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The authors examined and compared the direct effects of three volatile anesthetic agents and three sympathomimetic agonists on transmembrane action potential (AP) characteristics and automaticity of sinoatrial (SA) nodal pacemaker cells. SA nodal tissue was isolated from guinea pig hearts and suffused in vitro with oxygenated Krebs-Ringer solution. Electrophysiologic variables measured were: amplitude of the AP, slopes of phase 4 and of phase 0 of the AP, AP duration, and spontaneous sinus rate. The authors found that 1 and 2 MAC equivalents of each anesthetic, 0.8 and 1.6 vol % halothane, 1.4 and 2.8 vol % isoflurane, and 1.7 and 3.4 vol % enflurane similarly depressed the slopes of phase 4 and 0 of the AP, prolonged AP duration, and slowed the sinus rate at 1 and 2 MAC equivalents. Isoproterenol, 0.25 microM, and epinephrine, 50 microM, maximally enhanced the slopes of phase 4 and 0 of the AP, shortened AP duration, and increased the sinus rate, but phenylephrine, 50 microM, only moderately increased the slope of phase 4 and the sinus rate. Each of the three anesthetics caused baseline depressions of phase 4 and phase 0 slopes and of automaticity of SA nodal cells; the fall in sinus rate was counteracted, but was not reversed maximally by increasing the concentrations of isoproterenol, epinephrine, or phenylephrine. Regression analyses of linearly transformed data showed that each of the anesthetics similarly depressed basal sinus rate, so that changes in rate produced with isoproterenol and epinephrine were not different from those observed with beta agonists in the absence of anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of halothane on cat papillary muscle were studied in vitro at different pacing rates (60, 75, 100, and 150 beats/min). Simultaneous measurements of transmembrane potentials, intracellular Ca2+ transients, and isometric tension were made before and after introduction of 1 and 2 minimal alveolar concentration halothane. Anesthetic concentrations in the superfusion bath were measured using a gas chromatography procedure. The Ca2+-sensitive photoprotein, aequorin, was microinjected into papillary muscle cells. Aequorin light emission is a function of free intracellular [Ca2+] [( Ca2+]i). The most prominent effects of halothane were a dose-dependent decrease in the contractile force and a decrease in [Ca2+]i, at all pacing rates. The negative inotropic effect of halothane was associated with only small changes in the papillary muscle action potential duration. Increasing the extracellular [Ca2+] produced an increase in [Ca2+]i and counteracted the negative inotropic effects of halothane. Addition of the Ca2+ channel blocker, verapamil, and halothane, produced an additive decrease in [Ca2+]i compared with the control.

We examined the dynamic changes in venous outflow from the splanchnic and extrasplanchnic vascular beds in response to carotid sinus (CS) baroreflex and left ventricular (LV) distension in 12 dogs anesthetized with pentobarbital sodium. Splenic sympathetic nerve activity was measured in an additional group of six dogs. A heart-lung bypass was used with constant cardiac output and constant venous pressure. LV distension was produced by inflating a balloon in the LV. LV distension and an increase in CS pressure from 50 to 200 mmHg decreased blood pressure by 26 +/- 5 and 30 +/- 6 mmHg and increased vascular capacitance by 5.5 +/- 0.9 and 4.5 +/- 1.2 ml/kg, respectively. Splanchnic venous outflow exhibited a transient decrease, whereas extrasplanchnic venous outflow showed a transient increase, in response to LV distension and increasing CS pressure, accompanied by a sustained decrease in splenic nerve activity. The results indicate important differences between splanchnic and extrasplanchnic components of the total venous system in terms of the regulation of venous capacitance. It is suggested that changes in venous capacitance produced by LV distension and CS baroreflex are primarily due to active changes in splanchnic venous tone.

High blood concentrations of local anesthetics are cardiotoxic. The aim of this study was to compare the effects of lidocaine and bupivacaine on the intrinsic pacemaker activity of in vitro sinoatrial nodal cells of the adult and neonatal guinea pig in the presence and absence of hypoxia and acidosis. Fifteen pairs of adult (greater than 80 days old) and neonatal (0-3 days old) hearts were isolated. Nodal tissues were suffused with Krebs-Ringer solution at 37 degrees C and exposed to increasing concentrations of either lidocaine (0.05-0.8 mM) or bupivacaine (0.01-0.4 mM). The suffusate was equilibrated either with 5% CO2, 95% O2 (pH 7.40, PO2 482 torr) or with 12% CO2, 88% N2 (pH 7.01, PO2 58 torr). Transmembrane action potentials were recorded from sinoatrial nodal cells and impulse intervals were converted to rates. We found that hypoxia and acidosis alone reduced rates in both adults and neonates, and that the reduction was additive to the effects of local anesthetics. Bupivacaine was 4-5 times more potent in decreasing rates than was lidocaine in both age groups. Lidocaine was about twice as effective in depressing neonatal rates as adult rates, and bupivacaine caused cessation of pacemaker activity in a greater percentage of nodes than did lidocaine. Our results demonstrate, in vitro, that the neonatal sinoatrial node is more sensitive to lidocaine and bupivacaine than is the adult node, that bupivacaine is more potent in depressing and stopping nodal activity, and that hypoxia and acidosis enhance pacemaker depression caused by these agents.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of sustained lung inflation on systemic vascular capacitance (SVC), systemic vascular resistance (SVR), and cardiac sympathetic efferent nerve activity (SENA) were investigated in anesthetized dogs. By use of a total cardiopulmonary bypass, the lungs were inflated to tracheal pressures of 10, 15, and 20 mmHg. Tracheal pressures of 10, 15, and 20 mmHg increased system vascular capacitance by 1.4, 3.1, and 4.3 ml/kg and decreased systemic vascular resistance by 0.11, 0.15, and 0.16 mmHg.kg.min-ml-1, respectively, at low carotid sinus pressure (CSP) of 41 mmHg. SENA showed a concomitant decrease. Bilateral vagotomy attenuated the change in SVR by 69%, SVC by 62%, and SENA by 97% when lungs were inflated to a tracheal pressure of 20 mmHg at a low CSP. These results indicate that lung inflation causes a reflex induced increase in SVC as well as a decrease in both SVR and SENA. The lung inflation reflex is mediated primarily through vagal afferent nerve fibers with a small contribution from other afferent nerve pathways.

In vitro studies were conducted on the middle cervical ganglion (MCG) of the cat by recording intracellular action potentials from its neurons. The purpose of this study was to examine the possibility of a peripheral synaptic input to the MCG. Preganglionic electrical stimulation, via the ventral ansa (VA) and dorsal ansa (DA) subclavia, and post-ganglionic electrical stimulation, via the ventrolateral cardiac nerve (VCN), evoked graded synaptic responses that led to the discharge of one or more action potentials in the 14 ganglia studied. The conduction velocity of these pathways ranged from 0.4 to 0.9 m/s. Ten percent of the cells impaled were inexcitable, even with direct intracellular depolarizing current, whereas 80% of the neurons studied received a synaptic input from fibers of both central and peripheral origin. In addition, subthreshold synaptic inputs from peripheral and central origin sum to discharge the cell, suggesting an integration of neural inputs in the MCG. These responses were blocked by d-tubocurarine chloride. This evidence indicates that sympathetic efferent nerve activity can be modified by peripheral excitatory inputs and that these inputs may function as pathways for a peripheral reflex at the level of the MCG.

The effects of autonomic efferent stimulation on refractoriness of the specialized His-Purkinje system were examined in open-chest dogs anesthetized with 1.0% halothane. In eight animals submaximal bilateral stimulation of the ventral ansae subclavia decreased (P less than or equal to 0.01) the average functional refractory period for the propagation of His bundle extrastimuli to five ventricular recording sites (HP-FRP) by 10.9 +/- 0.6 ms. Submaximal stimulation of the decentralized vagal nerves that produced first degree atrioventricular block did not affect ventricular refractoriness. Combined vagosympathetic stimulation produced a smaller (P less than or equal to 0.01) decrease of the average HP-FRP (7.2 +/- 1.1 ms) than that produced by sympathetic stimulation alone. Administration of atropine abolished (P less than or equal to 0.05) vagal antagonism of the shortening effect of isoproterenol on the average HP-FRP. Treatment with propranolol reversed (P less than or equal to 0.01) the sympathetic effect on the average HP-FRP and nonuniformly increased refractoriness in the His-Purkinje system. The latter changes were abolished (P less than or equal to 0.05) by infusion of phentolamine. The autonomic nervous system modulates His-Purkinje refractoriness by actions mediated by cholinergic and both alpha- and beta-adrenergic receptors.

We have directly demonstrated that the mesenteric veins actively constrict and dilate in response to reflex stimuli in the in situ preparation. A segment of small intestine of 23 chloralose-anesthetized rabbits was exposed in a specially designed bath. Small vein diameter and intravenous pressure (575-1,375 microns and 6.2-11.4 mmHg at rest, respectively) of the mesentery were measured continuously at the same site with the use of videomicrometer and micropressure systems during celiac ganglion stimulation (CGS), bilateral carotid occlusion (BCO), and aortic nerve stimulation (ANS). Innervation to the mesenteric vein was evident by a frequency-dependent venoconstriction in response to CGS, which was completely abolished by local application of tetrodotoxin. Vein diameter and intravenous pressure changed from an average of 1,042 +/- 32 to 1,003 +/- 32 microns (-3.8 +/- 0.3%, P less than 0.01) and from 8.1 +/- 0.3 to 9.0 +/- 0.3 mmHg (10.6 +/- 0.8%, P less than 0.01), respectively, during BCO. During ANS, vein diameter increased from 990 +/- 32 to 1,012 +/- 31 microns (2.4 +/- 0.2%, P less than 0.01), and intravenous pressure decreased from 8.5 +/- 0.3 to 7.9 +/- 0.2 mmHg (-6.1 +/- 0.6%, P less than 0.01), respectively. Vein diameter changes of -3.8 and 2.4% corresponded to volume changes of -7.6 and 4.9%, respectively. During BCO, vein diameter decreased while intravenous pressure increased, whereas during ANS vein diameter increased while intravenous pressure decreased. These results indicate that the reflex change in vein diameter is due to an active response.

Fetal bradycardia during parturition may result both from autonomic reflex effects and from the direct effect of hypoxia on the myocardium. To compare the relative sensitivities of neonatal and adult sinoatrial nodes to hypoxia, action potentials were recorded simultaneously from isolated neonatal and adult sinoatrial nodal tissues of the guinea pig with intracellular microelectrodes. Action potential rates were measured during normoxia and hypoxia, with and without acidosis, glucose, and epinephrine. Control (PO2 greater than 450 torr) intrinsic pacemaker activity was higher in the neonate than in the adult (296 versus 222 beats per minute). Epinephrine maximally increased rates to similar levels in the two age groups. Hypoxia (PO2 equals 33 torr) markedly lowered adult (44%) and neonatal (35%) rates, but the fall in rates was similar. The addition of acidosis or the removal of glucose during hypoxia produced a greater fall of pacemaker rates in the neonates compared with the adults. The addition of epinephrine during hypoxia caused adult rates to increase to control normoxic levels, but neonatal rates remained significantly depressed below control levels. The results suggest that the neonatal pacemaker node is no better protected against bradycardia during hypoxia alone than is the adult node, but that the neonatal node is more susceptible to bradycardia induced by hypoxia with acidosis or removal of glucose. The hypoxic neonatal node, moreover, responds with a lesser increase in pacemaker rate during epinephrine stimulation than does the adult node.

The reflex effects of left ventricular distension on venous return, vascular capacitance, vascular resistance, and sympathetic efferent nerve activity were examined in dogs anesthetized with sodium pentobarbital. In addition, the interaction of left ventricular distension and the carotid sinus baroreflex was examined. Vascular capacitance was assessed by measuring changes in systemic blood volume, using extracorporeal circulation with constant cardiac output and constant central venous pressure. Left ventricular distension produced by balloon inflation caused a transient biphasic change in venous return; an initial small increase was followed by a late relatively large decrease. Left ventricular distension increased systemic blood volume by 3.8 +/- 0.6 mL/kg and decreased systemic blood pressure by 27 +/- 2 mmHg (1 mmHg = 133.3 Pa) at an isolated carotid sinus pressure of 50 mmHg. These changes were accompanied by a simultaneous decrease in sympathetic efferent nerve activity. When the carotid sinus pressure was increased to 125 and 200 mmHg, these responses were attenuated. It is suggested that left ventricular mechanoreceptors and carotid baroreceptors contribute importantly to the control of venous return and vascular capacitance.

The aim of this study was to investigate which of the processes involved in synaptic transmission are affected by morphine in concentrations comparable to those used during surgical procedures. The effects of morphine sulfate on ganglionic transmission were studied in the stellate ganglion of the cat using intracellular and extracellular recordings in vitro. The neurons of the stellate ganglion were depolarized using preganglionic nerve stimulation, postganglionic nerve stimulation, and intracellular stimulation before and after introduction of morphine sulfate (up to 20 micrograms/mL). Tissue concentrations of morphine were estimated using radiolabeled morphine. Axonal transmission and the excitability of the postganglionic neurons to direct intracellular stimulation was not affected at the concentrations of morphine studied. In addition, morphine had a dose-dependent depolarizing effect on the resting membrane potential of most of the neurons in the stellate ganglion. Such neuronal depolarizations alone could initially produce excitation in some cell populations, followed by inhibition, secondary to the membrane depolarization, leading to depression of sympathetic nerve activity. The overall ganglionic transmission as recorded using an evoked potential was biphasic. At low doses morphine facilitated transmission, while at larger doses morphine attenuated evoked potentials. These effects do not appear to be mediated through classical opiate receptors since they are not blocked by naloxone.

Depression of synaptic transmission is one of the actions common to many general anesthetics. They appear to act primarily on the chemical transmission process itself without affecting the conduction of impulses in nerve axons. The objective of the present study was to directly examine the effects of halothane on the release of acetylcholine and overall ganglionic transmission. The effects of halothane on ganglionic transmission were studied in the stellate ganglion of the cat in vitro. The preganglionic nerves of the stellate ganglion were stimulated electrically to generate threshold and suprathreshold evoked potentials in the postganglionic nerves. The picomole levels of released acetylcholine in the superfusate were determined with a radioenzymatic method using 32P-ATP following a 5-min preganglionic stimulation before and after the addition of 0.28 and 0.59 mM halothane (vaporizer settings of 1% and 2%, respectively). Halothane at both concentrations: 1) depressed sympathetic ganglionic transmission induced by either threshold or suprathreshold stimulation of the preganglionic nerves; and 2) caused a dose-dependent decrease in acetylcholine release during threshold stimulation with no change in neurotransmitter release during suprathreshold stimulation. In summary, the interruption of synaptic transmission by halothane involves at least two mechanisms: 1) decrease in acetylcholine release during low level of synaptic transmission; and 2) postsynaptic decrease in sensitivity to acetylcholine during low and high levels of synaptic transmission.

Histamine is released during allergic reactions, and is known to produce cardiac dysrhythmias. The authors compared the cardiac effects of histamine and epinephrine during exposure to halothane in the isolated perfused guinea pig heart. Responses studied were spontaneous sinus rate, intra-atrial conduction time, atrial-septal conduction time (ASCT), intraventricular conduction time (IVCT), and left ventricular pressure (LVP). The incidence and type of dysrhythmias with histamine and halothane and with epinephrine and halothane were analyzed from electrograms. The authors found that halothane alone (0.7 to 2.1 vol%) causes dose-dependent depressions of sinus rate and LVP, prolongs ASCT and IVCT, and produces atrioventricular (AV) block with junctional bradycardia. Histamine alone (.01-10 microM) increases sinus rate and LVP but, like halothane, prolongs ASCT. Halothane antagonizes the inotropic and chronotropic effects of histamine, but enhances ASCT compared with histamine alone. Histamine with halothane greatly increases the incidence of junctional tachycardia with AV dissociation from 0% with histamine alone up to 48%. Epinephrine alone (0.1-5 microM), like histamine, increases sinus rate and LVP, but does not cause a relative increase in ASCT. Halothane antagonizes the inotropic and chronotropic effects of epinephrine, but increases the incidence of ventricular tachycardia from 6% to 28%, and the incidence of premature ventricular excitations from 0% to 40%, compared with epinephrine alone. The authors' in vitro findings show that histamine and halothane, like epinephrine and halothane, can cause dysrhythmias, but that the genesis and type of dysrhythmias induced by these agents are dissimilar. Consequently, the release of histamine with an anaphylactoid reaction during halothane anesthesia, and the treatment of the reaction with epinephrine, could result in dangerous ventricular tachydysrhythmias.

In vitro studies of pharmacologic actions of local anesthetics are usually performed at room temperature using amphibian nerves exposed to local anesthetics for substantial periods of time. We performed in vitro studies of pharmacologic responses of motor A fibers and sensory C fibers to lidocaine and bupivacaine in clinically effective concentrations using a canine nerve preparation at body temperature with short exposure times to evaluate responses under clinically relevant conditions. Differential blockade of isolated, desheathed phrenic and vagus nerves was achieved with bupivacaine (0.58 mM), C fibers being blocked before A fibers (P less than 0.05). Lidocaine (2.8 mM) did not block A and C fibers differentially.

Studies of the stellate ganglion and middle cervical ganglion indicate that sympathetic efferent nerve activity can be modified by peripheral excitatory inputs and that these neural connections may function as pathways for a peripheral reflex at the level of the thoracic sympathetic ganglia. This excitatory synaptic input could have a soma in either the central or the peripheral nervous system. A study was designed to determine whether chronic decentralization (3 weeks) of the stellate ganglion in cats would 1) abolish sympathetic cardiac afferent nerve activity recorded at the stellate cardiac nerve and 2) abolish local thoracic reflexes that are generated by stimulation of peripheral nerves. The ansae subclaviae, T3 and T4 rami, and stellate ganglion were also examined by electron microscopy for the extent of Wallerian degeneration. Afferent cardiac activation of the axon collaterals arising from cell bodies located in the dorsal root ganglia was abolished due to degeneration. However, sympathetic afferent nerve activity from the left ventricular receptors was still present and was recorded from the stellate cardiac nerve in all cats. Cardiac receptors were sensitive to mechanical distortion, increases in the left ventricular pressure, and epicardial application of veratrine hydrochloride. These data imply that 1) cardiovascular afferent input to the stellate ganglion persists following chronic decentralization and 2) the sensory neurons are located in the peripheral sympathetic nervous system. Thus, we find that regulation of the heart occurs in part via thoracic ganglia, independently of the central nervous system.

Both halothane (HAL) and acid-base changes produce cardiac arrhythmias in humans. The authors' aim was to determine if HAL alters the effects of hypercapnic acidosis and hypocapnic alkalosis on action potential (AP) properties of ventricular muscle fibers. They superfused the paced right ventricle of 15 guinea pig hearts with non-HCO3- buffered salt solution and recorded transmembrane APs with 3 M KCl microelectrodes in 35 subendocardial cells. Random changes in the fractions of HAL were made during low (12% CO2 in O2), normal (5% CO2 in O2), and high (0% CO2 in O2) pH. Compared with controls at pH 7.44, AP duration (APD) and effective refractory period (ERP) significantly decreased by 7 and 4% at pH 8.08 and increased by 7 and 9% at pH 7.09. At pH 7.44, 0.7-2.1% HAL produced no change in APD; but 2.1% increased ERP, while 3.5% HAL decreased ERP. At pH 8.08, the decrease in ERP induced with alkalosis alone was converted to an increase with 1.4 and 2.1% HAL. At pH 7.09, 0.7-1.4% HAL had no additional effect on the acidosis-induced increases in APD and ERP, but 2.1 and 2.8% HAL greatly reduced these responses. At HAL fractions greater than 1.4% the marked inverse changes in APD and ERP, induced alone by acidosis and alkalosis, were no longer significantly different from control. This study shows that the opposing effects of alkalosis to shorten and of acidosis to lengthen APD and ERP were attenuated at low levels and abolished at high levels of HAL.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of 0.39 mM halothane (approx. 1.1 vol%) on the action potentials of proximal (false tendon) and distal (apical) left ventricular Purkinje fibers were compared in analogous in vitro preparations derived from normal dogs and animals surviving 1 day following acute myocardial infarction. In ten noninfarcted hearts, halothane reduced regional differences in repolarization by decreasing action potential duration (APD90, mean +/- SE) in proximal fibers from 300 +/- 7 to 277 +/- 6 msec (P less than or equal to 0.01) without decreasing APD90 in distal fibers (control 240 +/- 4 msec, halothane 249 +/- 5 msec). In ten infarcted hearts, halothane accentuated pathologic differences in repolarization by decreasing APD90 in the non-ischemic proximal fibers from 311 +/- 8 to 287 +/- 7 msec (P less than or equal to 0.01), while increasing APD90 in the ischemic distal fibers from 375 +/- 15 to 406 +/- 18 msec (P less than or equal to 0.01). Halothane also decreased the overshoot from 32.9 +/- 1.0 to 28.4 +/- 0.8 m V (P less than or equal to 0.01) and Vmax from 356 +/- 28 to 300 +/- 22 V/s (P less than or equal to 0.05) in ischemic fibers. In seven infarcts evaluated by extrastimulus techniques, halothane slowed the conduction of premature impulses and prolonged refractoriness, while, in five of the seven hearts, it reversibly increased the range of coupling intervals which induced probable reentrant responses. In a separate study of seven infarcts, halothane decreased the rate of spontaneous activity originating in the ischemic region. It is concluded that halothane facilitates the occurrence of re-entry while inhibiting the initiation of abnormal impulses in the in vitro canine infarction model.

The direct cardiac effects of volatile anesthetics and calcium channel blockers are obscured in vivo by autonomic reflexes and other extrinsic influences. The authors examined the direct in vitro effects of verapamil and the volatile anesthetics, halothane (HAL), enflurane (ENF), and isoflurane (ISO), in the isolated guinea pig heart. Each heart (N = 36) was perfused at constant pressure with an oxygenated Krebs-Ringer solution at 36 degrees C. Recording electrodes were placed in the right atrium, septum, and right ventricular wall. Left ventricular pressure (LVP) and coronary flow were measured. The combination of 75 or 150 ng/ml verapamil and 0.7 or 1.4 minimum alveolar concentrations (MAC) of each of the three anesthetics dose-dependently depressed spontaneous atrial rate (HR) and peak LVP, and prolonged atrial-septal (AV) time and intraventricular conduction time (IVCT). ENF decreased HR and LVP and increased IVCT more than did HAL or ISO at each anesthetic level. The combination of either level of ENF and 150 ng/ml verapamil reduced HR more than did the same level of verapamil with HAL or ISO; 1.4 MAC ENF with 150 ng/ml verapamil also caused sinus arrest in 17% of hearts. Although ENF, HAL, and ISO alone similarly depressed AV time, 1.4 MAC ENF synergistically increased, and 1.4 HAL and ISO additively increased, the delay in AV time due to each level of verapamil. In addition, 1.4 MAC ENF caused significant 25% and 67% incidences of complete AV block with low and high verapamil levels, respectively. Both levels of ENF with verapamil also increased IVCT more than did HAL or ISO with verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

The present study was performed to determine the extent and mechanism of carotid sinus baroreceptor sensitization due to halothane in an isolated, denervated carotid sinus in anesthetized dogs (thiopental 25 mg/kg; 5 mg X kg-1 X h-1, maintenance dose). Efferent sympathetic nerves to the sinus were sectioned to eliminate the contribution of these fibers to any sensitization observed. Halothane (H) administration was localized to the carotid sinus by an isolated perfusion system. The perfusion system was used to make standardized sine wave changes in carotid sinus pressure. Carotid sinus afferent nerve activity from single or few-fiber nerve preparations was recorded during carotid sinus pressure changes and the slopes of nerve activity versus carotid sinus pressure were used to determine the gain, or sensitivity, of the baroreceptors. The addition of 0.75% H and 1.5% H to the sinus perfusion produced a dose-dependent sensitization of the baroreceptors. A greater increase in carotid sinus afferent nerve activity for a given increase in sinus pressure was used as an indication of an increase in receptor sensitivity, or sensitization. In the presence of sodium nitroprusside, given in doses to maximally dilate the sinus prior to H administration, only 1.5% H produced baroreceptor sensitization. This suggests the changes in sinus wall tension due to halothane may have contributed to the sensitization seen during H administration. The remaining sensitization at 1.5% H was eliminated in the presence of nitroprusside and 7.5 mM Ca++. This remaining sensitization therefore appears to be Ca++-related and may be due to direct effects of H on the baroreceptors.

The effects of three hypotensive agents, sodium nitroprusside (SNP), nitroglycerin (NTG), and adenosine triphosphate (ATP), on blood flow distribution and vascular capacitance were examined in dogs anesthetized with sodium pentobarbital. To eliminate the modification by the baroreflex, carotid sinus was denervated and aortic and cardiopulmonary vagal fibers were sectioned. Total systemic circulation was divided into two parallel compartments, splanchnic (SP) and extra-splanchnic (ESP) vascular beds. Alteration of vascular capacitance was assessed by a change in systemic blood volume with constant cardiac output and constant venous pressure using a total heart-lung bypass. SNP- and ATP-induced hypotension caused blood flow redistribution from the SP to ESP beds, and this redistribution is greater (P less than 0.01) with ATP than that with SNP. In contrast, NTG-induced hypotension did not significantly cause redistribution. Systemic blood volume was increased during NTG- (10.4 +/- 2.2 ml/kg), and SNP-induced (4.8 +/- 1.1 ml/kg) hypotension. The increase by NTG was significantly greater (P less than 0.05) than that by SNP. In contrast, ATP-induced hypotension did not significantly change systemic blood volume. Since redistribution can result in a passive change in vascular capacitance, the differences in capacitance among SNP, NTG, and ATP can be explained in part by differences in redistribution of blood flow. Redistribution of blood flow from SP to ESP beds can increase venous return due to increasing the slope of the venous return curve. The results suggest that redistribution should be taken into consideration in evaluating the hemodynamic changes during induced hypotension.

This study was performed to test the hypothesis that halothane inhibits calcium accumulation associated with myocardial ischemia and calcium paradox. Using a Langendorff preparation in isolated guinea pig hearts, tissue 45Ca was measured after 40 and 60 min of loading with 45Ca, followed by 20 min of washout period. Myocardial ischemia was produced by a 30-min occlusion of the left anterior descending coronary artery (LAD). LAD occlusion caused an increase in 45Ca content in the anterior left ventricular muscle (ischemic area) of 215% compared to that of the posterior left ventricular muscle (normal myocardium). The increase in 45Ca content in the ischemic area was significantly less (P less than 0.05) in the presence of halothane (1%) compared to the non-halothane group. Halothane did not significantly alter 45Ca content in the non-ischemic myocardium. Myocardial injury associated with calcium paradox, which was produced by a 10-min perfusion of the heart with calcium-free Krebs solution followed by normal calcium repletion, caused a significant increase (P less than 0.05) in the 45Ca content compared to control. Addition of halothane (1%) significantly depressed (P less than 0.05) the increase in 45Ca content caused by calcium paradox. It is suggested that halothane might inhibit calcium accumulation associated with myocardial ischemia and calcium paradox under certain experimental situations. The inhibitory effect of halothane on calcium accumulation may be beneficial for the ischemic heart during halothane anesthesia.

The baroreceptor reflex has been found to be attenuated during anesthesia, but the effects of the relatively new anesthetic, isoflurane, on baroreflex function have not been examined thoroughly. This study was performed to determine the effects of isoflurane on each component of the baroreceptor reflex arc, including the receptors, afferent and efferent nerve pathways, central integratory centers, peripheral ganglia, and the heart. Baroreflex effects on heart rate initiated by systemic pressure changes were examined in conscious and anesthetized dogs (1.3% and 2.6% isoflurane). The effects on individual components of the reflex arc were determined by examining carotid sinus baroreceptor afferent activity, sympathetic efferent nerve activity, and heart rate response to direct sympathetic and parasympathetic efferent nerve stimulation in anesthetized dogs. Preganglionic and postganglionic nerve activities were recorded simultaneously during baroreflex activation to determine ganglionic effects of isoflurane. Baroreflex-induced changes in heart rate were not depressed significantly until 2.6% isoflurane if blood pressure changes due to anesthetic administration were prevented. Significant decreases in baseline sympathetic efferent nerve activity were found at 1.3% and 2.6% isoflurane, with depression of postganglionic activity significantly greater than preganglionic activity at 2.6% isoflurane, indicating a ganglionic effect of isoflurane. Cardiac chronotropic responses to direct stimulation of sympathetic and vagal fibers were attenuated significantly by isoflurane, with sympathetic stimulation showing the greater sensitivity to the anesthetic. Carotid baroreceptor afferent activity was increased by isoflurane, and this sensitization of the baroreceptors appeared to contribute to the decreased levels of sympathetic tone. Therefore, although isoflurane was found to alter the baroreceptor reflex through its effects at multiple sites of the baroreflex arc, significant depression of the cardiac chronotropic component of the reflex was seen only at 2.6% isoflurane.