David L. Roerig

Clonidine Reduces Sympathetic Activity but Maintains Baroreflex Responses in Normotensive Humans

Clonidine, an alpha 2-adrenergic agonist, has been shown to modify the hemodynamic responses to surgery. To examine further the mechanism underlying this action, we evaluated the neurocirculatory effects of oral clonidine and the ability of clonidine to alter the hemodynamic and sympathetic responses to a noxious stimulus (cold pressor test) and to baroreceptor perturbations in nine healthy men (ages 20-29 yr). Heart rate (ECG), blood pressure (radial artery catheter), central venous pressure (jugular vein), and cardiac output (impedance cardiography) were monitored before and after oral clonidine (0.3 mg) or placebo. Plasma norepinephrine was measured with high-performance liquid chromatography. Sympathetic nerve activity (SNA) to skeletal muscle blood vessels was recorded from a Tungsten needle positioned within the peroneal nerve. Baroreceptor testing was carried out by intravenous bolus injections of nitroprusside (100 micrograms) followed 60 s later by intravenous phenylephrine (150 micrograms). The slope of the linear relationship between the change in R-R interval versus the change in mean pressure (cardiac baroslope) or change in SNA versus change in diastolic pressure (sympathetic baroslope) was determined at baseline and 75 min after clonidine or placebo. In addition, peak responses to the cold pressor test (60-s hand immersion in ice water) were determined at the same intervals. Clonidine progressively decreased blood pressure and muscle SNA over the 75-min session. Clonidine subtly reduced the sympathoexcitation produced by the cold pressor test but did not alter the gain of the baroreceptor reflex regulating cardiac interval or peripheral SNA; baroslope relationships were simply shifted leftward (to operate at lower pressures).(ABSTRACT TRUNCATED AT 250 WORDS)

First pass uptake of fentanyl, meperidine, and morphine in the human lung

The first pass uptake of fentanyl, meperidine, and morphine in human lung was studied in patients using a double indicator dilution technique. A bolus containing one of the drugs and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia for surgery. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of drug taken up by the lung during the first pass and the instantaneous extraction of drug at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. The total uptake (mean ± SE) during the first pass through the human lung for fentanyl and meperidine was 75.2 ± 3.2% and 64.7 ± 7.8% of the injected dose, respectively. The pulmonary uptake of morphine was very small, with 96.5 ± 7.1% of the injected dose recovered in arterial blood after the first pass through the lung. The arterial blood concentration of drug and dye versus time showed a slight delay of the fentanyl and meperidine peaks compared to ICG, It was also observed that greater than 90% of these drugs were extracted from the blood in the early part of the first pass, but the extraction decreased with time during the first pass through the lung. These findings indicate that sonic of the drug taken up by the lung can diffuse back out into the blood. In spite of this back diffusion, 75% and 65% of the fentanyl and meperidine remained in the lung tissue at the end of the first pass. This high first pass pulmonary uptake of fentanyl and meperidine results in a large decrease in the amount of drug that enters the systemic circulation immediately after injection. This non-respiratory pulmonary function could play a major role in determining the plasma pharmacokinetics of these drugs immediately after intravenous administration. No such role of the lung exists for morphine.

The Effects of the Stereoisomers of the α2-adrenergic Agonist Medetomidine on Systemic and Coronary Hemodynamics in Conscious Dogs

The alpha 2-adrenergic agonist medetomidine produces systemic hemodynamic effects that are mediated by both peripheral and central nervous system actions. The current investigation was designed to characterize coronary and systemic hemodynamic effects of the D- and L-stereoisomers of medetomidine in conscious, chronically instrumented dogs with and without autonomic nervous system blockade. Dogs were instrumented for measurement of aortic pressure, coronary blood flow velocity, cardiac output, left ventricular pressure, rate of change in pressure (dP/dt), and subendocardial systolic shortening. Administration of the D-isomer of medetomidine (doses of 1.25, 2.5, and 5.0 micrograms/kg, each administered over 10 min, with 60 min between doses) significantly altered systemic hemodynamics, in a biphasic fashion. A decrease in respiratory rate without change in arterial blood gas tensions occurred. With the 5 micrograms/kg dose of D-medetomidine, an initial pressor response was followed by secondary, significant (P less than 0.05), and dose-related decreases in heart rate (74 +/- 3 to 57 +/- 4 beats per min), mean arterial pressure (109 +/- 2 to 100 +/- 3 mmHg) and the rate-pressure product (10.5 +/- 0.4 to 7.0 +/- 0.5 beats.min-1.mmHg.10(3] accompanied by a reduction in plasma concentrations of norepinephrine. No changes in left ventricular end diastolic pressure or coronary blood flow velocity occurred. In contrast to the D-isomer, the L-isomer (1.25, 2.5 and 5.0 micrograms/kg) produced no changes in hemodynamics or plasma concentrations of norepinephrine. In dogs pretreated with hexamethonium (20 mg/kg), propranolol (2 mg/kg), and atropine methylnitrate (3 mg/kg) to produce autonomic nervous system blockade, D-medetomidine also produced an initial pressor response, but no secondary reduction in heart rate or arterial pressure occurred. The results indicate that the D-isomer of medetomidine is stereospecific for alterations in hemodynamics: the active D-isomer produces decreases in heart rate, arterial pressure, and the rate-pressure product via diminished sympathetic and/or augmented parasympathetic tone. This conclusion is supported by the absence of these changes after pharmacologic blockade of the autonomic nervous system.

First-pass uptake of verapamil, diazepam, and thiopental in the human lung

The first-pass uptake of verapamil, diazepam, and thiopental in the human lung was determined using multiple-indicator dilution techniques. These three drugs represent lipid-soluble agents that differ in their ionic characteristics at physiological pH. Verapamil, a basic lipophilic amine, underwent significant uptake, with 50% of the drug accumulating in lung tissue during the first pass. With diazepam, a nonbasic lipophilic amine, there was 30% uptake during the first pass through the human lung-significantly less than that observed with verapamil. With thiopental, an acidic lipophilic barbiturate, only 14% of the injected drug accumulated in the lung during the first pass. Taken together, these data are consistent with observations from animal studies, which indicate that extensive pulmonary uptake is greater with basic amine drugs that are moderately to highly lipid-soluble. Also, the relatively high first-pass uptake of verapamil in the human lung suggests a quantitatively significant role of this nonrespiratoy function of the lung in the early pharmacokinetics of intravenous verapamil.

Halothane reduces release of adenosine, inosine, and lactate with ischemia and reperfusion in isolated hearts.

We investigated the protective effects of halothane on cardiac function of isolated hearts during global hypoperfusion and reperfusion by examining halothanes effects on altering coronary flow, myocardial oxygen utilization (MVO2), and release of adenosine (ADE), inosine (INO), and lactate (LAC). Isolated perfused guinea pig hearts were divided into three groups of perfusion at 25% (14 mm Hg), 10% (5.5 mm Hg), and 0% (no perfusion) from control perfusion pressure (PP, 55 mm Hg). Each of these PP groups was subdivided into three subgroups and perfused without halothane (control), with 0.23 ± 0.01 mM (0.74%) halothane, or with 0.51 ± 0.01 mM (1.65%) halothane. Halothane was present 10 min before reducing PP, during reduced PP (30 min), and for 10 min after reducing PP. Hypoperfusion was followed by 40 min of reperfusion at the control (100%, 55 mm Hg) PP. An additional group of control hearts was followed for the same period without reducing PP or perfusing with halothane. Exposure to 0.74% and 1.65% halothane, before reducing PP, decreased MVO2 and percent oxygen extraction (% O2E), but produced no significant change in coronary flow or release of ADE, ISO, or LAC. During early hypoperfusion (10 min) at 25% PP, 1.65% halothane significantly reduced release of ADE, INO, and LAC. During late hypoperfusion (40 min) the differences in LAC release diminished, but release of ADE and INO remained lower in the 1.65% halothane group. With early reperfusion there was a large increase in release of these metabolites, that was dependent on the decrease in perfusion pressure. The release of INO during reperfusion was reduced by halothane; however, ADE release increased with halothane suggesting less conversion of ADE to INO. The release of LAC was not affected by halothane. The reduction of cardiac work effected by halothane either before, during, or after graded reductions in PP may decrease the loss of purine substrate so that synthesis of high energy phosphates is less impaired. This study suggests that our earlier finding that halothane improved contractile function and reduced the severity of dysrhythmias in isolated hearts following graded reductions in PP is due, at least in part, to a decrease in oxygen demand relative to oxygen supply, resulting in a decrease in purine release.

Precursors and inhibitors of hydrogen sulfide synthesis affect acute hypoxic pulmonary vasoconstriction in the intact lung

The effects of hydrogen sulfide (H(2)S) and acute hypoxia are similar in isolated pulmonary arteries from various species. However, the involvement of H(2)S in hypoxic pulmonary vasoconstriction (HPV) has not been studied in the intact lung. The present study used an intact, isolated, perfused rat lung preparation to examine whether adding compounds essential to H(2)S synthesis or to its inhibition would result in a corresponding increase or decrease in the magnitude of HPV. Western blots performed in lung tissue identified the presence of the H(2)S-synthesizing enzymes, cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfur transferase (3-MST), but not cystathionine β-synthase (CBS). Adding three H(2)S synthesis precursors, cysteine and oxidized or reduced glutathione, to the perfusate significantly increased peak arterial pressure during hypoxia compared with control (P < 0.05). Adding α-ketoglutarate to enhance the 3-MST enzyme pathway also resulted in an increase (P < 0.05). Both aspartate, which inhibits the 3-MST synthesis pathway, and propargylglycine (PPG), which inhibits the CSE pathway, significantly reduced the increases in arterial pressure during hypoxia. Diethylmaleate (DEM), which conjugates sulfhydryls, also reduced the peak hypoxic arterial pressure at concentrations >2 mM. Finally, H(2)S concentrations as measured with a specially designed polarographic electrode decreased markedly in lung tissue homogenate and in small pulmonary arteries when air was added to the hypoxic environment of the measurement chamber. The results of this study provide evidence that the rate of H(2)S synthesis plays a role in the magnitude of acute HPV in the isolated perfused rat lung.

Effect of Propranolol on the First Pass Uptake of Fentanyl in the Human and Rat Lung

The first pass uptake of fentanyl in the human lung was studied in two groups of patients using a double indicator dilution technique. A bolus containing fentanyl and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of fentanyl taken up by the lung during the first pass and the instantaneous extraction of fentanyl at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. In patients who had been receiving no other drugs prior to the experiment, the total first pass uptake (mean +/- SE) of fentanyl was 82.6% +/- 1.4% of the injected dose. In patients who had been receiving 30-120 mg/day of propranolol the total first pass uptake (mean +/- SE) of fentanyl decreased to 52.8% +/- 6.3% of the injected dose. In one patient on 120 mg of propranolol per day, first pass uptake of fentanyl was only 20.3% of the injected dose. Additional studies in a rat isolated perfused lung preparation coperfused with fentanyl and propranolol also demonstrated that one basic lipophilic amine (propranolol) could inhibit the pulmonary uptake of a second basic lipophilic amine (fentanyl). The high first pass uptake of fentanyl in the human lung limits the rate of entry of this drug into the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of vasodilators and perfusion pressure on coronary flow and simultaneous release of nitric oxide from guinea pig isolated hearts

OBJECTIVE The aims were to validate the use of a direct reading NO electrode, to compare the effects of diverse acting drugs on altering coronary flow (CF) and NO release, and to examine the effects of altered perfusion pressure on flow-induced changes in NO concentration [NO] in the hemoglobin free effluent of guinea pig isolated hearts. METHODS Hearts were isolated and perfused initially at a constant perfusion pressure (55 mmHg) with a modified Krebs-Ringers solution equilibrated with 97% O2 and 3% CO2 at 37 degrees C. Heart rate, left ventricular pressure, CF, and effluent pH, pCO2, pO2, and NO generated current were monitored continuously on-line. Effluent was sampled for L-citrulline. Percent O2 extraction and O2 consumption were calculated. [NO] was quantitated with a sensitive amperometric sensor (sensitivity > or = 1 nmol/l approximately 3 pA) and a selective gas permeable membrane. RESULTS The electrode was not sensitive to changes in solution pO2, flow, or pressure. The electrode was sensitive to pCO2 (-0.50 nmol/l/mmHg) and temperature (+24.5 nmol/l/degree C), so coronary effluent pCO2 was measured to compensate for a small decrease in pCO2 that occurred with an increase in coronary flow, and effluent temperature was rigidly controlled. Serotonin, bradykinin, and nitroprusside increased NO release along with CF, whereas nifedipine, butanedione monoxime, zaprinast, and bimakalim comparably increased CF but did not increase [NO] or NO release. Increases in CF (ml/g/min) and NO release (pmol/g/min), respectively, were 5.0 +/- 1 and 100 +/- 17 for 1 mumol/l serotonin, 7.5 +/- 1 and 148 +/- 18 for 100 nmol/l bradykinin, and 7.8 +/- 1 and 173 +/- 28 for 100 mumol/l nitroprusside. The increases in effluent NO by bradykinin were proportional to the increases in L-citrulline. Tetraethylammonium decreased CF, but did not change NO release, indomethacin changed neither CF nor NO release, and NG-nitro-L-arginine methyl ester (L-NAME) reduced CF by 2.6 +/- 1 ml/g/min and NO release by 25 +/- 8 pmol/g/min. An increase of CF of 8.0 +/- 0.3 ml/g/min, produced by increasing perfusion pressure from 25 to 90 mmHg, increased [NO] by 30 +/- 4 nmol/l; L-NAME but did not reduce the pressure-induced increase in CF, but reduced the increase in [NO] to 10 +/- 5 nmol/l. CONCLUSIONS This study demonstrates in intact hearts real-time release of NO by several vasodilator drugs and by pressure-induced increases in flow (shear stress) and attenuation of these effects by L-NAME.

Oral Dexmedetomidine Attenuates Hemodynamic Responses during Emergence from General Anesthesia in Chronically Instrumented Dogs

This investigation evaluated the hemodynamic effects of orally administered dexmedetomidine in chronically instrumented dogs in the conscious state, during enflurane anesthesia, and after emergence. Four experimental groups (n = 9 each) were completed. In groups 1 and 2, dexmedetomidine (10 or 20 micrograms/kg, respectively) was administered orally, and hemodynamics, arterial blood gas tensions, and plasma norepinephrine concentrations were monitored for 6 h. Animals in groups 3 and 4 were given dexmedetomidine (20 micrograms/kg) or placebo orally, and hemodynamics, arterial blood gas tensions, and plasma norepinephrine concentrations were measured 1 h later with animals in the conscious state, after 30 min of enflurane anesthesia (1.0 MAC), and 2 and 7 min after extubation. Oral administration of dexmedetomidine resulted in sedation with significant decreases in heart rate (76 +/- 4 to 49 +/- 4 beats per min), rate-pressure product (11,500 +/- 650 to 6,100 +/- 600 mmHg. beats per min), cardiac output (2.2 +/- 0.2 to 1.2 +/- 0.4 l/min), and plasma norepinephrine concentrations (290 +/- 50 to 135 pg/ml). Peak effects occurred within 30 min and lasted approximately 3 h. No reduction in coronary blood flow velocity, decrease in regional contractile function, or respiratory depression was observed. Administration of dexmedetomidine before enflurane anesthesia also was associated with a reduction in heart rate and rate-pressure product, and dexmedetomidine prevented the increase in heart rate (146 +/- 9 vs. 60 +/- 7 beats per min) and arterial pressure (117 +/- 7 vs. 98 +/- 7 mmHg) during emergence from anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Baroreceptor reflex control of heart rate during morphine sulfate, diazepam, N2O/O2 anesthesia in humans.

The effect of morphine, diazepam, N2O/O2 anesthesia on baroreflex control of heart rate in humans was investigated in this study. Group 1 subjects (n = 11) received morphine 0.5 mg/kg, diazepam 0.25 mg/kg, and 70% N2O with O2. Group 2 subjects (n = 10) received morphine 0.75 mg/kg, diazepam 0.25 mg/kg, and 70% N2O with O2. Phenylephrine (the pressor test), sodium nitroprusside (the depressor test), and graded neck suction were employed to alter the stimulation of baroreceptor sites. The pressor, the depressor, and neck suction baroreflex slopes declined significantly in both groups from awake to anesthetized. There was no significant difference in the degree of depression between the two groups for all three tests. Neck suction derived slopes compared favorably to the pressor test slopes (r = 0.70, P < 0.01). This study indicates that the depression of arterial baroreflex–heart rate responses under morphine, diazepam, N2O/O2 anesthesia is similar to that seen with potent inhalational anesthetics such as isoflurane. Furthermore, there was no difference between the two morphine doses that were studied.