Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation.

UNLABELLED: Nitric oxide (NO) derived from inducible nitric oxide synthase (iNOS) mediates hypotension and metabolic derangements in sepsis. We hypothesized that selective iNOS-inhibition would prevent hypotension in septic rats without inhibiting endothelium-dependent vasodilation caused by the physiologically important endothelial NOS. Rats were exposed to lipopolysaccharide (LPS) for 6 h and the selective iNOS-inhibitor L-N6-(1-iminoethyl)-lysine (L-NIL), the nonselective NOS-inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME), or control. Mean arterial pressure (MAP) and vasodilation to acetylcholine (ACh, endothelium-dependent), sodium nitroprusside (SNP, endothelium-independent), and isoproterenol (ISO, endothelium-independent beta agonist) were determined. Exhaled NO, nitrate/nitrite-(NOx) levels, metabolic data, and immunohistochemical staining for nitrotyrosine, a tracer of peroxynitrite-formation were also determined. In control rats, L-NAME increased MAP, decreased the response to ACh, and increased the response to SNP, whereas L-NIL did not alter these variables. LPS decreased MAP by 18% +/- 1%, decreased vasodilation (ACh, SNP, and ISO), increased exhaled NO, NOx, nitrotyrosine staining, and caused acidosis and hypoglycemia. L-NIL restored MAP and vasodilation (ACh, SNP, and ISO) to baseline and prevented the changes in exhaled NO, NOx, pH, and glucose levels. In contrast, L-NAME restored MAP and SNP vasodilation, but did not alter the decreased response to ACh and ISO or prevent the changes in exhaled NO and glucose levels. Finally, L-NIL but not L-NAME decreased nitrotyrosine staining in LPS rats. In conclusion, L-NIL prevents hypotension and metabolic derangements in septic rats without affecting endothelium-dependent vasodilation whereas L-NAME does not. IMPLICATIONS: Sepsis causes hypotension and metabolic derangements partly because of increased nitric oxide. Selective inhibition of nitric oxide produced by the inducible nitric oxide synthase enzyme prevents hypotension and attenuates metabolic derangements while preserving the important vascular function associated with endothelium-dependent vasodilation in septic rats.

Ropivacaine attenuates pulmonary vasoconstriction induced by thromboxane A2 analogue in the isolated perfused rat lung.

BACKGROUND AND OBJECTIVES: Thromboxane A2 (TXA2) activation is involved in several pathophysiological states in producing pulmonary hypertension. Local anesthetics (LA) inhibit signaling of TXA2 receptors expressed in cell models. Therefore, we hypothesized that LA may inhibit pulmonary vasoconstriction induced by the TXA2 analogue U 46619 in an isolated lung model. METHODS: Isolated rat lungs were perfused with physiological saline solution and autologous blood with or without the LA lidocaine, bupivacaine, ropivacaine, or the permanently charged lidocaine analogue QX 314 (all 1 microg/mL) as a pretreatment. Subsequently, pulmonary vasoconstriction was induced by 3 concentrations of U 46619 (25, 50, and 100 ng/mL) and the change in pulmonary artery pressure (Pa) was compared with each LA. In a second experiment, Pa responses to angiotensin II (0.1 microg), hypoxic pulmonary vasoconstriction (HPV, 3% O2 for 10 minutes), or phenylephrine (0.1 microg) were assessed to determine the specificity of ropivacaine effects on TXA2 receptors. Finally, reversibility of pulmonary vasoconstriction was determined by adding ropivacaine to the perfusate after pulmonary vasoconstriction was established with U 46619. RESULTS: Ropivacaine, but not bupivacaine, lidocaine, or QX 314 significantly attenuated pulmonary vasoconstriction induced by 50 ng/mL U 46619 (35.9%, P<.003) or 100 ng/mL U 46619 (45.2%, P<.001). This effect of ropivacaine was likely to be specific for the thromboxane receptor because pulmonary vasoconstriction induced by angiotensin II, HPV, or phenylephrine was not altered. Ropivacaine did not reverse vasoconstriction when it was administered after U 46619. CONCLUSIONS: Ropivacaine, but not lidocaine, bupivacaine, or QX 314 at 1 microg/mL, attenuates U 46619-induced pulmonary vasoconstriction in an isolated perfused rat lung model. These results support evidence that the clinically used enantiomer S(-)-ropivacaine may inhibit TXA2 signaling.

Cyclooxygenase inhibitors attenuate bradykinin-induced vasoconstriction in septic isolated rat lungs.

UNLABELLED: Cyclooxygenase (COX) products play an important role in modulating sepsis and subsequent endothelial injury. We hypothesized that COX inhibitors may attenuate endothelial dysfunction during sepsis, as measured by receptor-mediated bradykinin (BK)-induced vasoconstriction and/or receptor-independent hypoxic pulmonary vasoconstriction (HPV). Rats were administered intraperitoneally a nonselective COX inhibitor (indomethacin, 5 or 10 mg/kg) or a selective COX-2 inhibitor (NS-398, 4 or 8 mg/kg) 1 h before lipopolysaccharide (LPS, 15 mg/kg), or saline (control). Three hours later, the rats were anesthetized, the lungs were isolated, and pulmonary vasoreactivity was assessed with BK (0.3, 1.0, and 3.0 microg) and HPV (3% O(2)). Perfusion pressure was monitored as an index of vasoconstriction. To investigate what receptor-subtype is mediating BK responses, the BK(1)-receptor antagonist des-Arg(9)-[Leu(8)]-BK, the BK(2)-receptor antagonist HOE-140, or the thromboxane A(2)-receptor antagonist SQ 29548 (all at 1 microM) were added to the perfusate. BK-induced vasoconstriction was significantly increased in LPS lungs (1.4-5.2 mm Hg) compared with control (0.1-1.1 mm Hg). In LPS lungs, indomethacin 10 mg/kg significantly decreased BK vasoconstriction by 78% +/- 9%, whereas 5 mg/kg did not. NS-398, 4 mg/kg, significantly attenuated BK vasoconstriction at 0.3 microg (71% +/- 7%) and 1.0 microg (56% +/- 12%), whereas 8 mg/kg attenuated 0.3 microg BK (57% +/- 14%), compared with LPS lungs. HPV was increased in LPS lungs (21.5 +/- 2 mm Hg) compared with control lungs (9.8 +/- 0.6 mm Hg). Indomethacin 5 mg/kg increased HPV in LPS lungs; otherwise, HPV was not altered by COX inhibition. BK-induced vasoconstriction was prevented by BK(2), but not BK(1) or thromboxane A(2)-receptor antagonism. This study suggests that nonselective COX inhibition, and possibly inhibition of the inducible isoform COX-2, may attenuate sepsis-induced, receptor-mediated vasoconstriction in rats. IMPLICATIONS: This study demonstrated that, in an isolated rat lung model, nonselective inhibition of the cyclooxygenase pathway, and possibly selective inhibition of the inducible cyclooxygenase-2 isoform, may attenuate sepsis-induced endothelial dysfunction.

The effect of nitric oxide on platelets when delivered to the cardiopulmonary bypass circuit.

UNLABELLED: Nitric oxide (NO) decreases platelet adhesion to foreign surfaces in the in vitro models of cardiopulmonary bypass (CPB). We hypothesized that NO, delivered into the membrane oxygenator (MO), would exert a platelet-sparing effect after CPB. Forty-seven patients scheduled for coronary artery surgery were randomized to either a NO group, in which NO (100 ppm) was delivered into the MO, or a control group, in which CPB was conducted without NO. Platelet numbers, platelet aggregation response to 2.5-20 microM adenosine diphosphate, and beta-thromboglobulin levels were measured after induction of anesthesia, after 1 h on CPB and 2 h after the end of CPB. Met-hemoglobin levels were measured during CPB. The amount of blood products administered and chest tube drainage were measured in the first postoperative 18 h. NO delivered into the MO for up to 180 min did not increase met-hemoglobin levels above 4%. NO inhibited the platelet aggregation response to 2.5 microM ADP during CPB, otherwise NO had no other detectable effect on the aggregation responses or the levels of beta-thromboglobulin. Platelet numbers were not significantly altered by NO. NO did not alter the use of blood products or chest tube drainage. In conclusion, this study suggests that NO delivered into the MO of the CPB circuit does not significantly alter platelet aggregation and numbers, and does not affect bleeding. IMPLICATIONS: Nitric oxide affects platelet function. We demonstrated that nitric oxide delivered into the gas inflow of the cardiopulmonary bypass circuit membrane oxygenator does not significantly alter platelet numbers or function.

Selective iNOS inhibition attenuates acetylcholine- and bradykinin-induced vasoconstriction in lipopolysaccharide-exposed rat lungs.

BACKGROUND: Nonselective nitric oxide synthase (NOS) inhibition has detrimental effects in sepsis because of inhibition of the physiologically important endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced endothelial dysfunction. METHODS: Rats were administered intraperitoneal lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg). Six hours later, the lungs were isolated and pulmonary vasoreactivity was assessed with hypoxic vasoconstrictions (3% O2), acetylcholine (1 microg), Biochemical Engineering, and bradykinin (3 microg). In additional lipopolysaccharide experiments, L-NIL (10 microM) or 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 100 microM), a selective muscarinic M3 antagonist, was added into the perfusate. RESULTS: Exhaled nitric oxide was higher in the lipopolysaccharide group (37.7+/-17.8 ppb) compared with the control group (0.4+/-0.7 ppb). L-NIL and dexamethasone decreased exhaled nitric oxide in lipopolysaccharide rats by 83 and 79%, respectively, whereas L-NAME had no effect. In control lungs, L-NAME significantly decreased acetylcholine- and bradykinin-induced vasodilation by 75% and increased hypoxic vasoconstrictions, whereas L-NIL and dexamethasone had no effect. In lipopolysaccharide lungs, acetylcholine and bradykinin both transiently increased the pulmonary artery pressure by 8.4+/-2.0 mmHg and 35.3+/-11.7 mmHg, respectively, immediately after vasodilation. L-NIL and dexamethasone both attenuated this vasoconstriction by 70%, whereas L-NAME did not. The acetylcholine vasoconstriction was dose-dependent (0.01-1.0 microg), unaffected by L-NIL added to the perfusate, and abolished by 4-DAMP. CONCLUSIONS: In isolated perfused lungs, acetylcholine and bradykinin caused vasoconstriction in lipopolysaccharide-treated rats. This vasoconstriction was attenuated by administration of the iNOS inhibitor L-NIL but not with L-NAME. Furthermore, L-NIL administered with lipopolysaccharide preserved endothelium nitric oxide-dependent vasodilation, whereas L-NAME did not.

Inhaled nitric oxide and nifedipine have similar effects on lung cGMP levels in rats.

UNLABELLED: Inhaled nitric oxide (NO) may downregulate the endogenous NO/cyclic guanosine monophosphate (cGMP) pathway, potentially explaining clinical rebound pulmonary hypertension. We determined if inhaled NO decreases pulmonary cGMP levels, if the possible down-regulation is the same as with nifedipine, and if regulation also occurs with the cyclic adenosine monophosphate (cAMP) pathway. Rats were exposed to 3 wk of normoxia, hypoxia (10% O2), or monocrotaline (MCT; single dose = 60 mg/kg) and treated with either nothing (control), inhaled NO (20 ppm), or nifedipine (10 mg x kg(-1) x day(-1). The lungs were then isolated and perfused with physiologic saline. Perfusate cGMP, prostacyclin, and cAMP levels were measured. Perfusate cGMP was not altered by inhaled NO or nifedipine in normoxic or MCT rats. Although hypoxia significantly increased cGMP by 128%, both inhaled NO and nifedipine equally prevented the hypoxic increase. Inhibition of the NO/cGMP pathway with N(G)-nitro-L-arginine methyl ester (L-NAME) decreased cGMP by 72% and 88% in normoxic and hypoxic lungs. Prostacyclin and cAMP levels were not altered by inhaled NO or nifedipine. L-NAME significantly decreased cGMP levels, whereas inhaled NO had no effect on cGMP in normoxic or MCT lungs, suggesting that inhaled NO does not inhibit the NO/cGMP pathway. Inhaled NO decreased cGMP in hypoxic lungs, however, nifedipine had the same effect, which indicates the decrease is not specific to inhaled NO. IMPLICATIONS: High pulmonary pressure after discontinuation of inhaled nitric oxide (NO) may be secondary to a decrease in the natural endogenous NO vasodilator. This rat study suggests that inhaled NO either does not alter endogenous NO or that it has similar effects as nifedipine.

The effect of prolonged inhaled nitric oxide on pulmonary vasoconstriction in rats.

UNLABELLED: Down-regulation of the endogenous nitric oxide (NO) pathway may explain rebound pulmonary hypertension after discontinuation of inhaled NO. We determined whether the prolonged administration of inhaled NO increases pulmonary vasoconstriction, which may occur from decreased endogenous NO. Rats were placed in normoxic (N; 21% O2) or hypoxic (H; 10% O2) chambers with or without inhaled NO (20 ppm) for 1 or 3 wk. Immediately after or 24 h after discontinuation of NO, vasoconstrictive responses were determined in isolated lungs to acute hypoxia (HPV; 0% O2 for 6 min), angiotensin II (0.05 microg), and the thromboxane analog U-46619 in the presence and absence of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 100 microM). Inhaled NO did not alter HPV or angiotensin II vasoconstriction in the N group immediately after or 24 h after discontinuation of NO. In the H group, inhaled NO decreased HPV but had no effect on the angiotensin II vasoconstriction compared with H alone. Inhaled NO did not alter the response to L-NAME. Inhaled NO did not alter, whereas L-NAME significantly decreased, the dose of U-46619 required to increase the pulmonary pressure by 10 mm Hg. In conclusion, prolonged inhaled NO decreased or did not alter HPV and did not alter vasoconstriction secondary to angiotensin II, U-46619, or L-NAME in N and H rats. These results suggest that prolonged inhaled NO does not increase pulmonary vasoconstriction, as would be expected from down-regulation of endogenous NO. IMPLICATIONS: High pulmonary pressure has been observed clinically after discontinuation of inhaled NO. This rat study suggests that 1-3 wk of inhaled NO does not increase pulmonary vasoconstriction, as would be expected from decreasing the endogenous vasodilator NO.

Regulation of the endogenous NO pathway by prolonged inhaled NO in rats.

Nitric oxide (NO) modulates the endogenous NO-cGMP pathway. We determined whether prolonged inhaled NO downregulates the NO-cGMP pathway, which may explain clinically observed rebound pulmonary hypertension. Rats were placed in a normoxic (N; 21% O2) or hypoxic (H; 10% O2) environment with and without inhaled NO (20 parts/million) for 1 or 3 wk. Subsequently, nitric oxide synthase (NOS) and soluble guanylate cyclase (GC) activity and endothelial NOS (eNOS) protein levels were measured. Perfusate cGMP levels and endothelium-dependent and -independent vasodilation were determined in isolated lungs. eNOS protein levels and NOS activity were not altered by inhaled NO in N or H rats. GC activity was decreased by 60 +/- 10 and 55 +/- 11% in N and H rats, respectively, after 1 wk of inhaled NO but was not affected after 3 wk. Inhaled NO had no effect on perfusate cGMP in N lungs. Inhaled NO attenuated the increase in cGMP levels caused by 3 wk of H by 57 +/- 11%, but there was no rebound in cGMP after 24 h of recovery. Endothelium-dependent vasodilation was not altered, and endothelium-independent vasodilation was not altered (N) or slightly increased (H, 10 +/- 3%) by prolonged inhaled NO. In conclusion, inhaled NO did not alter the endogenous NO-cGMP pathway as determined by eNOS protein levels, NOS activity, or endothelium-dependent vasodilation under N and H conditions. GC activity was decreased after 1 wk; however, GC activity was not altered by 3 wk of inhaled NO and endothelium-independent vasodilation was not decreased.

Nitric oxide synthase inhibitors alter ventilation in isoflurane anesthetized rats.

BACKGROUND: Nitric oxide (NO) is present in medullary structures and can modulate respiratory rhythm. The authors determined if spontaneous ventilation at rest and in response to increased carbon dioxide is altered by selective neuronal NO synthase (NOS; 7-nitro-indazole, 7-NI) or nonselective (neuronal plus endothelial) NOS (NG-L-arginine methyl ester [L-NAME] and NG-monomethyl L-arginine [L-NMMA]) inhibitors in rats anesthetized with isoflurane. METHODS: Fifty-four rats received either L-NAME or L-NMMA (1, 10, and 30 mg/kg) or 7-NI (20, 80, and 400 mg/kg) and were compared with time controls (isoflurane = 1.4%), with isoflurane concentrations (1.6%, 1.8%, and 2%) increased consistent with the increased anesthetic depth caused by NOS inhibitors, or with L-arginine (300 mg/kg). Tidal volume (VT), respiratory frequency (f), minute ventilation (VE), and ventilatory responses to increasing carbon dioxide were determined. RESULTS: L-NAME and L-NMMA decreased resting VT and VE, whereas 7-NI had no effect. Increasing concentrations of isoflurane decreased resting f, VT, and VE. L-NAME and L-NMMA decreased VT and VE, whereas 7-NI had no effect at 8%, 9%, and 10% end-tidal carbon dioxide (ETCO2). Increasing concentrations of isoflurane decreased f, VT, and VE at 8%, 9%, and 10% ETCO2. The slope of VE versus ETCO2 was decreased by isoflurane but was unaffected by L-NAME, L-NMMA, or 7-NI. L-arginine alone had no effect on ventilation. CONCLUSIONS: Nonselective NOS inhibitors decreased VT and VE at rest and at increased carbon dioxide levels but did not alter the slope of the carbon dioxide response. Selective neuronal NOS inhibition had no effect, suggesting that endothelial NOS may be the isoform responsible for altering ventilation. Finally, the cause of the decreased ventilation is not a result of the enhanced anesthetic depth caused by NOS inhibitors.

Prolonged inhaled NO attenuates hypoxic, but not monocrotaline-induced, pulmonary vascular remodeling in rats.

UNLABELLED: In concentrations of 10-20 ppm, inhaled nitric oxide (NO) decreases pulmonary artery pressure and attenuates vascular remodeling in pulmonary hypertensive rats. Because NO is potentially toxic, it is important to know whether lower concentrations attenuate vascular remodeling produced by different etiologies. Therefore, we determined the effects of prolonged, small-dose inhaled NO administration on hypoxic and monocrotaline (MCT)-induced pulmonary vascular remodeling. Rats were subjected to normoxia, hypoxia (normobaric 10% oxygen), or hypoxia plus NO in concentrations of 50 ppb, 200 ppb, 2 ppm, 20 ppm, and 100 ppm for 3 wk. A second group of normoxic rats was given MCT (60 mg/kg intraperitoneally) alone or in the presence of 2, 20, and 100 ppm of NO. Subsequently, pulmonary artery smooth muscle thickness and the number of muscular arteries (percentage of total arteries) were determined. Right ventricular hypertrophy was determined by right to left ventricle plus septum weight ratio (RV/LV + S). Pulmonary artery smooth muscle thickness and the percent muscular arteries were increased by hypoxia and MCT. The hypoxic increase in thickness was attenuated by all concentrations of NO, with 100 ppm being greatest, whereas NO had no effect on MCT rats. NO attenuated the increase in percent muscular arteries in hypoxic but not MCT rats. The RV/LV + S was increased by hypoxia and MCT compared with normoxia. Hypoxia-induced RV hypertrophy was decreased by all concentrations of inhaled NO, although attenuation with 50 ppb was less than with 200 ppb, 20 ppm, and 100 ppm. In MCT rats 2 and 100 ppm NO increased RV hypertrophy, whereas 20 ppm had no effect. In conclusion, inhaled NO in concentrations as low as 50 ppb attenuates the pulmonary vascular remodeling and RV hypertrophy secondary to hypoxia. In contrast, concentrations as high as 100 ppm do not attenuate MCT-induced pulmonary remodeling. These results demonstrate that extremely low concentrations of NO may attenuate remodeling but that the effectiveness is dependent on the mechanism inducing pulmonary remodeling. IMPLICATIONS: The authors determined whether inhaled NO, a selective pulmonary vasodilator, attenuates pulmonary vascular remodeling caused by two models of pulmonary hypertension: chronic hypoxia and monocrotaline injection. Analysis of pulmonary vascular morphology suggests that very low concentrations of NO effectively attenuate hypoxic remodeling but that NO is not effective in monocrotaline-induced pulmonary remodeling.

Inhaled nitric oxide as a selective pulmonary vasodilator in clinical anesthesia.

Inhaled nitric oxide (NO) is a selective pulmonary vasodilator in adult and pediatric patients. Inhaled NO diffuses into the pulmonary vascular smooth muscle where it results in vasodilation via stimulation of guanylyl cyclase. Systemic hemodynamics are not altered because inhaled NO is rapidly inactivated by hemoglobin. Oxygenation is also increased in certain patients as inhaled NO only vasodilates those segments of the pulmonary vasculature which are ventilated. There is growing evidence that inhaled NO may be a useful therapeutic agent in the treatment of pulmonary hypertension and hypoxemia from a variety of causes. Areas of greatest interest to anesthesia and critical care personnel may involve treatment of persistent pulmonary hypertension of the newborn (PPHN), adult respiratory distress syndrome (ARDS), and postoperative pulmonary hypertension secondary to cardiac disease. The potential toxicity of inhaled NO, particularly on immature and developing lungs, must be considered. While inhaled NO exerts acute beneficial effects, it is unclear if there are long-term benefits. Multicenter trials are currently underway to determine if inhaled NO decreases mortality from PPHN or decreases morbidity associated with ARDS.

Local anesthetic administration for awake direct laryngoscopy. Are glossopharyngeal nerve blocks superior?

BACKGROUND: Glossopharyngeal nerve (GPN) blocks may provide reliable analgesia for awake direct laryngoscopy, although this has not been evaluated prospectively. This study was designed to determine if GPN blocks provide a superior route of local anesthetic administration for awake direct laryngoscopy as measured by hemodynamic, gag, and subjective pain responses. METHODS: A prospective, randomized, single-blinded, crossover design was used. All participants (n = 11) were anesthesiologists. Three routes of local anesthetic administration were evaluated: 2 min of 2% viscous lidocaine swish and gargle (S&G); S&G combined with 10% lidocaine spray (S&G/spray); and S&G combined with 1% lidocaine bilateral GPN blocks (S&G/block; anterior tonsillar pillar method). Five minutes after the local anesthetic was administered, laryngoscopy was performed and sustained for 20 s. Noninvasive hemodynamic measurements and serum lidocaine concentrations were determined. Visual analogue scale scores and a poststudy questionnaire were used to assess participants' ability to tolerate local anesthetic administration and laryngoscopy and their choice for use in clinical practice. RESULTS: No significant hemodynamic changes were observed, although there was a modest increase (< 15%) in heart rate in the S&G/block group in the first minute after laryngoscopy. Serum lidocaine concentrations were higher (P < 0.05) in the S&G/block group at 5 and 10 min (0.5 +/- 0.1 and 1.0 +/- 0.2 microgram/ml) compared with the S&G group. Participants' visual analogue scale scores, which assessed their ability to tolerate laryngoscopy, showed that S&G (5.4 +/- 0.9) resulted in more discomfort (P < 0.05) than either S&G/spray (3.5 +/- 0.9) or S&G/block (3.3 +/- 0.7). The laryngoscopist's visual analogue scale scores, which assessed the ease of visualization, revealed a trend (P < 0.08) toward less coughing and gagging with S&G/spray (1.8 +/- 0.9) compared with S&G (4.0 +/- 1.3) and S&G/block (3.7 +/- 1.1). Oropharyngeal discomfort lasting 24 h or more was reported by 91% of participants after S&G/block, whereas no participant reported oropharyngeal discomfort after S&G or S&G/spray. Significantly more participants (73%) indicated their preference for using S&G/spray in future clinical practice compared with S&G (P < 0.01) and S&G/block (P < 0.05). CONCLUSIONS: Glossopharyngeal nerve blocks do not provide a superior route of local anesthetic administration for awake direct laryngoscopy. Two minutes of 2% viscous lidocaine S&G followed by 10% lidocaine spray was the anesthetic route preferred by participants and laryngoscopists.

Nitric oxide modulation of pulmonary vascular resistance is red blood cell dependent in isolated rat lungs.

Nitric oxide (NO) or endothelium-derived relaxing factor may play an important role in modulating pulmonary vascular resistance (PVR), although previous studies have produced conflicting results. Endogenous NO inhibition causes an increase in PVR in intact animals but not in saline-perfused isolated lungs. We hypothesized that blood is essential for NO to serve as a modulator of PVR. Therefore, the effects of endogenous NO inhibition (N omega-nitro-L-arginine methyl ester [L-NAME]) were determined in isolated rat lungs as related to the presence of different blood components under normoxic conditions and after 1 wk of hypoxia (fraction of inspired oxygen [FIO2] = 10%). Exogenously administered inhaled NO was evaluated in isolated lungs from normoxic and hypoxic rats. In normoxic rats, L-NAME (10-100 microM) caused a dose-dependent increase in PVR in whole (hematocrit [Hct] 40%) and diluted (Hct 12%) blood-perfused lungs. L-NAME (10-800 microM) had no effect in isolated lungs perfused with a modified salt solution of equal viscosity to blood either alone, or containing plasma (50%) or free oxyhemoglobin (10 microM). In whole blood perfused lungs, L-NAME (100 microM) increased PVR more in hypoxic versus normoxic isolated lungs (141% vs 100%). Inhaled NO decreased PVR in isolated lungs from hypoxic rats and partially reversed the effects of L-NAME, but had no effect in normoxic lungs. In conclusion, endogenous and inhaled NO modulate PVR in isolated rat lungs and this role is increased by prolonged hypoxia. The response to inhibition of endogenous NO is dependent on the presence of red blood cells and is independent of the changes in viscosity or the presence of oxyhemoglobin or plasma.

Endotoxin alters hypoxic pulmonary vasoconstriction in isolated rat lungs.

Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism for maintaining oxygenation, which may be altered by endotoxin. We determined that acute endotoxemia alters the HPV response secondary to changes in endothelium-derived vasoactive products. Rats were treated with Salmonella typhimurium lipopolysaccharide (LPS; 15 mg/kg i.p.) either 1 to 6 h before lung isolation and compared with control rats (no LPS). Additional 6-h LPS-treated and control rats were pretreated with either indomethacin (15 mg/kg i.p.), a cyclooxygenase inhibitor, or bosentan (10 mg/kg po), a nonselective endothelin-receptor antagonist. The rats lungs were isolated and challenged with 3% O2 for 10 min to elicit HPV responses before and after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME; 100 microM). LPS (6 h) significantly increased the peak HPV responses by 108%. L-NAME had no significant effect in LPS-treated lungs but increased the peak HPV response in control lungs to levels equal to LPS-treated lungs. Bosentan increased the peak HPV response in all lungs, and indomethacin increased the peak HPV in LPS-treated lungs. The HPV response was sustained in control lungs at 10 min and in additional 20-min studies. In contrast, in LPS-treated lungs the HPV response faded after 10 min to levels equal to control, and in 20-min studies it faded by 82% to levels significantly less than in control lungs. The 10-min fade in LPS-treated lungs was attenuated by indomethacin (51%) and bosentan (80%) but not by L-NAME. In conclusion, acute endotoxemia with LPS increased the peak HPV response, but this effect was not sustained and by 20 min was nearly abolished. Inhibition of endogenous NO by LPS may explain the increased peak HPV response, but NO is not involved in the fade. The fade is at least partially due to increased vasodilating cyclooxygenase products and endothelins.

The response to varying concentrations of inhaled nitric oxide in patients with acute respiratory distress syndrome.

We investigated the response to varying concentrations of inhaled nitric oxide (NO) in 18 patients with acute respiratory distress syndrome (ARDS). The study was divided into two parts. In Part 1, 5-40 ppm of inhaled NO was evaluated in 10 patients with ARDS. In Part 2, 0.1-10 ppm of inhaled NO was evaluated in eight patients with ARDS. Inhaled NO significantly (P < 0.05) decreased the mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance index (PVRI), and increased the arterial oxygenation (PaO2) at concentrations of 0.1 to 40 ppm. No dose response was detectable for the pulmonary artery pressure (PAP) or PVRI over this dose range. The increase in PaO2 at 10 ppm of NO was significantly greater than that at 0.1 ppm but not 1 ppm. The decrease in PVRI and the increase in PaO2 were both significantly correlated with the baseline PVRI. While the maximum hemodynamic and oxygenation responses to inhaled NO are achieved at approximately 1 ppm, it appears that the maximum hemodynamic response is observed at lower concentrations (0.1 ppm) of inhaled NO than the improvement in oxygenation (1-10 ppm). Higher concentrations of NO do not produce any further change in these variables. It appears that the baseline PVRI may be the best marker predicting a beneficial response to NO.

Chronic inhaled nitric oxide: effects on pulmonary vascular endothelial function and pathology in rats.

Nitric oxide (NO) is a potent endogenous vasodilator produced in endothelial cells. Inhaled NO selectively vasodilates the pulmonary circulation. We determined the effects of chronic inhaled NO on hypoxic pulmonary vascular remodeling and endothelium NO-dependent and -independent vasodilation during normoxic and hypoxic conditions in rats. Rats were exposed to 3 wk of normoxia (N), normoxia + 20 ppm inhaled NO (N+NO), chronic hypoxia with 10% normobaric oxygen (CH), or CH and 20 ppm inhaled NO (CH+NO). Inhaled NO decreased the number of muscular pulmonary arteries, the medial smooth muscle thickness, and the right ventricular hypertrophy associated with chronic hypoxia but had no effect on these parameters in normoxic rats. All groups were evaluated with isolated perfused lungs. The pulmonary artery pressure increased by the same amount in the CH and CH+NO rats compared with N rats. Inhibition of NO synthase with N omega-nitro-L-arginine methyl ester (L-NAME) caused greater pulmonary vasoconstriction in CH (19.2 +/- 3.7 mmHg) vs. N (7.8 +/- 3.0 mmHg) and less in CH+NO (9.1 +/- 0.8 mmHg) vs. CH rats. Bradykinin (3 micrograms) caused greater vasodilation in CH (76 +/- 12%) vs. N (29 +/- 5%) but significantly less in CH+NO (41 +/- 11%) vs. CH rats. Vasodilation with acute inhaled NO (40 ppm) was no different in CH vs. N rats but was lower in CH+NO (19 +/- 5%) vs. CH (34 +/- 6%) rats. This study demonstrates that chronic inhaled NO attenuates hypoxic pulmonary vascular remodeling. Furthermore, these results suggest that chronic inhaled NO decreases endothelium NO-dependent and -independent vasodilation.