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The effect of β-adrenoceptor blockade on infarct size in the anaesthetised dog
59 157 EFFECTS OF BEPRIDIL ON REGIONAL MYOCARDIAL CONTRACTION IN NORMAL AND ISCHAEMIC CANINE HEART. J.C. Lamar, M. Beaughard, P. Piris, J. Tisn~-Versailles, RL-CERM, Route de Marsat, 63203 Riom Cedex, France. The efficacy of bepridil, a new calcium antagonist, in improving functional and haemodynamic disorders resulting from myocardial ischaemia was studied in anaesthetized open-chest dogs. The reduction (60-80%) of blood flow in the circumflex artery caused, in controls, stable changes in cardiac haemodynamics and in segmental contractility in nonischaemic (NI), moderately ischaemic (MI), and severely ischaemic (SI) zones, as determined with ultrasonic crystals. The end-diastolic segment length (EDL) was significantly increased in the three zones, whereas the regional systolic shortening of the segment, expressed as percent of EDL (%AL) was increased in the NI zone (+31.2+10.1%, p<0.02) and decreased in the MI zone (-50.8+7.2%,p<0.01). Marked dyskinesia occurred in the SI zone, causing paradoxical lengthening (+7.3+1.4%) of the segment in systole (bulge). Bepridil administered 18.5 min after the onset of stenosis, produced a longlasting reduction in heart rate (-15.6+2.3%,p<0.00|) and LV dP/dt max (-|2.0+3.7%,p< 0.02). It increased total coronary blood flow (+40.7+|8.2%,p<0.05) for more than 15min. Its hypotensive effect on systolic (-20.8_+3.0%,p<0.001) and diastolic (-31.6+4.2%,p< 0.001) blood pressure was brief. Bepridil increased %AL in the NI zone (+20.4+8.0%,p< 0.05) and in the MI zone (+48.2+8.4%,p<0.0|). In the SI zone there was complete inhibition of the bulge for more than 15 min.
158 S A L V A G E 0F H Y P C X I C ~.~0CARDIU~: B Y T R Z F L U 0 ~ E R A Z I N E / T F P / A}~ CAL~IDAZ0LIUN/C~/.A . B e r ~ s e w i c z ,E ~ .Dep. of C l i n i c a l P h y s i o logo,,~edical C e n t e r of P o s t g r a d u a t e Education,Warsaw,Poland. To assess whether calmodulin/C~/-mediated processes are involved in the development of h ~ p o x i c i n j u r y we s t u d i e d t h e e f f e c t of i n h i b i t o t s of C M - C a c o m p l e x on L a n g e n d o r f f - p e r f u s e d rabbit hearts subjected t o 3 hr h y p o x i a / p 0 o 40 m m H g / . T h e r e d u c t i o n of L D H r e l e a s e d u r i n g hypoxia and reox~g@nation a n d the r e c o v e r y of f u n c t i o n u p o n r e o x ~ g e n a tien:coronary flow/CF/,oxygen consumption/V02/,force of c o n t r a c t i o n / F q Preparations
LDH
/IU/g
dry
wt/
Reox~en.
Recover~
"'CF
O o:UnctionF~% /
Untreated /~=7/ qz~9.~z17.5 4 0 . 3 ~ 4 . 2 20.0• 15.6~q.8 #.I• TFP 2.5xq0-/M/n=6/ 55.1• ~ qq.8~4.7~ 37.2• ~ 40.4~5.q * 1q.3~2.6~ TFP 2.5~q0-6~/n=6/ 4 4 . 7 ~ 6 . 8 * I 0 . 6 i 2 . 2 ~ 41.6~-4.2 ~ 4 0 . 0 • ~ 1~.8• C ~ Z 10-/~I / n = 6 / ~5.0~7.6 ~ 8.1• ~ #2.8~5,# ~ ~5.3• ~ 2~.0~3.~ ~ ~p< 0.016 was more complete inC~than TFP-treated hearts,an effect consistent with the reports that C~ is a m o r e p o t e n t i n h i b i t o r of C ~ t h a n TFP. This suggests that inhibition of s o m e C ~ - m e d i a t e d reaction/s/ is r e s p o n s i b l e f o r s a l v a g e of the h y p o x i c m ~ o c a r d i u m by T F P a n d C ~ Z .
159 THE EFFECT OF 6-ADRENOCEPTOR BLOCKADE ON INFARCT SIZE IN THE ANAESTHETISED DOG. A.T. Sullivan & D.J. Baker, Department of Cardiovascular Pharmacology, Glaxo Group Research Ltd., Ware, Hefts., U.K. There is now considerable evidence to suggest that B-adrenoceptor antagonists and Ca-antagcnists are clinically useful in myocardial infarction. However, while thc Caantagonists have been shown to limit infarct size in animal models with permanent coronary artery occlusion, there is some controversy over whether S-adrenoceptor antagonists work in these models. We have therefore investigated the effects of DLpropranelol (DLP) and its D-isomer (DP) on infarct size in the anaesthetised beagle, and compared them with the effects of verapamil (V). The area of myocardium at risk (AR) was determined autoradiographically 15 min after LAD occlusion; areas of ischaemia (AI) and necrosis (AN) were determined post-mortem, 5h after occlusion. The ratios AI/AR and AN/AR were calculated. Haemodynamic and myocardial blood flow measurements were made before and at intervals after occlusion. DLP or DP (I mg/kg i.v.) or V (0.2 mg/kg + continuous infusion of 5 ~g/kg/min i.v.) was administered 15 min after occlusion. As reported by other groups, V reduced AI/AR and AN/AR (by approximately 35% and 65% respectively) and caused small increases in flow to AR. Similar effects were seen with DLP, but DP had no effect. It is concluded that 6-adrenoceptor blockade caused a reduction in infarct size resulting from 5h ischaemia, and that this may be due to a combination of decreased 02 requirement and increased blood flow to AR.
158 S A L V A G E 0F H Y P C X I C ~.~0CARDIU~: B Y T R Z F L U 0 ~ E R A Z I N E / T F P / A}~ CAL~IDAZ0LIUN/C~/.A . B e r ~ s e w i c z ,E ~ .Dep. of C l i n i c a l P h y s i o logo,,~edical C e n t e r of P o s t g r a d u a t e Education,Warsaw,Poland. To assess whether calmodulin/C~/-mediated processes are involved in the development of h ~ p o x i c i n j u r y we s t u d i e d t h e e f f e c t of i n h i b i t o t s of C M - C a c o m p l e x on L a n g e n d o r f f - p e r f u s e d rabbit hearts subjected t o 3 hr h y p o x i a / p 0 o 40 m m H g / . T h e r e d u c t i o n of L D H r e l e a s e d u r i n g hypoxia and reox~g@nation a n d the r e c o v e r y of f u n c t i o n u p o n r e o x ~ g e n a tien:coronary flow/CF/,oxygen consumption/V02/,force of c o n t r a c t i o n / F q Preparations
LDH
/IU/g
dry
wt/
Reox~en.
Recover~
"'CF
O o:UnctionF~% /
Untreated /~=7/ qz~9.~z17.5 4 0 . 3 ~ 4 . 2 20.0• 15.6~q.8 #.I• TFP 2.5xq0-/M/n=6/ 55.1• ~ qq.8~4.7~ 37.2• ~ 40.4~5.q * 1q.3~2.6~ TFP 2.5~q0-6~/n=6/ 4 4 . 7 ~ 6 . 8 * I 0 . 6 i 2 . 2 ~ 41.6~-4.2 ~ 4 0 . 0 • ~ 1~.8• C ~ Z 10-/~I / n = 6 / ~5.0~7.6 ~ 8.1• ~ #2.8~5,# ~ ~5.3• ~ 2~.0~3.~ ~ ~p< 0.016 was more complete inC~than TFP-treated hearts,an effect consistent with the reports that C~ is a m o r e p o t e n t i n h i b i t o r of C ~ t h a n TFP. This suggests that inhibition of s o m e C ~ - m e d i a t e d reaction/s/ is r e s p o n s i b l e f o r s a l v a g e of the h y p o x i c m ~ o c a r d i u m by T F P a n d C ~ Z .
159 THE EFFECT OF 6-ADRENOCEPTOR BLOCKADE ON INFARCT SIZE IN THE ANAESTHETISED DOG. A.T. Sullivan & D.J. Baker, Department of Cardiovascular Pharmacology, Glaxo Group Research Ltd., Ware, Hefts., U.K. There is now considerable evidence to suggest that B-adrenoceptor antagonists and Ca-antagcnists are clinically useful in myocardial infarction. However, while thc Caantagonists have been shown to limit infarct size in animal models with permanent coronary artery occlusion, there is some controversy over whether S-adrenoceptor antagonists work in these models. We have therefore investigated the effects of DLpropranelol (DLP) and its D-isomer (DP) on infarct size in the anaesthetised beagle, and compared them with the effects of verapamil (V). The area of myocardium at risk (AR) was determined autoradiographically 15 min after LAD occlusion; areas of ischaemia (AI) and necrosis (AN) were determined post-mortem, 5h after occlusion. The ratios AI/AR and AN/AR were calculated. Haemodynamic and myocardial blood flow measurements were made before and at intervals after occlusion. DLP or DP (I mg/kg i.v.) or V (0.2 mg/kg + continuous infusion of 5 ~g/kg/min i.v.) was administered 15 min after occlusion. As reported by other groups, V reduced AI/AR and AN/AR (by approximately 35% and 65% respectively) and caused small increases in flow to AR. Similar effects were seen with DLP, but DP had no effect. It is concluded that 6-adrenoceptor blockade caused a reduction in infarct size resulting from 5h ischaemia, and that this may be due to a combination of decreased 02 requirement and increased blood flow to AR.