- Email: [email protected]
Potential deleterious effects of inhaled nitric oxide in heart failure
The 2nd Annual Scientific Meeting
017 ATRIAL NATRIURETIC PEPTIDE AND RESPONSE OF PULMONARY VASCULATURE TO INHALED NITRIC OXIDE AFTER VASODILATiNGTHERAPY Shingo Kyotani, Tom Satoh, Noritoshi Nagaya, Fumio Sakamaki, Nodfumi Nakanishi, Mikio Kakishit& Toshio Nishikimi, Yoshiaki Okano*, Takeyoshi Kunieda** National CardiovascularCenter, Osaka 565-8565, Japan *Shinshiro City Hospital, Aich,**lse Keio Hospital, Mie In pulmonary hypertensions the responses of pulmonary vasculature to inhaled nitric oxide (NO) correlate to plasma atrial natriuretic peptide (ANP) levels. To certify whether this correlation represents only stage of disease or underlying relating mechanism, we investigated response to inhaled NO before and after treatment of heart failure using vasodilator. Subjects were 7 patients with severe precapillary pulmonary hypertension aged 38.6 years old. Their mean pulmonary arterial pressure (PAP), cardiac output (CO), and total pulmonary resistance (TPR) were 61.3 4- 18.1 mmHg, 2.7 4- 0.7 I/min, and 24.1 + 10.1 units respectively. They were medicated with continuous drip infusion of prostaglandin E1 for 1 month. After that their PAP, CO, and TPRtumed to 52.3 _+14.3 mmHg, 3.4 -+ 0.4 I/min, and 15.9 4- 5.0 units respectively. Before and after prostaglandin therapy their responses of pulmonary vasculature to inhaled nitdc oxide were examined. Just before inhaJing nitdc oxide, blood was drawn from artery to measure plasma ANP. Their plasmaANP were 204 4- 164 pg/mI, and changed to 109 463 pg/ml after therapy. Five of 7 patients reduced their ANP levels and increased vascular response to inhaled NO, and other 2 patients increased ANP and decreased response. In conclusion response of pulmona~ vasculature to inhaled NO were not fixed but affected by ANP levels.
019 EFFECT OF TAURINE ON INTRACELLULAR Ca 2* CONCENTRATION IN ISCHEMIA-REPERFUSED FAILING RAT HEARTS Shingo Seki, Tatsuyuki Onodera, Kazuaki Horikoshi, Makoto Nagai, Motoo Ishiki, Seibu Mochizuki. Department of Medicine 4, Aoto Hospital, The Jikei University, School of Medicine, Tokyo 125-8506, Japan
Objective: We observed the alterations in cytoplasmic Ca 2+ concentration ([Ca2*]i) in whole heart during ischemia and reperfusion, and tested the hypothesis that protective effect of taurine, sulfur-containing amino acid was due to a reduction of intracellular Ca2÷overload. Methods: Hearts from male Sprague-Dawley rats were perfused by Langendorff's mode and were loaded with fura-2. [Ca2÷]iwas measured by monitoring the ratio of 600nm fluorescence excited at 340nm/380nm using Ca ~+ analyzer (CAF110, Japan Spectroscopic Inc.). Low-flow ischemia was induced by reduction of flow to 10% with pacing for 30 rain, and the hearts were reperfused. Treatment of 40raM taurine was started at 10 min prior to the induction of ischemia and was continued throughout the ischemic period. ReSults: In untreated hearts (n=9), left ventricular pressure decreased from 85.3 mmHg to 14.4 mmHg (p
•
JHFS
018 POTENTIAL DELETERIOUS EFFECTS OF INHALED NITRIC OXIDE IN HEART FAILURE. Shunsuke Natori, Naoyuki Hasebe, Yin-Tie Jin, Tomoyuki Matsusaka, Hideki Nakamura, Takafumi Ohta, Masahiko Morihira,Akira Ido, Hironobu Matsuhashi, Kenjiro Kikuchi First Department of Internal Medicine, AsaNkawa Medical College Asahikawa, 076-8510, JAPAN It is controversial whether the nitric oxide (NO) inhalation is effec~:ive in the treatment of congestive heart failure, because of its potential negative inotropic action on myocardium despite its vasodilating action. We studied cardio-nemodynamic effects of inhaled NO in a dog heart failure model. Sixteen open chest dogs were instrumented with a catheter-tip transducer in the left ventricle (LV) to measure LV pressure and LV dP/dt. We used tau (~) as an index of LV diastolic function. Tygon catheters in pulmonary and femoral arteries were used to mesure their pressure. An electromagnetic and a doppler probe were set on main pulmonary artery and left anterior descending coronary artery, respectively. We tested continuous infusion of norepinephdne (NE; 0.2-1.0 pg/kg/min.) and angiotensin-ll (ATII: 10-50 ng/kg/min) with or without inhalation of 70 ppm NO iv, normal (Control) an~ procainamide-induced heart failure (HF) dogs. NE and ATI[ increased LV end-diastolic pressure (EDP) in a dose dependent manner:. +0.5-+3.8 mmHg by NE, +1.0-+5.5 mmHg by ATII. Inhaled NO affected neither LV function nor hemodynamics at baseline. In Control, increases in LVEDP and pulmonary arterial pressure (PAP) by either NE and ATII were suppressed by NO inhalation. In contrast, increases in LVEDP and PAP by either NE and ATll were rather enhanced in HF by NO inhalation. LV diastolic function assessed by tau was not significantly affected by NO inhalation. In conclusion, inhaled NO affected neither LV systolic nor diastoiic function in Control. However, the increases in LVEDP and PAP by either NE and ATII were enhanced by inhaled NO in HF, indicating that the potential increase in LV preload by inhaled NO may aggravate HF when LV dysfunction is cdtical.
020 THE ROLE OF CPP32/YAMA(-LIKE) PROTEASE MYOCARDIAL ISCHMIA-REPERFUSION INJURY .
IN
Yoshlhlsa Naka, Yoshlkl Sawa, Motonobu Nlshlmura, Aklra Amenl:/a, Hldekl Ueda, Takahlro Yamagutl, Shlgeakl Ohtake, Htkaru Matuda Department of First Surgery, Oasaka UntverslW, Sutta 565-0871, Japan Apoptosis is reported to play a role In myocardial lschemlareperfusIon l.njury. Recently It has been suggested that CPP32/ 'Lama (-like) proyease, which Is one of the members of lnterleukln-1 ~ converting enzyme (ICE) protease family, be associated with lschemla-reperfuslon Injury .To clarify whether CPP32 Is activated during lsehemla-reperfuston Injury, we evaluated actlviW of CPP32 during lschemla-repeffuslon in isolated rat heart.Adult SD rats were divided Into the repeffusion group(R group n=5) and the not reperfuslon group(NR group n=5).R group hearts were subjected to normothermlc global lschemla for 45 minutes followed by 30 minutes of repefuslon,whlle NR group hearts were not repeffuslon.Tbe appearance of activated form of CPP32/Yama (-like) protease was evaluated by Westen blotting and the activity of CPP32 was measured. In the Western blotting analysis the activlted form CPP32/Yama(-ltke) protease (17kDa), were detected both R groups and NR group. The activities of CPP32/Yama(-llke) protease were stgnlficantl:/ higher in R group than In NR group. These data, suggested that CPP32 is activated by reperfuslon.The activation of CPP32 may play a role In lschernla-reperfuslon
69
017 ATRIAL NATRIURETIC PEPTIDE AND RESPONSE OF PULMONARY VASCULATURE TO INHALED NITRIC OXIDE AFTER VASODILATiNGTHERAPY Shingo Kyotani, Tom Satoh, Noritoshi Nagaya, Fumio Sakamaki, Nodfumi Nakanishi, Mikio Kakishit& Toshio Nishikimi, Yoshiaki Okano*, Takeyoshi Kunieda** National CardiovascularCenter, Osaka 565-8565, Japan *Shinshiro City Hospital, Aich,**lse Keio Hospital, Mie In pulmonary hypertensions the responses of pulmonary vasculature to inhaled nitric oxide (NO) correlate to plasma atrial natriuretic peptide (ANP) levels. To certify whether this correlation represents only stage of disease or underlying relating mechanism, we investigated response to inhaled NO before and after treatment of heart failure using vasodilator. Subjects were 7 patients with severe precapillary pulmonary hypertension aged 38.6 years old. Their mean pulmonary arterial pressure (PAP), cardiac output (CO), and total pulmonary resistance (TPR) were 61.3 4- 18.1 mmHg, 2.7 4- 0.7 I/min, and 24.1 + 10.1 units respectively. They were medicated with continuous drip infusion of prostaglandin E1 for 1 month. After that their PAP, CO, and TPRtumed to 52.3 _+14.3 mmHg, 3.4 -+ 0.4 I/min, and 15.9 4- 5.0 units respectively. Before and after prostaglandin therapy their responses of pulmonary vasculature to inhaled nitdc oxide were examined. Just before inhaJing nitdc oxide, blood was drawn from artery to measure plasma ANP. Their plasmaANP were 204 4- 164 pg/mI, and changed to 109 463 pg/ml after therapy. Five of 7 patients reduced their ANP levels and increased vascular response to inhaled NO, and other 2 patients increased ANP and decreased response. In conclusion response of pulmona~ vasculature to inhaled NO were not fixed but affected by ANP levels.
019 EFFECT OF TAURINE ON INTRACELLULAR Ca 2* CONCENTRATION IN ISCHEMIA-REPERFUSED FAILING RAT HEARTS Shingo Seki, Tatsuyuki Onodera, Kazuaki Horikoshi, Makoto Nagai, Motoo Ishiki, Seibu Mochizuki. Department of Medicine 4, Aoto Hospital, The Jikei University, School of Medicine, Tokyo 125-8506, Japan
Objective: We observed the alterations in cytoplasmic Ca 2+ concentration ([Ca2*]i) in whole heart during ischemia and reperfusion, and tested the hypothesis that protective effect of taurine, sulfur-containing amino acid was due to a reduction of intracellular Ca2÷overload. Methods: Hearts from male Sprague-Dawley rats were perfused by Langendorff's mode and were loaded with fura-2. [Ca2÷]iwas measured by monitoring the ratio of 600nm fluorescence excited at 340nm/380nm using Ca ~+ analyzer (CAF110, Japan Spectroscopic Inc.). Low-flow ischemia was induced by reduction of flow to 10% with pacing for 30 rain, and the hearts were reperfused. Treatment of 40raM taurine was started at 10 min prior to the induction of ischemia and was continued throughout the ischemic period. ReSults: In untreated hearts (n=9), left ventricular pressure decreased from 85.3 mmHg to 14.4 mmHg (p
•
JHFS
018 POTENTIAL DELETERIOUS EFFECTS OF INHALED NITRIC OXIDE IN HEART FAILURE. Shunsuke Natori, Naoyuki Hasebe, Yin-Tie Jin, Tomoyuki Matsusaka, Hideki Nakamura, Takafumi Ohta, Masahiko Morihira,Akira Ido, Hironobu Matsuhashi, Kenjiro Kikuchi First Department of Internal Medicine, AsaNkawa Medical College Asahikawa, 076-8510, JAPAN It is controversial whether the nitric oxide (NO) inhalation is effec~:ive in the treatment of congestive heart failure, because of its potential negative inotropic action on myocardium despite its vasodilating action. We studied cardio-nemodynamic effects of inhaled NO in a dog heart failure model. Sixteen open chest dogs were instrumented with a catheter-tip transducer in the left ventricle (LV) to measure LV pressure and LV dP/dt. We used tau (~) as an index of LV diastolic function. Tygon catheters in pulmonary and femoral arteries were used to mesure their pressure. An electromagnetic and a doppler probe were set on main pulmonary artery and left anterior descending coronary artery, respectively. We tested continuous infusion of norepinephdne (NE; 0.2-1.0 pg/kg/min.) and angiotensin-ll (ATII: 10-50 ng/kg/min) with or without inhalation of 70 ppm NO iv, normal (Control) an~ procainamide-induced heart failure (HF) dogs. NE and ATI[ increased LV end-diastolic pressure (EDP) in a dose dependent manner:. +0.5-+3.8 mmHg by NE, +1.0-+5.5 mmHg by ATII. Inhaled NO affected neither LV function nor hemodynamics at baseline. In Control, increases in LVEDP and pulmonary arterial pressure (PAP) by either NE and ATII were suppressed by NO inhalation. In contrast, increases in LVEDP and PAP by either NE and ATll were rather enhanced in HF by NO inhalation. LV diastolic function assessed by tau was not significantly affected by NO inhalation. In conclusion, inhaled NO affected neither LV systolic nor diastoiic function in Control. However, the increases in LVEDP and PAP by either NE and ATII were enhanced by inhaled NO in HF, indicating that the potential increase in LV preload by inhaled NO may aggravate HF when LV dysfunction is cdtical.
020 THE ROLE OF CPP32/YAMA(-LIKE) PROTEASE MYOCARDIAL ISCHMIA-REPERFUSION INJURY .
IN
Yoshlhlsa Naka, Yoshlkl Sawa, Motonobu Nlshlmura, Aklra Amenl:/a, Hldekl Ueda, Takahlro Yamagutl, Shlgeakl Ohtake, Htkaru Matuda Department of First Surgery, Oasaka UntverslW, Sutta 565-0871, Japan Apoptosis is reported to play a role In myocardial lschemlareperfusIon l.njury. Recently It has been suggested that CPP32/ 'Lama (-like) proyease, which Is one of the members of lnterleukln-1 ~ converting enzyme (ICE) protease family, be associated with lschemla-reperfuslon Injury .To clarify whether CPP32 Is activated during lsehemla-reperfuston Injury, we evaluated actlviW of CPP32 during lschemla-repeffuslon in isolated rat heart.Adult SD rats were divided Into the repeffusion group(R group n=5) and the not reperfuslon group(NR group n=5).R group hearts were subjected to normothermlc global lschemla for 45 minutes followed by 30 minutes of repefuslon,whlle NR group hearts were not repeffuslon.Tbe appearance of activated form of CPP32/Yama (-like) protease was evaluated by Westen blotting and the activity of CPP32 was measured. In the Western blotting analysis the activlted form CPP32/Yama(-ltke) protease (17kDa), were detected both R groups and NR group. The activities of CPP32/Yama(-llke) protease were stgnlficantl:/ higher in R group than In NR group. These data, suggested that CPP32 is activated by reperfuslon.The activation of CPP32 may play a role In lschernla-reperfuslon
69