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The opposing effects of an inhibitor of nitric oxide synthesis and of a donor of nitric oxide in rabbits undergoing myocardial ischemia reperfusion
Life Sciences, Vol. 54, No. 26, pp. PL 491-I%, 1994 Copyright 0 1994 Fkmier Science Ltd Printed in the USA. All rights rcrervcd om-3205/w s6.00 t .oo
0024-3205(94)00070-O Pl%Riu4coLoGY LETrERs Accelerated Communication
THE OPPOSING
EFFECTS OF AN INBIBITOR OF NITRIC OXIDE SYETHESIS AND OF A DONOR OF NITRIC OXIDE IN RABBITS UNDERGOING MYOCARDIAL ISCBEEIA REPERFUSION
Kwok-Pui Fung, Tai-Wing Wu, Ling-Hua Zeng and Jun Wu Department of Clinical Biochemistry, University of Toronto and Centre for Cardiovascular Research, Toronto General Hospital, Toronto, Canada M5G 2C4. (Submitted March14,1994; accepted March23,1994; received in final form April 12, 1994)
ABSTRACT
: We observed that N-nitro-L-arginine (NOLA), a nitric oxide biosynthesis inhibitor, exacerbated necrosis in the rabbit heart during ischemia-reperfusion while 3-morpholino-sydnoniminehydrochloride (SIN-l) (a nitric oxide donor) reduced myocardial damage in the same model. In rabbits undergoing l-h ligation of the anterior ventricular coronary artery, a single bolus injection of NOLA (30 mg/kg) or continuous infusion of SIN-l (3 mg/kg) were introduced into the post-ischemic heart immediately before 4-h Against negligible necrosis in 6 sham-operated reperfusion. control animals, and 33.8 (SD 13.5)% necrosis in the area at risk for the saline control group (n=8), the NOLA-treated group (n=8) had a necrosis of 44.3 (SD 8.6)% whereas the SIN-l-treated group (n=lO) showed a necrosis of 16.8 (SD 4.9)% (both with ~~0.05 vs saline control group). The pressure-rate index increased in the NOLA-treated group but decreased in the SIN-l-treated group. These data support the contention that a nitric oxide donor is an effective cardioprotector during ischemia-reperfusion in vivo.
KeyWords: nitric oxide, &hernia-reperfusion,N-nitro-L-argiaine,3-morpholino-sydnonimimine-hydrochloride
Introduction Nitric oxide (NO) derived from vascular endothelial cells is a powerful endogenous vasodilator influencing blood pressure, and an inhibitor for platelet aggregation and adhesion (review in ref. 1) * NO can also scavenge oxyradicals produced by leukocytes (2). It is expected that manipulating NO biology should have the potential to treat cardiovascular diseases (3). NO is formed from the amino acid L-arginine by the enzyme nitric oxide synthase (4). Some structural analogues of L-arginine such as NG-monomethyl-Larginine or N-nitro-L-arginine (NOLA) inhibit NO biosynthesis in endothelial cells (5). When these NO biosynthesis inhibitors are injected into anaesthetized animals, they raise the blood pressure Correspondence should be addressed to T.-W. Wu
PL-492
Nitric Oxide Donor as Cardioprotector
Vol. 54, No. 26,1994
of the animals (6, 7). On the other hand, injection of NO donor such as SIN-l (3-morpholino-sydnonimine-hydrochloride) causes vasodilatation in animals (8). It is of importance to study the effect of NO biosynthesis and NO donors in inhibitors cardiovascular pathology. For example, NO synthase inhibitors have been reported to be successful in treating hypotension in patients with septic shock (9, lo), and increasing endogenous NO production is promising in the treatment and prevention of atherosclerosis (3). The effect of NO on other cardiovascular diseases is still being ascertained. In this study, we examined the effect of NO in myocardial ischemia-reperfusion in a rabbit model. It has been observed that myocardial interferes with endothelium-dependent ischemia relaxation of coronary artery rings, producing an endothelial dysfunction (11). Reperfusion further causes myocyte necrosis which is induced by oxyradicals associated with neutrophil influx (12). From the standpoint of heart protection in the setting of ischemia-reperfusion, administration of NO inhibitor or its donor is a special challenge because NO causes relaxation of blood vessel (1) and scavenge oxyradicals (2) and should therefore alleviate the injury during ischemia-reperfusion. By the administration of NOLA or SIN-l in the rabbits suffering from ischemia-reperfusion, we have shown in the present study that NO is beneficial for cardioprotection to this animal. Materials and Methods Chemicals. Unless otherwise stated, all chemicals used were reagent grade, and were supplied by Sigma Chemical Co. (St. Louis, MO). SIN-l was generously supplied by Dr. Rainer Henning of Cassella AG (Frankfurt, Germany). In vivo model of mvocardial ischemia-renerfusion. As described previously (13, 14), New Zealand white rabbit (3.0-3.5 kg) were injected intramuscularly with Ketamine HCl (35 mg/kg) and Atravet (0.4 mg/kg). After shaving the frontal area of the neck and chest of the animal, anaesthesia was maintained by tracheotomy and ventilating the animal with positive pressure respiration using a Harvard small animal respirator and a gas mixture of 2.5% enflurane with oxygen (0.6 L/min). The right femoral artery was exposed and cannulated for measuring the arterial blood pressure and the right femoral vein for intravenous drip of normal saline. A dose of 50 IU/kg of heparin sulfate was given intravenously via the ear vein. Following a midline sternotomy, the pericardium was opened and the heart was exposed. The main branch of the anterior ventricular coronary artery (AVCA) was ligated temporarily with a 5-O silk thread for 1 h at the site between l/2 to l/3 the distance from apex to the atrioventricular groove. Attainment of ischemia was evidenced colour of the left ventricle from red to by marked elevations in the S-T segment for saline-infused control and the NOLASuch change in S-T segment was not noted animals (n=6).
by the rapid change in pale purple, accompanied of the electrocardiogram or SIN-l-infused hearts. in sham-operated control
For the treatment of NOLA (n=8), approximately 1 min before releasing the occlusion, a bolus of NOLA (30 mg/kg) in saline was
Vol. 54, No.26,1994
Nitric Oxide DonorasCardioprotector
PL-493
injected into the animal through the right external jugular vein followed by a 4-h reperfusion with saline. This dosage of NOLA has For the been reported to cause hypertension in animals (15). treatment of SIN-l (n=lO), the drug was infused over the whole reperfusion period according to Siegfried et al. (16). Infusion for the total reperfusion period was required because the half-life of NO, the active portion of SIN-l, is less than 30 sec. (16). Approximately 1 min before releasing the occlusion, a bolus of SIN1 (0.08 mg/kg) in saline was injected followed by infusion at 0.73 The total dose of SIN-l in each animal iS 3 mg/kg/h over 4 h. mg/kg in saline. Control animals (n=8) received saline by a bolus injection followed by infusion over the reperfusion period. After reperfusion, the heart was harvested, and the AVCA was A 15-ml bolus of 0.25% Evans Blue in saline was ligated again. infused into the heart via the aorta. In the area at risk, there was no staining by Evans Blue. The heart was sliced transversely into 5-6 0.2-cm thick slices and incubated in 1.25% tetrazolium red In the area of necrosis (confirmed by for 25 min at 25'C. histopathology), no staining of the dye was found, while in the non-necrotic area, a red stain developed. Computerized planimetry was done on both surfaces of each slice as documented previously (13). In this study, tetrazolium-positive versus -negative (i.e. necrotic) myocardial tissue in the area at risk were also confirmed by transmission electron microscopy. The percent myocardial salvage was calculated as previously described (14). Statistical analvsis. Either the Student's t-test, or the analysis of variance (ANOVA) method was applied. All data was expressed as the mean + SD. Significance was indicated by ~~0.05. Results Fig. 1 shows the percent of ared at risk and the necrotic area in the hearts of rabbits in control, NOLA- and SIN-l-treated group. The percent of area at risk in treated groups were similar to that of control (p>O.O5). Note that in the control, the percent of area at risk and the percent of necrotic area are not statistically significantly different whether it is a single bolus or continuous infusion with saline. However, the percent of necrotic area in NOLA-treated animals (44.3 f 8.6%) was significantly (p
larger In contrast, (16.8 k 4.9%) was significantly smaller (~~0.05) than that in control group. The percent myocardial salvage of rabbits treated with SIN-l was
calculated to be 50.5 f 14.6%. As cited before (14), the percent myocardial salvage was calculated by the following formula: percent myocardial salvage =
( % necrosis without SIN-l - % necrosis with SIN-I)
x 100% % neCrOSiS without SIN-l
NitricOxide Donor as Cardioprotector
PL494
1
0
Areaat risk
fl
Necrotic area
Vol.54,No.26,1994
*
Saline
NOIA
SIN-l
FIG. 1 Effect of NOLA or SIN-l on the necrosis of the myocardium ischemia-reperfusion in rabbits. after Myocardial necrosis was obtained by infusion of saline (control, n = 8) or 30 mg/kg NOLA in saline (n =8) or 3 mg/kg SIN-l in saline (n = 10) into rabbits that underwent l-hischemia and I-h-reperfusion. Results are mean f SD. *, ~~0.05 comparing with control group. Fig. 2 shows the hemodynamic condition of the animals in control versus drugs-treated groups. The pressure-rate index (i.e. the product of mean arterial blood pressure and heart rate, in units of mm Hg.min-'. 103) of the normal rabbits (n=26) before ischemia was 17.4 f 3.9. In control group, the index declined -20% throughout the ischemia period and -30% during the reperfusion period. The pressure-rate index of the Nom-treated animals were larger than that of control over the reperfusion period, and the index of the SIN-l-treated animals were smaller than that of control. Discussion Ischemia-reperfusion causes and loss of vasodilatation myocardial damage (12). In this study, we found that NOLA which is a potent NO synthase inhibitor (5) increased the injury to the heart of rabbits and increased their pressure-rate index during ischemia-reperfusion, whereas SIN-l which is a NO donor (8) protected the animals' hearts from damage and decreased the pressure-rate index of the animals (Fig. 1 & 2). Our data imply that increasing endogenous NO level during ischemia-reperfusion is beneficial to the rabbit. Actually, similar findings have been reported by using isolated perfused heart or other animals during ischemia-reperfusion. For example, Yang et al. (17) reported that perfusion of isolated rat hearts with L-arginine which is the
Nitric Oxide DonorasCardioprotector
Vol.S4,No.26,1994
s : a .c *.
5 p-45
PL.495
Saline NOIA
5 -
!
,a,.
SIN-1
I.,.,
a,.
0 5 10 15 30 I< ----lschemia----->ll<
I.,.,
60 Time
FIG.
.,.,‘,.,
75 SO 120 150 180 ___--__Reperfusion_______>I
240
300
(min) 2
Effect of NOLA or SIN-l on the percentage change of pressure-rate index of rabbitswithischemia-reperfusion. The index for rabbits before ischemia is 17.4 + 3.9 mmHg.min-'.lo3 (n = 26) which is expressed as 100%. The change in index in each group during the 1-h-ischemia and 4-h reperfusion period was recorded. precursor of NO biosynthesis could protect the tissue during ischemiaischemia-reperfusion. In the feline myocardial reperfusion model, Siegfried et al. (18, 19) showed that NO donors such as SIN-l, C87-3754 or SPM-5185 exerted beneficial effects to the animals. The mechanistic reason(s) for the in vivo efficacy of NO or its donors thus demonstrated in ischemia-reperfused animals is not totally understood. NO is a potent endothelium-derived relaxing factor (I) and also a scavenger for oxyradicals (2) in*. Recently, Ma et al. reported that NO can alleviate the neutrophil adherence to coronary endothelium during ischemia-reperfusion (20). These properties of NO may contribute to the myocardial protective effect of NO donors in ischemia-reperfusion. Further fundamental insights into the action of NO donors may permit one to better design cardioprotectors of potential therapeutic value. ficknowledsements This work was supported by an MRC grant of Canada (MT-12299) to T.-W. Wu. We thank Dr. Rainer Henning of Cassella AG (Frankfurt, Germany) for the generous supply of SIN-l.
Nitric Oxide
PL-4%
DonorasCardioprotector
Vol.54,No.26,1994
References 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17. 18. 19. 20.
S. MONCADA, R.M.J. PALMER, and E.A. HIGGS. Pharmacol. Rev. 43 109-141 (1991). G.M. RUBANYI, E.H. HO, E.H. CANTOR, W.C. LUMMA and L.H. PARKER BOTELHO. Biochem. Biophys. Res. Commun. 181 1392-7 (1991). J.B. WARREN, F. PONS and A.J.B. BRADY. Cardiovas. Res. 28 25-30 (1994). R.M.J. PALMER, D.S. ASHTON and S. MONCADA. Nature 333 6646 (1988). P.N. DUBBIN, M. ZAMBETIS and G.J. DUSTING. Clin. Exp. Pharmacol. Physiol. 17 281-6 (1990). D.D. REES, R.M.J. PALMER and S. MONCADA. Proc. Natl. Acad. Sci. 86 3375-8 (1989). and 0-L. WOODMAN. M. ZAMBETIS, G.J. DUSTING, S. RAJANAYAGAM J. Cardiovas. Pharmacol. 17 S191-7 (1991). J. Cardiovas. Pharmacol. 14 S23E. BASSENGE and A. MULSCH. 28 (1989). Lancet 338 1557-8 A. PETROS, D. BENNET and P. VALLANCE. (1991). A. PETROS, G. LAMB, A. LEONE, S. MONCADA, D. BENNETT and P. VALLANCE. Cardiovasc. Res. 28 34-39 (1994). J.L. MEHTA, W.W. NICHOLS, W.M. DONNELLY, D.S. LAWSON and T.G.P. GALDEEN. Circ. Res. 64 43-54 (1989). A.J. BRADY, F.M. WILLIAMS and T.J. WILLIAMS. Clin. Sci. 83 511-8 (1992). T.W. WU, J. WU, L.H. ZENG, H. SUGIYAMA, D. MICKLE and J.X. AU. Cardiovasc. Res. 27 736-739 (1993). T.W. WU, L.H. ZENG, K.P. FUNG, J. WU, G. PANG, A.A. GREY, Biochem. Pharmacol. 46 2327-2332 R.D. WEISEL and J.Y. WANG. (1993). M. ZAMBETIS, G.J. DUSTING, S. RAJANAYAGAM and O.L. WOODMAN. J. Cardiovasc. Pharmacol. 17 S191-S197 (1991). M.R. SIEGFRIED, J. ERHARDT, T. RIDER, X.L. MA and A.M. LEFER. J. Pharmacol. Exp. Ther. 260 668-675 (1992). Circ. B.C. YANG, R. VIRMANI, W.W. NICHOLS and J.L. MEHTA. Res. 72 1181-90 (1993). M.R. SIEGFRIED, J. ERHARDT, T. RIDER, X.L. MA and A.M. LEFER. J. Pharmacol. Exp. Ther. 260 668-675 (1992). M.R. SIEGFRIED, C. CAREY, X.L. MA and A.M. LEFER. Amer. J. Physiol. 263 H771-7 (1992). Circ. Res. 72 403-412 X.1. MA, A.S. WEYRICH and D.J. LEFER. (1993) .
0024-3205(94)00070-O Pl%Riu4coLoGY LETrERs Accelerated Communication
THE OPPOSING
EFFECTS OF AN INBIBITOR OF NITRIC OXIDE SYETHESIS AND OF A DONOR OF NITRIC OXIDE IN RABBITS UNDERGOING MYOCARDIAL ISCBEEIA REPERFUSION
Kwok-Pui Fung, Tai-Wing Wu, Ling-Hua Zeng and Jun Wu Department of Clinical Biochemistry, University of Toronto and Centre for Cardiovascular Research, Toronto General Hospital, Toronto, Canada M5G 2C4. (Submitted March14,1994; accepted March23,1994; received in final form April 12, 1994)
ABSTRACT
: We observed that N-nitro-L-arginine (NOLA), a nitric oxide biosynthesis inhibitor, exacerbated necrosis in the rabbit heart during ischemia-reperfusion while 3-morpholino-sydnoniminehydrochloride (SIN-l) (a nitric oxide donor) reduced myocardial damage in the same model. In rabbits undergoing l-h ligation of the anterior ventricular coronary artery, a single bolus injection of NOLA (30 mg/kg) or continuous infusion of SIN-l (3 mg/kg) were introduced into the post-ischemic heart immediately before 4-h Against negligible necrosis in 6 sham-operated reperfusion. control animals, and 33.8 (SD 13.5)% necrosis in the area at risk for the saline control group (n=8), the NOLA-treated group (n=8) had a necrosis of 44.3 (SD 8.6)% whereas the SIN-l-treated group (n=lO) showed a necrosis of 16.8 (SD 4.9)% (both with ~~0.05 vs saline control group). The pressure-rate index increased in the NOLA-treated group but decreased in the SIN-l-treated group. These data support the contention that a nitric oxide donor is an effective cardioprotector during ischemia-reperfusion in vivo.
KeyWords: nitric oxide, &hernia-reperfusion,N-nitro-L-argiaine,3-morpholino-sydnonimimine-hydrochloride
Introduction Nitric oxide (NO) derived from vascular endothelial cells is a powerful endogenous vasodilator influencing blood pressure, and an inhibitor for platelet aggregation and adhesion (review in ref. 1) * NO can also scavenge oxyradicals produced by leukocytes (2). It is expected that manipulating NO biology should have the potential to treat cardiovascular diseases (3). NO is formed from the amino acid L-arginine by the enzyme nitric oxide synthase (4). Some structural analogues of L-arginine such as NG-monomethyl-Larginine or N-nitro-L-arginine (NOLA) inhibit NO biosynthesis in endothelial cells (5). When these NO biosynthesis inhibitors are injected into anaesthetized animals, they raise the blood pressure Correspondence should be addressed to T.-W. Wu
PL-492
Nitric Oxide Donor as Cardioprotector
Vol. 54, No. 26,1994
of the animals (6, 7). On the other hand, injection of NO donor such as SIN-l (3-morpholino-sydnonimine-hydrochloride) causes vasodilatation in animals (8). It is of importance to study the effect of NO biosynthesis and NO donors in inhibitors cardiovascular pathology. For example, NO synthase inhibitors have been reported to be successful in treating hypotension in patients with septic shock (9, lo), and increasing endogenous NO production is promising in the treatment and prevention of atherosclerosis (3). The effect of NO on other cardiovascular diseases is still being ascertained. In this study, we examined the effect of NO in myocardial ischemia-reperfusion in a rabbit model. It has been observed that myocardial interferes with endothelium-dependent ischemia relaxation of coronary artery rings, producing an endothelial dysfunction (11). Reperfusion further causes myocyte necrosis which is induced by oxyradicals associated with neutrophil influx (12). From the standpoint of heart protection in the setting of ischemia-reperfusion, administration of NO inhibitor or its donor is a special challenge because NO causes relaxation of blood vessel (1) and scavenge oxyradicals (2) and should therefore alleviate the injury during ischemia-reperfusion. By the administration of NOLA or SIN-l in the rabbits suffering from ischemia-reperfusion, we have shown in the present study that NO is beneficial for cardioprotection to this animal. Materials and Methods Chemicals. Unless otherwise stated, all chemicals used were reagent grade, and were supplied by Sigma Chemical Co. (St. Louis, MO). SIN-l was generously supplied by Dr. Rainer Henning of Cassella AG (Frankfurt, Germany). In vivo model of mvocardial ischemia-renerfusion. As described previously (13, 14), New Zealand white rabbit (3.0-3.5 kg) were injected intramuscularly with Ketamine HCl (35 mg/kg) and Atravet (0.4 mg/kg). After shaving the frontal area of the neck and chest of the animal, anaesthesia was maintained by tracheotomy and ventilating the animal with positive pressure respiration using a Harvard small animal respirator and a gas mixture of 2.5% enflurane with oxygen (0.6 L/min). The right femoral artery was exposed and cannulated for measuring the arterial blood pressure and the right femoral vein for intravenous drip of normal saline. A dose of 50 IU/kg of heparin sulfate was given intravenously via the ear vein. Following a midline sternotomy, the pericardium was opened and the heart was exposed. The main branch of the anterior ventricular coronary artery (AVCA) was ligated temporarily with a 5-O silk thread for 1 h at the site between l/2 to l/3 the distance from apex to the atrioventricular groove. Attainment of ischemia was evidenced colour of the left ventricle from red to by marked elevations in the S-T segment for saline-infused control and the NOLASuch change in S-T segment was not noted animals (n=6).
by the rapid change in pale purple, accompanied of the electrocardiogram or SIN-l-infused hearts. in sham-operated control
For the treatment of NOLA (n=8), approximately 1 min before releasing the occlusion, a bolus of NOLA (30 mg/kg) in saline was
Vol. 54, No.26,1994
Nitric Oxide DonorasCardioprotector
PL-493
injected into the animal through the right external jugular vein followed by a 4-h reperfusion with saline. This dosage of NOLA has For the been reported to cause hypertension in animals (15). treatment of SIN-l (n=lO), the drug was infused over the whole reperfusion period according to Siegfried et al. (16). Infusion for the total reperfusion period was required because the half-life of NO, the active portion of SIN-l, is less than 30 sec. (16). Approximately 1 min before releasing the occlusion, a bolus of SIN1 (0.08 mg/kg) in saline was injected followed by infusion at 0.73 The total dose of SIN-l in each animal iS 3 mg/kg/h over 4 h. mg/kg in saline. Control animals (n=8) received saline by a bolus injection followed by infusion over the reperfusion period. After reperfusion, the heart was harvested, and the AVCA was A 15-ml bolus of 0.25% Evans Blue in saline was ligated again. infused into the heart via the aorta. In the area at risk, there was no staining by Evans Blue. The heart was sliced transversely into 5-6 0.2-cm thick slices and incubated in 1.25% tetrazolium red In the area of necrosis (confirmed by for 25 min at 25'C. histopathology), no staining of the dye was found, while in the non-necrotic area, a red stain developed. Computerized planimetry was done on both surfaces of each slice as documented previously (13). In this study, tetrazolium-positive versus -negative (i.e. necrotic) myocardial tissue in the area at risk were also confirmed by transmission electron microscopy. The percent myocardial salvage was calculated as previously described (14). Statistical analvsis. Either the Student's t-test, or the analysis of variance (ANOVA) method was applied. All data was expressed as the mean + SD. Significance was indicated by ~~0.05. Results Fig. 1 shows the percent of ared at risk and the necrotic area in the hearts of rabbits in control, NOLA- and SIN-l-treated group. The percent of area at risk in treated groups were similar to that of control (p>O.O5). Note that in the control, the percent of area at risk and the percent of necrotic area are not statistically significantly different whether it is a single bolus or continuous infusion with saline. However, the percent of necrotic area in NOLA-treated animals (44.3 f 8.6%) was significantly (p
larger In contrast, (16.8 k 4.9%) was significantly smaller (~~0.05) than that in control group. The percent myocardial salvage of rabbits treated with SIN-l was
calculated to be 50.5 f 14.6%. As cited before (14), the percent myocardial salvage was calculated by the following formula: percent myocardial salvage =
( % necrosis without SIN-l - % necrosis with SIN-I)
x 100% % neCrOSiS without SIN-l
NitricOxide Donor as Cardioprotector
PL494
1
0
Areaat risk
fl
Necrotic area
Vol.54,No.26,1994
*
Saline
NOIA
SIN-l
FIG. 1 Effect of NOLA or SIN-l on the necrosis of the myocardium ischemia-reperfusion in rabbits. after Myocardial necrosis was obtained by infusion of saline (control, n = 8) or 30 mg/kg NOLA in saline (n =8) or 3 mg/kg SIN-l in saline (n = 10) into rabbits that underwent l-hischemia and I-h-reperfusion. Results are mean f SD. *, ~~0.05 comparing with control group. Fig. 2 shows the hemodynamic condition of the animals in control versus drugs-treated groups. The pressure-rate index (i.e. the product of mean arterial blood pressure and heart rate, in units of mm Hg.min-'. 103) of the normal rabbits (n=26) before ischemia was 17.4 f 3.9. In control group, the index declined -20% throughout the ischemia period and -30% during the reperfusion period. The pressure-rate index of the Nom-treated animals were larger than that of control over the reperfusion period, and the index of the SIN-l-treated animals were smaller than that of control. Discussion Ischemia-reperfusion causes and loss of vasodilatation myocardial damage (12). In this study, we found that NOLA which is a potent NO synthase inhibitor (5) increased the injury to the heart of rabbits and increased their pressure-rate index during ischemia-reperfusion, whereas SIN-l which is a NO donor (8) protected the animals' hearts from damage and decreased the pressure-rate index of the animals (Fig. 1 & 2). Our data imply that increasing endogenous NO level during ischemia-reperfusion is beneficial to the rabbit. Actually, similar findings have been reported by using isolated perfused heart or other animals during ischemia-reperfusion. For example, Yang et al. (17) reported that perfusion of isolated rat hearts with L-arginine which is the
Nitric Oxide DonorasCardioprotector
Vol.S4,No.26,1994
s : a .c *.
5 p-45
PL.495
Saline NOIA
5 -
!
,a,.
SIN-1
I.,.,
a,.
0 5 10 15 30 I< ----lschemia----->ll<
I.,.,
60 Time
FIG.
.,.,‘,.,
75 SO 120 150 180 ___--__Reperfusion_______>I
240
300
(min) 2
Effect of NOLA or SIN-l on the percentage change of pressure-rate index of rabbitswithischemia-reperfusion. The index for rabbits before ischemia is 17.4 + 3.9 mmHg.min-'.lo3 (n = 26) which is expressed as 100%. The change in index in each group during the 1-h-ischemia and 4-h reperfusion period was recorded. precursor of NO biosynthesis could protect the tissue during ischemiaischemia-reperfusion. In the feline myocardial reperfusion model, Siegfried et al. (18, 19) showed that NO donors such as SIN-l, C87-3754 or SPM-5185 exerted beneficial effects to the animals. The mechanistic reason(s) for the in vivo efficacy of NO or its donors thus demonstrated in ischemia-reperfused animals is not totally understood. NO is a potent endothelium-derived relaxing factor (I) and also a scavenger for oxyradicals (2) in*. Recently, Ma et al. reported that NO can alleviate the neutrophil adherence to coronary endothelium during ischemia-reperfusion (20). These properties of NO may contribute to the myocardial protective effect of NO donors in ischemia-reperfusion. Further fundamental insights into the action of NO donors may permit one to better design cardioprotectors of potential therapeutic value. ficknowledsements This work was supported by an MRC grant of Canada (MT-12299) to T.-W. Wu. We thank Dr. Rainer Henning of Cassella AG (Frankfurt, Germany) for the generous supply of SIN-l.
Nitric Oxide
PL-4%
DonorasCardioprotector
Vol.54,No.26,1994
References 1.
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
15. 16. 17. 18. 19. 20.
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