Continuous Infusion Of Nitroglycerin Research Articles

Bolus versus continuous infusion of nitroglycerin for the treatment of acute hypertensive heart failure

Background: The use of intravenous nitroglycerin by intermittent bolus doses in hypertensive acute heart failure patients (AHF) is still unclear. Aim and Objectives: This study aimed to determine intermittent bolus nitroglycerin's effect on the use of resources, admissions to intensive care unit (ICU), hospital length of stay (LOS), and safety. Patients and Methods: This prospective, randomized, parallel, single-blind clinical study, which included patients diagnosed with hypertensive AHF, was conducted from May 2019 to October 2020 at Benha University Hospital. Two hundred patients were recruited and randomly allocated into two groups, each composed of 100 patients. Results: The prevalence of hypertension and chronic obstructive pulmonary disease patients was significantly higher in patients given intermittent boluses of nitroglycerin than in standard therapy (88.0 vs. 77.0%, P = 0.041) and (27.0 vs. 15.0%, P = 0.037), respectively. Dyslipidemia was significantly lower in patients on intermittent doses of nitroglycerin than those on standard infusion therapy (30 vs. 66%, P < 0.001). The median initial troponin was significantly higher in group I compared to group II (0.145 vs. 0.065 ng/ml, P < 0.001). Conclusion: Nitroglycerin intravenous boluses were associated with fewer ICU admissions and a shorter LOS in the hospital as opposed to ordinarily infusion therapy. In addition, the mean mechanical ventilation duration was slightly shorter. Finally, continuous nitroglycerin infusion use in AHF management is being questioned.

Features of infusion therapy with gastrointestinal bleeding

Background. Ulcers of the stomach and 12-duodenal ulcers, complicated by gastrointestinal bleeding (GIB), become more life threatening, especially in patients with concomitant coronary heart disease (CHD). The composition of infusion therapy can significantly affect the coagulation potential of blood and the prognosis of treatment.&#x0D; Objective. The aim of this work is to identify the features of the infusion therapy performed in patients with GIB.&#x0D; Materials and methods. We analyzed the composition of infusion therapy in 457 patients who received intensive therapy for GIB in the period 2015-2019. The study protocol included a general and biochemical blood test, coagulogram, acid base balance, endoscopic and/or X-ray contrast examination of the gastrointestinal tract, ultrasound and, if necessary, CT or MRI of the abdominal organs, ECG, EchoCG.&#x0D; Results and discussion. Upon admission to the intensive care unit, all patients underwent catheterization of one of the central veins and continuous monitoring of the main indicators: pulse, blood pressure, ECG, pulse oximetry (SpO2), Hb level, coagulogram indicators. The main principles of intensive care were to stop all previously taken anticoagulants and antiplatelet agents, the appointment of H2-blockers – histamine receptors and proton pump inhibitors, Almagel or Maalox for 3-4 days, continuous infusion of nitroglycerin under hemodynamic control, transfusion of a polarizing mixture. The composition of the infusion given to these patients is one of the important factors that can affect the prognosis of treatment. To replenish the circulating blood volume, erythrocyte mass, fresh frozen plasma (FFP) and, if necessary, colloidal solutions under the control of central venous pressure and diuresis were given preference. At the same time, they tried to maintain the Hb level not lower than 8 g/dL, hematocrit 25 %, and FFP was used in large (15-20 ml/kg) doses.&#x0D; Conclusions. Considering the danger of thrombosis of the coronary arteries of the heart, shunts or stands on these vessels, in patients with GIB and concomitant CHD, the use of hemostatics is inappropriate. Resuming the use of anticoagulants can only be after the bleeding has stopped.

Effects of Nicorandil Versus Nitroglycerin on Arterial Oxygenation During Two-Lung Ventilation and One-Lung Ventilation in Patients With Risk Factors for Myocardial Ischemia: A Prospective, Randomized, Double-Blind Study

To compare the effects of nicorandil and nitroglycerin on arterial oxygenation during two-lung ventilation (TLV) and one-lung ventilation (OLV) in patients with risk factors for myocardial ischemia. A prospective, randomized, double-blind study. A tertiary care hospital. Fifty-six patients scheduled for elective video-assisted thoracic surgery were assigned randomly to either the nicorandil group or the nitroglycerin group. Patients in the nicorandil group received a bolus dose of nicorandil, 0.08 mg/kg during induction of anesthesia, followed by a continuous infusion at a rate of 0.08 mg/kg/h. Patients in the nitroglycerin group received a continuous infusion of nitroglycerin at a rate of 1 µg/kg/min from the induction of anesthesia. Arterial blood gas analysis was performed at the following points: before induction of anesthesia; during TLV; at 5, 10, 20, and 30 minutes after the initiation of OLV. PaO2 at TLV (479.7 ± 57.1 v 408.2 ± 70.9 mmHg, p < 0.001); and at 5 minutes (344.8 ± 85.1 v 282.6 ± 85.8 mmHg, p = 0.012), 20 minutes (215.7 ± 103.0 v 158.2 ± 74.5 mmHg, p = 0.027), and 30 minutes (198.8 ± 103.5 v 147.5 ± 64.1 mmHg, p = 0.039) after OLV was significantly higher in the nicorandil group than in the nitroglycerin group. This study demonstrated that oxygenation during TLV and OLV was significantly higher in patients receiving nicorandil than in those receiving nitroglycerin.

Impact of nitroglycerin infusion on weaning off hypertensive mechanically ventilated chronic obstructive pulmonary disease patients

IntroductionMechanical ventilation (MV) weaning trial can be compared to a cardiac stress test where spontaneous ventilation is a form of an exercise and therefore hemodynamic compromise can occur during the weaning process in critically ill patients. The combined increase in arterial pressure and heart rate during unsuccessful weaning is quite suggestive of weaning failure of cardiac origin. Assessment and prediction of weaning failure from cardiac origin remain complicated in patients with chronic obstructive pulmonary disease (COPD). Recent data showed that COPD itself is a powerful independent risk factor for cardiovascular morbidity and mortality, suggesting that occult cardiac dysfunction could be frequent in patients with COPD. The immediate transition from positive pressure mechanical ventilation to spontaneous ventilation may generate significant cardiopulmonary alterations that are complex and mainly include the inspiratory fall in intrathoracic pressure, the increase in work of breathing, and the catecholamine discharge that occur during abrupt transfer from mechanical ventilation to spontaneous breathing. Therefore, it could be suggested that a treatment targeting the cardiovascular system decreasing the preload might help the heart to tolerate the critical period of weaning more effectively. MethodsThis study was carried on 60 adult male and female patients admitted to the Critical Care Medicine Departments in the Alexandria Main University Hospital and who fulfilled the diagnosis of acute exacerbation of COPD according to the Global initiative for chronic obstructive lung disease (GOLD) [1], and considered eligible for weaning after at least 24h of invasive mechanical ventilation exhibiting systemic arterial hypertension during the start of spontaneous breathing trial. 30 of them were adult patients and served as the study group (Group I), and the other 30 were age-matched adults who served as the control group (Group II). Each group was subjected to spontaneous breathing trial (SBT) using a T-piece receiving FiO2 the same as during mechanical ventilation. Control group underwent SBT alone while the nitroglycerin group underwent continuous nitroglycerin infusion started at the beginning of the SBT and titrated to maintain normal arterial systolic blood pressure that is; 120–139mmHg). Hemodynamic, oxygenation and respiratory measurements were performed on the start of SBT, and after a 2-h T-piece SBT. ResultsCompared to the start of SBT, systolic arterial blood pressure and mean arterial blood pressure decreased [from (Mean±SD) 150.33±14.26, 112.56±9.37mmHg to 134.33±11.04, 92.78±5.81mmHg, respectively] in the nitroglycerin group, while the opposite occurred in the control group as systolic arterial blood pressure and mean arterial blood pressure increased [from (Mean±SD) 144.67±13.58, 109.78±10.09mmHg to 158.0±19.43, 114.73±10.82mmHg, respectively]. Mixed central venous saturation (ScvO2) decreased significantly in the control group at the end of SBT [from (Mean±SD) 71.90±1.84 to 69.25±2.20%], while in the nitroglycerin group, ScvO2 did not change at the end in comparison to the start of SBT [from (Mean±SD) 71.63±1.75 to 71.12±1.65%]. Nitroglycerin infusion at the start of SBT enabled a successful weaning from mechanical ventilation in 90% of patients in comparison to a successful weaning from mechanical ventilation of only 63.3% in the control group. ConclusionsNitroglycerin infusion might facilitate the weaning off hypertensive COPD patients by alleviating the cardiovascular compromise occurring during liberation from MV.

The calcitonin gene-related peptide receptor antagonist MK-8825 decreases spinal trigeminal activity during nitroglycerin infusion

BackgroundCalcitonin gene-related peptide (CGRP) and nitric oxide (NO) are regarded as key mediators in migraine and other primary headaches. Migraineurs respond to infusion of nitroglycerin with delayed headaches, and inhibition of CGRP receptors has been shown to be effective in migraine therapy. In animal experiments nitrovasodilators like nitroglycerin induced increases in spinal trigeminal activity, which were reversed after inhibition of CGRP receptors. In the present study we asked if CGRP receptor inhibition can also prevent spinal trigeminal activity induced by nitroglycerin.MethodsIn isoflurane anaesthetised rats extracellular recordings were made from neurons in the spinal trigeminal nucleus with meningeal afferent input. The non-peptide CGRP receptor inhibitor MK-8825 (5 mg/kg) dissolved in acidic saline (pH 3.3) was slowly infused into rats one hour prior to prolonged glyceryl trinitrate (nitroglycerin) infusion (250 μg/kg/h for two hours).ResultsAfter infusion of MK-8825 the activity of spinal trigeminal neurons with meningeal afferent input did not increase under continuous nitroglycerin infusion but decreased two hours later below baseline. In contrast, vehicle infusion followed by nitroglycerin was accompanied by a transient increase in activity.ConclusionsCGRP receptors may be important in an early phase of nitroglycerin-induced central trigeminal activity. This finding may be relevant for nitroglycerin-induced headaches.

Adequate time of initiation of continuous infusion of nitroglycerin for controlling pulmonary arterial pressure during ethanol embolotherapy of congenital arteriovenous malformation of the extremities

Adequate time of initiation of continuous infusion of nitroglycerin for controlling pulmonary arterial pressure during ethanol embolotherapy of congenital arteriovenous malformation of the extremities

Efficacy of Milrinone versus Nitroglycerin in Controlling Pulmonary Arterial Hypertension Induced by Intravenous Injections of Absolute Ethanol in Anesthetized Dogs

To compare the attenuating effects of milrinone versus nitroglycerin on pulmonary artery pressure (PAP) increase caused by repeat intravenous bolus injection of absolute ethanol in anesthetized dogs. Twenty-four dogs were randomly distributed into three groups: a control group (group C), a nitroglycerin group (treated with a continuous infusion of nitroglycerin at 5.0 microg/kg/min; group N), and a milrinone group (treated with a continuous infusion of milrinone at 3.0 microg/kg/min after an initial bolus dose of 100 microg/kg; group M). Absolute ethanol (0.1 mL/kg) was injected at 10-minute intervals via a 5-F angiographic catheter advanced into the proximal portion of the inferior vena cava. Immediately before and after each intravenous injection of absolute ethanol, hemodynamic values were obtained through a pulmonary arterial catheter. Group M showed more stable hemodynamic values of systolic, mean, and diastolic PAP and pulmonary vascular resistance (PVR) compared with groups C and N. In addition, group M showed significantly higher values of cardiac output versus group C at 10 minutes after the 10th bolus of ethanol. After restoration of spontaneous breathing, group M also showed the least hemodynamic changes in systolic, mean, and diastolic PAPs and PVR among the groups. Although a continuous infusion of nitroglycerin or milrinone effectively prevented cardiovascular deterioration, milrinone was superior to nitroglycerin in managing the acute hemodynamic changes that resulted from repeated intravenous bolus injections of absolute ethanol (0.1 mL/kg) in healthy anesthetized dogs.

Coadministration of Carvedilol Attenuates Nitrate Tolerance by Preventing Cytochrome P450 Depletion

Long-term administration of nitroglycerin (NTG) causes tolerance secondary to increased vascular formation of reactive oxygen species. Carvedilol, which has potent antioxidant activity in addition to functioning as an adrenergic blocker, prevents nitrate tolerance by a still to be elucidated mechanism. The present study investigated how carvedilol attenuates nitrate tolerance, particularly with reference to cytochrome P450 (CYP), an enzyme involved in the development of tolerance. Male Wistar rats were subjected to 48-h continuous infusion of NTG alone (0.5 mg/h) or NTG with concomitant carvedilol (20 or 100 microg/h), and then compared with vehicle-treated rats (4 groups; n=6 in each group). Following the continuous administration, nitrate tolerance, assessed by bolus NTG injections, was hemodynamically prevented by coadministration of carvedilol. Levels of CYP1A1/1A2, superoxide production, and phosphorylated vasodilator-stimulated phosphoprotein at serine 239 (P-VASP) were examined in the aortic wall and heart tissue. When NTG alone was continuously administered, vascular superoxide was produced, there was a decrease in the cardiac CYP1A1/1A2 level, and depletion of P-VASP. However, each of these changes induced by continuous NTG administration was significantly attenuated by coadministration of carvedilol and the extent of attenuation was more pronounced at the higher dose (100 microg/h). Coadministration of carvedilol attenuates nitrate tolerance through maintenance of NO/cGMP pathway activity by preventing free radical generation and CYP depletion.

Anesthetic management for severe aortic regurgitation in an infant repaired by Ross procedure

We report the anesthetic management of a 7-month-old male infant with severe aortic regurgitation (AR) scheduled for the Ross procedure. To the best of our knowledge, this is the first report from the viewpoint of anesthetic management for the Ross procedure performed in an infant. He had been suffering from severe AR that occurred suddenly when he was 5 months old. The cause of the AR was considered to be spontaneous rupture of a fenestrated aortic valve, owing to congenital tissue defect in part of the aortic valvular leaflet. The Ross procedure was scheduled to be performed under general anesthesia using deep hypothermic cardiopulmonary bypass (CPB). Continuous infusion of nitroglycerin was started during CPB and continued after CPB to dilate the newly implanted coronary arteries for the prevention of myocardial ischemia and to decrease afterload and pulmonary vascular resistance. Weaning from CPB was performed without difficulty, but after the prolonged CPB he had a bleeding tendency that needed transfusion and a hemostatic drug. Monitoring with transesophageal echocardiography was very useful for evaluating myocardial ischemia, and for assessing the procedure and the completion of surgical repair. His postoperative course was uneventful and he was discharged on the 25th postoperative day.

Nitroglycerin- and Nicardipine-Induced Hypotension Does Not Affect Cerebral Oxygen Saturation and Postoperative Cognitive Function in Patients Undergoing Orthognathic Surgery

The aim of this study was to investigate the influence of nitroglycerin- and nicardipine-induced hypotension on regional cerebral oxygen saturation (rSO(2)) and postoperative cognitive function in patients undergoing orthognathic surgery. Sixty adult patients scheduled for orthognathic surgery were randomly assigned to either the nitroglycerin group (group 1) or nicardipine group (group 2). After induction of anesthesia, hypotension was induced with continuous infusion of nitroglycerin or nicardipine. Mean arterial pressure (MAP), heart rate (HR), and rSO(2) were measured at the following time points: before induction of anesthesia, immediately before commencing induced hypotension, at 30 and 60 minutes after induced hypotension, and immediately before the end of surgery. Cerebral desaturation was defined as a reduction of rSO(2) less than 75% of baseline for > or = 15 seconds. The Mini Mental State Examination (MMSE) was conducted before surgery and then repeated after 1 week. Baseline rSO(2) values were similar in the 2 groups. There were no significant differences in rSO(2) values between the 2 groups. Cerebral desaturation was not observed in any of the patients. Both nitroglycerin and nicardipine reduced MAP and increased HR during induced hypotension as compared with the baseline values (P < .05). No differences in MAP and HR during baseline and induced hypotension were observed between the 2 groups. Decreased MMSE scores were not observed in any of the patients. Cerebral oxygen saturation and postoperative cognitive function were not impaired during nitroglycerin- and nicardipine-induced hypotension in patients undergoing orthognathic surgery.

Vitamin E deficiency accelerates nitrate tolerance via a decrease in cardiac P450 expression and increased oxidative stress

Organic nitrates, such as nitroglycerin (NTG), have been used to relieve the symptoms of angina pectoris. However, their biochemical mechanisms of action, particularly in relation to the development of tolerance, are incompletely defined. It has been reported that supplemental antioxidants such as vitamin E attenuate the development of nitrate tolerance. Therefore, we examined the role of vitamin E in the regulation of nitrate tolerance. Continuous NTG infusion induced nitrate tolerance in rats after 48 h, and vitamin E concentrations decreased in a time-dependent manner in tissues and plasma. Vitamin E supplementation (0.5 g/kg diet) maintained higher concentrations of vitamin E during NTG infusion. The onset and extent of the tolerance, estimated by the decrease in blood pressure following NTG bolus injection during the infusion of NTG, were accentuated in the vitamin E-deficient group. Vitamin E supplementation inhibited nitrate tolerance 48 h after NTG infusion. Cardiac P450 expression (CYP1A2) assessed by immunoblotting, markedly decreased 48 h after NTG administration in control rats. The supplementation of vitamin E significantly attenuated the decrease in P450. Treatment of NTG enhanced vascular superoxide production (L-012 chemiluminescence, DHE fluorescence). The peak of lipid peroxidation and free radical generation in the heart was reached before tolerance developed. In contrast, vitamin E-deficient hearts had lower P450 expression and higher free radical generation than control hearts. To evaluate other vitamin E-inhibitable mechanisms of nitrate tolerance, we studied the NO-cGMP pathway. NTG markedly reduced the vasodilator-stimulated phosphoprotein (VASP) serine 239 phosphorylation (specific substrate of cGMP-activated protein kinase I; cGK-I) in tolerant hearts. Vitamin E inhibited the depletion of pVASP. In conclusion, because continuous NTG infusion causes vitamin E depletion as well as nitrate tolerance, vitamin E deficiency may further accelerate nitrate tolerance via an increase in oxidative stress, the reduced bioconversion because of decreased P450 expression, and impairment of the NO/cGMP pathway in tolerant heart tissues.

Continuous infusion of nitroglycerin improves pulmonary graft function of non-heart-beating donor lungs.

The warm ischemic period of lungs harvested from a non-heart-beating donor (NHBD) results in an increased ischemia-reperfusion injury after transplantation. The intravenous application of nitroglycerin (NTG), a nitric oxide (NO) donor, proved to be beneficial during reperfusion of lung grafts from heart-beating donors. The objective of the present study was to investigate the effect of nitroglycerin on ischemia-reperfusion injury after transplantation of long-term preserved NHBD-lungs. Sixteen pigs (body weight, 20-30 kg) underwent left lung transplantation. In the control group (n=5), lungs were flushed (Perfadex, 60 mL/kg) and harvested immediately after cardiac arrest. In the NHBD group (n=5) and the NHBD-NTG group (n=6), lungs were flushed 90 min (warm ischemia) after cardiac arrest. After a total ischemia time of 19 hr, lungs were reperfused and graft function was observed for 5 hr. Recipient animals in the NHBD-NTG group received 2 microg/kg/min of NTG administered intravenously during the observation period starting 5 min before reperfusion. Tissue specimens and bronchoalveolar lavage fluid (BALF) were obtained at the end of the observation period. Compared with the control group, pulmonary gas exchange was significantly impaired in the NHBD group, whereas graft function in the NHBD-NTG group did not change. Leukocyte fraction and protein concentration in the BALF and histologic alteration of the NHBD-NTG group were not different from controls. Continuous infusion of NTG in the early reperfusion period improves pulmonary graft function of NHBD lungs after long-term preservation. The administration of an NO donor during reperfusion may favor the use of NHBD lungs to alleviate the critical organ shortage in lung transplantation.

Moderate Systemic Hypotension During Reperfusion Reduces the Coronary Blood Flow and Increases the Size of Myocardial Infarction in Pigs

s: To examine the effects of low arterial BP (ABP) during reperfusion on the extent of myocardial infarction and on coronary blood flow (CBF) in an occlusion/reperfusion experimental model. Prospective, randomized animal study. University hospital. Normal pigs that were anesthetized, intubated, and mechanically ventilated. Twenty-seven open-chest pigs underwent occlusion of the mid left anterior descending (LAD) coronary artery for 1 h followed by reperfusion for 2 h. During reperfusion, the animals were randomly assigned to either continuous infusion of nitroglycerin in therapeutic doses and fluid infusion at rates to maintain a mean ABP >or= 80 mm Hg (group 1, n = 13), or continuous nitroglycerin infusion at rates to maintain a mean ABP between 60 mm Hg and 75 mm Hg (group 2, n = 14). The hemodynamics and the coronary ABP distal to the occlusion were recorded throughout the experiment. In addition, the LAD CBF and peak hyperemia CBF before occlusion and during reperfusion periods were measured by transit-time flowmetry. At the end of the experiment, the infarcted left ventricular myocardial size was measured. There were no significant hemodynamic differences, including the distal coronary arterial pressure, between the two groups before or during the LAD artery occlusion period. During reperfusion, mean ABP was 90 +/- 3 mm Hg in group 1 vs 69 +/- 3 mm Hg in group 2 (p < 0.001). In group 1, the infarcted myocardium represented 50.3 +/- 4.3% of the myocardium at risk, vs 69.4 +/- 7.2% in group 2 (p < 0.001). During reperfusion, CBF and peak hyperemia CBF were significantly higher in group 1 than in group 2. Low ABP during reperfusion increases the size of myocardial infarction and decreases CBF.

Continuous administration of organic nitrate decreases hepatic cytochrome P450.

We previously reported that cytochrome P450 (P450) is a key enzyme of organic nitrate biotransformation and that P450 levels of the heart and its vessels markedly decreased at the development of nitrate tolerance. Although our attention was mainly focused on the circulatory organs, most organic nitrates, including nitroglycerin (NTG), are metabolized in the liver, where nitric oxide (NO) is concomitantly produced from the organic nitrates. NO reacts with various molecules such as superoxide, heme, thiols, and oxygen. This paper examined whether hepatic P450 levels are also affected after organic nitrate administration, since the liver is the major organ of P450 related metabolism. Male Wistar rats were intravenously administrated NTG or isosorbide dinitrate (ISDN) for 24-96 h. We observed the level of hemeoxygenase-1 (HO-1) as the functional marker of hepatic P450, since one of the acute phase target proteins of NO induction is an inducible type of HO-1. Hepatic P450 was drastically decreased after 48 or 72 h of continuous NTG or ISDN infusion, when nitrate tolerance was observed, but it recovered 48 h after cessation of the NTG administration. HO-1 was induced within 24 h of continuous NTG infusion, but it returned to normal levels 48 h after cessation of NTG. The administration of sodium nitroprusside, an agent to which the animals showed no tolerance, did not induce HO-1 or P450 depletion. Chronic administration of organic nitrates significantly decreased hepatic P450. These results suggest that P450-dependent drug metabolism may be drastically affected after continuous organic nitrate administration.

Profound Pain Due to Propofol Injection Triggered Myocardial Ischemia in a Patient with a Suspected Pheochromocytoma

To the Editor: Propofol-induced pain is one of side effects observed during injection (1). However, to our knowledge, there are no reports of serious accidents associated with propofol-induced pain. We describe a patient who had a suspected pheochromocytoma and developed myocardial ischemia triggered by propofol-induced pain during induction of anesthesia. The patient, a 52-year-old man (height, 165 cm; weight, 55 kg), was scheduled for a laparoscopic adrenalectomy for a suspected pheochromocytoma detected by CT scan at health screening. Preoperative examinations revealed slight increases in plasma catecholamines and 24-hour urinary catecholamines excretion. Preparation involved a period of preoperative α-blockade with prazosin hydrochloride. Before induction, the patient’s hemoglobin was 13.3 g/dL, the electrocardiogram (ECG) findings were within normal limits, baseline heart rate was 65 bpm, and arterial blood pressure was 95/55 mm Hg. Under continuous monitoring of blood pressure through a radial artery catheter, general anesthesia was induced by IV administration of propofol (100 mg/30 s) through the 18-gauge catheter at his forearm. The patient complained of a profound vascular pain during the infusion of propofol. After loss of consciousness, arterial blood pressure increased to 230/130 mm Hg and a sinus tachycardia (130 bpm) was observed. Immediately, 0.5 mg nicardipine and 50 mg propofol combined with inhalation of 2% sevoflurane were administered and his blood pressure normalized. The trachea was intubated after adequate muscle relaxation was attained and simultaneously the ECG in lead II showed an elevation of the ST segment (Fig. 1), then arterial blood pressure decreased to 80/50 mm Hg. After intravenous 0.1-mg phenylephrine and continuous infusion of nitroglycerin (0.5 μg/kg/min), diltiazem (1 μg/kg/min), and dopamine (3 μg/kg/min) were infused, the ST segment returned to normal in 10 min and his blood pressure improved to 110/55 mm Hg. The coronary angiography performed a week later revealed normal coronary arteries. We speculated that propofol-induced pain could cause a sudden increase in plasma catecholamine levels derived from a pheochromocytoma and eventually develop myocardial ischemia. Propofol should be used carefully in such patients.Figure 1: (A) Electrocardiogram recorded before the induction of anesthesia. It revealed a normal sinus rhythm. (B) Immediately after induction of anesthesia, elevation of the ST segment was noted but it normalized in 10 minutes after treatment of hypotension and myocardial ischemia.Tetsuro Morishima, MD Kazuya Sobue, MD, PhD Hajime Arima, MD Sayuki Tanaka, MD MinHye So, MD Hiroshi Ando, MD, PhD Hirotada Katsuya, MD, PhD

Nitroglycerin tolerance: different mechanisms in vascular segments with or without intact endothelial function.

In vivo tolerance to nitroglycerin seems to be induced by an increase in vascular superoxide anion levels. In rabbits with normal endothelial function, in vivo induced tolerance is functionally reversed by ex vivo removal of the endothelium, probably due to a reduction in superoxide anion levels. However, the impact of in vivo endothelial dysfunction on tolerance development has not been examined. This study investigated how in vivo endothelium denudation affects the development of in vivo nitroglycerin tolerance. The effect of in vivo endothelium denudation was examined ex vivo (myograph experiments) after prolonged continuous nitroglycerin infusion in a conscious rat model. The vascular reactivity to nitroglycerin was studied in vivo in endothelium-denuded and corresponding endothelium-intact arteries. The results show that in vivo endothelium denudation does not affect the degree of tolerance development but significantly alters the effect of interventions targeted to inhibit tolerance development. In endothelium-intact vessels, superoxide dismutase and the angiotensin II receptor blocker losartan significantly inhibited tolerance-inducing properties of the prolonged nitroglycerin infusion (E[max, nitroglycerin] response in % of normal controls: nitroglycerin tolerant 70%, superoxide dismutase 93%, losartan 99%). This effect was absent in in vivo endothelium-denuded segments (nitroglycerin tolerant 57%, superoxide dismutase 72%, losartan 60%). These findings suggest that interventions against in vivo tolerance development, within the same animal, may elicit different results depending on the presence or absence of an in vivo dysfunctional endothelium.

Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance.

The efficacy of nitroglycerin (NTG) as a vasodilator is limited by tolerance, which develops shortly after treatment begins. In vascular smooth muscle cells (VSMCs), NTG is denitrated to form nitric oxide (NO), which activates guanylyl cyclase and generates cGMP. cGMP plays a key role in nitrate-induced vasodilation by reducing intracellular Ca(2+) concentration. Therefore, one possible mechanism for development of nitrate tolerance would be increased activity of the cGMP phosphodiesterase (PDE), which decreases cGMP levels. To test this hypothesis, rats were made tolerant by continuous infusion of NTG for 3 days (10 microgram kg(-1). min(-1) SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca(2+)/calmodulin (CaM)-stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca(2+)/CaM-stimulated PDE revealed that PDE1A1 was increased 2.3-fold in NTG-tolerant rat aortas. Increased PDE1A1 was due to mRNA upregulation as measured by relative quantitative reverse transcription-polymerase chain reaction. The PDE1-specific inhibitor vinpocetine partially restored the sensitivity of the tolerant vasculature to subsequent NTG exposure. In cultured rat aortic VSMCs, angiotensin II (Ang II) increased PDE1A1 activity, and vinpocetine blocked the effect of Ang II on decrease in cGMP accumulation. Induction of PDE1A1 in nitrate-tolerant vessels may be one mechanism by which NO/cGMP-mediated vasodilation is desensitized and Ca(2+)-mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.

Vasodilator responses of coronary conduit and resistance arteries to continuous nitroglycerin infusion in humans: a Doppler guide wire study.

To examine the responses of coronary conduit and resistance arteries to the continuous i.v. administration of nitroglycerin in 15 patients with atypical chest pain, we measured coronary blood flow velocity in the left anterior descending coronary artery using a Doppler guide wire and the lumen diameter and cross-sectional area by quantitative coronary angiography. Systolic flow, diastolic flow, total coronary flow, and coronary vascular resistance were calculated. Stepwise increases in dose of nitroglycerin resulted in significant dose-dependent decrease in mean aortic pressure (p < 0.01) and increase in lumen diameter (p < 0.05). After nitroglycerin administration of 0.5 microg/kg/min, systolic flow decreased significantly by 89.9+/-15.7% (p < 0.01), and diastolic flow increased significantly by 74.2+/-37.1% (p < 0.05). Total coronary flow did not change significantly with the various doses of nitroglycerin. However, coronary vascular resistance decreased significantly at concentrations greater than 0.5 microg/kg/min nitroglycerin. Continuous nitroglycerin infusion did not reduce either diastolic or total coronary blood flow despite a significant reduction in coronary perfusion pressure. These results indicate that subendocardial blood flow might be maintained during continuous i.v. infusion of nitroglycerin within the clinical dose range.

Effects of Inhalation of Nitroglycerin on Hypoxic Pulmonary Vasoconstriction

Recent studies suggest that nitric oxide (NO) may play an important role in the pathophysiology of pulmonary hypertension. Nitroglycerin is metabolized to NO, which is a potent vascular smooth muscle relaxant. The aim of the present study was to compare the effects of inhaled and infused nitroglycerin on pulmonary hemodynamics and gas exchange in anesthetized, artificially ventilated dogs. Nitroglycerin was administrated either by inhalation or by infusion. Systemic blood pressure (SBP), pulmonary arterial pressure (PAP), and pulmonary capillary wedge pressure (PCWP) were measured, and cardiac output was estimated by an electromagnetic flowmeter. Blood gas measurements were performed during hypoxic gas exposure (FiO₂; 0.1) with a continuous inhalation or infusion of nitroglycerin (1, 2.5 µg/kg/min). Inhaled (n = 4) and infused (n = 4) nitroglycerin (1 µg/kg/min) did not produce any detectable effects on the hemodynamics. Inhaled nitroglycerin (2.5 µg/kg/min) reduced SBP, PAP and calculated pulmonary vascular resistance (PVR) in all dogs. Cardiac output did not change. In addition, inhaled nitroglycerin increased PaO₂. In contrast, the continuous infusion of nitroglycerin (2.5 µg/kg/min) did not change in PAP, whereas infused nitroglycerin decreased the mean SBP. Infused nitroglycerin did not alter cardiac output and calculated PVR. A decreased PaO₂ was noted in 2 dogs on nitroglycerin infusion. These findings indicate that inhaled nitroglycerin effects the pulmonary circulation relatively more than infused nitroglycerin, which tends to have more of a general effect on the systemic circulation. The effects of inhaled nitroglycerin may thus be comparable to the effects of NO inhalation.

Application of pharmacodynamic modeling for designing time-variant dosing regimens to overcome nitroglycerin tolerance in experimental heart failure.

Prolonged continuous administration of nitroglycerin (NTG) leads to hemodynamic tolerance. We used a previously developed pharmacokinetic-pharmacodynamic (PK/PD) model of NTG tolerance in experimental heart failure to test whether dosage regimens, designed from this model, may allow avoidance of tolerance development upon continuous NTG infusion. Simulation experiments (using ADAPT II) were performed to evolve a time-variant infusion regimen that would theoretically provide sustained hemodynamic effect (30% reduction in left ventricular end-diastolic pressure, LVEDP) throughout 10 hours of drug dosing. A computer controlled infusion pump was utilized to deliver this time-variant input. Infusion experiments were then conducted in CHF rats to challenge the predictability of the applied PK/PD model. Simulations showed that exponentially increasing input functions provided more sustained LVEDP effects when compared to linear or hyperbolic input functions delivering the same total NTG dose. A computer-selected infusion regimen of 6.56e0.00156 x minutes micrograms/min was anticipated to provide the desired hemodynamic profile in our animal model. Experiments conducted in rats with congestive heart failure (n = 4) confirmed the prediction of sustained hemodynamic effect without tolerance (28 +/- 4% reduction in LVEDP at 10 hrs). These findings support the utility of our PK/PD model of NTG tolerance in predicting NTG action, and serve as an example of therapeutic optimization through PK/PD considerations.