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In addition to central effects, which are the basis of their use in anesthesiology, alpha 2-adrenergic agonists have direct peripheral cardiovascular effects. Dexmedetomidine (DM) has been found to depress cardiac function in dogs, even after autonomic denervation. The present experiments evaluated the effects of DM on coronary flow, myocardial oxygen extraction, and cardiac function in intact, open chest dogs under enflurane anesthesia. Heart rate (HR), mean arterial pressure (MAP), left ventricular end-diastolic pressure (LVEDP), the first derivative of systolic left ventricular pressure (dP/dtmax), and flow in the left anterior descending coronary artery (CBF) were measured and continuously recorded. Cardiac output (CO), plasma catecholamines (CA), hemoglobin and oxygen saturation in arterial, mixed venous, and coronary sinus blood were measured at intervals. Cardiac index (CI), systemic vascular resistance index (SVRI), regional coronary vascular resistance (CVR), and oxygen concentration differences across the systemic [C(a-v)O2], and coronary [C(a-cs)O2] circulations were calculated. DM doses of 0.25, 0.5, 1.0, 2.0, and 4.0 micrograms/kg were given IV at 20-minute intervals. Measurements and samples were taken at peak drug effects and just prior to the next dose. The alpha 2-antagonist atipamezole, 0.5 mg/kg, was given after the last dose of DM. DM caused immediate dose-dependent increases in SVRI, CVR, LVEDP, C(a-v)O2, and C(a-cs)O2, and decreases in HR, and CI, with recovery between doses. DP/dtmax declined after the first two doses and stabilized thereafter, as plasma CA fell to minimal levels. Atipamezole completely reversed all changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexmedetomidine (DM) was studied in the isolated dog heart in the form of a Starling heart-lung preparation, (HLP). Hearts were subjected to increased loading by (a) increasing cardiac output, and (b) increasing systemic resistance. Results are depicted by cardiac function curves, prepared by plotting left atrial pressure against either systemic cardiac output or mean arterial pressure. DM, given in divided doses up to 44 micrograms, had no effect on heart rate or cardiac function, nor did injection of 0.5 mg of atipamezole, a selective alpha 2-antagonist. Additional injections of very large doses of DM, up to 4,444 micrograms, caused an increase in heart rate and a leftward shift of the function curves, ie, positive chronotropic and inotropic effects. Plasma catecholamine levels increased markedly between the 444 micrograms and the 4,444 micrograms cumulative doses of DM. Administration of 1 mg of prazosin had no effect, but 1 mg of propranolol returned the rate to baseline and markedly shifted function curves to the right and depressed their slopes. Thus, whereas low doses (corresponding to between 1 and 30 micrograms/kg in intact animals) of DM, given acutely IV, have been shown to depress cardiac function in intact and denervated dogs, this effect is not due to a direct effect on the myocardium. High doses, far beyond doses maximally effective in intact animals and man, release catecholamines from cardiac stores. Plasma DM levels after low doses in the HLP were between 1 to 10 times those seen in intact animals and human volunteers after the usual doses given clinically for their central effects. Because DM caused no myocardial depressant effect in the isolated, blood-perfused canine HLP, decreases in cardiac function seen after this drug is given to intact and autonomically denervated dogs must be due to factor(s) other than a direct action on the myocardium.

The hemodynamic effects of the alpha 2-adrenergic agonist, dexmedetomidine (DM), were studied in eight anesthetized, autonomically denervated dogs. Autonomic block decreased mean arterial pressure (MAP) and cardiac index (CI) by approximately 20% to 95 +/- 8 mm Hg and 4.1 +/- 0.1 L/min/m2, respectively (mean +/- SEM), and reduced norepinephrine (NE) and epinephrine plasma levels to almost undetectable levels. DM, administered intravenously (i.v.) either by bolus injection or by slow (20 min) infusion in doses between 1 and 30 micrograms/kg, had no effect on heart rate (HR), increased MAP significantly by 98%, decreased CI by 59%, and increased calculated systemic vascular resistance index (SVRI) significantly by 376%, maximally. The effect of the lowest dose was mediated mainly by arteriolar vasoconstriction, and that of higher doses was mediated by vasoconstriction and decreased CI. Left ventricular end-diastolic pressure (LVEDP) increased significantly from 6 +/- 2 to greater than 30 mm Hg. maximally. The effects were cumulative, and the first dose caused near maximal pressor effect; the resistance increase was as great with slow infusion as with bolus injection. Prazosin (1 mg/kg) did not affect the changes, but 0.3 mg/kg atipamezole, a selective alpha 2-antagonist, completely antagonized them. These observations demonstrate potent constriction of both arteriolar resistance and venous capacitance vasculature in dogs. The combination of decreased CI and increased filling pressure implies marked decrease in cardiac function which was, however, fully reversible by atipamezole.

Reversal of opioid effects by naloxone (NX) can lead to significant cardiovascular problems. We have reported previously that hypercapnic dogs develop greater increases in blood pressure and plasma catecholamine (CA) levels than hypocapnic ones when reversed with naloxone. We have also demonstrated differences between NX and nalbuphine (NBPH) in producing excitatory adrenergic responses when administered during normocapnia. The present study was designed to investigate possible dissimilarities in cardiovascular and sympathetic events after administration of either NX or NBPH in dogs made hypercapnic following fentanyl administration. After induction of anaesthesia with thiopentone and intubation, two groups of dogs were maintained with controlled ventilation on enflurane in oxygen anaesthesia and given 50 micrograms.kg-1 fentanyl IV. This caused a significant decrease in heart rate (HR) (P less than 0.001), mean arterial blood pressure (MAP) (P less than 0.001), and plasma concentrations of norepinephrine (NE) (P less than 0.002). Then, ventilation was decreased to produce a PaCO2 of 60 mmHg; this was accompanied by a significant elevation in plasma level of both epinephrine (EPI) (P less than 0.02) and NE (P less than 0.001). Administration of 20 micrograms.kg-1 NX to six dogs resulted in immediate increases in HR (P less than 0.01) and MAP (P less than 0.01), and a further rise in CA levels to greater than pre-fentanyl baseline values. In six other dogs, NBPH (0.3 mg.kg-1) caused increases in HR (P less than 0.001) and MAP (P less than 0.001) only, and the MAP rise was significantly less than that seen in the NX group (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil may have application in the field of obstetrics for treatment of maternal and fetal tachyarrhythmias. This study was performed to assess the maternal and fetal hemodynamic effects of this drug, as well as to determine its placental transfer and effects on maternal and fetal atrioventricular conduction in the pregnant ewe. Verapamil, 0.2 mg/kg, administered intravenously over 3 min, resulted in a transient decrease in maternal mean and diastolic blood pressures. There was, however, no significant change in fetal systolic, diastolic, and mean blood pressures. Maternal and fetal heart rates also were unchanged throughout the experiment. Atrioventricular conduction, assessed by measurement of PR intervals, was prolonged in both the ewe (41%) and the fetus (78%). Placental transfer of verapamil was limited, as shown by the umbilical vein to uterine artery drug concentration ratios of 0.35-0.45 throughout most of the experiment. Fetal hepatic extraction of the drug appeared to be substantial, since the drug concentration in the fetal carotid artery was less than that of the umbilical vein at 1, 3, and 5 min after drug injection.

The antiarrhythmic and cardiovascular effects of the slow channel inhibitor, verapamil, were studied during 1.1 MAC halothane anesthesia in the dog. The control epinephrine arrhythmogenic dose to induce ventricular arrhythmias was 2.58 +/- 0.77 microgram . kg-1 . min-1 (mean +/- SEM). Three consecutive doses of 0.2 mg/kg verapamil each elevated the dose of epinephrine required to produce a ventricular arrhythmia to 5.17 +/- 1.27, 8.07 +/- 1.85, and 12.03 +/- 2.76 microgram . kg-1 . min-1, respectively, all of which were significantly elevated above the control value of the preceding values. A second group of dogs, unperturbed by epinephrine, received the same sequence of verapamil doses at similar time intervals for evaluation of effects on cardiovascular function and atrioventricular conduction. Heart rate remained unchanged. Mean arterial pressure decreased maximally by 37 per cent of control, left ventricular dP/dt by 24 per cent, and systemic vascular resistance by 51 per cent. These effects were transient with recovery times up to one hour. Central venous pressure increased by 44 per cent and left ventricular end diastolic pressure by 27 per cent, while PR interval was prolonged by 40 per cent. Thus, verapamil raised the dose of epinephrine required to elicit a ventricular arrhythmia during halothane anesthesia promptly and cumulatively. At the same time verapamil produced transient peripheral vasodilation, direct depression of myocardial contractility, and prolongation of atrioventricular conduction time that was not cumulative at the intervals studied.

The effects of clonidine, a potent central alpha-adrenergic agonist, and of tolazoline, an alpha-adrenergic antagonist, on the minimal anesthetic concentration (MAC) of halothane were studied in male mongrel dogs. Control halothane MAC was 0.8 +/- 0.04 vol% (determined in each dog by gas chromatography of arterial blood, n = 30). Clonidine, 5 microgram/kg (n = 10) and 20 microgram/kg (n = 10), give slowly intravenously, maximally reduced MAC by 42% (at 2.3 hours after clonidine) and 48% (at 2.6 hours after clonidine) for each dose. In another set of animals (n = 5) an alpha-adrenergic antagonist, tolazoline, 5 mg/kg IV, reversed the clonidine-induced reduction in halothane MAC rapidly and completely. Tolazoline alone, 5 mg/kg, (n = 5) had no significant effect on halothane MAC. Thus, the administration of the central alpha-adrenergic agonist clonidine decreased the required anesthetic concentration of halothane, as defined by MAC, by almost half. This effect, as it is reversed by tolazoline, is likely to be mediated through a central alpha-adrenergic receptor mechanism.

In contrast to reports of the untoward hemodynamic effects of fentanyl and diazepam in intact organisms, we found that neither a bolus of 100 micrograms/kg fentanyl nor the addition of intravenous doses of diazepam, up to and including 1 mg/kg (cumulative dose 2 mg/kg) caused cardiovascular depression in 13 anesthetized dogs after elimination of their sympathetic and parasympathetic tone. There were no significant changes in mean arterial blood pressure, cardiac output, heart rate, peak left ventricular dP/dt, cardiac filling pressures, or systemic vascular resistance. Rapid bolus injection of 3 mg/kg diazepam (cumulative dose 5 mg/kg) caused a significant (P less than 0.05) but transient (time to 50% recovery less than 2 min) decrease in systemic vascular resistance, blood pressure, and dP/dt. When corrected for pressure changed (dP/dt divided by simultaneous left ventricular pressure), the decrease in dP/dt did not attain statistical significance, nor did changes in cardiac output or filling pressures, even after this large dose of diazepam. We conclude that previously reported decreases in hemodynamic function in subjects with intact autonomic function after fentanyl alone, or after the combination of fentanyl and diazepam, are indirect in nature, that is, are caused by a centrally mediated decrease in vasoregulatory (mainly sympathetic) outflow from the central nervous system.

Clinical reports, as well as animal studies, have described cardiovascular and sympathetic stimulation after the administration of naloxone (NX) to reverse opioid-induced respiratory depression. This investigation examines the effect of PaCO2 on hemodynamic and adrenergic responses to NX, by means of 24 experiments carried out in six dogs. Each dog underwent NX reversal of fentanyl (FEN) at three different PaCO2 levels: 20, 35, and 60 mm Hg. In a final series of six experiments, the dogs were exposed to increasing PaCO2 after autonomic block by total spinal anesthesia and vagotomy. During enflurane anesthesia, 50 micrograms/kg FEN decreased mean arterial blood pressure (MAP), heart rate (HR), and plasma concentrations of norepinephrine (NE) and epinephrine (EPI) significantly. NX 0.4 mg promptly returned HR and MAP to baseline or above in all experiments; catecholamine (CA) levels increased only in hypercapnic dogs. Increases in HR were the same in all series. MAP, EPI, and NE levels were significantly greater than pre-FEN baseline values only in hypercapnic dogs 1 minute after NX and were also significantly higher in hypercapnic than in hypocapnic dogs at this time. NE levels were greater in hypercapnic dogs at all time periods after NX. In blocked dogs, neither F nor NX had any effects on hemodynamic functions or plasma CA levels; the institution of hypercapnia caused significant decreases in HR, MAP, and systemic vascular resistance. This direct circulatory depressant action of an elevated PCO2 may have attenuated the indirectly mediated excitatory hemodynamic effects of NX in intact dogs, thus explaining the relatively greater effect of hypercapnia on adrenergic than on hemodynamic responses to reversal.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe an isothermal gas-liquid chromatographic procedure developed for measuring thiamylal and thiopental in plasma. The unchanged drug is extracted into ethyl acetate from acidified plasma, together with an internal standard. The solvent is removed, the residue methylated, aliquots, diluted with benzene, are injected into a 183-cm gas-liquid chromatographic column containing 3% OV-17. Sensitivity of detection is in the nanogram to picogram range.

Hypotensive effects of the intravenous injection of adenine compounds [adenosine triphosphate (ATP), adenosine] were compared with those of sodium nitroprusside (SNP) in rabbits during light, stable halothane anesthesia. ATP and adenosine were almost equipotent in their effects on blood pressure and heart rate. The hypotensive potencies of ATP and adenosine were approximately 1/6 (bolus injection) and 1/40 (continuous infusion) that of SNP, but the adenine compounds had a more rapid onset of action and shorter recovery times than SNP. With bolus injection, SNP invariably caused a baroreceptor-mediated reflex increase in heart rate. In contrast, ATP and adenosine caused a dose-related decrease in heart rate and hypotension. With continuous infusion, ATP and adenosine produced immediate onset of hypotension without tachycardia. Blood pressure remained remarkably stable throughout the infusion; neither tachyphylaxis nor rebound hypertension were observed. Thus, the adenine compounds offer possible advantages over SNP as they are physiologic agents with little or no acute toxicity and may be devoid of tachycardia, tachyphylaxis, and rebound hypertension.

The effect of verapamil, 0.2 mg/kg i.v. over 30 s, on the amount of epinephrine required to elicit a reproducible ventricular arrhythmia during 0.9% halothane in oxygen anesthesia was investigated in two groups of dogs after three consecutive doses of verapamil given at 90 (group I) and 120 min (group II) intervals, respectively. Verapamil caused a stepwise cumulative increase in the arrhythmogenic dose of epinephrine in both groups despite plasma verapamil levels that declined to low levels (28 and 22 ng/ml, respectively) between doses. Control epinephrine arrhythmogenic doses were 2.89 +/- 0.54 and 2.74 +/- 0.19 microgram/kg/min (mean +/- SEM), respectively, for groups I and II, and rose to 4.58 +/- 0.72 and 4.55 +/- 0.30 microgram/kg/min after the first verapamil dose, to 6.20 +/- 0.74 and 6.13 +/- 0.40 microgram/kg/min after the second verapamil dose, and 8.16 +/- 0.85 and 8.09 +/- 0.95 microgram/kg/min after the third verapamil dose, respectively. All postverapamil epinephrine arrhythmogenic dose values were significantly elevated above control and above the preceding values, although there was no significant difference between the two groups. Changes in heart rate or blood pressure were similar among the three doses of verapamil in each group. These results can be interpreted to indicate that, unlike hemodynamic effects that appear to parallel plasma verapamil concentrations, the protective effects of verapamil against halothane--epinephrine ventricular arrhythmias may not be accurately reflected by plasma verapamil levels and may be significantly present when plasma levels are too low to cause measurable hemodynamic effects.

The cardiovascular responses to increasing infusion rates of the slow calcium channel inhibitor, verapamil, were studied in three groups of dogs during either enflurane, isoflurane, or halothane anesthesia. Control hemodynamic values and plasma samples were taken after 2 h of anesthesia with the given agent. Increasing infusion rates of verapamil were given to achieve a range of plasma verapamil levels up to approximately 500 ng X ml-1. Each infusion rate was administered for 30 min, at which time repeat measurements and plasma samples for verapamil were taken. Mean arterial blood pressure, cardiac index, and left ventricular dP/dt decreased with increasing plasma verapamil levels in the enflurane and isoflurane groups compared with the control values. The values for the enflurane-verapamil combination were significantly lower than those for the other anesthetics at comparable verapamil levels. Compared with enflurane, higher verapamil levels were required with isoflurane to achieve the equivalent degree of hemodynamic depression. A higher incidence of conduction abnormalities also was noted in the enflurane group. In the halothane group, the only significant change observed at these verapamil levels, achieved by continuous infusion, was a prolongation of the PR interval of the ECG. In this animal model, verapamil was least well tolerated by the cardiovascular system during enflurane anesthesia.

A double-blind study comparing four narcotic analgesics of different potencies, meperidine, morphine, fentanyl, and sufentanil, was performed on consenting patients undergoing general or orthopedic surgery under balanced anesthesia. Blood pressure, measured through an indwelling arterial catheter, was recorded continuously, as were ECG and heart rates. The narcotics, made up in equipotent concentrations, were given as indicated by hemodynamic and clinical signs. Arterial blood samples were taken before and after induction, after intubation, before and after incision, at intervals during the operation, and postoperatively. Hemodynamic values and plasma levels of catecholamines during and after induction, intubation, incision, and throughout the operation were least in patients given sufentanil and greatest in those who received morphine or meperidine. Heart rates increased significantly after induction with meperidine and were significantly higher after intubation in morphine-treated and meperidine-treated patients than they were in patients receiving sufentanil. Intraoperatively, mean arterial blood pressure, rate-pressure product, and plasma norepinephrine levels were lowest in patients receiving sufentanil. Intraoperative plasma epinephrine levels were lowest in patients receiving sufentanil and meperidine. Because of increases in blood pressure, heart rate, or both to greater than 15% above control values, supplementation with a potent inhalational agent was necessary in 38%, 30%, and 29% of the patients given meperidine, morphine, and fentanyl, respectively. No sufentanil patient required supplementation. Side effects, including histamine release accompanied by tachycardia and hypotension, were most frequent and most severe in patients who received meperidine. After extubation, marked increases in heart rate, blood pressure, and plasma norepinephrine and epinephrine occurred in some patients in each group. The incidence of postoperative respiratory depression was greatest in patients given morphine (mean dose of naloxone 8.6 micrograms/kg) and least with sufentanil (mean dose of naloxone 1.8 micrograms/kg) and fentanyl (3.2 micrograms/kg naloxone).

Adenosine triphosphate (ATP) has been reported to be a hypotensive agent similar in effect to sodium nitroprusside (SNP). The purpose of this study was to examine and compare the effects of both SNP and ATP on general coronary hemodynamics, myocardial O2 consumption, and circulating catecholamines. Twelve dogs were anesthetized with 1.0% halothane and given either SNP or ATP by controlled infusion to reduce their systemic blood pressure by 50% for a 2-h period followed by a (blood pressure) recovery period. The ATP-induced hypotension was rapid, easily controlled, not accompanied by tachyphylaxis over the 120 min studied, and resulted in an increase in coronary sinus blood flow (CSBF), which plateaued at 260% above control. The increase in CSBF was almost immediate and remained at this elevated level for the duration of the induced hypotension. During the ATP-induced hypotension, there was no change in heart rate or circulating catecholamines. A 60% reduction in myocardial O2 uptake was observed, presumably from the cardiac unloading. In contrast, SNP-induced hypotension required a marked increase in dose over time, did not significantly increase CSBF, did increase heart rate, and resulted in large increases in circulating plasma catecholamines. Neither agent affected cardiac output. ATP-induced hypotension resulted in no change in cardiac lactic acid uptake, while SNP caused lactic acid production, indicating possible cardiac ischemia or cyanide toxicity.

The relationship between halothane concentration and tachyphylaxis to sodium nitroprusside (SNP) was studied in a rabbit model. Three groups of six rabbits (groups A, B, and C) were anesthetized with halothane at 0.75, 1.0, and 1.25 vol% end-tidal, respectively. SNP-induced hypotension was maintained for 135 min or until a cumulative total dose of 12 mg/kg had been infused (defined as "marked tachyphylaxis"). Plasma norepinephrine (NE), epinephrine (EPI) levels, and plasma renin activity (PRA) were measured. Initial mean arterial pressure (MAP) (72 +/- 2 mm Hg), heart rate (325 +/- 12 beats/min), and the amount of SNP required to induce 40% hypotension (19 +/- 4 micrograms/kg/min) did not differ significantly among the three groups. In group A, five out of six animals exhibited "marked tachyphylaxis." In group B, only one animal showed "marked tachyphylaxis"; the remaining five required a dose rate of 104 +/- 38 micrograms/kg/min at 135 min to maintain a 40% reduction in MAP. In group C, none of the animals showed "marked tachyphylaxis"; the dose rate of SNP required after 135 min was 29 +/- 14 micrograms/kg/min. In all groups, SNP dose rate was found to best correlate (p less than 0.0005, r = 0.79) with NE levels and not with PRA or arterial blood pH. This implies that reflex sympathetic activation is the measured mediator of SNP tachyphylaxis. Halothane blunted the tachyphylaxis (sympathetic response) to SNP-induced hypotension at higher concentrations.

The authors examined the effect of clonidine, a preferential alpha 2-adrenergic agonist, upon narcotic requirements, hemodynamics, and adrenergic responses during the perioperative period in patients undergoing CABG surgery. Anesthesia was provided by sufentanil supplemented with isoflurane; sodium nitroprusside was given as needed for hemodynamic control. Ten patients received oral clonidine preoperatively at the time of premedication, and again intraoperatively by nasogastric tube. Another group of ten untreated patients were otherwise managed identically. Intergroup differences in required anesthetic and vasoactive drug doses and recovery times were measured and evaluated, as well as hemodynamics and plasma catecholamines prior to induction, after intubation, and at intervals intra- and postoperatively. Patients who received clonidine required less diazepam prior to induction, and received 40% less sufentanil during the anesthetic period, than did untreated controls. More control patients required the addition of isoflurane to prevent hypertension. Mean blood pressures and heart rates were elevated at many sampling points in patients not treated with clonidine. Four of the clonidine-treated group required atropine for treatment of bradycardia in the pre-incision period. Plasma catecholamines were significantly lower throughout most of the study period in patients treated with clonidine. After cardiopulmonary bypass and postoperatively, cardiac outputs were significantly higher in the treated group. Patients who had received clonidine were extubated significantly earlier, and fewer of them shivered postoperatively. We conclude that perioperative treatment with clonidine reduced narcotic and anesthetic requirements, improved hemodynamics, reduced plasma catecholamines, and shortened the period of postoperative ventilation in patients undergoing coronary artery surgery.

A 50-micrograms/kg dose of fentanyl, given intravenously in divided doses to dogs under enflurane-nitrous oxide anesthesia caused sharp decreases in heart rate (HR), arterial blood pressure (AP), left ventricular dP/dt, and plasma levels of catecholamines. Naloxone, 20 micrograms/kg given 65-70 min later, completely and rapidly reversed these changes. Because the cardiovascular effects of fentanyl and naloxone occurred in unparalyzed animals under surgical anesthesia without eliciting any motor responses, it seems unlikely that they can be ascribed to changes in awareness and surgical stimulation, especially pain. The brief duration of exposure to the narcotic makes it improbable that the naloxone response is due to acute dependence and precipitated withdrawal. Pretreatment with 20 micrograms/kg of atropine only attenuated the decrease in HR, indicating a minor role of vagal mechanisms under these conditions. Administration of 20 micrograms/kg of clonidine by slow infusion after fentanyl further reduced sympathetic activity and greatly attenuated the naloxone response. Injection of 5 mg/kg of tolazoline after administration of clonidine produced massive cardiovascular stimulation by antagonizing clonidine and unmasking the naloxone reversal of fentanyl. Thus, in fully anesthetized dogs, fentanyl decreased the level of cardiovascular function mainly by reducing sympathetic activity. This effect does not seem to be secondary to analgesia or other sensory depressant effects of the narcotic, but rather to an action on central opioid-sensitive mechanisms regulating cardiovascular function.

In chloralose-anesthetized dogs the hypotensive and reflex cardiovascular responses to infusions of sodium nitroprusside were studied before and during halothane and enflurane, and before after divided doses of cryptenamine. The latter drug, a mixture of hypotensive veratrum alkaloids, lowers blood pressure reflexly by acting on afferent receptors (baroreceptors). Control infusions of nitroprusside, which caused 10% to 15% decreases im mean arterial blood pressure, markedly increased heart rate, myocardial contractility, cardiac output, rate-pressure product, and left ventricular minute work in spite of decreases in peripheral vascular resistance. Except for increases in contractility, these reflexly mediated effects were not blocked by the addition of 1% halothane or 2% enflurane. Cryptenamine, on the other hand, potentiated nitroprusside-induced hypotension, markedly diminished increases in heart rate, and eliminated increases in myocardial contractility, rate-pressure product, and left ventricular work. Measurements of cardiovascular function returned promptly to preinfusion values when the nitroprusside was stopped. We conclude that under conditions when a high degree of central vasomotor tone is present, homeostatic reflexes may counteract the direct vasodilator effect of nitroprusside, resulting in the need for a greater dose of nitroprusside and obviating the expected beneficial effects on myocardial oxygen supply/demand ratio. Combining cryptenamine with nitroprusside eliminates these problems and at the same time allows retention of the evanescent action of nitroprusside.

Histamine release and hemodynamic changes associated with four narcotics were studied in 60 adults (28 men, 32 women) scheduled for general surgery under balanced anesthesia. Under double-blind conditions, incremental equipotent doses of meperidine, morphine, fentanyl, or sufentanil were administered IV for induction of anesthesia, prior to thiopental, succinylcholine, and intubation. Arterial blood samples were drawn before and 1, 6, and 20 min after narcotic administration. Of the 16 patients given meperidine (mean dose 4.3 +/- 0.2 (SEM) mg/kg), five (31%) had clinical signs (hypotension, tachycardia, erythema) and elevations in plasma histamine levels ranging from 3.2 to 49.7 ng/ml 1 min after narcotic administration. Plasma epinephrine levels at this time were also elevated in these five patients. One of the ten patients given morphine (0.6 +/- 0.02 mg/kg) developed hypotension, tachycardia, and an increase in plasma histamine level to 12.4 ng/ml. None of 34 patients given either fentanyl (7 +/- 0.4 micrograms/kg) or sufentanil (1.3 +/- 0.1 microgram/kg) had clinical signs of histamine release or elevations of plasma histamine levels. In the six patients in whom histamine release occurred, there was a significant correlation between the histamine levels at 1 min and the magnitude of change in heart rate, blood pressure, and plasma epinephrine level. All six histamine releasers were young women, ranging in age from 18 to 35 yr. Histamine release occurred more frequently after meperidine than after the other narcotics, including morphine, and the degree of hemodynamic compromise was related to the increase in plasma histamine concentration.

Supplementation of the antihypertensive action of the peripheral vasodilator sodium nitroprusside (SNP) with clonidine, a centrally-acting agent, was studied in ten dogs anesthetized with isoflurane to evaluate the efficacy of clonidine for reducing the amount of SNP required during induced hypotension. The dose of SNP required to lower mean arterial blood pressure (MAP) by 40% was determined prior to the administration of intravenous clonidine (control), and after incremental doses of 1, 4, and 15 micrograms/kg. After each dose of clonidine, hypotension was induced with SNP and maintained for 30 min, followed by a 30-min recovery period. Plasma levels of norepinephrine (NE) and epinephrine (EPI) were determined before hypotension, at 5 min and 30 min during hypotension, and at 5 min and 30 min during recovery. During the control period (no clonidine), SNP-induced hypotension resulted in increases in plasma catecholamine levels, with larger increases in EPI (from 70 +/- 26 to 851 +/- 140 pg/ml, at 30 min) than NE (from 171 +/- 26 to 334 +/- 58 pg/ml, at 30 min). There was no significant difference between the control MAP and the MAP after each incremental dose of clonidine. In these anesthetized dogs with low sympathetic tone there was no significant decrease in EPI levels after administration of up to 20 micrograms/kg of clonidine. Increasing doses of clonidine correlated inversely with depression in catecholamine output during induced hypotension and the dose of SNP required to produce this hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)