-induced hypotension. PGE1 significantly decreased end-diastolic diameter in a similar manner to trinitroglycerin. Thus PGE1 appears to have little influence on left ventricular contractility aside from its effects on afterload and preload, indicating that it is a useful agent for producing controlled hypotension during anesthesia.

Regional venous outflow, blood volume, and sympathetic nerve activity during severe hypoxia

We examined the dynamic changes in venous outflow from the splanchnic, coronary, and remaining other vascular beds and changes in systemic blood volume (SBV) in response to severe hypoxia (PO2 = 17 mmHg) in dogs using cardiopulmonary bypass and a reservoir. Splanchnic venous outflow, which also includes renal outflow in this study, decreased by 40%, and coronary venous outflow increased by 400% at 3.5 min after initiating severe hypoxia. Severe hypoxia caused a marked decrease in SBV of 23 +/- 1 and 9 +/- 2 ml/kg in spleen-intact and splenectomized dogs, respectively. The decrease in SBV was attenuated by 60 (P less than 0.01) and 83% (P less than 0.01) after the carotid and aortic chemoreceptor denervation (which was accompanied by baroreceptor denervation) and after hexamethonium infusion (10 mg/kg), respectively. Sympathetic efferent nerve activity revealed a tremendous augmentation, which began to rise at a PO2 of 40 mmHg before chemoreceptor denervation and at a PO2 of 22 mmHg after denervation. These results show that severe hypoxia causes a marked decrease in SBV, 60% of which is caused by active splenic contraction, and suggest that the sympathetic efferent nerve activity, which is augmented by the stimulation of chemoreceptors as well as the central nervous system, contributes greatly to those hypoxic changes.

Alteration of vascular capacitance and blood flow distribution during halothane anesthesia

We examined the effect of halothane on systemic vascular capacitance as well as on systemic vascular resistance using cardiopulmonary bypass in dogs. Venous outflows from two different vascular beds, the splanchnic and extrasplanchnic beds, were also measured. Under constant perfusion flow and constant central venous pressure, a change in reservoir blood volume inversely represented a change in systemic blood volume and then in systemic vascular capacitance, and a change in mean arterial pressure directly reflected a change in systemic vascular resistance. Administration of 1% and 2% halothane produced the blood concentrations of 0.58±0.14 mM and 1.34±0.06 mM, respectively. Systemic vascular resistance decreased by 12±6% and 40±4% during 1% and 2% halothane, respecitively. Systemic blood volume increased by 7±2 ml·kg−1 and 15±4 ml·kg−1 during 1% and 2% halothane, respectively. Halothane did not cause significant blood flow redistribution between the splanchnic and extrasplanchnic vascular beds. These results suggest that halothane causes an increase in systemic vascular capacitance as well as a decrease in systemic vascular resistance. This increase in vascular capacitance may contribute in part to a decrease in cardiac output during halothane anesthesia.