Marie-Francoise Doursout

Effects of Sevoflurane and Isoflurane on Cardiac and Coronary Dynamics in Chronically Instrumented Dogs

To assess the hemodynamic properties of the new inhalational anesthetic sevoflurane, 22 dogs were chronically instrumented for measurement of heart rate, aortic, left ventricular and left atrial pressures, cardiac output, and coronary blood flow. Dogs were randomly assigned to two groups, receiving either 1.2 and 2 MAC of sevoflurane (n = 11) or isoflurane (n = 11). At 1.2 and 2 MAC, sevoflurane produced an increase in heart rate (+60 +/- 12% and +54 +/- 9%, respectively), dose-dependent aortic hypotension (-22 +/- 4% and -38 +/- 4%, respectively), systemic vasodilation (-22 +/- 5% and -19 +/- 5%, respectively), dose-dependent decrease in stroke volume (-31 +/- 6% and -48 +/- 4%, respectively), and left ventricular dP/dt (-40 +/- 4% and -61 +/- 10%, respectively). Cardiac output decreased only at 2 MAC (-17 +/- 6%). Finally, coronary blood flow increased at 1.2 MAC of sevoflurane (+29 +/- 8%). Except for heart rate, sevoflurane and isoflurane produced similar effects. At 1.2 MAC, sevoflurane produced a greater increase in heart rate than isoflurane (+60 +/- 12% vs. +33 +/- 9%). The authors conclude that, except for heart rate, the effects of sevoflurane on cardiac function and coronary blood flow are almost identical to those induced by isoflurane in the chronically instrumented dog.

Comparison of the effects of isoflurane and desflurane on cardiovascular dynamics and regional blood flow in the chronically instrumented dog

Seven mongrel dogs were chronically instrumented for the measurement of aortic and left ventricular blood pressures, cardiac output, left ventricular wall thickening, left ventricular dP/dt, and circumflex coronary, renal, hepatic and portal blood flows under the influence of desflurane (D) and isoflurane (I). Administration of the two anesthetics, was randomized, as was the order of the concentrations administered. Each dog was studied awake and at 1.2, 1.4, 1.75, and 2.0 MAC of each anesthetic on different days. Both anesthetics decreased mean arterial pressure, stroke volume, systemic vascular resistance, left ventricular dP/dt, and wall thickness. The decreases were dose-dependent for mean arterial pressure (percent of awake values: D 78, I 85 at 1.2 MAC, and D 67, I 69 at 2.0 MAC); stroke volume (D 66, I 72 at 1.2 MAC, and D 52, I 57 at 2.0 MAC); dP/dt (D 61, I 64 at 1.2 MAC, and D 46, I 49 at 2.0 MAC); and WT (D 68, I 70 at 1.2 MAC, and D 47, I 60 at 2.0 MAC). Systemic vascular resistance decreased approximately the same at 1.2 MAC (D 71, I 87%) as at 2.0 MAC (D 71, I 79%). Heart rate increased but also not in a dose-dependent fashion (percent of awake values: D 177, I 145 at 1.2 MAC, and D 176, I 155 at 2.0 MAC). Coronary blood flow was increased by both anesthetics at all concentrations (percent of awake values: I 136 at 1.2 MAC and 161 at 2.0 MAC of awake, and D 131 at 1.2 MAC and 138 at 2.0 MAC.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sevoflurane and isoflurane on hepatic circulation in the chronically instrumented dog

To compare the effects of sevoflurane and isoflurane on hepatic circulation, eighteen dogs were chronically instrumented for measurements of mean aortic blood pressure and cardiac output and for simultaneous measurements of hepatic and portal blood flows. Each animal was studied while awake and during 1.2 and 2 MAC of either isoflurane or sevoflurane. Both anesthetics induced tachycardia and a dose-dependent decrease in mean aortic blood pressure (isoflurane -27% and -39%; sevoflurane -22% and -37%). Cardiac output decreased only at the highest concentration (isoflurane -10%; sevoflurane -21%). During sevoflurane, portal blood flow decreased at both 1.2 and 2 MAC (-14 and -33%, respectively), whereas an increase in hepatic arterial blood flow was recorded at 2 MAC (+33%). During isoflurane, the only significant change was a decrease in portal blood flow (-16%) at 1.2 MAC. Neither anesthetic significantly changed renal blood flow. Therefore, both anesthetics led to similar systemic and hepatic vasodilation.

Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats.

Purpose: To assess the role of esmolol, a β1 receptor blocker, in the modulation of pain in the absence of anesthesia.Methods: Rats were chronically instrumented to record mean arterial blood pressure (MAP) and heart rate (HR). Animals were divided into three groups. Group 1 [esmolol high (EH) 150 mg·kg−1·hr−1; n=9], Group 2 [esmolol low (EL) 40 mg·kg−1·hr−1; n=7] and Group 3 saline (n=9). Formalin 5% was injected in the rat hind paw. Formalin-induced lifting, MAP and HR were recorded at five minute intervals for 35 min after formalin injection.Results: Formalin was associated with an early (Phase 1; 0–5 min) and late nociceptive response (Phase 2; 10–35 min). Esmolol did not affect Phase 1. Although low dose esmolol had minimum effects on nociceptive Phase 2, it was diminished with high dose esmolol. Formalin induced biphasic increases in MAP and HR. Although esmolol did not affect the initial increase in MAP, high dose esmolol blunted the secondary increase in MAP. Both low and high doses of esmolol inhibited formalin-induced tachycardia during the first 30 min.Conclusion: Our data suggest that esmolol leads to analgesia and reduction of cardiovascular responses to pain.RésuméObjectif: Cette étude a été réalisée pour étudier le rôle de l’esmolol, un bloqueur des récepteurs béta 1 dans la modulation de la douleur en l’absence d’anesthésie.Méthode: Des rats ont été instrumentés pour enregistrer la tension artérielle moyenne (TAM), et la fréquence cardiaque (FC). Les animaux ont été divisés en 3 groupes. Le groupe 1 [esmolol à la dose de 150 µg·kg−1·hr−1; n=9], le groupe 2 [esmolol à la dose de 40 µg·kg−1·hr−1; n=7] et le groupe 3 [chlorure de sodium isotonique; n=9]. Le formol (5%) a été injecté par voie sous-cutanée dans la patte du rat. Les mouvements de la patte ainsi que la TAM et la FC ont été enregistrés à 5 min d’intervalles pendant 35 min après l’injection du formol.Résultats: L’activité physique qui accompagnait l’administration de formol a été représentée par une phase immédiate (Phase 1; 0–5 min) et une phase secondaire (Phase 2; 10–35 min). L’esmolol n’a pas produit d’effets significatifs sur les mouvements de la patte en Phase 1. Alors qu’à faible dose, l’esmolol n’a provoqué que peu d’effets sur les mouvements de la patte en Phase 2, à forte dose il a engendré une réponse significative. Le formol a produit des augmentations significatives de la TAM et de la FC. Bien que l’esmolol, à forte dose, n’a pas produit de changements significatifs sur la TAM, il a fortement diminué l’augmentation secondaire de la TAM. Les 2 doses d’esmolol ont diminué la tachycardie provoquée par l’injection de formol.Conclusion: Nos résultats suggèrent que l’administration d’esmolol s’associe à une diminution de l’hyperactivité liée à l’injection de formol dans la patte.

Cardiovascular Effects of and Interaction between Calcium Blocking Drugs and Anesthetics in Chronically Instrumented Dogs. I. Verapamil and Halothane

In order to assess the interaction between halothane and verapamil on the cardiovascular system, mongrel dogs were instrumented so that the following measurements could be made awake and under the influence of the drugs: aortic, left ventricular, and left atrial blood pressures; myocardial segment length shortening; heart rate and rhythm; and coronary, carotid, and renal blood flows. The effect of two infusion doses of verapamil (3 μg.kg−1.min−1and 6 μg. kg−1after 200 μg.kg−1bolus) were examined awake. On a different day in the same dogs, two concentrations of halothane (1.2-low and 2.4-high % end-tidal) and the effect of the two infusion doses of verapamil during low and high halothane were studied. Thirty minutes of either infusion dose of verapamil produced only heart rate and electrocardiographic P-R interval increases in conscious dogs. Halothane produced dose-related decreases in mean aortic pressure, left ventricular maximum rate of tension development (dP/dt), and segment length shortening and increases in heart rate and left atrial pressure. Carotid blood flow was increased by low halothane concentrations and returned to control with high halothane concentrations. There were no significant changes in coronary or renal blood flow produced by halothane. Verapamil infusion during low halothane concentration produced minimal effects. However, both the 3 and 6 μg.kg−1. min−1verapamil doses further depressed hearts already depressed by the high concentrations of halothane and decreased renal and carotid blood flows. Verapamil plasma levels were significantly higher during both low and high halothane concentrations than when the same dose was given to the same dogs awake. The authors conclude that: 1) the predominant effect of the combination of halothane and verapamil was from halothane; 2) halothane alters the pharmacokinetics of intravenous verapamil, resulting in marked increases in plasma verapamil levels when compared with the same dose awake; 3) verapamil infusion is well tolerated during low concentrations of halothane, but the combination of high halothane concentrations and verapamil produces profound cardiovascular depression.

Pharmacological properties of AR-C239, 2-[2-[4(o-methoxyphenyl)-piperazine-1-Yl]-ethyl]4,4-dimethyl-1,3(2H-4H) isoquinolinedione, a new alpha-adrenoceptor blocking drug.

In pentobarbital-treated dogs and rats, AR-C239, a new and potent alpha-adrenoceptor blocking drug, competitively antagonized pressor responses to adrenaline and inhibited pressor responses to noradrenaline, phenylephrine, tyramine, and dimethylphenylpiperazinium. Injected intravenously into closed-chest dogs, AR-C239 (3-50 micrograms/kg) induced a progressive fall in blood pressure, heart rate, and sympathetic nerve activity. The drug appears to be devoid of direct vasodilator action, and the fall in blood pressure results from the peripheral alpha-blockade. AR-C239 did not change the tachycardia induced by stimulation of the cardiac nerve in dogs and, at least in this preparation, seems to be a specific alpha 1-adrenoceptor blocking drug. When administered into the cisterna magna of dogs, AR-C239 did not have any centrally mediated cardiovascular actions and heart rate. AR-C239 did not modify the functioning of the baroreflex arc. Due to its specificity for alpha 1-Adrenoceptors, AR-C239 may be useful for characterizing alpha-adrenoceptors.

Effects of enflurane and isoflurane on hepatic and renal circulations in chronically instrumented dogs

Seven dogs were chronically instrumented for measurements of mean aortic blood pressure and cardiac output and for simultaneous measurements of hepatic, portal, and renal blood flows. Each animal was studied on two separate occasions, awake and during 1.2, 1.4, 1.75, and 2.0 MAC isoflurane and enflurane. Both anesthetics induced tachycardia; to a greater degree than isoflurane, enflurane lowered mean aortic blood pressure in a dose-dependent manner (-37, -45, -48, and -62% vs. -19, -25, -41, and -44%, respectively) and cardiac output (-20, -26, -41, and -48% vs. -3, -5, -11, and -15%, respectively). With isoflurane, cardiac output decreased only at 1.75 and 2.0 MAC, and portal blood flow did not change significantly, whereas hepatic arterial blood flow increased at 1.75 and 2 MAC (by 28 and 33%, respectively). With enflurane, no significant changes were recorded in hepatic arterial blood flow, whereas portal blood flow decreased in a dose-dependent manner. Except at 2 MAC, hepatic circulation did not differ between anesthetics. Likewise, neither anesthetic significantly changed renal blood flow, except for enflurane at 2.0 MAC, which was associated with a 35% reduction. Both anesthetics led to similar systemic, hepatic, and renal vasodilations. Our data suggest that high concentrations of enflurane are associated with decreases in portal, total hepatic, and renal blood flows, most likely as a result of an anesthetic-induced cardiac depression.

Cardiovascular Effects of Acute Changes in Extracellular Ionized Calcium Concentration Induced by Citrate and CaCl2 Infusions in Chronically Instrumented Dogs, Conscious and during Enflurane, Halothane, and Isoflurane Anesthesia

To study the cardiovascular effects of low blood ionized calcium ion concentrations [Ca2+] induced by citrate infusion followed by high [Ca2+], induced by CaCl2 infusion awake and during enflurane (2.5% ET), halothane (1.2% ET), and isoflurane (1.6% ET) anesthesia, dogs were chronically instrumented to measure heart rate, aortic, left atrial, and left ventricular (LV) blood pressures, and cardiac output. In conscious dogs low [Ca2+] (decreased 0.35 mM); increased heart rate (HR) and mean aortic pressure (MAP) and decreased stroke volume (SV) and LV dP/dtmax. Low [Ca2+] increased HR during all three anesthetics and decreased LV dP/dtmax except during isoflurane anesthesia. Low [Ca2+] produced more hemodynamic depression during enflurane anesthesia than during anesthesia with halothane or isoflurane increasing left atrial pressure and decreasing MAP and SV. The differences seen were partially related to decreased systemic vascular resistance during halothane and isoflurane anesthesia. In conscious dogs following high [Ca2+] (increased 0.37 mM); only MAP and LV dP/dtmax increased. LVdP/dtmax was also increased by high [Ca2+] during all three anesthetics without a change in MAP. Cardiac output increased during halothane and isoflurane anesthesia but was unchanged during enflurane. It would appear that the hemodynamic sensitivity for the effects of changing [Ca2+] was enflurane greater than halothane greater than isoflurane greater than awake. The results suggest that the effects of changes in [Ca2+] induced by citrate and CaCl2 infusion are modified by the three volatile anesthetics.

Cardiovascular Effects of and Interaction Between Calcium Blocking Drugs and Anesthetics in Chronically Instrumented Dogs. Vi. Verapamil and Fentanyl-pancuronium

To assess the interaction between verapamil and fentanyl-pancuronium, dogs were chronically instrumented to measure heart rate; PR interval; nortic, left ventricular, and left atrial pressures; and coronary, carotid, and renal blood flows. The effect of fentanyl citrate infusion on single-dose verapamil pharmacokinetics was examined in six animals. The effects of verapamil infusion (3 μg · kg−1 · min−1 and 6 μg · kg−1 · min−1) were examined in the conscious state and during fentanyl infusion plus pancuronium on two separate occasions in nine dogs. In addition, the effects of fentanyl citrate (500 μg · kg−1 followed by 1.5 μg · kg−1 · min−1) were examined over 1 h of infusion. Fentanyl infusion did not affect single-dose verapamil pharmacokinetics. In the conscious animals, verapamil increased heart rate and PR interval, and slightly decreased LV dP/dt. Fentanyl combined with pancuronium increased mean arterial pressure and LV dP/dt. During fentanyl infusion, verapamil decreased mean arterial pressure and LV dP/dt, increased PR interval, and did not change heart rate. The hemodynamic effects of fentanyl infusion were steady over 1 h. In contrast to the inhalational anesthetics, which alter verapamil pharmacokinetics and have mainly additive effects with verapamil on left ventricular contractility, cardiac conduction, and regional blood flows, fentanyl-pancuronium had no effect on verapamil pharmacokinetics and minimal effect on verapamil pharmacokinetics in healthy dogs.

Role of heparin and nitric oxide in the cardiac and regional hemodynamic properties of protamine in conscious chronically instrumented dogs.

Background Because protamine is administered to reverse heparin, a drug that might itself affect the pharmacologic properties of protamine, this study was designed to assess the properties of protamine alone and in the presence of heparin in conscious dogs. Methods Twelve dogs were instrumented to continuously record cardiac and regional hemodynamics. On separate occasions, a dose of protamine (0.5, 1, 3, 5, and 8 mg/kg) was randomly administered either alone or in the presence of heparin (ratio 100 IU/mg). Heparin (300 IU/kg) and protamine (3 mg/kg) were administered in the presence of N-methyl-l-arginine, a specific nitric oxide synthase inhibitor. Identical experiments were performed with protamine (8 mg/kg) in the absence of heparin on a separate occasion. Results Protamine alone produced limited cardiac and regional changes. In the presence of heparin, protamine produced hypotension at 3, 5, and 8 mg/kg, vasodilatation at 3 and 5 mg/kg, and a more pronounced dose-dependent increase in pulmonary pressure at 3, 5, and 8 mg/kg. Simultaneously, transient carotid vasodilatation at 3 and 5 mg/kg, coronary and hepatic vasodilatation at 3, 5, and 8 mg/kg, as well as a decrease in vertebral vascular resistance were recorded at 1, 3, and 8 mg/kg. Protamine produced an immediate increase followed by a secondary decrease in renal vascular resistance. Protamine-induced secondary pulmonary pressor effects were attenuated. In the presence of heparin, nitric oxide synthase blockade selectively attenuated protamine-induced immediate hypotension, systemic vasodilatation, and coronary, mesenteric, and hepatic vasodilations as well as the decrease in portal blood flow and accentuated the renal vasoconstriction. Conclusions The presence of heparin accentuated the decrease in cardiac function induced by protamine as well as its effects on regional circulation. The data provide evidence that the nitric oxide pathway is involved in the systemic and selective regional heparin–protamine-mediated vasodilatation in conscious dogs.