Sites of vasodilation by inhaled nitric oxide vs. sodium nitroprusside in endothelin-constricted isolated rat lungs.

We localized the sites of vasodilation of inhaled nitric oxide (NO), a selective pulmonary vasodilator, and sodium nitroprusside (SNP) in isolated rat lungs. The sites were determined by analyzing the arterial, venous, and double-occlusion data with a two-resistor (small arteries and veins) three-capacitor (large arteries, large veins, and capillaries) model of the pulmonary vascular bed. Inhaled NO (170 and 670 ppm) and SNP (22.5 and 45.0 micrograms) decreased the small-artery resistance by 7.4 +/- 1.6, 17.2 +/- 2.2, 14.2 +/- 2.8, and 21.4 +/- 3.4% and the small-vein resistance by 13.5 +/- 3.2, 20.3 +/- 3.4 (SNP of 22.5 micrograms not significant), and 9.3 +/- 3.3%, respectively, in blood-perfused lungs (n = 12). Similar results were observed in Krebs-perfused lungs (n = 12). Capillary compliance was unaffected by inhaled NO and SNP. SNP increased the large-artery capacitance by 40.0 +/- 8.6 and 69.3 +/- 9.7%, whereas inhaled NO had no effect. SNP increased the large-vein capacitance by 31.0 +/- 8.7 and 48.0 +/- 10.7%, whereas inhaled NO had no effect in blood-perfused lungs. However, in Krebs-perfused lungs inhaled NO and SNP (45.0 micrograms only) increased the large-vein capacitance by 43.3 +/- 11.9, 41.4 +/- 14.2, and 44.2 +/- 11.0%. In conclusion, in blood-perfused isolated rat lungs inhaled NO and SNP dilate small-resistance arteries and veins, whereas SNP but not inhaled NO dilates larger capacitance arteries and veins. Furthermore, blood appears to prevent the downstream vasodilation by inhaled NO on larger capacitance pulmonary veins.

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.

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.

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.

Inhaled nitric oxide: dose response and the effects of blood in the isolated rat lung.

Inhaled nitric oxide (NO) is a vasodilator selective to the pulmonary circulation. Using isolated rat lungs, we determined the dose-response relationship of NO and the role of blood in mediating pulmonary vasodilation and selectivity. Inhaled 20, 50, 100, and 1,000 ppm NO attenuated (P < 0.001) hypoxic pulmonary vasoconstriction by 16.1 +/- 4.9, 22.6 +/- 6.8, 28.4 +/- 3.5, and 69.3 +/- 4.2%, respectively. Inhaled 13, 34, 67, and 670 ppm NO attenuated the increase in pulmonary arterial pressure secondary to angiotensin II more (P < 0.001) in Greenberg-Bohr buffer- (GB) than in blood-perfused lungs (51.7 +/- 9.9, 71.9 +/- 8.9, 78.2 +/- 5.3, and 91.9 +/- 2.1% vs. 14.3 +/- 4.1, 23.8 +/- 4.6, 28.4 +/- 3.8, and 55.5 +/- 5.9%, respectively). Samples from GB- but not blood-perfused lungs contained NO (93.0 +/- 26.3 nM). Intravascular NO attenuated the response to angiotensin II more (P < 0.001) in GB- (with and without plasma) than in blood- (hematocrit = 41 and 5%) perfused lungs (75.6 +/- 6.4 and 70.9 +/- 4.8% vs. 22.2 +/- 2.4 and 39.4 +/- 7.6%). In conclusion, inhaled NO produces reversible dose-dependent pulmonary vasodilation over a large range of concentrations. Inhaled NO enters the circulation, but red blood cells prevent systemic vasodilation and also a significant amount of pulmonary vasodilation.

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.

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.

Continuous end-tidal CO2 sampling within the proximal endotracheal tube estimates arterial CO2 tension in infants.

End-tidal CO2 (ETCO2) sampled using a 22-gauge needle inserted through the wall of the proximal endotracheal tube was compared with ETCO2 obtained from the standard proximal connector to determine which was the more accurate sampling site for estimation of arterial CO2 tension (PaCO2). Fourteen infants were anaesthetized and their lungs ventilated using a Drager ventilator and a paediatric circle system. Blood gas determination of PaCO2 was obtained from an arterial catheter and compared with continuous sampling of ETCO2 analyzed by raman spectroscopy. The PaCO2 (35.3 +/- 4.9 mmHg, x +/- SD) was not different from the ETCO2 sampled within the proximal endotracheal tube (34.7 +/- 3.8 mmHg), but was greater (P less than 0.05) than the ETCO2 at the proximal connector (31.6 +/- 4.0 mmHg). We conclude that in infants during ventilation with a circle system, the PaCO2 can be accurately assessed by continuous sampling of ETCO2 from the proximal endotracheal tube.

Differences between aortic and radial artery pressure associated with cardiopulmonary bypass.

Previous investigators have identified an aortic-to-radial artery pressure gradient thought to develop during rewarming and discontinuation of cardiopulmonary bypass. The authors measured mean aortic and radial artery pressures before, during, and after cardiopulmonary bypass in 30 patients, to determine when the pressure gradient develops. The pressure gradient was also measured before and after intravenous injections of sodium nitroprusside (1 microgram/kg) and phenylephrine (7 micrograms/kg) to determine the effect of changes in systemic vascular resistance. A significant (P less than 0.05) pressure gradient (mean +/- SEM = 4.9 +/- 0.7 mmHg) developed upon initiation of cardiopulmonary bypass. This gradient did not change significantly during the middle of bypass (4.2 +/- 0.5 mmHg), with rewarming (4.8 +/- 0.7 mmHg), immediately prior to discontinuation of bypass (4.6 +/- 0.7), or 5 and 10 min following bypass (4.9 +/- 0.9 and 4.8 +/- 0.7 mmHg). Sodium nitroprusside significantly decreased systemic vascular resistance, by 15 +/- 2%, during the middle of bypass but did not affect the pressure gradient. Likewise, phenylephrine increased the systemic vascular resistance by 52 +/- 6% and 34 +/- 4% during the middle of bypass and rewarming, respectively, without affecting the pressure gradient. Although the exact mechanisms responsible for the pressure gradient remain unknown, these results suggest its etiology is associated with events occurring during initiation of cardiopulmonary bypass rather than with rewarming or discontinuation of cardiopulmonary bypass.

Effect of chloride transport blockade on the MAC of halothane in the rat.

There is a growing evidence that central nervous system chloride transport via gamma-aminobutyric acid (GABAA) related Cl- conductance or Cl-/HCO3- exchange affects anesthetic requirements. To delineate the effects of GABAA-related Cl- conductance blockade versus Cl-/HCO3- exchange inhibition, we determined the change in minimum alveolar anesthetic concentration (MAC) of halothane in rats after intracisternal infusion of 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene (DIDS). DIDS inhibits Cl-/HCO3- exchange transport in concentrations greater than 1 microM and in GABAA-related Cl- channels in concentrations greater than 0.1 mM. After control MAC determination, rats were given intracisternal mock cerebrospinal fluid (n = 6), 1.0 microM DIDS (n = 8), or 1 mM DIDS (n = 8) at a rate of 2 microL/min for 30 min. Mock cerebrospinal fluid did not change the MAC of halothane. The MAC of halothane increased significantly (P less than 0.001) from 0.96% +/- 0.02% to 1.11% +/- 0.03% (mean value +/- SEM) with 1 microM DIDS and from 0.94% +/- 0.02% to 1.16% +/- 0.04% with 1 mM DIDS. The increases in MAC with 1 microM and 1 mM DIDS were not statistically different. This suggests that Cl-/HCO3- exchange inhibition increases halothane requirements, whereas GABAA-related Cl- channel blockade does not.

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.

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.

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.

Is distal sampling of end-tidal CO2 necessary in small subjects?

The authors compared PaCO2 with end-tidal CO2 (ETCO2) sampled at multiple sites along the endotracheal tube (ETT) in seven anesthetized rabbits (weight, 2.7-3.6 kg) to determine the most convenient, yet accurate, sampling location. Comparisons were made during spontaneous and controlled ventilation with fresh gas flows (FGF) of two and ten times the minute ventilation using a Mapleson D circuit. An Engstrom Eliza analyzer with a continuous sampling rate of 100 ml/min was used to measure ETCO2. A 0.75-mm ID polyethylene tube inserted in the side of the ETT sampled ETCO2 at the distal tip and at the 6-, 12-, and 15-cm marks on the ETT. ETCO2 was also measured at the standard proximal connector. The differences (P less than 0.05) between PaCO2 and ETCO2 at the distal, 6-, 12-, and 15-cm marks were 2.9 +/- 0.4, 3.1 +/- 0.4, 3.6 +/- 0.4, and 4.6 +/- 0.5 mmHg (mean +/- SEM), respectively, and did not change with FGF or mode of ventilation. The difference between PaCO2 and ETCO2 measured at the proximal connector was always large but significantly (P less than 0.05) greater during spontaneous than controlled ventilation (24.2 +/- 1.5 versus 15.0 +/- 1.4 mmHg) and at higher FGF (19.4 +/- 1.3 versus 16.8 +/- 1.6 mmHg). The differences (P less than 0.05) between ETCO2 at the distal tip and ETCO2 at the 6-, 12-, and 15-cm marks were 0.24 +/- 0.07, 0.73 +/- 0.11, and, 1.77 +/- 0.20 mmHg, respectively. This demonstrates that the change in ETCO2 between the distal tip and the 12-cm mark on the ETT is less than 1 mmHg, and that this clinically insignificant difference is independent of FGF and mode of ventilation. The 12 cm-mark is outside of the mouth on a newborn, and sampling ETCO2 at that point, which may be accomplished simply by inserting a small needle in the side of the ETT, may be the most appropriate sampling location.

Ketorolac does not decrease the MAC of halothane or depress ventilation in rats.

To determine the effects of intravenous (IV) ketorolac on anesthesia and the mechanisms involved, we evaluated its effects on minimum alveolar anesthetic concentration (MAC) and ventilation in halothane-anesthetized rats. Ketorolac in clinical (0.2 and 2 mg/kg) and large (20 and 40 mg/kg) IV doses did not affect the MAC of halothane (0.82% +/- 0.02%). Resting end-tidal CO2 tension (5.1% +/- 0.1%) and the slope of the CO2 response curves (70 +/- 6 mL.min-1.%-1) were also unaffected by IV ketorolac. The mean arterial blood pressure did not significantly change after ketorolac in doses of 0.2, 2, or 20 mg/kg but decreased significantly (P less than 0.05) after 40 mg/kg (placebo 99 +/- 8 mm Hg; ketorolac 87 +/- 6 mm Hg). This study demonstrates that MAC, ventilation, and mean arterial blood pressure are unaffected by clinical doses of IV ketorolac. Furthermore, the lack of effect on MAC and ventilation from larger doses suggests that ketorolac does not have mechanisms of action in the central nervous system.

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.

Fluid restitution and blood volume redistribution in anesthetized rabbits in response to vasoactive drugs.

BACKGROUND: Vasoactive drugs could alter the fluid restitution from the tissue and redistribute blood volume between the macrocirculation and microcirculation. METHODS AND RESULTS: With bolus injections of vasoactive drugs in anesthetized rabbits, we measured the changes in blood and plasma density for the determination of the volume of restitution and redistribution. Epinephrine 3.5 micrograms/kg caused a fluid loss to the tissue, leading to a transient decrease in total blood volume by 2.30 mL/kg. Because of blood volume redistribution, the peak volume reduction was accompanied by a volume reduction of 0.81 mL/kg from the macrocirculation and 1.49 mL/kg from the microcirculation. Phenylephrine 70 micrograms/kg caused a peak reduction in total blood volume of 1.40 mL/kg (with 0.41 mL/kg from macrocirculation and 0.99 mL/kg from microcirculation). Nitroprusside 7 micrograms/kg increased the blood volume by 1.44 mL/kg (0.83 mL/kg macro and 0.61 mL/kg micro), nitroglycerin 7 micrograms/kg by 1.48 mL/kg (0.97 mL/kg macro and 0.51 mL/kg micro), and isoproterenol 7 micrograms/kg by 2.07 mL/kg (0.68 mL/kg macro and 1.39 mL/kg micro). All plasma (or blood) density changes measured for the five drugs (with epinephrine, phenylephrine, and nitroprusside done over a wide dosage range) correlated linearly with the drug-induced changes in arterial pressures. CONCLUSIONS: These results indicate that vasoactive drugs alter total blood volume and the volume of microcirculation and macrocirculation.

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.

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.

Inhaled nitric oxide. Selective pulmonary vasodilation in cardiac surgical patients.

BACKGROUND: Inhaled nitric oxide (NO), an endothelium-derived relaxing factor, is a selective pulmonary vasodilator. The authors investigated whether the pulmonary vasodilation resulting from 20 ppm inhaled NO is related to the degree of pulmonary hypertension or affected by cardiopulmonary bypass (CPB) or the presence of intravenous nitrates. METHODS: In patients undergoing cardiac surgery (n = 20) or in whom the circulation was supported with a ventricular assist device (VAD; n = 5), the lungs were ventilated with 80% O2 and 20% N2 followed by the same gas concentrations containing 20 ppm NO for 6 min. RESULTS: Inhaled NO decreased (P < 0.05) the pulmonary artery pressure from 36 +/- 3 to 29 +/- 2 mmHg and 32 +/- 2 to 27 +/- 1 mmHg, before and after CPB, respectively, and from 68 +/- 12 to 55 +/- 9 mmHg in patients with a VAD. Similarly, the pulmonary vascular resistance (PVR) decreased (P < 0.05) from 387 +/- 44 to 253 +/- 26 dyne.cm.s-5 and 260 +/- 27 to 182 +/- 18 dyne.cm.s-5, before and after CPB, respectively, and from 1,085 +/- 229 to 752 +/- 130 dyne.cm.s-5 in patients with a VAD. Central venous pressure, cardiac output, systemic hemodynamics, and blood gases did not change after inhalation of NO before or after CPB, whereas arterial oxygen tension, mixed venous hemoglobin saturation, and mean arterial pressure increased (P < 0.05) in patients supported with a VAD. All hemodynamic and laboratory data returned to control 6 min after discontinuation of NO. The decrease in PVR was proportional to baseline PVR (delta PVR = -0.45 PVRb + 39.9) before CPB. The pre- and post-CPB slopes were identical despite possible damage to the endothelium resulting from CPB and the post-CPB presence of intravenous nitroglycerin (17 of 20 patients). CONCLUSIONS: This study demonstrates that 20 ppm inhaled NO is a selective pulmonary vasodilator in cardiac surgical patients before and after CPB and in patients in whom the circulation is supported with a VAD. Furthermore, NO-induced pulmonary vasodilation is proportional to PVRb and does not appear to be altered by CPB, the presence of a VAD, or infusion of nitrates.