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Purpose: To assess the pharmacokinetics and biodistribution of gentamicin, delivered as PulmoSpheres formulations in rabbit serum and lung tissue following intratracheal instillation in a perflubron vehicle., Methods: Rabbits were anesthetized, intubated, and mechanically ventilated with O2 (FiO2 = 0.50). Animals were then given 5 mg/kg gentamicin either intravenously, intramuscularly (TM), or intratracheally (IT) gentamicin PulmoSpheres formulation, instilled in 1.8 ml/kg of liquid perflubron vehicle. Serum and lung lobe sections were collected at multiple time points and assayed for gentamicin content., Results: Serum gentamicin levels peaked at 64.7 microg/ml, 11.2 microg/ml, and 5.0 microg/ml following intravenous, TM, and IT administration, respectively. Absolute bioavailabilitv at 8 h for IM administration was 76.8% and 57.0% when delivered IT. Although peak lung levels of drug were reached within 1 h, total lung gentamicin concentration after IT administration was more than two orders of magnitude greater than that achieved following TM administration (680,540 vs. 4,985 microg min, respectively) with significant levels of the antibiotic remaining in the lung even after 1 week., Conclusions: High levels of gentamicin in lung tissue can be achieved by instillation of a gentamicin PulmoSpheres formulation in a perflubron vehicle, termed liquid dose installation, without reaching toxic systemic levels allowing for increased local delivery of agents such as gentamicin at the site of the infection.

1. The aim of the present study was to assess interactions between nitric oxide (NO) and prostacyclin (PGI2) during endothelium-dependent relaxations evoked by bradykinin, calcium ionophore (A23187) and acetylcholine in canine isolated pulmonary artery. 2. Relaxations to low concentrations of bradykinin and A23187 were abolished by combined inhibition of NO-synthase (by N omega-nitro-L-arginine methyl ester L-NAME, 30 microM) and cyclo-oxygenase (indomethacin, 10 microM), suggesting mediation by NO and PGI2. The individual contributions of NO and PGI2 to the dilator responses were quantified by use of areas above the separate indomethacin-insensitive and L-NAME-insensitive components of the concentration-effect curves, respectively. Individually, NO and PGI2 accounted for only 53 +/- 5% and 16 +/- 9% of total bradykinin-induced relaxation, and 46 +/- 10% and 20 +/- 9% of total A23187-induced relaxation, suggesting that NO and PGI2 acted synergistically to cause endothelium-dependent relaxation. 3. Relaxation to low concentrations of acetylcholine was abolished by L-NAME but not affected by indomethacin, suggesting the response was mediated solely by NO with no interaction from PGI2. 4. Glibenclamide (1 microM), an inhibitor of ATP-sensitive potassium (K+ATP) channels, inhibited responses to bradykinin or A23187 but did not affect relaxations evoked by acetylcholine. Glibenclamide did not affect endothelium-independent relaxations to PGI2 or the NO-donor, 3-morpholinosydnonimine (SIN-1). 5. With bradykinin, glibenclamide attenuated total relaxation by 49 +/- 8%, but did not alter the individual NO and PGI2-mediated components of the response. Glibenclamide abolished the synergistic interaction between endothelium-derived NO and PGI2. 6. At high concentrations, bradykinin, A23187 or acetylcholine caused endothelium-dependent relaxation that was insensitive to L-NAME + indomethacin. With bradykinin or A23187, this component of relaxation was inhibited by glibenclamide, whereas with acetylcholine, glibenclamide had no effect. 7. The synergistic interaction between endothelium-derived NO and PGI2 in canine pulmonary artery is mediated by activation of K+ATP channels, presumably by an endothelium-derived hyperopolarizing factor (EDHF). The pattern of endothelial dilator mediators and the presence of this synergistic interaction is dependent on the nature of the endothelial stimulus.

Background: Endothelium-derived nitric oxide causes vasodilation in part by increasing the dilator activity of other endothelium-derived mediators, including prostacyclin and a K+ATP channel-dependent hyperpolarizing factor. Although previous studies have proposed that isoflurane (ISO) depresses endothelium-dependent vasorelaxation by inhibiting endothelium-derived nitric oxide activity, the effects of ISO on the interactions among endothelium-derived dilators have not been characterized. The aim of this study was to determine the mechanisms underlying the inhibitory effect of ISO on endothelium-dependent relaxation in canine pulmonary arteries. Specifically, the goal was to assess the effects of ISO on the individual actions and on the synergistic interactions of these endothelium-derived mediators., Methods: Canine pulmonary arterial rings were suspended for isometric tension recording. The effects of 1 minimum alveolar concentration ISO (0.4 mM) on vasorelaxation responses to bradykinin, A23187, acetylcholine, cromakalim, and SIN-1 were assessed in phenylephrine-precontracted rings with and without pretreatment with a nitric oxide synthase inhibitor (N omega-nitro-L-arginine methyl ester; L-NAME), a cyclooxygenase inhibitor (indomethacin), or a K+ATP channel inhibitor (glybenclamide)., Results: Isofluane attenuated pulmonary vasorelaxation induced by bradykinin, A23187, and cromakalim but had no effect on relaxation induced by acetylcholine or SIN-1. Neither the nitric oxide-mediated nor the prostacyclin-mediated components of relaxation induced by bradykinin and A23187 were altered by ISO. However, ISO abolished the K+ATP-mediated component of relaxation and the K+ATP-dependent synergistic interaction between nitric oxide and prostacyclin., Conclusions: These results suggest that ISO selectively attenuates endothelium-dependent relaxation in canine pulmonary arteries. It exerts its inhibitory effect by interfering with a synergistic interaction between nitric oxide and prostacyclin, possibly via an effect on K+ATP channels.

We have recently reported that halothane (Hal) anesthesia attenuates the pulmonary vasodilator responses to both bradykinin (BK) and sodium nitroprusside (SNP) compared with responses measured in the conscious state. These agonists have been classically used to activate endothelium-dependent and -independent vasodilator pathways, respectively. Our present goal was to assess the effect of isoflurane (Iso) anesthesia on pulmonary vasodilation activated via these pathways. Left pulmonary vascular pressure-flow (P-Q) plots were used to measure the pulmonary vascular responses to cumulative intravenous doses of BK, SNP, and 3-morpholinosydonimine-N-ethylcarbamide (SIN-1), a nitric oxide donor, in chronically instrumented dogs in the conscious state and during Iso anesthesia after matched preconstriction with the thromboxane analogue U-46619. Iso attenuated the vasodilator response to BK (P < 0.05). However, Iso had a differential effect on the responses to SIN-1 and SNP. Iso potentiated the vasodilator response to SIN-1 (P < 0.05), whereas Iso attenuated the response to SNP (P < 0.05). The vasodilator response to SIN-1 was unchanged during Hal anesthesia. The ATP-sensitive potassium (KATP)-channel inhibitor glibenclamide attenuated the vasodilator response to SNP (P < 0.05) but not to SIN-1. Thus Iso and Hal selectively attenuate the endothelium-dependent pulmonary vasodilator response to BK. Both anesthetics attenuate vasodilation induced by SNP but not by SIN-1. Moreover, a component of SNP-induced vasodilation involves KATP-channel activation.

We tested the hypothesis that inflammatory cells mediate the loss of neuronal M2 muscarinic receptors in the lung after ozone exposure. Pathogen-free guinea pigs treated with cyclophosphamide (30 mg.kg-1.day-1 i.p. for 7 days) before exposure to ozone were compared with untreated ozone-exposed animals. This dose of cyclophosphamide significantly reduced leukocytes in peripheral blood and bronchoalveolar lavage fluid. Twenty-four hours after ozone, muscarinic receptor function was tested in anesthetized animals. In air-exposed guinea pigs, vagally induced bronchoconstriction was attenuated by the muscarinic agonist pilocarpine (0.1-100 micrograms/kg i.v.) and potentiated by the selective M2 antagonist gallamine (0.1-10 mg/kg i.v.), indicating that the neuronal M2 muscarinic receptors were functioning. These responses were significantly reduced after ozone, indicating loss of neuronal M2 muscarinic receptor function. However, in those animals treated with cyclophosphamide, M2 muscarinic receptor function was not altered by ozone. These data suggest that ozone-induced loss of neuronal muscarinic receptor function is mediated via inflammatory cells and that the link between ozone-induced hyperresponsiveness and inflammation may be the neuronal M2 muscarinic receptor.

Study Objective: To evaluate the effects of nifedipine, diltiazem, and verapamil overdose on systemic hemodynamics and blood flows to the coronary, superior mesenteric, renal, and iliac arteries in the unanesthetized dog., Design: Nonblinded, controlled animal study., Setting: Research laboratory of a large pharmaceutical company., Type of Participants: Nineteen healthy mongrel dogs obtained from a commercial supplier., Interventions: Under general anesthesia, flow probes were placed about the ascending aorta, circumflex coronary, superior mesenteric, renal, and iliac arteries; a micromanometer was implanted into the tip of the left ventricle; and a catheter was inserted into the descending aorta. Experiments were performed after a recovery period of at least two weeks., Measurements and Main Results: Arterial blood pressure, heart rate, cardiac output, left ventricular pressure, and regional blood flows were measured prior to drug administration, and after 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg IV administration of the study drugs. Dogs receiving diltiazem or verapamil also received a dose of 10.0 mg/kg. When the blood pressure had been reduced from baseline by 30%, 1.43 mg/kg nifedipine IV (six dogs) decreased total peripheral resistance by 51%, increased cardiac output by 35%, and increased heart rate by 132%. Coronary blood flow and iliac blood flow increased 93% and 45%, respectively, but mesenteric blood flow and renal blood flow were not significantly altered. Diltiazem (eight) and verapamil (seven) at equivasodepressor doses (1.43 to 4.43 mg/kg) caused less peripheral vasodilation and reflex tachycardia. At severely toxic levels when arterial blood pressure fell by 50%, all three drugs decreased cardiac output. Nifedipine still increased heart rate. Diltiazem and verapamil caused high-grade atrioventricular block, resulting in bradycardia. All three drugs caused a redistribution of cardiac output favoring the coronary bed over the other beds., Conclusions: In the conscious dog, calcium channel blocker-induced hypotension at the moderate level is associated with disparate effects on systemic hemodynamics, probably resulting from differential reflex sympathetic activation. However, at a more severe level, their toxic effects are similar and manifested predominantly by their actions on the slow calcium channel.