Mechanisms mediating the positive inotropic and chronotropic changes induced by dopexamine in the anesthetized dog

Mechanisms contributing to the increments in heart rate (HR) and cardiac contractile force (CCF) produced by dopexamine (DPX) were studied in anesthetized dogs. Intravenous infusions of DPX (4.0 micrograms/kg/min) produced increments in HR, CCF and renal blood flow and decrements in mean arterial pressure (MAP). The sequential administration of atenolol (0.5 mg/kg i.v.) administered at a dose selective for beta-1 adrenoceptors, propranolol (2.5 mg/kg i.v.) and the DA1 dopamine receptor antagonist, SCH 23390 (10 micrograms/kg i.v.) blocked the DPX-induced changes in HR, CCF, MAP and renal blood flow, respectively. After ganglionic blockade, the increments in HR and CCF produced by DPX (4.0 and 16.0 micrograms/kg i.v.) were reduced 90 and 76%, respectively, with little or no change in its hypotensive effect. In separate dogs, administration of the beta-2 adrenoceptor agonist salbutamol (0.55 microgram/kg i.v.) produced a comparable decrement in MAP but smaller increments in HR and CCF than produced by DPX (16.0 micrograms/kg i.v.). DPX (64 micrograms/kg i.v.) also produced greater increments in HR during cardioaccelerator nerve stimulation (1 Hz, 0.5 msec, supramaximal voltage) than before nerve stimulation. Therefore, we tested the effect of DPX (1.0, 4.0 and 8.0 micrograms/kg/min i.v.) on the increments in HR, CCF and MAP produced by norepinephrine (0.25 microgram/kg i.v.) and the indirect acting sympathomimetic amine, tyramine (60 micrograms/kg i.v.). DPX potentiated the increments in HR, CCF and MAP produced by norepinephrine and suppressed those produced by tyramine. Thus, the positive inotropic and chronotropic effects of DPX in the intact dog are due primarily to baroreceptor-mediated stimulation and inhibition of neuronal uptake of norepinephrine.     

Ventilatory response to intravenous methionine enkephalin in awake dogs

In conscious, microfilaria-free, adult mongrel dogs, i.v. bolus administration of methionine enkephalin (Met5-ENK) produced a transient elevation of both inspiratory minute ventilation (VI) and heart rate (HR). Both VI and HR increased progressively with increasing doses of Met5-ENK over the range of 6 to 18 micrograms/kg, thereafter plateauing at doses up to 36 micrograms/kg. Maximum changes in VI and HR occurred within 30 to 45 sec after injection, both variables returning to control levels in approximately 2 min. In four out of five dogs, mean inspiratory flow (tidal volume/inspiratory time), and consequently, tidal volume, accounted for this enkephalin-mediated increase in ventilation. In one of the dogs, respiratory rate, rather than tidal volume, increased after Met5-ENK. This change in respiratory rate was due to an increase in "effective timing" of the respiratory cycle, the latter defined as the ratio of inspiratory time to total respiratory time. Despite significant changes in VI and HR, neither end tidal oxygen nor carbon dioxide levels were significantly different from control after i.v. injections of Met5-ENK. Pretreatment with naltrexone methylbromide, a quaternary opiate antagonist that does not cross the blood-brain barrier, abolished all enkephalin-induced changes in VI and HR, thus suggesting that systemic enkephalins modulate ventilation via opiate receptors outside the blood-brain barrier. Activation of these receptors produce an increase in both cardiovascular and respiratory activity, as one might expect during stress conditions. These data further support a potential role for peripheral enkephalins as excitatory stress hormones.     

Changes in plasma glucose and lactate evoked by α and β2-adrenoceptor stimulation in conscious fasted rabbits

In conscious fasted rabbits, the iv infusion of salbutamol (3 micrograms/kg per min) and clonidine (2 micrograms/kg per min) induced a blood glucose increase amenable to blockade, respectively by ICI 118551 (1 micrograms/kg per min) and idazoxan (20 micrograms/kg per min). Amidephrine (10 micrograms/kg per min) and salbutamol mediated an increase in plasma lactate which was attenuated by prazosin (50 micrograms/kg, sc) and ICI 118551 respectively. Clonidine did not alter basal plasma lactate. The iv infusion of adrenaline (0.3 micrograms/kg per min) evoked an increase in plasma lactate more sensitive to blockade by ICI 118551 than by prazosin. ICI 118551 also shortened the hyperglycaemic response to adrenaline, 3-Mercaptopicolinic acid (25 mg/kg) reduced salbutamol- and adrenaline-mediated hyperglycaemia and increased at the same time the lactate/glucose ratio. Our data show that plasma lactate levels may be regulated by alpha 1- and beta 2-excitatory adrenoceptor stimulation. However, only the increase in blood lactate derived from beta 2-adrenergic stimulation seems to contribute to the overall catecholamine-mediated hyperglycaemia.     

Hemodynamic effects of dobutamine in an intact animal model.

BACKGROUND AND METHODS: Actions of dobutamine at the beta 1, beta 2, and alpha 1 adrenoreceptors were studied in anesthetized dogs. Six animals received dobutamine (at infusion rates of 0 to 160 micrograms/kg/min) with and without beta-adrenergic receptor blockade. Five animals received phenylephrine (0 to 16 micrograms/kg/min), with and without concurrent dobutamine (20 micrograms/kg/min); this procedure was repeated in five animals after beta-blockade. RESULTS: Dobutamine (10 to 160 micrograms/kg/min) increased heart rate (HR), cardiac output, and left ventricular change in pressure over time, and decreased systemic vascular resistance. beta-blockade prevented only dobutamine-induced changes in HR. Mean arterial pressure (MAP), unaffected by dobutamine alone, decreased with concurrent beta-blockade. Phenylephrine (1 to 16 micrograms/kg/min)-induced increases in MAP were unaffected by dobutamine; with beta-blockade, phenylephrine reduced MAP. Dobutamine prevented a phenylephrine-induced increase in systemic vascular resistance, an effect eliminated by beta-adrenergic receptor blockade. CONCLUSIONS: Dobutamine appeared to be an agonist at the beta 1- and beta 2-adrenoreceptors and at the myocardial alpha-adrenoreceptor. Dobutamine appeared to be an alpha-adrenergic receptor antagonist in the peripheral vasculature.     

Renal actions of a new adenosine agonist, CGS 21680A selective for the A2 receptor

This study compares the renal actions of the A2 selective adenosine agonist, CGS 21680A, with the A1 selective adenosine agonist, N6-cyclopentyladenosine (CPA), and the nonselective agonist, 5'-N-ethylcarboxamide adenosine (NECA), in the anesthetized dog. Initial receptor binding studies in dog brain demonstrated that CPA and CGS 21680A were selective for the A1 and A2 adenosine receptor, respectively, whereas NECA displayed slightly greater affinity for A1 than A2 adenosine receptors in the canine brain. Intravenous infusion of CGS 21680A (0.25 and 2.5 micrograms/kg/min) decreased blood pressure (BP) and increased heart rate (HR). CGS 21680A transiently increased renal blood flow (RBF) and either did not change or, at the highest dose infused, decreased glomerular filtration rate (GFR). Both urine volume (UV) and urinary sodium excretion (UNaV) also were decreased by CGS 21680A. At the lowest infusion rate (0.025 micrograms/kg/min) CGS 21680A produced a slowly developing increase in RBF, no change in GFR and a significant decrease in sodium excretion. Intravenous infusion of CPA (15 micrograms/kg/min) lowered BP and HR RBF and GFR. UNaV, UV and renin release also were inhibited by CPA. At a lower infusion rate (2.5 micrograms/kg/min), CPA markedly inhibited UNaV in the absence of a significant change in either BP or renal hemodynamic parameters. Infusion of NECA (0.01 and 0.1 micrograms/kg/min) lowered BP but did not change HR. Furthermore, RBF was increased by NECA, whereas UV and UNaV were inhibited in the absence of a change in GFR. These results may be explained by the relative selectivity of each analog for A1 or A2 adenosine receptors.     

Cardiovascular and renal effects of dopamine and dobutamine in healthy, conscious piglets

The pharmacologic effects of dopamine and dobutamine (2 to 32 micrograms/kg.min) were evaluated in 12 1 to 2-month-old piglets. Dopamine increased cardiac output at 16 to 32 micrograms/kg.min (p less than .05) and increased heart rate (HR) at 4 to 32 micrograms/kg.min (p less than .05). Dobutamine produced an increased cardiac output at doses of 16 to 32 micrograms/kg.min (p less than .05), and increased HR at 32 micrograms/kg.min (p less than .05), decreased systemic arterial pressure and systemic vascular resistance at 16 to 32 micrograms/kg.min (p less than .05), decreased renal vascular resistance at 16 to 32 micrograms/kg.min, and increased renal blood flow at 4.8 and 32 micrograms/kg.min (p less than .05). We conclude that dopamine and dobutamine increase cardiac output in healthy, conscious piglets primarily by increasing HR. Neither agent was effective in increasing stroke volume, although a positive inotropic effect obscured by tachycardia cannot be ruled out. Dobutamine was the superior agent for renal vasodilation, whereas neither agent produced significant pulmonary vasodilation.     

Response to dopamine and dobutamine in the preterm infant less than 30 weeks gestation

Mean arterial pressure (MAP) and heart rate (HR) were studied in 12 hypotensive preterm neonates given dopamine. A significant, although temporary, elevation in MAP (8 +/- 3 mm Hg; p less than .01) occurred in five neonates in response to 5 micrograms/kg.min, but an increase in MAP was found in all infants (11 +/- 6 mm Hg; p less than .01) when the infusion rate was doubled. This elevation was sustained only in five who previously showed some response to the slower infusion. HR was unaffected except for an increase of 22 +/- 12 beat/min (p less than .01) in the five showing sustained MAP elevation with 10 micrograms/kg.min. Dobutamine failed to raise MAP in the seven who relapsed, and refractory shock resulted. We conclude that time should not be wasted when starting dopamine at less than 10 micrograms/kg.min in hypotensive preterm infants, as lower rates are unlikely to produce a response and delay may cause further compromise.     

Effects of nebulized salbutamol on respiratory mechanics in adult respiratory distress syndrome

Objective: To determine whether nebulized salbutamol improves the respiratory mechanics of patients with adult respiratory distress syndrome (ARDS). We also assessed the mechanisms that contribute to high respiratory system resistances during this disease. Patients and setting: Eleven consecutive patients with ARDS without clinical evidence of chronic obstructive pulmonary disease, admitted to a polivalent intensive care unit, and mechanically ventilated with Siemens Elema Servo C ventilator at constant inspiratory flow. Method: Peak airway pressure (Ppeak), airway pressure immediately after end inspiratory occlusion (P1), plateau pressure (P2) and intrinsic positive end-expiratory pressure (PEEPi) were measured at baseline condition and then 5, 15, and 30 min after 1 mg of salbutamol had been administered via a nebulizer through the endotracheal tube. Partial pressure of arterial oxygen (PaO₂), heart rate (HR) and mean blood pressure (BP) were monitored and minimal respiratory system resistances (Rrs, m), additional resistances (DRrs) and static compliance (Cst) were computed Results: Between baseline and post-salbutamol, we observed changes in Ppeak, P1, P2, PEEPi and Rrs, m. As there were no significant differences between values at the different intervals during post administration, the results are described comparing baseline and 15 min post-salbutamol administration values. We found a significant decrease in Ppeak (4.9±0.8 cmH₂O), P1 (3±0.6 cmH₂O), P2 (2.1±0.6 cmH₂O), PEEPi (1.9±0.5 cmH₂O) and Rrs, m (1.9±0.3 cmH₂O/1 s^-1); DR, rs decreased in five patients, did not change in four and increased in two. HR, PaO₂ and BP did not change. Conclusions: a) Salbutamol administered through the endotracheal tube by a nebulizer device lessens respiratory system resistances and airway and alveolar pressures, and therefore could decrease the risk of barotrauma and alveolar damage; b) high respiratory system resistances in ARDS have an increased smooth muscle tone component that can be reversible with salbutamol. Received: 20 January 1995 Accepted: 15 September 1996     

The Efficacy of Nebulized Racemic Epinephrine in Children with Acute Asthma: A Randomized, Double-blind Trial

OBJECTIVES: Recent work in bronchiolitis has demonstrated a significant clinical improvement in children treated with epinephrine over nebulized salbutamol. The objective of this study was to determine whether nebulized epinephrine, as compared with nebulized salbutamol, causes a greater clinical improvement in children with acute asthma. METHODS: Children, aged 1 to 17 years, with acute asthma presenting to the emergency department (ED) were eligible. In this double-blind study, patients were randomly allocated to receive either salbutamol or racemic epinephrine by nebulization at 0, 20, and 40 minutes. All patients received oral steroids. The primary outcome measure was a change in pulmonary index score (PIS). RESULTS: One hundred twenty patients were randomized. The groups were comparable in terms of age, gender, asthma severity, previous treatments, and use of inhaled steroids. There was no significant difference between treatments in the change in PIS, length of stay, admission to hospital, or relapse rate. The epinephrine-treated group had significantly more minor side effects (such as excess or brownish nasal discharge). CONCLUSIONS: There is no significant clinical benefit of nebulized epinephrine over salbutamol in children 1-17 years old with mild to moderate acute asthma. Salbutamol remains the treatment of choice in children with known asthma.     

异丙酚复合氯胺酮持续输注在小儿静脉全麻的应用与评价

目的评估异丙酚复合氯胺酮静脉麻醉用于婴幼儿手术的麻醉效果。方法选60名患儿术前30min肌注阿托品0．02mg／kg,术中持续静脉输注异丙酚2-4mg／kg、氯胺酮1-2mg／kg维持麻醉状态,并观察术中平均动脉压（MAP）、心率（HR）、脉搏血氧饱和度（SpO2）及呼吸频率（RR）的变化。结果术中各时间与术前比较MAP、HR、SpO2、RR无显著差异性（P〉0．05）,术中各时间间比较差异亦无显著性（P〉0．05）。结论异丙酚复合氯胺酮静脉全身麻醉效果满意,是一种安全、有效的婴幼儿手术麻醉方式。     

Pharmacokinetics and renal tolerance of aztreonam in premature infants.

Aztreonam (30 mg/kg of body weight) was administered intravenously over 3 min every 12 h to 30 preterm neonates divided into two groups according to gestational age (mean age for group A was less than 30 weeks and mean age for group B was greater than 30 weeks) and birth weight (mean weight for group A was less than 1,500 g and mean weight for group B was greater than 1,500 g). Blood and urine samples were analyzed by microbiological assay. The pharmacokinetics were described by one-compartment and noncompartment models. The mean half-life and clearance for premature infants weighing less than 1,500 g were 5.33 +/- 3.61 h and 1.52 +/- 1.33 ml/min/kg, respectively; for those weighing more than 1,500 g, the values were 4.08 +/- 2.28 h and 2.41 +/- 2.10 ml/min/kg, respectively. The mean urinary concentration of aztreonam in 15 premature infants during the first 6 h of therapy was 242.72 +/- 188.19 micrograms/ml, with a mean percentage of elimination of 13.29%. Urinary excretion of N-acetyl-beta-D-glucosaminidase (a specific and sensitive test for the detection of drug-induced renal tubule damage) did not show significant differences in our group of premature infants compared with that in a control group. The dose of 30 mg/kg and a dosage interval of 8 to 12 h could be recommended for the treatment of suitable bacterial infections in all premature infants.     

Effect of inspiratory flow rate on β2-agonist induced bronchodilation in mechanically ventilated COPD patients

OBJECTIVES: To test the effect of two different inspiratory flow rates on the bronchodilation induced by beta2-agonists administered by metered dose inhaler (MDI). PATIENTS: Ten patients with acute exacerbation of chronic obstructive pulmonary disease and receiving mechanical ventilation with constant inspiratory flow (V'I). DESIGN: Patients received four puffs of salbutamol (100 microg/puff) with either low V'I (0.6 l/s) or high V'I (1.2 l/s) administered with an MDI adapted to inspiratory limb of the ventilator circuit using an aerosol cloud enhance spacer. After a 6-h washout patients were crossed-over to receive the drug by the alternative mode of administration. MEASUREMENTS AND RESULTS: Static and dynamic airway pressures, intrinsic positive end-expiratory pressure, and minimum and maximum inspiratory resistance values showed a significant decrease after salbutamol. These changes were not affected by the inspiratory flow rate and were evident 15, 30, and 60 min after administration. Heart rate, static end-inspiratory respiratory system compliance, and the difference between minimum and maximum inspiratory resistance were unchanged after salbutamol. CONCLUSIONS: Salbutamol delivered by MDI and spacer device induces significant bronchodilation in mechanically ventilated patients with chronic obstructive pulmonary disease, but the magnitude of the effect is not affected by the inspiratory flow rate. These results do not support flow rate manipulations when bronchodilators are administered during controlled mechanical ventilation.     

Ranitidine does not impair oxidative or conjugative metabolism: noninteraction with antipyrine, diazepam, and lorazepam

Potential interactions of ranitidine with antipyrine, diazepam, and lorazepam were evaluated. Ten healthy male subjects were injected intravenously with antipyrine (1.2 gm), diazepam (10 mg), or lorazepam (2 mg) on two randomly assigned occasions, once in the otherwise drug-free state and once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Kinetic analysis for antipyrine showed no change in elimination t1/2 between trials (mean, 11.6 and 11.5 hr) with no change in volume of distribution (Vd) or total clearance (0.77 and 0.75 ml/min/kg). Diazepam analysis also showed unchanged t1/2 (32.3 and 28.9 hr) with no change in Vd or total clearance (0.42 and 0.39 ml/min/kg). Lorazepam as well had unchanged t1/2 (11.7 and 11.3 hr), Vd, and total clearance (1.52 and 1.65 ml/min/kg). Therefore ranitidine, unlike cimetidine, has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.     

Effect of inhaled nitric oxide on respiratory mechanics in ventilated infants with RSV bronchiolitis

Objective: To evaluate the bronchodilator effect of inhaled nitric oxide (NO) in infants with respiratory failure caused by respiratory syncytial virus (RSV) bronchiolitis and to compare the effect with the one obtained by salbutamol. Design: Prospective study. Setting: Pediatric intensive care unit of a university children's hospital. Patients: Twelve acutely ill, intubated infants (mean age 4.5 months, mean weight 4.9 kg) with respiratory failure due to documented RSV bronchiolitis. Interventions: Total respiratory system resistance (Rrs) was measured by single breath occlusion at the baseline and after inhaling NO at 20, 40 and 60 ppm for 1 h, and after inhalation of a standard β ₂-agonist, salbutamol. Arterial blood gas analysis was performed at each study level on 6 of the 12 patients. Results: The baseline mean Rrs (SE) was 0.29 (0.04) cm H₂O/ml per s. At each dose of NO, the mean Rrs (SE) was 0.28 (0.04) cm H₂O/ml per s. With salbutamol, the mean Rrs (SE) was 0.21 (0.03) cm H₂O/ml per s. These values were not significantly different from each other (by ANOVA). Inhaled NO produced a significant decrease in Rrs of greater than 4 times the coefficient of variation of the baseline measurement in 3 of 12 patients. Seven of 12 patients had no significant change while two patients had a significant increase in Rrs. Inhaled salbutamol produced a significant decrease in Rrs in 5 of 11 patients, while 6 showed no change in Rrs. Conclusion: Inhaled NO has no apparent bronchodilator effect in the majority of acutely ill infants with RSV bronchiolitis and does not appear to provide any additional benefit over the use of salbutamol. The clinical benefit of inhaled NO as a bronchodilator is questionable under these conditions. Received: 15 June 1998 Final revision received: 23 September 1998 Accepted: 29 September 1998     

Aminoglycoside pharmacokinetics: dosage requirements and nephrotoxicity in trauma patients

We evaluated prospectively gentamicin and tobramycin pharmacokinetics in 37 patients with multiple system trauma and seven patients with isolated closed head trauma. The mean apparent volume of distribution (Vd) was 0.38 +/- 0.10 and 0.27 +/- 0.04 L/kg actual body weight (ABW) in patients with multiple trauma and closed head trauma, respectively. The difference in Vd between the two groups of patients was significant (p less than .002). Vd was not predictable on the basis of age, sex, weight, trauma score, or hospital day that therapy was initiated. Mean aminoglycoside clearance (Cl) was 123 +/- 46 ml/min. Neither serum creatinine nor estimated creatinine Cl predicted aminoglycoside Cl with sufficient accuracy to be clinically useful (r = .33 and .67, respectively). The mean daily dose was 6.1 +/- 1.6 mg/kg. The mean peak serum level was 5.8 +/- 1.3 micrograms/ml. Only one patient developed clinically significant renal dysfunction. Our data indicate that a loading dose of gentamicin or tobramycin of 3 mg/kg ABW in patients with multiple trauma and 2.5 mg/kg ABW in patients with isolated head trauma will obtain a mean initial peak serum level of 6.6 micrograms/ml. Although adequate maintenance dosing requires individualization based on pharmacokinetic analyses, large aminoglycoside doses can be used safely in patients with blunt trauma if appropriate monitoring is employed.     

Tolerance and beta-adrenergic blocking activity of flestolol, a short-acting beta blocker

The tolerance and beta-adrenergic blocking activity of flestolol, a short-acting beta-blocker, was investigated in 30 subjects. Flestolol infused intravenously at doses up to 100 micrograms/kg/min was found to be well tolerated. A dose-dependent attenuation of isoproterenol-induced tachycardia and increase in systolic blood pressure occurred with flestolol at doses ranging from 0.5 to 15.0 micrograms/kg/min. The average percent reduction in isoproterenol-induced tachycardia (beta-blockade) at each dose of flestolol, 0.5, 2.5, 5.0, 15.0, and 50.0 micrograms/kg/min, was 15.1%, 45.9%, 67.0%, 85.9%, and 90.3%, respectively. The onset of beta-blockade occurred within 30 minutes. After the end of flestolol infusion there was a marked reduction in beta-blockade within 6 minutes, with complete recovery from beta-blockade within 30 to 45 minutes. There was a statistically significant (P less than 0.01) positive correlation between flestolol dosage and its blood levels (r = 0.91) as well as between the flestolol-induced beta-blockade and its dosage (r = 0.62).     

盐酸戊乙奎醚应用于小儿氯胺酮麻醉前用药

【目的】探讨盐酸戊乙奎醚作为全麻术前用药在减少腺体分泌以及对循环功能、体温的影响及其用于术前用药的安全性和有效性。【方法】手术患儿60例,随机分为盐酸戊乙奎醚组（A组）和东莨菪碱组（B组）,每组30例。两组均于术前30min分别肌注盐酸戊乙奎醚（0．01mg／ks）和东莨菪碱（0．01mg／kg）。静脉给予氯胺酮（1mg／kg）常规复合臂丛神经阻滞（利布合剂0．5mL／kg）,记录给药前15min、给药后15min、20min、30min,给氯胺酮15min后血压（BP）、心率（HR）、脉搏血氧饱和度（SPO2）、体温（T）、呼吸道唾液分泌物、面色、皮肤、口干等情况。【结果】B组术前及用药后HR、BP均比A组升高（P〈0．05）。氯胺酮麻醉后,B组HR、BP与A组比较差异无统计学意义（P〉0．05）。SPO2两组时点值无显著差别,B组用药后30min后T升高,呼吸道分泌物明显多于A组。【结论】盐酸戊乙奎醚具有显著的心率稳定作用及强大持久的腺体分泌抑制作用,作为术前用药效果满意且优于东莨菪碱,可安全用于小儿全麻手术术前给药。     

Single- and multiple-dose metronidazole kinetics

Kinetics of metronidazole and its metabolites were examined after single oral and intravenous doses and multiple oral doses in seven subjects by a sensitive HPLC assay. After 400 mg metronidazole IV, mean Vd beta was 1.05 l/kg. Mean plasma t1/2 was 8.3 hr with a ClTBC of 1.31 ml/min/kg. Clearance to the major metabolites, 2-hydroxy-metronidazole and 1-acetic acid metronidazole, accounted for over 90% of the ClTBC. After a single oral 400-mg metronidazole dose, the development of peak metronidazole plasma concentrations of 6.9 micrograms/ml averaged 2.3 hr after dosing. Systemic oral bioavailability was complete (98.9%). During twice-daily multiple metronidazole dosing, 400 mg, metronidazole kinetics were the same. Elimination t1/2 was 8.3 hr and average predicted steady-state metronidazole concentrations during one dosing interval (6.3 +/- 0.5 micrograms/ml; mean +/- SE) were equal to the observed concentrations (6.9 +/- 1 micrograms/ml). Urinary excretion of unchanged metronidazole was below 10% of the total dose. Seventy-five percent of the dose was 2-hydroxy-metronidazole and 1-acetic acid metronidazole, and 15% was conjugates of metronidazole and 2-hydroxy-metronidazole.     

CARDIOVASCULAR CHARACTERIZATION OF THE DA2 DOPAMINE RECEPTOR AGONIST QUINPIROLE IN RATS

In normotensive anesthetized rats, 15-min IV infusions of quinpirole (2.5-40.0 micrograms/kg/min) produced dose-related, rapidly appearing, and long-lasting decreases in mean carotid artery BP and HR. Hemodynamically, the hypotensive effects of quinpirole (10.0 micrograms/kg/min) were due to a fall in total peripheral vascular resistance inasmuch as CO did not undergo significant changes. Mesenteric, hindquarter, and renal blood flows were, respectively, reduced, unchanged, and increased by quinpirole; thus, the renal vascular resistance fell more than either the total peripheral or hindquarter vascular resistance. Biochemically, the hypotensive effects of quinpirole were accompanied by a decrease in the plasma level of norepinephrine and plasma renin activity. The peak fall in blood pressure produced by quinpirole was not significantly modified by atenolol, idazoxan, ranitidine, SCH 23390 (DA1 dopamine receptor antagonist), enalapril, or SK&F 100273 (V1 vasopressin receptor antagonist), but was entirely blocked by S-sulpiride or removal of autonomic nerve drive to the cardiovascular system with chlorisondamine. The effect of quinpirole on systemic and regional vascular resistances was antagonized by S-sulpiride. Furthermore, SK&F 100273 prevented the fall in mesenteric flow produced by quinpirole. Intracerebroventricular injection of quinpirole (10.0 micrograms/kg over 2 min) in saline- or SK&F 100273-pretreated rats produced the same hypotensive effects as an identical IV dose of the compound. In pithed rats, quinpirole (10 micrograms/kg/min IV over 15 min) decreased pressor responses to electrical stimulation of spinal cord outflow without affecting those to exogenously injected angiotensin II, B-HT 920, cirazoline, norepinephrine, or 5-hydroxytryptamine. This inhibitory effect was antagonized by S-sulpiride. The bradycardia produced by quinpirole in intact rats was mediated by the autonomic nervous system inasmuch as it was slightly modified by bilateral vagotomy, partly reduced by atenolol, and entirely prevented by pithing even when the low HR of the last preparation had been raised by IV infusion of isoprenaline. Furthermore, S-sulpiride, but not SCH 23390 or idazoxan, antagonized this effect. In pithed rats, quinpirole similarly inhibited the tachycardic responses elicited by electrical stimulation of either the spinal cord outflow (preganglionic) or postganglionic cardioaccelerator nerve fibers. This effect of quinpirole was susceptible to S-sulpiride but not idazoxan blockade. Finally, in conscious spontaneously hypertensive rats (SHR) but not in normotensive rats, quinpirole (10 micrograms/kg/min IA over 15 min) lowered blood pressure.(ABSTRACT TRUNCATED AT 400 WORDS)     

Hemodynamic and sedative effects of dexmedetomidine in dog.

This study investigated hemodynamic and sedative effects of a single dose of the selective alpha-2 adrenoceptor agonist dexmedetoimidine (DMED) in isoflurane-anesthetized dogs. DMED (20 micrograms/kg i.v. 2-min infusion) was given to all dogs. In Group 1 the effects of DMED (time control; N = 10) were studied over 4 hr. In Group 2 (N = 11) glycopyrrolate (40 micrograms/kg initial dose followed by 20 micrograms/kg repeated every 30 min) was used to modulate the DMED-induced vagally mediated changes in heart rate. In Group 3 (N = 8), two doses of nifedipine were used to offset the DMED-induced increase in arterial blood pressure, low dose nifedipine = 10 micrograms/kg bolus followed by 2.5 micrograms/kg/min infusion for 20 min, high dose nifedipine = 20 micrograms/kg bolus followed by 5 micrograms/kg/min infusion for 20 min. DMED administration reduced isoflurane anesthetic requirements by 89% at 30 min and by 50% at 4 hr. Maximum increase in mean arterial blood pressure (MABP) +67 mm Hg occurred 1 min after DMED. MABP remained significantly elevated throughout the 4 hr studied (about +20%). Concomitant with the transient peak in MABP, heart rate (129 +/- 6 to 60 +/- 8 bpm) and cardiac output (3.5 +/- 0.3 to 0.9 +/- 0.1 l/min) decreased, whereas systemic vascular resistance (2460 +/- 210 to 14,700 +/- 1330 dynes.sec.cm-5) and left ventricular end diastolic pressure (4 +/- 1 to 27 +/- 4 mm Hg) increased.(ABSTRACT TRUNCATED AT 250 WORDS)