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The aim of this study was to test if myocardial and coronary vascular effects of desflurane and isoflurane were similar in the isolated heart. The cardiac effects of these anesthetics were examined in 12 guinea pig hearts perfused in a retrograde manner. Spontaneous heart rate, atrioventricular (AV) conduction time, systolic left ventricular pressure and coronary flow were measured. To differentiate direct vasodilatory effects of these anesthetics from an indirect metabolic effect due to autoregulation of coronary flow, O2 delivery (DO2), myocardial O2 consumption (MVO2) and percent O2 extraction were also monitored. Isoflurane and desflurane were injected directly into sealed bottles containing oxygenated perfusate solution. Each heart was perfused randomly with these anesthetics. Anesthetic concentrations in the perfusate were 0.28 +/- 0.02 and 0.52 +/- 0.02 mM for isoflurane and 0.59 +/- 0.01 and 1.02 +/- 0.09 mM for desflurane (mean +/- standard error of the mean). Calculated vapor concentrations were 1.3 and 2.5 vol % for isoflurane and 6.8 and 11.8 vol % for desflurane which correspond to approximately 1 and 2 MAC in vivo. Each anesthetic similarly decreased heart rate and prolonged AV conduction time in a concentration-dependent manner. Left ventricular pressure (control 93 +/- 4 mmHg) decreased by 11 +/- 1% and 24 +/- 2% with isoflurane and by 15 +/- 1% and 30 +/- 2% with desflurane. The decreases in heart rate and pressure were accompanied by decreases in MVO2 of 12 +/- 2% and 30 +/- 3% with isoflurane and of 19 +/- 3% and 40 +/- 4% with desflurane from a control of 57 +/- 2 microliters.g-1.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors examined direct myocardial and coronary vascular responses to the anesthetic induction agents etomidate, ketamine, midazolam, propofol, and thiopental and compared their effects on attenuating autoregulation of coronary flow as assessed by changes in oxygen supply/demand relationships. Spontaneous heart rate, atrioventricular conduction time during atrial pacing, left ventricular pressure (LVP), coronary flow (CF), percent oxygen extraction, oxygen delivery, and myocardial oxygen consumption (MVo2) were examined in 55 isolated guinea pig hearts divided into five groups of 11 each. Hearts were perfused at constant pressure with one of the drugs administered at steady-state concentrations increasing from 0.5 microM to 1 mM. Adenosine was given to test maximal CF. At concentrations below 10 microM no significant changes were observed; beyond 50 microM for midazolam, etomidate, and propofol, and 100 microM for thiopental and ketamine, each agent caused progressive but differential decreases in heart rate, atrioventricular conduction time (leading to atrioventricular dissociation), LVP, +dLVP/dtmax, percent oxygen extraction, and MVo2. The concentrations (microM) at which +dLVP/dtmax was reduced by 50% were as follows: etomidate, 82 +/- 2 (mean +/- SEM); propofol, 91 +/- 4; midazolam, 105 +/- 8; thiopental, 156 +/- 11; and ketamine, 323 +/- 7; the rank order of potency was etomidate = propofol = midazolam greater than thiopental greater than ketamine; results were similar for LVP. At the 100 microM concentration, CF was decreased 11% +/- 2% by ketamine and 5% +/- 3% by thiopental but was increased 17% +/- 6% by etomidate, 21% +/- 5% by midazolam, and near maximally to 57% +/- 10% by propofol; MVo2 was decreased 8% +/- 4% by thiopental, 10% +/- 5% by ketamine, 19% +/- 5% by midazolam, 29% +/- 7% by etomidate, and 37% +/- 5% by propofol; oxygen delivery/MVo2 was unchanged by thiopental and ketamine but was increased 62% +/- 7% by midazolam, 71% +/- 9% by etomidate, and 150% +/- 15% by propofol. Between 100 microM and 1 mM, thiopental and ketamine did not increase CF but decreased MVo2 and percent oxygen extraction, whereas propofol maximally increased CF and decreased MVo2 and midazolam and etomidate had intermediate effects. These results indicate that on a molar basis, propofol, and less so midazolam and etomidate, depress cardiac function moderately more than thiopental and ketamine, and that propofol markedly attenuates autoregulation by causing coronary vasodilation. With doses used to induce anesthesia, propofol and thiopental appear to depress cardiac function more than ketamine or etomidate.

We investigated the effects of halothane on changes in cardiac function during hypoperfusion and recovery of function after reperfusion in the isolated perfused guinea pig heart. Heart rate, atrioventricular (AV) conduction time, the incidence and severity of dysrhythmias, and isovolumetric left ventricular systolic pressure (LVSP) and its derivative were measured. Hearts (n = 85) were divided into three groups for 30 min of perfusion at 0% (no flow), 10%, and 25% of the control perfusion pressure (PP, 55 mm Hg). These groups were subdivided and exposed to 0%, 0.74% (0.23 +/- 0.01 mM), or 1.65% (0.51 +/- 0.01 mM) halothane 10 min before, during, and 10 min after hypoperfusion. Hypoperfusion was followed by 40 min of reperfusion at control PP. Exposure to 0.74% and 1.65% halothane before hypoperfusion produced a 9% and 13% decrease in heart rate, a 2% and 30% increase in AV conduction time, and a 25% and 51% decrease in LVSP and dLVP/dtmax, respectively. During the 30 min of hypoperfusion, heart rate decreased and AV conduction time increased; second- and third-degree AV block occurred in all hearts in the 0% and 10% PP groups, but only in some hearts in the 25% PP groups. Left ventricular systolic pressure rapidly decreased during hypoperfusion in all groups. During early reperfusion ventricular fibrillation and ventricular tachycardia occurred in the 0% and 10% PP groups but not in the 25% PP groups. During reperfusion 0.74% and 1.65% halothane greatly reduced the duration of ventricular fibrillation from 8.1 +/- 3.3 min to 1.5 +/- 0.8 and 1.9 +/- 1.2 min in the 0% and 10% PP groups, respectively. A concentration of 0.74% halothane increased the incidence of supraventricular tachycardia on reperfusion in the 10% group (from a control of 20% to 65%), and 1.65% halothane increased the duration (2.6 +/- 2.5 min) and incidence (38%) of supraventricular tachycardia on reperfusion in the 0% PP group. A concentration of 1.65% halothane facilitated recovery of LVSP after hypoperfusion in the 25% group but not in the 0% and 10% PP groups. These results indicate that halothane, in some instances, can have protective cardiac effects after graded hypoperfusion as assessed by improved contractility and by reduced severity of some dysrhythmias during reperfusion; however halothane may also increase the incidence of supraventricular tachycardia. The cardiac protection by halothane could be a result of reduced cardiac work before, during, and after hypoperfusion, or of some other direct protective cellular effects.

Although it is generally accepted that isoflurane can cause cerebral vasodilation, the sensitivity of the cerebral vessels to this anesthetic agent remains controversial. Furthermore, the mechanism by which isoflurane produces its direct effects on the cerebral vasculature remains unknown. The purpose of this study was to determine if isoflurane-induced relaxation of canine middle cerebral arteries is dose-dependent and/or endothelium-dependent. In an additional series of experiments, isoflurane-induced relaxation was studied in the presence of indomethacin to inhibit prostacyclin release, and endothelium-independent relaxation was examined with sodium nitroprusside. The response to isoflurane was examined in middle cerebral arteries prior to and following pretreatment with 300 microM NG-monomethyl-L-arginine (LnMMA), an inhibitor of endothelium-dependent vasodilation. Vascular rings (2.5 mm in length and 600-800 microns in diameter) were suspended in tissue baths and isometric tension recorded. The rings were constricted with either 0.2 microM 5-hydroxytryptamine or 5 microM prostaglandin F2 alpha and subsequently exposed to increasing concentrations of isoflurane (0.65-4.9%). In separate experiments the procedure was repeated in vessels with and without endothelium. Isoflurane produced a dose-dependent relaxation in all vessels. This relaxation was not inhibited by LnMMA and was unaffected by the absence of endothelium. The isoflurane response was independent of cyclooxygenase inhibition. These results demonstrate that isoflurane-induced relaxation of canine middle cerebral arteries: 1) is dose-dependent; 2) is not mediated by modulation of endothelium-derived relaxing factor or a release of prostacyclin; and 3) is endothelium-independent.

Objective: To study the effect of serum from patients with fungemia and control patients on sinoatrial node function., Design: Prospective, observational study., Setting: Surgical ICU in a university hospital., Patients: Fourteen patients with fungemia and 14 control patients., Measurements and Main Results: Serum samples from all patients were assayed in an in vitro sinus node preparation. Serum samples from 11 (78%) of the 14 fungemic patients caused a decrease in sinus node activity, while serum samples from only one (7%) of 14 control patients caused slowing of the sinus node., Conclusions: Serum from many patients with fungemia causes slowing of an in vitro sinus node preparation. This in vitro finding may explain bradyarrhythmias seen clinically in the setting of fungemia.

These studies were designed to examine the effects of inhalational anesthetics on rapid changes in myocardial intracellular Ca2+ and Ca2+ sensitivity of the contractile apparatus. The effects of halothane, enflurane, and isoflurane on rapid changes in intracellular Ca2+ (Ca2+ transients as measured with bioluminescent protein aequorin) and contractile characteristics were compared in guinea pig right ventricular papillary muscles. In addition to examination of their potencies at equianesthetic concentrations, the effects of these agents on alterations in Ca2+ sensitivity at myofilaments were also investigated. The negative inotropic effects of halothane (0.65 and 1.15%) and enflurane (1.0 and 2.2%) were dose-dependent and closely related to a decrease in Ca2+ transients. In the presence of isoflurane (0.77 and 1.6%), the contractile force decreased in a dose-dependent manner, but the decrease was significantly less as compared to that with equianesthetic concentrations of halothane and enflurane. An additional feature observed in the presence of isoflurane was a dissociation between intracellular Ca2+ availability and contractile force. Although the magnitude of the Ca2+ transients did not change when the percentage of isoflurane was increased from 0.77 to 1.6, the contractile force decreased. Because of these findings, the effects of halothane (1.2%), enflurane (2.2%), and isoflurane (1.6%) on the relationship between intracellular Ca2+ and tension developed in the papillary muscle were examined in order to assess myofibrillar responsiveness to Ca2+. The results indicate that only isoflurane slightly but significantly shifted the Ca2+/isometric tension curve toward higher intracellular Ca2+ concentrations; no differences were observed in the absence and presence of equianesthetic concentrations of halothane and enflurane.(ABSTRACT TRUNCATED AT 250 WORDS)

Background and Methods: We hypothesized that beta-adrenergic receptor blockade would result in an increase in serum potassium concentration in hypothermic rats given a potassium load compared to non-beta-blocked, hypothermic, potassium-loaded rats. To test this hypothesis, we investigated the interaction between body temperature and beta-adrenergic receptor blockade on serum potassium concentrations in ureter-ligated rats with and without potassium loading. To achieve this goal, we performed three experiments. In the first experiment, serum potassium concentrations were determined in 16 rats as they were continuously cooled from 37 degrees C to 22 degrees C. In the second experiment, 12 ureter-ligated rats were cooled to 31 degrees C, after which they were rewarmed to 37 degrees C. Serum potassium concentrations were determined before and after cooling and on rewarming. Twelve other ureter-ligated rats were cooled to 31 degrees C, then given a potassium load until their serum potassium concentrations returned to their baseline values, after which they were rewarmed to 37 degrees C. Serum potassium concentrations were determined before and after cooling, during the potassium infusion, and on rewarming. In the third experiment, 14 rats were pretreated with propranolol and 14 rats served as controls. Half of the rats in each of these two groups were kept at 37 degrees C and half were cooled to 25 degrees C. All rats were then given a 690-mumol potassium chloride infusion. Serum potassium concentrations were determined before and after the potassium infusion., Results: The rats developed hypokalemia with cooling, which spontaneously resolved in the rats without supplementation on rewarming to 37 degrees C. The hypothermic hypokalemic rats that had their serum potassium concentrations corrected to normothermic status (2.93 +/- 0.17 mmol/L) had marked increases in serum potassium concentrations (4.22 +/- 0.15 mmol/L) on rewarming. In the normothermic rats, potassium loading after beta-adrenergic receptor blockade resulted in even higher serum potassium concentrations (5.65 +/- 0.36 mmol/L) compared with non-beta-blocked rats given equal potassium loads (4.6 +/- 0.4 mmol/L). However, in hypothermic (25 degrees C) rats given the same potassium load, there was no difference in serum potassium concentrations in beta-blocked (6.5 +/- 0.35 mmol/L) and non-beta-blocked rats (6.63 +/- 0.3 mmol/L)., Conclusions: These results suggest that acute hypothermia causes a decrease in serum potassium, probably secondary to redistribution, which is reversible on rewarming. Supplementation of potassium during hypothermia can cause a significant increase in serum potassium concentration on rewarming. Blocking beta-adrenergic receptors with propranolol did not effect hypothermia-induced hypokalemia, suggesting that the beta-adrenergic mechanism may not be functional in hypothermia.

The objective of this study was to determine whether endothelium-mediated relaxation occurs in canine coronary collateral vessels. Responses to endothelium-dependent vasodilators in coronary collateral vessels (250-350 microns) were compared with those obtained in normal native coronary arteries of similar size. Rings of small arteries and collateral vessels were suspended in baths, and tension was recorded. All rings were constricted with prostaglandin F2 alpha (3 microM) and subsequently exposed to cumulative concentrations of acetylcholine or bradykinin. In separate experiments, the procedure was repeated in the presence of 300 microM NG-monomethyl-L-arginine (L-NMMA) to inhibit endothelium-mediated vasodilation. Endothelium-dependent relaxation was further studied in the presence of indomethacin, and endothelium-independent relaxation was examined with sodium nitroprusside. Acetylcholine and bradykinin relaxed both normal native and collateral rings. In preconstricted small arteries and collateral vessels the concentration at 50% of maximal response of acetylcholine was 85.5 +/- 19.5 and 61.0 +/- 14.0 microns, and bradykinin was 11.9 +/- 7.4 and 10.7 +/- 2.1 microns, respectively. L-NMMA attenuated the response to acetylcholine and bradykinin in both groups. The results indicate that endothelium is present and functional in canine coronary collateral vessels. Both small coronary arteries and collateral vessels are equally responsive to endothelium-dependent vasodilators and inhibition of endothelium-dependent relaxing factor.

The authors' aim was to examine direct cardiac responses to isoflurane, enflurane and halothane, as altered during mild hypoxia by the substitution of nitrogen (N2) for oxygen (O2), and additionally by the substitution of nitrous oxide (N2O) for N2. Heart rate, atrioventricular conduction time, left ventricular pressure (LVP), peak positive and negative derivatives of LVP (dLVP/dtmax), coronary flow, O2 delivery (DO2), percent O2 extraction, and myocardial O2 consumption (MVo2) were examined in 47 isolated guinea pig hearts. Changes in the ratio of DO2 to MVO2 indicated the relationship of autoregulation of coronary flow to myocardial O2 utilization. Each heart was first exposed to 96% O2 and then randomly exposed to 48% N2 and 48% N2O alone and with three equivalent concentrations of one of three volatile anesthetics: isoflurane (n = 15), halothane (n = 16), or enflurane (n = 16). Results were as follows: 1) N2 alone significantly decreased LVP, +dLVP/dtmax and -dLVP/dtmax, DO2 and MVO2; increased coronary flow; and produced no change in heart rate, atrioventricular conduction time, percent O2 extraction, or the DO2/MVO2 ratio. 2) Compared to N2, N2O alone only produced additional significant decreases in LVP and +dLVP/dtmax. 3) In the presence of N2 or N2O, each volatile anesthetic caused significant stepwise decreases in heart rate, LVP, +dLVP/dtmax and -dLVP/dtmax, MVO2, and percent O2 extraction; no additional change in coronary flow or DO2; and a stepwise increase in the DO2/MVO2 ratio. The effects of halothane and enflurane were generally greater than those of isoflurane. 4) Each volatile anesthetic caused an additive, parallel depression of LVP and percent O2 extraction as a function of MAC with N2O compared to N2. This study demonstrates that the direct negative inotropic effects of halothane and enflurane are more pronounced than those of isoflurane and are accompanied by a greater reduction in O2 utilization by halothane and enflurane than by isoflurane in the presence of mild hypoxia alone or with the addition of N2O. The study also demonstrates that N2O accentuates the negative inotropic effects of volatile anesthetics during reduced O2.

The effects of halothane, isoflurane, and enflurane on proximal (false tendon) and distal (apical) canine Purkinje fibers were measured in vitro to assess their comparative effects on fibers exhibiting characteristically long (proximal) and short (distal) action potential duration. High- and low-dose anesthetic effects were evaluated in three groups of six left ventricular preparations and were compared with the changes occurring at identical times in six control preparations using analysis of variance with repeated measures. Under control conditions in all groups, the action potential duration, measured at 90% repolarization (APD90, mean +/- SEM), of proximal fibers was longer than that of distal fibers (320 +/- 16 vs 252 +/- 11 ms, P less than or equal to 0.01). Halothane (0.3 and 0.7 mM), isoflurane (0.4 and 0.8 mM), and enflurane (0.6 and 1.0 mM) produced a dose-dependent decrease (P less than or equal to 0.01) of proximal fiber APD90 with less (P less than or equal to 0.01) change of distal fiber APD90 and reduced (P less than or equal to 0.05) regional differences of APD90 at the higher dose. The decreases of proximal fiber APD90 were greater (P less than or equal to 0.01) for 1.0 mM (1.7 MAC) enflurane (-66 +/- 7 ms) and 0.8 mM (3.0 MAC) isoflurane (-69 +/- 9 ms) than for 0.7 mM (2.9 MAC) halothane (-33 +/- 8 ms). We conclude that the regional actions of anesthetics on Purkinje fiber repolarization may influence conduction during the relative refractory period and the occurrence of arrhythmias associated with disparity of regional refractory characteristics in the ventricular conduction system.

The effects of inhalation anesthetics halothane, enflurane, and isoflurane on spontaneous impulse initiation (automaticity) and triggered sustained rhythmic activity were examined in Purkinje fibers derived from normal (n = 38) and 24-h-old infarcted canine hearts (n = 27) to further understanding of their influence on the cellular mechanisms underlying generation of cardiac arrhythmias. Purkinje fibers from normal or infarcted hearts were superfused with modified Krebs' solution (37 degrees C) with or without epinephrine (2 or 15 microM) and equilibrated with a 97% O2-3% CO2 gas mixture (control). Transmembrane action potentials were recorded using conventional microelectrode techniques, and Purkinje fibers were exposed to anesthetic concentrations equivalent to 2.0 MAC. Normal Purkinje fibers were not spontaneously active unless exposed to epinephrine. All anesthetics (enflurane greater than halothane, isoflurane; P less than 0.05) increased automaticity of normal Purkinje fibers exposed to either epinephrine concentration. Partially depolarized Purkinje fibers from infarcted hearts were either spontaneously active or were quiescent. For ischemic fibers that beat spontaneously, abnormal automaticity was sustained (duration greater than 300 s) or periodic (duration less than 300 s). Sustained abnormal automaticity was elicited by epinephrine (15 microM) in some quiescent partially depolarized fibers. None of the anesthetics affected the rate of sustained abnormal automaticity, regardless of whether the induction of such automaticity required epinephrine, nor did anesthetics significantly affect the duration of trains of periodic abnormal automaticity. Finally, quiescent, partially depolarized Purkinje fibers were tested for triggered rhythmic activity during pacing at a cycle length of 800 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct cardiac effects of KT-362 (5-[3 [[-2-(3,4-dimethoxyphenyl)-ethyl]amino]-1-oxopropyl]-2,3,4,5- tetrahydro-1,5-benzothiazepine fumarate), a drug that may inhibit intracellular calcium mobilization as well as extracellular calcium influx was compared to verapamil. Guinea pig hearts (n = 19) were used to examine the changes in atrial rate, atrioventricular conduction time (AVCT), coronary flow, myocardial oxygen consumption (MVO2), and isovolumetric left ventricular pressure (LVP). Both drugs concentration-dependently and reversibly decreased atrial rate, contractility, and MVO2; AVCT increased during spontaneous rhythm. The increases in AVCT and the incidence of AV dissociation were accentuated during cardiac pacing. Verapamil significantly increased coronary flow, while KT-362 did not. Median effective concentration (EC50) was about 25 times lower for verapamil in depressing LVP and about three times lower in depressing atrial rate and AV conduction. The changes in calcium channel current in voltage-clamped single canine Purkinje cells (n = 6) were also examined. Verapamil (0.3 microM) and KT-362 (7 microM) decreased peak Ca2+ channel current at maximum activation (+10 mV) by 38.1 +/- 8% and 28.6 +/- 6%, respectively, without shifting the current-voltage relationship. This study indicates that verapamil is more potent than KT-362 in depressing contractile function, heart rate, and AV conduction in isolated hearts and calcium current in isolated cardiac Purkinje cells. Moreover, there was a much greater difference between the EC50 for verapamil and that for KT-362 for the depression of indices of contractility (23-30-fold) than for the depression of sinoatrial and atrioventricular nodal function (2.5-4-fold).

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Knowledge of anesthetic effects on the automaticity of dominant and subsidiary cardiac pacemakers is fundamental to an understanding of mechanisms of arrhythmia during anesthesia, as well as to the management of patients with sinus node dysfunction or atrioventricular (AV) conduction block. Among potential pacemakers of the heart are subsidiary atrial pacemakers (SAP), which are located outside the classic sinoatrial (SA) node region but still within the right atrium. SAP have a higher inherent rate of automaticity than AV junctional pacemakers, may contribute to a multicentric atrial pacemaker complex, and can control the rhythm of the heart when the SA node is absent or inhibited. How halothane, epinephrine (E), or norepinephrine (NE), alone or in combination, would affect the relation between the automaticity of the SA node and SAP was tested using an isolated, perfused canine right atrial preparation (n = 78). This preparation was perfused via the SA node artery with Krebs' solution (36.0 +/- 0.5 degrees C) equilibrated with 97% oxygen-3% carbon dioxide. Delivered concentrations of halothane of 1 or 2% corresponded to measured perfusate concentrations of 0.50 +/- 0.02 or 0.80 +/- 0.04 mM in experiments with E (n = 24) and 0.45 +/- 0.02 or 0.75 +/- 0.04 mM in experiments with NE (n = 54). E or NE perfusate concentrations were 1, 2, and 5 micrograms/l or 2, 5, and 10 micrograms/l, respectively. To determine the site of earliest activation (SEA), extracellular recordings were made from the SA node region and distal sites (approximately 1, 2, and 3 cm) along the sulcus terminalis, the previously reported locations of SAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial tachyarrhythmias are a common manifestation of digitalis toxicity. Such arrhythmias could be due to enhanced automaticity of subsidiary atrial pacemakers (SAP) compared to the sinoatrial (SA) node. Halothane is known to oppose digitalis-induced ventricular arrhythmias. Its effect on digitalis-caused atrial arrhythmias is unknown. Therefore, we tested two hypotheses, as follows. First, increasing ouabain concentrations would enhance automaticity of SAP compared to the SA node and that such enhanced automaticity could explain digitalis-caused atrial tachyarrhythmias. Second, halothane would oppose such enhanced automaticity of SAP, thereby opposing digitalis-caused atrial tachyarrhythmias. A canine right atrial preparation was perfused via the SA node artery with Krebs' solution (36.0 +/- 0.5 degrees C) equilibrated with 97% oxygen-3% carbon dioxide. Four bipolar extracellular electrodes recorded the site of earliest activation (SEA), which in this preparation could be the SA node or increasingly remote sites of SAP approximately 1, 2, and 3 cm distal to the SA node along the sulcus terminalis. Pacemaker shifts to SAP during exposure to drugs were scored for magnitude of shift as 1, 2, or 3 depending on which SAP site was the SEA. Magnitude scores were summed for each test condition and normalized by dividing the total number of preparations tested. Preparations (n = 48) were exposed to 1 or 2% halothane (perfusate concentrations of 0.51 +/- 0.01 or 0.79 +/- 0.03 mM, respectively) and/or to low- or mid-therapeutic (2.5 or 5 x 10(-8) M) or borderline toxic ouabain (1 x 10(-7) M). Normalized magnitude scores were not significantly different from zero (control value) with any halothane or ouabain concentration alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Knowledge of arrhythmic or antiarrhythmic actions of anesthetics on automaticity of latent pacemaker fibers has relevance to the intraoperative management of patients with bradyarrhythmia due to sinus node dysfunction or heart block. The authors determined the effects of halothane, enflurane, and isoflurane on automaticity and recovery of automaticity from overdrive suppression in canine Purkinje fibers derived from normal hearts. Purkinje fibers were superfused with a modified Krebs' solution (37 degrees C) containing epinephrine (2 or 15 microM) and equilibrated with a 97% O2-3% CO2 gas mixture (control). Transmembrane action potentials (AP) were recorded using standard microelectrode techniques. Purkinje fibers were then exposed to anesthetics at vaporizer settings of 0.75 or 1.5% (halothane), 1.75 or 3.5% (enflurane), and 1 or 2% (isoflurane), which were equivalent to measured superfusate concentrations of 0.22 or 0.47 mM (halothane), 0.44 or 0.94 mM (enflurane), and 0.28 or 0.53 mM (isoflurane). Compared to control, there was no significant effect of either concentration of the anesthetics on upstroke (phase 0) depolarization, AP amplitude or duration (50% repolarization), or maximum diastolic potential. All three anesthetics increased spontaneous rate. The increase in rate with all three anesthetics was due to enhanced diastolic depolarization (rate dV/dt, phase-4 depolarization). Recovery times from overdrive suppression were determined after 30 or 60 s of pacing at drive cycle lengths of 800, 500, and 400 ms and only at higher anesthetic concentrations. Recovery of automaticity was shortened by halothane only in slowly paced fibers exposed to the lower concentration of epinephrine. Under all other conditions recovery times were not affected by halothane.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors examined the direct myocardial and coronary vascular responses to isoflurane, enflurane, and halothane and compared their effects on attenuating autoregulation of coronary flow (CF) as assessed by changes in the O2 supply-demand relationship. The effects of these anesthetics on left ventricular pressure (LVP), CF, percentage of O2 extraction, O2 delivery (DO2), and myocardial O2 consumption (MVO2) were examined in 47 isolated guinea pig hearts perfused at constant pressure. An increase in DO2 from control relative to MVO2 was used to indicate attenuation of autoregulation, and a decrease in MVO2 relative to DO2 to indicate a reduction of myocardial work and O2 utilization. Each heart was exposed to 0.51, 0.70, and 1.20 vol% halothane (n = 16); 0.91, 1.41, and 2.04 vol% enflurane (n = 16); or 0.45, 0.87, and 1.22 vol% isoflurane (n = 15). Adenosine (2 mM) was given to test maximal CF in arrested and in paced hearts. Mean results for increasing concentrations of each agent were as follows: LVP (average control 92 +/- 5 mmHg) (standard error of mean [SEM]) decreased by 15%,* 25%,* and 34%* with halothane; 13%,* 24%,* and 34%* with enflurane; and only 3%, 7%, and 13%* with isoflurane (*P less than 0.05 vs. controls). CF (control 6.1 +/- 0.3 ml.min-1.g-1) was not altered significantly with halothane or enflurane but increased by 6%, 9%, and 16%* with isoflurane and maximally by 86 +/- 7%* with adenosine. The percentage of O2 extraction (control 69.2 +/- 1.8%) decreased by 9%,* 16%,* and 22%* with halothane; 7%,* 15%,* and 22%* with enflurane; and only 1%, 4%, and 7%* with isoflurane.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of halothane (0.45 and 0.9 mM, equivalent to 0.7 and 1.5%, respectively), isoflurane (0.54 and 1.23 mM, equivalent to 0.9 and 2.0%, respectively) and enflurane (0.65 and 1.48 mM, equivalent to 1.2 and 2.5%, respectively) on macroscopic L- and T-type Ca2+ channel currents were compared in single canine cardiac Purkinje cells using the whole-cell voltage-clamp technique. Cells were dialyzed with pipette solution containing CsCl and superfused with an external solution containing 10 mM BaCl2 and tetraethylammonium chloride. The long-lasting (L) and transient (T)-type Ca2+ channel currents were measured by depolarizing the membrane from different holding potentials (HPs). Voltage steps from an HP of either -80 or -70 mV elicited a low threshold, rapidly inactivating inward current at -40 to -30 mV, which maximally activated at -14 +/- 0.9 mV. This current was reduced by Ni2+ (100 microM) but not by nifedipine (1 microM), therefore resembling T-type Ca2+ channel current. In contrast, depolarizing steps from an HP of -40 mV elicited a sustained inward current that maximally activated at +4.1 +/- 0.8 mV and was nifedipine-sensitive, showing the characteristics of an L-type Ca2+ channel current. Halothane, isoflurane, and enflurane produced a concentration-dependent suppression of total Ca2+ channel current in every cell studied. Separation of Ca2+ channel types showed that both L- and T-type Ca2+ channel currents were depressed to a similar extent by anesthetic administration. These agents reduced peak L- and T-type current elicited at each pulse potential but did not shift the current-voltage (I-V) relationship for either T- or L-type current activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Isolated, perfused guinea pig hearts were used to determine the effects of diacetyl monoxime (DAM) on atrial rate, atrioventricular conduction time (AVCT), and left ventricular peak systolic pressure (LVSP). Contractile force and calcium transients were also monitored in isolated papillary muscles injected with aequorin in the absence and presence of ryanodine (RYA). In the isolated heart, 0.2-5 mM DAM caused significant dose-dependent decreases in LVSP (up to 51%) without change in atrial rate and AVCT. DAM (10 mM) produced a small slowing of atrial rate, no change in AVCT, and a 76% decrease in LVSP; 20 and 30 mM DAM further reduced LVSP, decreased atrial rate 38%, and produced AV dissociation. In isolated, paced papillary muscles, 2, 10, and 30 mM DAM decreased contractile force 27, 58, and 87%, respectively, while calcium transients increased by -9, 38, and 225%, respectively. All cardiac effects of DAM were readily reversible. RYA (1 microM) alone and with DAM (30 mM) decreased contractile force by 30 and 99%, respectively and decreased calcium transients by 59 and 74%, respectively. This study shows that low concentrations of DAM have little effect on electrical activity but greatly depress contractility and modify intracellular handling of calcium.

Chronically administered verapamil can accumulate in cardiac tissues and may depress cardiac function despite low plasma concentration. To examine this, two groups of rabbits were injected intraperitoneally twice a day with either 1 mg/kg verapamil or saline for 28 days. Fourteen hours after the last dose, right atrial tissue and right ventricular papillary muscle were isolated. Plasma and myocardial tissue concentrations of verapamil were determined. Plasma samples contained no detectable amounts of verapamil, but the myocardium contained 2.1 +/- 0.6 (mean +/- SE) ng of verapamil per gram of wet tissue. Spontaneous action potentials recorded from the sinoatrial node in the verapamil-treated group showed decreases in the phase 0 and phase 4 depolarization rates, a slower pacemaker rate, and an attenuated response to epinephrine compared with the saline-treated group. Papillary muscle in the verapamil-treated group exhibited a significantly lower force of contraction and a depressed contractile response to epinephrine compared with the control group. There were no differences in rate or contractile responses the day after single injection with 2 mg/kg verapamil or saline twice a day. Myocardial verapamil concentration increased with the duration of treatment and with the doses given; myocardial verapamil concentration was 3.0 +/- 0.6 ng/g wet tissue in the group treated for 28 days with 2 mg/kg verapamil. Our study shows that chronic treatment of rabbits with verapamil decreases cardiac chronotropic and inotropic responses to adrenergic stimuli despite no detectable verapamil in plasma, and that accumulation of verapamil in the myocardium is probably associated with these effects.

The antidysrhythmic drug amiodarone may be given during general anesthesia. We examined the single and combined direct cardiac effects of amiodarone and halothane in the isolated guinea pig heart. Guinea pig hearts were isolated and perfused retrogradely through the aorta with oxygenated Krebs-Ringer solution at 37 degrees C at constant pressure (55 mm Hg). Variables measured in 61 hearts included spontaneous heart rate (HR), atrioventricular conduction time (AVCT), isovolumetric left ventricular pressure (LVP), and coronary flow (CF). Amiodarone was administered as a single bolus into the retrogradely perfused aortic root and halothane was vaporized into the perfusing solution. Mean control values of pooled data before treatment were as follows: HR, 228 +/- 4 (SEM) beats/min; AVCT (during atrial pacing at 240 beats/min), 82 +/- 2 ms; LVP, 97 +/- 4 mm Hg; and CF, 6.1 +/- 0.2 mL.min-1.g-1. Amiodarone, 100 micrograms and 200 micrograms, decreased HR by 8% +/- 2% and 8% +/- 2%, increased AVCT by 5 +/- 2 and 15 +/- 3 ms, decreased LVP by 22% +/- 3% and 27% +/- 3%, and increased CF by 20% +/- 1% and 40% +/- 2%, respectively; all these changes were sustained for 60 min and, except for HR, were dose dependent. Halothane, 0.5% and 1%, transiently and dose-dependently decreased HR by 6% +/- 2% and 12% +/- 2% increased AVCT by 4 +/- 2 and 8 +/- 2 ms, decreased LVP by 15% +/- 3% and 31% +/- 3%, and increased CF by 2% +/- 1% and 6% +/- 2%.(ABSTRACT TRUNCATED AT 250 WORDS)

The direct effects of isoflurane, halothane, and enflurane alone or combined with diltiazem were examined in 49 isolated perfused guinea pig hearts. Recording electrodes were placed in the right atrium and left ventricular septal wall to measure spontaneous atrial rate and atrioventricular conduction time (AVCT). The right atrium was paced at 3-7 Hz (n = 10) to examine rate-dependent effects on AVCT, Wenckebach's periodicity, and ventricular response rates with atrioventricular (AV) block. Isovolumetric left ventricular pressure (LVP) was measured with a saline-filled balloon placed through the mitral valve. Hearts were perfused with oxygenated Krebs-Ringer's solution at 55 mmHg equilibrated with low or high concentrations of isoflurane (0.7 and 1.5%), halothane (0.5 and 1%), or enflurane (1.1 and 2.2%). Hearts were also perfused with a low or high concentration of diltiazem (75 and 150 ng/ml) alone and during anesthetic exposure. Significant findings of combined exposure were as follows: 1) the low isoflurane, halothane, or enflurane concentration plus a low or high diltiazem concentration decreased LVP compared with control and diltiazem alone; low isoflurane plus the high diltiazem concentration decreased LVP more than isoflurane alone. The high isoflurane, halothane, or enflurane concentration plus the low or the high diltiazem concentration decreased LVP from control, anesthetics and diltiazem alone. Diltiazem plus halothane or enflurane decreased LVP more than diltiazem plus isoflurane. 2) Diltiazem plus low or high isoflurane, halothane, or enflurane concentrations decreased spontaneous atrial rate from control and the agents alone, except the high isoflurane concentration plus the low diltiazem concentration was not greater than that of isoflurane alone. Diltiazem plus halothane or enflurane decreased atrial rate more than diltiazem plus isoflurane. 3) Low and high diltiazem concentration plus low isoflurane, halothane, or enflurane concentrations did not prolong AVCT more than the individual agents alone, but low or high diltiazem plus high isoflurane, halothane, or enflurane concentrations increased AVCT more than each anesthetic alone. In nonpaced hearts, AV block occurred only with high diltiazem plus low enflurane (23%) concentrations and the high enflurane concentration (31%). 4) In hearts paced at 5 and 6 Hz, AVCT increased above controls during a low or high concentrations of diltiazem, during enflurane, and during the low or high concentration of diltiazem plus enflurane; AVCT increased more with the low concentration of diltiazem plus enflurane than with the low diltiazem concentration alone.(ABSTRACT TRUNCATED AT 400 WORDS)

Although venous capacitance has been studied in the neurally isolated tissue or in the in vitro vein segment, this is the first study of sympathetic regulation of the pressure-diameter relation in mesenteric veins in situ, where innervation is kept intact. In 25 alpha-chloralose-anesthetized rabbits, mesenteric vein diameter (679 +/- 27 microns, ranges of 380-1,050 microns at initial state) and intravenous pressure were measured continuously at the same site by using videomicrometer and micropressure systems. Intravenous pressure was increased in a stepwise fashion from the baseline of 6-9 mm Hg to approximately 10, approximately 13, approximately 16, approximately 19, and occasionally to approximately 22 or approximately 26 mm Hg by occluding the portal vein with a pneumatic occluder. Each intravenous pressure was maintained for 90-120 seconds or 4-5 minutes until the diameter increase reached a plateau. Pressure-diameter curves were generated for the control state, during celiac ganglion stimulation, and during local tetrodotoxin or intravenous hexamethonium administration. Diameter was plotted as a function of pressure, and the curves were nonlinear or sigmoid. These results are different from the linear or curvilinear characteristics of the pressure-diameter or pressure-volume relation observed in the pharmacologically or chemically denervated preparation. Tetrodotoxin and hexamethonium attenuated the sigmoid shape of the pressure-diameter curve and shifted it toward the diameter axis of the curve. On the other hand, celiac ganglion stimulation did not change the sigmoid nature of the curve but shifted the curve toward the volume axis.(ABSTRACT TRUNCATED AT 250 WORDS)

Amrinone is a positive inotropic and vasodilatory agent and may be administered during anesthesia with isoflurane. The authors' aims were 1) to examine if amrinone produces coronary artery vasodilation through an increase in metabolic demand or through a direct vasodilatory effect or through both and 2) to test if amrinone attenuates cardiac depression and enhances coronary artery vasodilation produced with exposure to isoflurane. The effects of these drugs were examined in 11 isolated perfused guinea pig hearts. Variables measured were: heart rate (HR), atrioventricular conduction time (AVCT), isovolumetric peak left ventricular pressure (LVP), coronary flow, percent O2 extraction, myocardial O2 consumption (MVO2), and the ratio of O2 delivery (DO2) to MVO2. Each heart was exposed for 10-min periods to 10, 50, 100, and 500 microM amrinone alone, and to 0.5 or 1% isoflurane before, during, and after amrinone. Initial control values were: heart rate 216 +/- 5 beats per min; AVCT 56 +/- 1 ms; peak LVP 86 +/- 3 mmHg; coronary flow 6.3 +/- 0.3 ml.min-1.g-1 (11.4 +/- 0.7 ml.min-1.g-1 with adenosine bolus), percent O2 extraction 52 +/- 3%; DO2 107 +/- 3 microliters.min-1.g-1; MVO2 56 +/- 4 microliters.min-1.g-1; and DO2/MVO2 1.75 +/- 0.08. Amrinone 500 microM alone increased (P less than 0.05) heart rate by 9%, LVP by 13%, coronary flow by 18%, and MVO2 by 23%; AVCT decreased by 3%.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of halothane, enflurane, and isoflurane on voltage-dependent Ca2+ channel current (ICa) were compared in canine ventricular cells by the whole-cell voltage-clamp technique. ICa was elicited in each cell by progressively depolarizing pulses, from -80 or -40 mV to more positive membrane potentials. The peak amplitude and inactivation rate of the inward current were analyzed before, during, and after the external application of equianesthetic concentrations (0.5, 1.0, and 2.0 MAC) of halothane, enflurane, or isoflurane. The concentrations of these agents in the Krebs' solution were as follows (percentage in the gas phase): halothane 0.36, 0.68, and 1.50%; isoflurane 0.50, 1.00, and 1.90%; and enflurane 0.66, 1.36, and 2.39%. Halothane, enflurane, and isoflurane rapidly reduced peak ICa amplitude at all voltages studied, resulting in a depression of the entire current-voltage relationship for ICa activation. This depression was concentration-dependent and completely reversible upon wash-out of the anesthetic agents. Quantitatively, the three anesthetic agents produced a similar inhibition of peak ICa at approximately equianesthetic concentrations. Inactivation of ICa during 200-ms depolarizing pulses was not affected by two lower concentrations of the anesthetic agents, but was accelerated by the highest concentration of enflurane used. These findings suggest that the negative inotropic and chronotropic actions of halothane, enflurane, and isoflurane on the ventricular myocardium are related, at least in part, to their inhibition of ICa at the sarcolemma. However, since all three anesthetic agents depressed ICa amplitude similarly, their quantitatively different effects on cardiac performance are due most likely to differences in actions at other cellular sites.

Potent inhalational anesthetics depress autonomic reflex responses at multiple sites. Most studies emphasize cardiac chronotropic changes and changes in systemic blood pressure. Recently, active reflex venoconstriction of 500-1,000 microns O.D. mesenteric veins has been demonstrated. In the current study, the effects of halothane on the reflex responses of similar mesenteric veins were measured. Mesenteric vein diameter and intravenous pressure were measured in 500-1,000 microns O.D. veins from the mesentery of segments of terminal ileum externalized in situ from 27 New Zealand white rabbits anesthetized with alpha-chloralose. Mean arterial pressure was measured with femoral arterial cannulation, and heart rate was determined from the arterial pressure signal. In a separate group of six animals, sympathetic efferent nerve activity was measured from a postganglionic splanchnic nerve. Reflex venoconstriction and increases in mean arterial pressure and mesenteric vein pressure in response to bilateral carotid occlusion were attenuated by 0.5% and 1% inhaled halothane but not by superfusate equilibrated with 3% halothane. Decreases in mesenteric vein diameter and increases in mesenteric vein pressure in response to celiac ganglion stimulation were unaffected by both 0.5% inhaled halothane and superfusate equilibrated with 5% halothane. The bilateral carotid occlusion reflex-mediated increase in sympathetic efferent nerve activity was depressed by both 0.5% and 1% inhaled halothane. The effect of inhaled halothane on prestimulation baseline vein diameter was inconsistent. Superfusate equilibrated with 5% but not 3% halothane caused baseline venodilation. These results suggest a mechanism whereby control of venous tone is inhibited by halothane proximal to the postganglionic neuron. This could involve central or ganglionic inhibition.

The effects of halothane, tetrodotoxin (TTX), veratridine (VTD), and alterations of extracellular calcium ion concentration [Ca++]0) on regional differences of canine Purkinje fiber action potential duration (APD50 and APD90) were investigated in vitro at a paced rate of 75 beats per min. Under control conditions (n = 15 hearts) APD90 of proximal (false tendon) fibers (289 +/- 6 ms) always exceeded (P less than or equal to 0.01) that of distal (apical) fibers (213 +/- 4 ms). Halothane (0.35-1.07 mM) reduced regional differences of APD90 by producing dose-dependent decreases of proximal APD90 without decreases of distal APD90. The regional actions of halothane were similar to those of low (0.33-1.0 microM) concentrations of the Na+ channel antagonist TTX, which also decreased proximal APD90 more than distal APD90. The actions of halothane in combination with TTX further decreased proximal APD90, whereas the Na+ channel agonist VTD, which increased proximal APD90 more than distal APD90, reversed the regional actions of halothane. Decreasing Ca++ influx by reducing [Ca++]0 from 1.8 to 0.6 mM increased proximal APD90 more than distal APD90 in a manner opposite to the regional actions of halothane. Although there was no difference between the values of APD90 obtained for each region in the presence of halothane at 0.6, 1.8, and 3.6 mM [Ca++]0, the action of halothane decreasing APD90 of proximal fibers was more prominent at 0.6 mM [Ca++]0 because of the increased APD90 of fibers under this condition. The findings are consistent with, but do not definitively prove, the hypothesis that halothane may decrease APD90 of proximal Purkinje fibers by a mechanism similar to that of TTX involving inhibition of plateau-phase inward Na+ current.

Nitrous oxide has a long clinical history, but its effects on the heart remain controversial. The direct effects of N2O on global myocardial function have not been reported. The authors' aim was to examine the inotropic, chronotropic, dromotropic, and vascular effects of N2O, compared with its N2 control, on hearts isolated from the guinea pig. Hearts (N = 31) were isolated and perfused at 37 degrees C with Krebs-Ringer solution at constant pressure. Isovolumetric left ventricular pressure (LVP) and its derivative (maximum rate of tension development [dP/dtmax]) were measured by placing a saline-filled, latex balloon into the left ventricle. Bipolar electrodes were placed in the right atrium and right ventricle for measurement of heart rate (HR) and atrioventricular conduction time (AVCT). The venae cavae were ligated, and the right ventricle was cannulated through the pulmonic valve to collect coronary sinus effluent for measurement of coronary outflow O2 tension, adenosine, and inosine. After stabilization and perfusion with 96% O2 (plus 4% CO2), each heart was exposed for 10 min either to 48% N2O or to 48% N2 with 48% O2. After repeated perfusion with 96% O2 for 10 min, hearts were exposed in the reverse order to 48% N2O or 48% N2. In the postcontrol period, hearts were again exposed to 96% O2. Inflow Po2 (in mmHg) was 506 +/- 5 (standard error of the mean [SEM]) during 96% O2 and 258 +/- 5 during both 48% N2 and 48% N2O. Effluent Po2 was 155 +/- 7 during 96% O2, 81 +/- 5 during 48% N2, and 83 +/- 5 during 48% N2O.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors investigated the effects of halothane (HAL) and isoflurane (ISO) on cardiac depression produced by global hypoxia and the recovery of function following reoxygenation is isolated guinea pig hearts perfused with Krebs' solution at constant pressure. Isovolumetric left ventricular systolic (LVSP) and end-diastolic pressures (LVEDP) were measured by placing a saline filled, latex balloon into the left ventricle. Bipolar electrodes were placed in the right atrium and right ventricle for measurements of heart rate (HR), atrioventricular conduction time (AVCT), and determination of the incidence and severity of dysrhythmias occurring during hypoxia and reoxygenation. Hearts were divided into three groups: control (n = 20), halothane (n = 12), and isoflurane (n = 13). All hearts were exposed in sequence to oxygenated perfusate (PO2, 530 mmHg), moderately hypoxic perfusate (PO2, 91 mmHg) for 30 min, and then to oxygenated perfusate for 40 min. Halothane (1%, 0.4 mM) or isoflurane (1.5%, 0.5 mM) were administered 10 min before hypoxia, during hypoxia, and during the first 10 min of reoxygenation. Exposure to halothane and isoflurane before hypoxia produced a 14 and 11% decrease in heart rate, a 32 and 23% increase in AVCT, and a 47 and 28% decrease in LVSP (all P less than or equal to 0.001) for halothane and isoflurane, respectively, and no significant change in LVEDP. During hypoxia, HR decreased and AVCT increased similarly in both groups. Left ventricular systolic pressure (LVSP) decreased sharply with a narrowing of the prehypoxic differences among the groups. In the control and isoflurane groups, LVEDP increased during hypoxia but remained unchanged in the halothane group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of halothane on the response of small isolated mesenteric capacitance veins to exogenous norepinephrine and electrically induced endogenous norepinephrine release was studied. The role of extra- and intracellular Ca2+ in norepinephrine-induced contractions was also examined. Two-millimeter-long segments from the second-order branch of the mesenteric vein were stretched to twice their resting diameter, and the generated tension was measured with a force transducer. Dose-dependent effects of norepinephrine on generated tension were examined before and after exposure to 0.75 and 1.5% halothane. (These concentrations produced perfusate halothane concentrations of 0.31 and 0.49 mM respectively.) Norepinephrine produced an increase in the basal vessel tension along with a superimposed rhythmic oscillation in tension. Although the magnitude of the tension increase was not affected by either concentration of halothane, the amplitude of the oscillations was reduced. Ryanodine (a blocker of Ca2+ release from the sarcoplasmic reticulum), like halothane, decreased the amplitude of the oscillations, but did not affect overall tension development. In the Ca2(+)-free medium the contractile response to norepinephrine was greatly attenuated as compared to control, whereas the oscillatory behavior was completely abolished. Norepinephrine release was examined indirectly by measuring the increase in tension during electric field stimulation. Response to endogenously released norepinephrine was significantly decreased by exposure to halothane 1.5% (0.49 mM) and blocked by pretreating the vessel with phentolamine. At concentrations used clinically, halothane did not affect overall developed tension in response to exogenously applied norepinephrine. However, 1.5% (0.49 mM) halothane decreased both sarcoplasmic-reticulum-dependent oscillations in tension and electrically induced release of endogenous norepinephrine.

The present experiments were undertaken to investigate the effects of atropine and d-tubocurarine on acetylcholine (ACh) release and ganglionic synaptic transmission in the isolated cat stellate ganglion. Ganglionic release of picomole amounts of ACh was measured by radioenzymatic assay, and ganglionic transmission was estimated on the basis of the compound action potential recorded from the postganglionic stellate cardiac nerve. Atropine (5 microM) produced a significant increase in both spontaneous and evoked ACh release from the ganglion while depressing synaptic transmission. d-Tubocurarine (20 microM) also caused a significant, though smaller, increase in spontaneous release of ACh but had little effect on evoked release of ACh. These results suggest that ACh release and synaptic transmission in the cat stellate ganglion are subject to cholinergic feedback regulation, which appears to be mediated predominantly via muscarinic presynaptic receptors.

Paroxysmal supraventricular tachycardia (PSVT) is likely due to reentry involving the atrioventricular (AV) node, AV node with AV bypass pathway, sinus node, or atria. Intravenous diltiazem (DIL) or verapamil (VER) might be used to treat PSVT in anesthetized patients, and either drug could be more or less effective or produce adverse circulatory effects in this circumstance because the available inhalation anesthetics are known to elevate plasma concentrations of acutely administered iv DIL or VER. Because human studies were precluded and there are no reliable animal models for most reentrant PSVT, the authors determined the effects of iv DIL or VER and potent inhalation anesthetics (enflurane, halothane, isoflurane) on supraventricular electrophysiologic (EP) properties affecting the likelihood of reentrant PSVT in chronically instrumented dogs. Measurements of supraventricular EP properties in awake dogs without drugs served as control. DIL and VER were then administered iv to achieve clinically relevant plasma concentrations in awake dogs and EP properties were again measured. Finally, anesthetic effects on EP properties in dogs with DIL or VER were tested at end-tidal concentrations equivalent to 1.2 or 1.6 MAC for enflurane, halothane, or isoflurane. In awake dogs, DIL or VER increased AV node conduction time. Wenckebach point and functional refractoriness, and also reduced the range of premature atrial intervals for and likelihood of producing sinus node interpolation or reentry with atrial extrastimulation (P less than 0.05, ANOVA). AV node conduction time, Wenckebach point, and functional refractoriness were further increased in anesthetized dogs (all agents) with DIL or VER compared with control (P less than 0.05, ANOVA). All anesthetics with DIL or VER abolished sinus node interpolation and reentry. Atrial effective and functional refractory periods were not affected by DIL or VER in awake dogs and were increased by any of the anesthetics in dogs with DIL (P less than 0.05, ANOVA). Atrial refractory periods were little affected by anesthetics with VER. Adverse circulatory effects, including systolic arterial pressure less than 50 mmHg and second-degree (type 1) AV block or sinus arrest with escape rhythms, were most common with VER and any (especially enflurane) of the anesthetics. Finally, anesthetized animals with sinus arrest and escape rhythms (any test condition) could be paced from the atrium at physiologic rates (up to 120 beats/min).(ABSTRACT TRUNCATED AT 400 WORDS)

The changes in left ventricular segmented contractile force induced by brief periods of ischemia (15-90 s) and subsequent reperfusions were analyzed in anesthetized dogs. Segmental coronary artery occlusion (left anterior descending or left circumflex) produced a decrease in segmental ventricular function in the occluded area and an increase in contractile force in the myocardial segment away from the occluded area. With reperfusion, a transient overshoot in contractile force above preischemic control levels was observed in the occluded segment. This overshoot was shown not to be dependent on adrenergic mechanisms but appears to indicate changes in calcium permeability.

The hypothesis tested was that some cardiac reflexes can be mediated by the neural mechanisms in thoracic sympathetic ganglia in addition to those existing in the spinal cord or brain stem. In mongrel dogs anesthetized with pentobarbital sodium the left stellate (SG) and middle cervical (MCG) ganglion were decentralized, and the left thoracic vagosympathetic trunk was cut cranial to the MCG and caudal to the MCG but above the heart. The left thoracic vagosympathetic trunk below the MCG was then stimulated afferently. A single bolus of 2-[14C]deoxyglucose was injected intravenously and the stimuli repeated periodically toward the decentralized ganglia for 45 min. The heart and ganglia were then removed, frozen, and sectioned for autoradiography. Significant increases in glucose utilization were found in both the SG and MCG compared with ganglia from nonstimulated control animals. Significant increases in the glucose utilization of the endocardial third of the left ventricle were also observed in the reflexly stimulated hearts. Neural mechanisms in the acutely decentralized SG and MCG could modify cardiac glucose utilization within specific areas of the heart. In addition, such ganglionic mechanisms may be concentrated within the caudal half of the SG. These data suggest that many neurons in the thoracic autonomic ganglia may be involved in local cardiac reflexes.

Acute myocardial infarction in the intra or perioperative period may be accompanied by either bradycardia and hypotension or tachycardia and hypertension. Different degrees of activation of cardiac and arterial receptors stimulated by the infarction may produce the seemingly dichotomous results. When infarction occurs intraoperatively, the effects of anesthesia may also play a role on the reflex responses observed. This study was performed for two reasons: 1) to study the effects of acute coronary artery occlusion (ACO) on vascular resistance; and 2) to study the effects of halothane (H) anesthesia on this ACO reflex. Snare occlusions of the left coronary arteries were performed in pentothalanesthetized mongrel dogs, and changes in arterial pressure, left ventricular length, hindlimb vascular resistance, and lumbar sympathetic efferent nerve activity were measured during 30- to 60-s occlusions at 0, 0.5, 1.0, and 1.5 per cent end tidal halothane concentrations. ACO produced a consistent depressor response, produced by withdrawal of sympathetic efferent activity, that was significantly attenuated by vagotomy. Increasing levels of H blunted the reflex depression in vascular resistance, and also produced decreases in baseline resistance and increases in left ventricular and diastolic length (LVEDL). Vagotomy blunted the dose-dependent decrease in baseline resistance with H. Therefore, the study has shown that: 1) ACO activates vagal afferents to initiate a reflex decrease in vascular resistance; 2) this reflex dilation is attenuated with increasing levels of H; and 3) by producing increases in LVEDL,H stimulates cardiac receptors and reflexly reduces vascular resistance.

In vitro and in vivo studies were conducted on the stellate ganglion (SG) of the dog by recording action potentials from its nerves and its neurons. For in vitro preparations, the SG and its nerve trunks were dissected from the animal and secured in an organ bath. Peripheral input to the SG was produced by electrical stimulation of the ventral ansa subclavia (VA), dorsal ansa subclavia (DA), and stellate cardiac nerve (SC) in 15 ganglion preparations studied in vitro. Electrical stimulation of the VA elicited action potentials recorded at the DA. This conducting pathway did not involve direct anatomic continuity, since the evoked potentials were blocked by injection of hexamethonium chloride into the SG. Most neurons in the SG received synaptic input from fibers of both central and peripheral origin. In 12 in vivo preparations, all nerves to the SG except the VA were cut. When peripheral sympathetic afferent input to the SG was increased, some of the postganglionic fibers of the dissected DA exhibited an increase in efferent nerve discharge. This response was also blocked by hexamethonium chloride. These results indicate that some of the functions of the SG might be independent of the central nervous system.

We have studied the general morphology of cat stellate ganglion cells in relation to the synaptic input that each neuron receives. Horseradish peroxidase (HRP) was injected intracellularly into single neurons of the isolated cat stellate ganglia. Neurons of the stellate ganglion receive synaptic information from central and peripheral nerves. Electrical stimulation of the preganglionic nerves (T3 ramus), and postganglionic stimulation of the ventral or dorsal ansa subclavia, evoked graded excitatory responses that led to the discharge of one or more action potentials. The neurons receiving synaptic input from preganglionic and postganglionic nerves have a complex dendritic morphology. These neurons were located close to the postganglionic nerves and had an axon emerging from these nerves. Other neurons located closer to the preganglionic nerves had no identifiable axons leaving the ganglion and could not be excited antidromically by electrical stimulation. These neurons appear to be interneurons. These results indicate that neurons of the cat stellate ganglion are organized in a complex fashion that could be important in the integrative properties of these neurons.

The hypotension accompanying isoflurane suggests that the anesthetic produces an attenuation of sympathetic tone. Previous studies examining the effects of isoflurane on sympathetic efferent nerve activity have required concomitant use of a basal anesthetic or decerebration, both of which independently alter sympathetic activity. This study was performed to examine the effects of isoflurane on sympathetic efferent nerve activity in the absence of basal anesthetic or decerebration. Five mongrel dogs were anesthetized with 4% isoflurane by mask. Platinum electrodes chronically were implanted around a renal nerve adjacent to the renal artery in order to measure renal sympathetic efferent nerve activity in the conscious and anesthetized animal. After 5-24 h for recovery, renal nerve activity and arterial pressure (via an implanted femoral artery cannula) were measured in the conscious, resting animal (control); during induction (4% isoflurane) and intubation; in the anesthetized animal (1.5% and 2.5% isoflurane); and during recovery and extubation. Isoflurane produced a significant dose-dependent depression of arterial blood pressure but did not significantly change heart rate from control. Renal sympathetic efferent nerve activity at 1.5% isoflurane was not significantly different from that in conscious animals, but nerve activity at 2.5% isoflurane was depressed significantly from both control and 1.5% isoflurane. Both intubation and extubation were accompanied by an increase in sympathetic nerve activity. Isoflurane appeared to directly depress sympathetic activity at both levels of anesthesia, but the direct depression of activity at 1.5% isoflurane seemed to be countered by reflex increases in sympathetic tone due to the hypotension accompanying the anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of halothane on ganglionic transmission were studied in the stellate ganglion of the guinea pig using intracellular recordings in vitro. Depression of synaptic transmission is one of the actions common to many general anesthetics. The aim of this study was to investigate which of the processes involved in synaptic transmission are affected by halothane in concentrations comparable to those used during surgical anesthesia. The neurons of the stellate ganglion were depolarized using preganglionic nerve stimulation, postganglionic nerve stimulation, and intracellular stimulation before ad after introduction of halothane (vaporizer settings of 0.75% and 1.5% produced bath concentrations of 8 and 18 mg/dl, respectively). Halothane at both concentrations depressed sympathetic ganglionic transmission which was induced by stimulation of preganglionic nerves. Axonal transmission and the excitability of the postganglionic neurons to direct intracellular stimulation was far less sensitive to halothane than synaptic transmission. The depression of ganglionic transmission seen in the present study was most likely due to a decrease in transmitter release although alterations in postsynaptic receptor properties could have been involved as well. The decrease in sympathetic activity resulting from depression of ganglionic transmission probably contributes to the arterial hypotension seen during halothane anesthesia, along with direct myocardial depression, inhibition of catecholamine release from the adrenal medulla, direct action on vascular smooth muscle, and central sympathetic depression.

We examined how changes in solution pH alter myocardial cell action potentials (AP) with and without changes in free [Ca2+] caused by pH induced effects on calcium binding. Guinea pig ventricular tissue was isolated, superfused either with Krebs-Ringer (K-R) bicarbonate, phosphate buffered solution, or with Hepes buffered solution, and electrically paced during control (5% CO2 in O2), acidic (12% CO2), and alkalotic (0% CO2) conditions. Action potentials were recorded with intracellular microelectrodes. Extracellular free [Ca2+] was measured with a calcium ion selective electrode and total soluble calcium was measured by ultrafiltration and spectrophotometry. With a total [CaCl2] of 2.5 mM in the K-R solution, we found a free [Ca2+] of 2.14 mM at pH 7.44 (control), 2.48 mM at pH 6.97 and 1.60 mM at pH 8.19; total soluble calcium concentration was 2.00 mM at pH 8.19. In the Hepes solution, free [Ca2+] was only slightly altered (2.42 to 2.55 mM) within this pH range. Equivalent acidosis of either K-R or Hepes suffusate significantly, and similarly, prolonged the AP and its refractory period. Alkalosis of the Hepes suffusate shortened the AP; but equivalent alkalosis of the K-R suffusate prolonged the AP as did a reduction of [CaCl2] in Hepes suffusate from 3.0 to 1.5 mM at pH 7.43. Our study demonstrates that a paradoxical increase in APD occurs because free Ca2+ ion activity falls in K-R solution and overrides the effect of alkalosis alone to decrease APD.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Intracellular recordings were made, in vitro, and in situ, from neurones of the cat stellate ganglion. 2. Preganglionic stimulation, in vitro, via the T3 ramus or post-ganglionic stimulation via the ventral ansa, dorsal ansa or stellate cardiac nerve evoked graded synaptic responses which led to the discharge of one or more action potentials. Since the conduction velocities of fibres converging onto a single cell may vary, their convergence may mean that there is an interaction in the stellate ganglion between functionally different pathways. 3. Most neurones in the stellate ganglion receive synaptic input from fibres of both central and peripheral origin. 4. Intracellular recordings were made, in situ, from neurones of the cat stellate ganglion attached via the stellate cardiac nerve to the rest of the animal. When peripheral sympathetic afferent input to the stellate ganglion was increased by occluding the descending aorta, some of the neurones exhibited an increase in excitatory post-synaptic potentials (e.p.s.p.s) and/or action potentials. Most of the synaptic input recorded from the ganglion cells in situ had a close relationship with the cardiac cycle and/or respiration. 5. These data and our previous studies support the contention that sympathetic efferent nerve activity can be modified by peripheral excitatory inputs and that these neural connexions may function as pathways for a peripheral reflex at the level of the paravertebral ganglion.