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Intravenous nitrate vasodilators and exhaled nitric oxide
THE LANCET
Nándor Marczin, Bernhard Riedel, David Royston, Magdi Yacoub
Isoenzymes that generate nitric oxide (NO) are present in the respiratory tract and NO is believed to play a part in controlling lung function in both health and disease. Endogenous NO can be detected in exhaled air.1,2 Measuring exhaled NO concentrations is becoming a useful diagnostic test.2 The biological effect of nitrate vasodilators, such as nitroglycerin (GTN) and sodium nitroprusside (SNP), is thought to be mediated by NO and subsequent activation of vascular smooth muscle soluble guanylate cyclase. The release of NO from these drugs is thought to be through non-enzymic release for SNP and thiol-dependent cellular biotransformation for GTN.3 Studies have shown that in rabbits and lambs intravenous GTN and SNP cause increased concentrations of exhaled NO.4,5 The effect of nitrate vasodilators on exhaled NO in human beings remains unknown. Measurements were made in patients undergoing openheart surgery for coronary-artery-bypass grafting or aorticvalve replacement by a real-time, computer-controlled, integrated system (Logan Research Ltd 2000 series). Exhaled NO and carbon dioxide (CO2) was sampled through a Teflon tube positioned at the distal end of the endotracheal tube with ventilation standardised for inspired gas (100% O2), tidal volume (5 mL/kg), and respiratory rate (10 per min). Seven patients were investigated, NO was detectable in the exhaled air with a characteristic oscillating signal which appeared to increase with expiration (as judged by the CO2 signal) reaching peak NO concentrations of 3–13 ppb. No NO signal was detected when the patient was replaced with a reservoir bag, suggesting that the NO signal was derived from the patient’s lungs. In all patients, intravenous bolus administration of GTN resulted in a rapid, marked, and transient increase in exhaled concentrations of NO which coincided with reduction of arterial blood pressure. The figure shows representative results in a patient before and after bolus injection of 250 mcg GTN. This patient exhibited baseline peak exhaled NO concentrations of 5·5 ppb, which increased to 16·8 ppb 11 s after the injection into a central vein. There were dosedependent effects of GTN boluses on exhaled NO: increases of 3·1, 6·0, and 8·1 ppb from baseline in peak exhaled NO concentrations after injecting 125, 250, and 500 mcg GTN. In one patient, a high rate of GTN infusion was clinically indicated to control blood pressure after replacement of the stenotic aortic valve. At baseline, peak exhaled NO concentrations of 12·6 (0·2) were observed. After infusing 45 mg/h GTN for 5 min, peak exhaled NO concentrations increased significantly to 14·1 (0·1) ppb. 5 min after stopping the GTN infusion, NO concentrations returned to baseline: 12·6 (0·2) ppb. To investigate whether the proposed different mechanisms of NO release from the nitrate vasodilators affects exhaled NO concentrations, we tested clinically equipotent doses of SNP and GTN. Injection of 150 mcg SNP caused only a small increase (0·8 ppb) in exhaled NO concentrations, whereas injection of 125 mcg GTN produced a substantial increase (4·2 ppb) in exhaled NO in the same patient. To investigate if release of NO could be observed from bolus injections of small amounts of GTN after prolonged intravenous administration of GTN—relevant to understanding nitrate tolerance—250 mcg GTN boluses were injected before and after intravenous administration of
1742
18
NO CO2
16 Exhaled NO and CO2 (ppb, %)
Intravenous nitrate vasodilators and exhaled nitric oxide
14 12 10
GTN
8 6 4 2 0 0
6 12 18 24 30 36 42 48 54 60 66 72
Time (sec) Effects of nitroglycerin (GTN) bolus on exhaled nitric oxide (NO) and carbon dioxide (CO2)
20 and 40 mg GTN in the postoperative period. Large amounts of NO were released from 250 mcg GTN boluses into exhaled air even after administering large quantities of GTN (40 mg) over 6 h. We have shown that there is endogenously produced NO in exhaled breath or artificially-ventilated, anaesthetised patients undergoing open-heart surgery, and that there is a transient, proportionate, and dose-dependent increase in NO in exhaled air after administration of GTN and to a lesser extent SNP. Our findings may provide a new way to monitor metabolic function of the pulmonary endothelium, as well as investigating nitrate pharmacology and tolerance. 1
2 3
4
5
Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991; 181: 852–57. Kharitonov SA, Barnes PJ. Exhaled nitric oxide: a marker of airway inflammation? Curr Opin Anaesth 1996; 9: 542–48. Feelisch M, Kelm M. Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells. Biochem Biophys Res Commun 1991; 180: 286–93. Persson MG, Agvald P, Gustafsson LE. Detection of nitric oxide in exhaled air during administration of nitroglycerin in vivo. Br J Pharmacol 1994; 111: 825–28. Husain M, Adrie C, Ichinose F, Kavosi M, Zapol WM. Exhaled nitric oxide as a marker for organic nitrate tolerance. Circulation 1994; 89: 2498–502.
Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science Technology and Medicine (M Yacoub) and Department of Anaesthetics, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK
Widespread occurrence of integrons causing multiple antibiotic resistance in bacteria Mark E Jones, Edith Peters, Anne-Marie Weersink, Ad Fluit, Jan Verhoef
Antibiotic resistance in bacteria has reached a near crisis point in nosocomial health care, with many bacterial isolates now multiresistant as a result of the acquisition of additional DNA elements.1 The evolution of multidrugresistant plasmids often involves a site-specific integration of antibiotic-resistance determinants.2,3 This recombination is mediated, in part, by a distinct family of DNA elements—integrons. Integrons comprise an integraseencoding gene which allows for site-specific insertion of resistance-gene cassettes between two highly conserved adjacent nucleotide sequences (3' CS and 5' CS). 4 Integrons are located on transposons which facilitate the rapid spread of integrons to other strains and bacterial
Vol 349 • June 14, 1997
Nándor Marczin, Bernhard Riedel, David Royston, Magdi Yacoub
Isoenzymes that generate nitric oxide (NO) are present in the respiratory tract and NO is believed to play a part in controlling lung function in both health and disease. Endogenous NO can be detected in exhaled air.1,2 Measuring exhaled NO concentrations is becoming a useful diagnostic test.2 The biological effect of nitrate vasodilators, such as nitroglycerin (GTN) and sodium nitroprusside (SNP), is thought to be mediated by NO and subsequent activation of vascular smooth muscle soluble guanylate cyclase. The release of NO from these drugs is thought to be through non-enzymic release for SNP and thiol-dependent cellular biotransformation for GTN.3 Studies have shown that in rabbits and lambs intravenous GTN and SNP cause increased concentrations of exhaled NO.4,5 The effect of nitrate vasodilators on exhaled NO in human beings remains unknown. Measurements were made in patients undergoing openheart surgery for coronary-artery-bypass grafting or aorticvalve replacement by a real-time, computer-controlled, integrated system (Logan Research Ltd 2000 series). Exhaled NO and carbon dioxide (CO2) was sampled through a Teflon tube positioned at the distal end of the endotracheal tube with ventilation standardised for inspired gas (100% O2), tidal volume (5 mL/kg), and respiratory rate (10 per min). Seven patients were investigated, NO was detectable in the exhaled air with a characteristic oscillating signal which appeared to increase with expiration (as judged by the CO2 signal) reaching peak NO concentrations of 3–13 ppb. No NO signal was detected when the patient was replaced with a reservoir bag, suggesting that the NO signal was derived from the patient’s lungs. In all patients, intravenous bolus administration of GTN resulted in a rapid, marked, and transient increase in exhaled concentrations of NO which coincided with reduction of arterial blood pressure. The figure shows representative results in a patient before and after bolus injection of 250 mcg GTN. This patient exhibited baseline peak exhaled NO concentrations of 5·5 ppb, which increased to 16·8 ppb 11 s after the injection into a central vein. There were dosedependent effects of GTN boluses on exhaled NO: increases of 3·1, 6·0, and 8·1 ppb from baseline in peak exhaled NO concentrations after injecting 125, 250, and 500 mcg GTN. In one patient, a high rate of GTN infusion was clinically indicated to control blood pressure after replacement of the stenotic aortic valve. At baseline, peak exhaled NO concentrations of 12·6 (0·2) were observed. After infusing 45 mg/h GTN for 5 min, peak exhaled NO concentrations increased significantly to 14·1 (0·1) ppb. 5 min after stopping the GTN infusion, NO concentrations returned to baseline: 12·6 (0·2) ppb. To investigate whether the proposed different mechanisms of NO release from the nitrate vasodilators affects exhaled NO concentrations, we tested clinically equipotent doses of SNP and GTN. Injection of 150 mcg SNP caused only a small increase (0·8 ppb) in exhaled NO concentrations, whereas injection of 125 mcg GTN produced a substantial increase (4·2 ppb) in exhaled NO in the same patient. To investigate if release of NO could be observed from bolus injections of small amounts of GTN after prolonged intravenous administration of GTN—relevant to understanding nitrate tolerance—250 mcg GTN boluses were injected before and after intravenous administration of
1742
18
NO CO2
16 Exhaled NO and CO2 (ppb, %)
Intravenous nitrate vasodilators and exhaled nitric oxide
14 12 10
GTN
8 6 4 2 0 0
6 12 18 24 30 36 42 48 54 60 66 72
Time (sec) Effects of nitroglycerin (GTN) bolus on exhaled nitric oxide (NO) and carbon dioxide (CO2)
20 and 40 mg GTN in the postoperative period. Large amounts of NO were released from 250 mcg GTN boluses into exhaled air even after administering large quantities of GTN (40 mg) over 6 h. We have shown that there is endogenously produced NO in exhaled breath or artificially-ventilated, anaesthetised patients undergoing open-heart surgery, and that there is a transient, proportionate, and dose-dependent increase in NO in exhaled air after administration of GTN and to a lesser extent SNP. Our findings may provide a new way to monitor metabolic function of the pulmonary endothelium, as well as investigating nitrate pharmacology and tolerance. 1
2 3
4
5
Gustafsson LE, Leone AM, Persson MG, Wiklund NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun 1991; 181: 852–57. Kharitonov SA, Barnes PJ. Exhaled nitric oxide: a marker of airway inflammation? Curr Opin Anaesth 1996; 9: 542–48. Feelisch M, Kelm M. Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells. Biochem Biophys Res Commun 1991; 180: 286–93. Persson MG, Agvald P, Gustafsson LE. Detection of nitric oxide in exhaled air during administration of nitroglycerin in vivo. Br J Pharmacol 1994; 111: 825–28. Husain M, Adrie C, Ichinose F, Kavosi M, Zapol WM. Exhaled nitric oxide as a marker for organic nitrate tolerance. Circulation 1994; 89: 2498–502.
Department of Cardiothoracic Surgery, National Heart and Lung Institute, Imperial College of Science Technology and Medicine (M Yacoub) and Department of Anaesthetics, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK
Widespread occurrence of integrons causing multiple antibiotic resistance in bacteria Mark E Jones, Edith Peters, Anne-Marie Weersink, Ad Fluit, Jan Verhoef
Antibiotic resistance in bacteria has reached a near crisis point in nosocomial health care, with many bacterial isolates now multiresistant as a result of the acquisition of additional DNA elements.1 The evolution of multidrugresistant plasmids often involves a site-specific integration of antibiotic-resistance determinants.2,3 This recombination is mediated, in part, by a distinct family of DNA elements—integrons. Integrons comprise an integraseencoding gene which allows for site-specific insertion of resistance-gene cassettes between two highly conserved adjacent nucleotide sequences (3' CS and 5' CS). 4 Integrons are located on transposons which facilitate the rapid spread of integrons to other strains and bacterial
Vol 349 • June 14, 1997