Inhibition of nitric oxide synthesis causes systemic and pulmonary vasoconstriction in isoflurane-anesthetized dogs

doi:10.1016/1053-0770(94)90243-7

Journal of Cardiothoracic and Vascular Anesthesia

Volume 8, Issue 3, June 1994, Pages 310-316

https://doi.org/10.1016/1053-0770(94)90243-7 Get rights and content

Abstract

The postulate that the hemodynamic changes produced by isoflurane (1.5%) involve release of nitric oxide (NO) was examined. Fifteen dogs were anesthetized with thiamylal (15 mg/kg) and ventilated with isoflurane and oxygen. Catheters were inserted for measurement of aortic pressure, pulmonary artery pressures, and determination of cardiac output. Left thoracotomy was performed and complete heart block was induced by injection of 37% formaldehyde (0.3 mL) into the atrioventricular node; ventricular rate was fixed at 100 beats/min by external pacing. An apical microtransducer was inserted into the left ventricle (LV) via the apex for measurement of left ventricular pressure (LVP) and its first derivative (dP/dt). Flow probes were mounted on the left circumflex (Cx) and anterior descending (AD) coronary arteries. Measurements were obtained before (control period) and during NO inhibition using IV N^G-nitro-l-arginine methyl ester (l-NAME) by a 50 mg/kg bolus plus 1 mg/kg/min. Infusion of l-NAME caused immediate and sustained increases in mean arterial pressure to 145 ± 3% (P < 0.001), mean pulmonary arterial pressure to 128 ± 5% (P < 0.001), pulmonary capillary wedge pressure to 144 ± 8% (P < 0.001), coronary perfusion pressure to 163 ± 4% (P < 0.001), systemic vascular resistance to 209 ± 9% (P < 0.001), pulmonary vascular resistance to 142 ± 12% (P < 0.005), anterior descending flow to 115 ± 4% (P < 0.005), and circumflex flow to 113 ± 3% (P < 0.01) of control levels. Decreases in cardiac output to 73 ± 2% (P < 0.001), anterior descending conductance to 71 ± 3% (P < 0.001), and circumflex conductance to 70 ± 3% (P < 0.001) of control, were also observed; LV dP/dt and end-diastolic pressure were unchanged. Inhibition of NO caused systemic and pulmonary vasoconstriction and depression of cardiac output. Responses to NO inhibition unmasked an intense background vasoconstriction during isoflurane, yet coronary blood flow increased due to an increase in perfusion pressure. It is concluded that NO plays a significant role in the systemic and pulmonary vasomotor and cardiac responses during isoflurane anesthesia. On the other hand, the coronary vasomotor effects appear to be mediated indirectly through changes in coronary perfusion pressure (ie, autoregulatory) rather than directly through withdrawal of NO activity.

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Citation Excerpt :
Changes in the neurons, astrocytes, microglia and endothelial cells are primarily due to oxygen deprivation and energy shortage in the cells [26–29]. This in turn is signaled in the endothelium which then alters the smooth muscle layer to regulate blood flow to counter the oxygen shortage by increasing the circulatory volume in the cerebral region through vasodilatation induced by nitric oxide [27,30]. Findings from histology reveal that the physical properties of the arteries are intrinsically linked with the endothelia and smooth muscle thickness in the cerebral arteries [31].
Vascular occlusion and cyanide neurotoxicity induces oxidative stress and degeneration in the brain. This oxidant induced stress changes the vascular dynamics of cerebral blood vessels, and participates in homeostatic response mechanisms which balance oxygen supply to hypoxic stress-sensitive neurons. The associated changes in vascular morphology include remodeling of the microvasculature and endothelial changes, alterations in regional circulation and variations in the blood brain barrier (BBB). This study compares alterations in physiology of the cerebral artery after a short-term oxidative stress induced by cyanide toxicity and vascular occlusion.
Adult Wistar rats (N = 30) were divided into three groups; vascular occlusion (VO) (n = 12), potassium cyanide administration (CN) (n = 12) and Control-CO (n = 6). The CN rates were treated with 30 mg/kg of orally administered KCN while the VO was subjected to global vascular occlusion, both for a duration of 10 days, described as the treatment phase. Control animals were fed on normal rat chow and water for 10 days. At the end of the treatment phase, n = 6 animals in each of the VO, CN and VO groups were anesthetized with sodium pentobarbital (50IP) and the CCA exposed, after which pin electrodes were implanted to record the spikes form the tunica media of the CCA. After day 10, treatment was discontinued for these animals, each remaining in the VO and CN groups (VO-I and CN-I) until day 20 (withdrawal phase) following which the spikes were recorded using the procedure described above.
Vascular occlusion and cyanide toxicity increased vascular resistance in the MCA (reduced lumen thickness ratio) and increased the diameter of the CCA after the treatment phase of 10 days. After 10 days of withdrawal, the VO group showed a reduction in resistance and an increase in the lumen width/wall thickness ratio (LWR) while the CN group showed increased resistance and a reduction in LWR.
Cyanide toxicity increased vascular resistance by inducing degenerative changes in the wall of the artery while vascular occlusion increased resistance through mechanical stress and increased thickness of arterial wall. After the withdrawal phase, vascular resistance diminished in the VO to a significantly greater extent than the CN.
Histochemical Alterations in One Lung Ventilation
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The high variability of these nitrite levels and the fact that there was a significant change in the face of this high variability strengthens our finding that serum nitrite level were lowered over the experimental period. This high variability in serum nitrite levels may be a reflection of variable responses of individual pigs to isoflurane, where isoflurane has been reported to cause systemic pulmonary vasodilation by increasing levels of NO [19]. Inflammation associated with lung injury is characterized by neutrophil infiltration [20].
One lung ventilation is a commonly performed surgical procedure. Although there have been several reports showing that one-lung ventilation can cause pathophysiological alterations such as pulmonary hypoxic vasoconstriction and intrapulmonary shunting, there have been virtually no reports on the effects of one-lung ventilation on lung histology.
Yorkshire pigs (11–17 kg) were anesthetized, a tracheotomy performed and a tracheal tube inserted. The chest was opened and one lung ventilation (OLV), was induced by clamping of the right main bronchus. OLV was continued for 60 min before the clamp was removed and two lung ventilation (TLV) started. TLV was continued for 30 to 60 min. Blood and lung biopsies were taken immediately before OLV, 30 min and 60 min of OLV and after restoration of TLV.
Histological analyses revealed that the non-ventilated lung was totally collapsed during OLV. On reventilation, there was clear evidence of vascular congestion and alveolar wall thickening at 30 min after TLV. At 60 min of TLV, there was still vascular congestion. Serum nitrite levels (as an index of nitric oxide production) showed steady decline over the course of the experimental period, reaching a significantly low level on reventilation (compared with baseline levels before OLV). Lung MPO activity (marker of neutrophil sequestration) and serum TNFα levels were not raised during the entire experimental period.
These results suggest that there was lung vascular injury after OLV, which was associated with reduced levels of nitric oxide production and not associated with an inflammatory response.
Inhaled nitric oxide administration during one-lung ventilation in patients undergoing thoracic surgery
2001, Journal of Cardiothoracic and Vascular Anesthesia
Citation Excerpt :
Isoflurane and epidural analgesia can lead to decreased pulmonary vascular resistance. Isoflurane causes systemic and pulmonary vasodilation,24 and Moore et al25 showed that the systemic and pulmonary vasodilation caused by isoflurane are likely mediated by NO. Compared with intravenous agents, however, the increase in QS/QT related to isoflurane at <1 MAC was shown to be moderate in humans.26 Epidural block combined with general anesthesia has been shown to decrease pulmonary vascular resistance during surgery.27
Objective: To evaluate the effects of inhaled nitric oxide (iNO) on hemodynamics and oxygenation during one-lung ventilation (OLV) in the lateral decubitus position in patients undergoing elective thoracic surgery. Design: Prospective study. Setting: University hospital. Participants: Thirty consecutive patients scheduled for thoracotomy. Interventions: Anesthesia consisted of thoracic epidural analgesia combined with general anesthesia (isoflurane, fentanyl, and vecuronium bromide). Systemic and pulmonary circulations were monitored with a radial artery catheter and a pulmonary artery catheter. Inhaled NO, 40 ppm, was administered during OLV, and the inhaled gas mixture was monitored for NO and nitrogen dioxide (NO₂). Hemodynamic and oxygenation data were collected before and during inhaled NO administration. Measurements and Main Results: Inhaled NO caused a reduction of pulmonary vascular resistance index from 249 ± 97.6 dyne · sec · cm⁻⁵ to 199.3 ± 68.9 dyne · sec · cm⁻⁵ (p < 0.05), without effects on systemic hemodynamics or impairment of oxygenation. A stratification of the patients according to values of Q_S/Q_T (<30%, 30% to 44%, ≥45%), PaO₂/fraction of inspired oxygen (≥200, 100 to 199, <100), and pulmonary hypertension (mean pulmonary arterial pressure <24 or ≥24 mmHg) showed that inhaled NO causes a significant reduction of mean pulmonary artery pressure in patients with pulmonary hypertension, mainly as a result of a reduction of pulmonary vascular resistance index, and improves oxygenation by reducing intrapulmonary shunt in patients with severe hypoxemia during OLV. Conclusions: Inhaled NO administration neither significantly decreased mean pulmonary arterial pressure in patients with normal pulmonary artery pressure nor improved oxygenation in nonhypoxic patients. Nevertheless, inhaled NO is effective in patients with pulmonary hypertension and hypoxemia during OLV. Copyright © 2001 by W.B. Saunders Company
Placebo-controlled study of inhaled nitric oxide to treat hypoxaemia during one-lung ventilation
1999, British Journal of Anaesthesia
The aim of this prospective, placebo-controlled study was to assess if unilaterally inhaled nitric oxide 20 ppm could treat hypoxaemia during one-lung ventilation. Sixty patients undergoing pulmonary resection using a lateral thoracotomy were allocated randomly to a control or nitric oxide group (NO group). During one-lung ventilation in the lateral decubitus position, the lungs were ventilated mechanically with 90% oxygen–10% nitrogen. After randomization, if PaO2 decreased to less than 9.3 kPa during one-lung ventilation, nitric oxide 20 ppm or nitrogen was added to the inspired gas. The criterion for treatment efficacy was an increase in PaO2 to greater than 9.3 kPa after gas administration. Eight patients in the control group and eight in group NO experienced hypoxaemia during one-lung ventilation. PaO2 was not significantly different in the two groups at the time of gas administration (control group mean 8.0 (SD 0.6) kPa; NO group 8.5 (0.5) kPa). The efficacy criterion was reached in two of eight patients in the control and NO groups. The results of this study showed that inhaled nitric oxide 20 ppm, administered in the dependent lung, was not superior to nitrogen in the treatment of hypoxaemia during one-lung ventilation. Nitric oxide should not be recommended as an alternative to conventional management of hypoxaemia in this condition.
Inhaled nitric oxide (40 ppm) during one-lung ventilation, in the lateral decubitus position, does not decrease pulmonary vascular resistance or improve oxygenation in normal patients
1997, Journal of Cardiothoracic and Vascular Anesthesia
$Objectives:$ To determine the effects of inhaled nitric oxide (NO) on venous admixture (Qs/Qt), mean pulmonary artery pressure (MPAP), and pulmonary vascular resistance (PVR) in patients undergoing one-lung ventilation (1LV) in the lateral decubitus position.
$Design:$ Prospective, blinded, crossover.
$Setting:$ University hospital.
$Participants:$ Six adult patients scheduled for thoracotomy.
$Interventions:$ Patients were anesthetized with thoracic epidural lidocaine, intravenous fentanyl, and inhaled isoflurane and were monitored with a systemic and pulmonary artery catheter (PAC). In the lateral decubitus position, the dependent lung was ventilated with 70% oxygen (O₂) and 30% nitrogen (N₂) for the control 1LV condition. For the experimental 1LV condition, the dependent lung was ventilated with the same gas concentration + NO at 40 ppm. Patients were alternated between the control and the experimental NO (40 ppm) conditions every 15 minutes for as long as the case would allow.
$Measurements and Main Results:$ During all conditions, oxygenation, Qs/Qt, and pulmonary and systemic hemodynamics were measured in a double-blinded fashion. The mean PVR during 1LV was 128 ± 39 (SD) dyne · s · cm⁻⁵. Inhaled NO at 40 ppm did not affect MPAP, PVR, or Qs/Qt.
$Conclusions:$ Inhaled NO at 40 ppm, during 1LV in the lateral decubitus position, did not significantly decrease MPAP in patients with normal baseline PVR. Oxygenation and Qs/Qt did not change in this setting because MPAP was not altered. At present, interventions other than administration of inhaled NO should be applied to patients with normal PVR who experience hypoxia during one-lung ventilation.
Nitric oxide synthesis inhibition and right ventricular systolic function in swine
1996, Journal of Cardiothoracic and Vascular Anesthesia
The present study was designed to evaluate the effects of the nitric oxide synthesis inhibitor N^G-nitro-L-arginine methyl ester (L-NAME) on right ventricular (RV) contractility, both pulsatile and nonpulsatile contributions to afterload, and relate any changes to alterations in performance of the RV as a pump.
Prospective drug response.
University animal laboratory.
Swine.
Six pigs anesthetized with thiopental and fentanyl were instrumented for measurement of RV pressure and pulmonary arterial (PA) pressure, internal diameter, and blood flow. Total RV afterload was calculated as effective PA elastance, with the steady-state component expressed as total arterial resistance, and the pulsatile component assessed by calculation of characteristic impedance and global compliance. The ratio of peak PA flow to RV end-diastolic pressure (RVEDP) was recorded as an index of RV pump function, and the peak ejection rate-of-change of RV power (dPower/dt) was calculated as index of contractility. In each animal, measurements were obtained before (baseline) and 15 minutes after intravenous injection of 33 mg/kg of L-NAME.
Mean PA pressure increased from 14 ± 3 mmHg at baseline to 23 ± 6 mmHg after L-NAME, whereas cardiac output, stroke volume, and peak PA flow/RVEDP demonstrated declines and dPower/dt was unchanged. Simultaneously, effective PA elastance increased more than twofold. This increase in total RV afterload was primarily the result of a marked elevation in total arterial resistance (+ 156%), whereas vascular compliance was reduced by only 30% and characteristic impedance unchanged.
These data indicate that L-NAME produces constriction of resistance vessels within the lung, leading to increased steady-state RV afterload, but has little direct effect on large pulmonary vessels and pulsatile RV load. RV pump performance declines after L-NAME, but contractility is preserved, indicating that the change in systolic performance results primarily from the increase in steady-state afterload.

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Original articleInhibition of nitric oxide synthesis causes systemic and pulmonary vasoconstriction in isoflurane-anesthetized dogs

Abstract

J Cardiothorac Anesth

Cell Calcium

Biochem Biophys Res Commun

Am J Cardiol

J Mol Cell Cardiol

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Original article
Inhibition of nitric oxide synthesis causes systemic and pulmonary vasoconstriction in isoflurane-anesthetized dogs