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Effect of D-600 on ischaemic and reperfused rabbit myocardium: Relation with timing and modality of administration
J Mol
Cell
Cardiol
21 (Supplement
II) (1989)
436mcr
OF DSCO GNEQKDE~A~~ RWEXWSDRABBITiWKARDlUM: A!Ei3l3TRATIoN. R. Fewari, G.M. E'offa, C. Cexni, S. Cwello, Chair ofCardiologyandChe%nistzy, UniversityofBrescia, Brescia, Intbis studywekwe inv&cigatedthepossibility thatD6c0,
REJ.ATICN!NIW TIMING AND Iv'EDAL,ITY A. Ekxaso, A. Caqxni and A. Albertini. Italy. aphenylalkylamines calciunantagonst,
OF
protects theisolatedrabbit hearts againstischaemic andreperfusicsl (R) induced damage. n-603 was either subcutaneoxly injected (2 r&kg, twice daily for 5 to 6 days) to the rabbit before the isolation of the hearts or delivered to the isolated hearts in the perfizate (lcr6 M) either at the cnset of iscbaemia (I) and dwiq R or onlydwingpost-ischaemicR. I (1 ml/min) wds for 90 min followed by 30 min of R. Myccardial danage wss de-4 interms ofmechanical fimcticn, releaseof cpI( and noradrenaline, isolated mitxxkoxkial of L!-KO to the
faction, calcim hcmmtasis andendqenxs stores ofATP and CP. A&ninistration rabbits or to the isolated hearts at the time of I exerted protection: -1) 'Ihe rise in diastolic pressdurjng Iwas diminshedwithgreaterrecoveryofdevelopedpressure duringR; -2) CPK andnoradrenalinerelease duringRwerereduced; 3) the oxygenccns~ticnarx3ATPgener&ing capacities of mitochcndrial werebetternxxintained; 4) calciunl-smeostasis andofendcgenous ATF and CP storeswere near d. The two differentmodalities ofadninistition did not ptice stitantially different results. When adninistiM totheisolatedhearts after theischaemicpericd, D-&X failedto improve mechanical recovery and releaseofendogenous substances. However, it reduced mitozhondrial calcium overloadand irr@rovedATPproducticm.
437
?HEDFECrSOFL-PRGPI~INECN~ R. Ferrari, A. Cargnoni, E. Pasini, G.M. University of Brescia, Brescia, Italy. To assess whether the adninistraticn
3XXWMl'CANDREPERFUSEDW~IUM:A~~~~Y. Boffa, C. Ceconi, S. Cwello, 0.
Visioli.
Chair
of
Cardi.ology,
of L-prcpionyl-carni tine protects the heart against the causedbyischaemia (I) andrqerfusion (R) ;old to es'c&lishifI.+~ionyl~&tine effwts df?pmdent, iso$ated-pbit sm were inf&wl with three different concentsations of L.p~ionyl-c.arnitine: 10 , 10 and10 M. &ring control, nomvxic perfUsicn and6omi.n of 1o.v flop I (37OC) followed by 30 min of R, diastolic and developed pressures were roni'cored, colonary effluent was collectedandassayedforlactateandfor~atinephosphokinase (CFK),m?tcch~driawere harvested and deterioration are dose
assayed forrespiraixryactivity, ATPpnxlucticn andcalciun content and tissue concentration of ATP andCP were determined. Lpropiorgrl-carni' kne reduced the ischaanic induced detesicratia of mitcchcnclrisl fxxtion and the depsoq3wation of tissue stores of A'IP. On R, hearts treated with Lprcpionyl~tine recover4better than theunlreatedhearts with respect to left ventricular perfcamanc e,Epleniskmentof A'IPandCP s'coresandmitokcndr ial fwtion. Ihe R-inticed mitcchondrial calcium overload and release of m$ers (10 A fm
436
also reduced. lhe effect of Lpmpioqylxarni M) failed tomodify ixhaanic ti4reperfwion increase of the dosage to10 Mdidnotresultti
tine was dose dependent. damage. 'Ihebestprckective ftierprotection.
PRESERVATION
The lmer ccncentra$i~ effectfound at10
M.
OF CONTRACTILE FUNCTION IN THE POST-ISCHEMIC CANINE MYOCARDIUM WITH THE ANALOG, RO 23-6152. P. Dahlen, R. Vergona, and A.J. Higgins. Department of Pharmacology and Chemotherapy, Hoffmann-La Roche Inc., Nutley, New Jersey, USA. The left anterior descending coronary artery (LAD) in anesthetized dogs was ligated for 30 min, followed by 120 min reperfusion. Subendocardial segment shortening (%SS) in ischemic and non-ischemic zones of the heart was measured with ultrasonic transducers. In saline-treated (S) dogs, %SS in the ischemic zone ceased Reciprocal increases and was replaced by systolic bulging during the LAD ligation. in %SS in the non-ischemic zone accompanied these changes. On reperfusion, a transien-t recovery of %SS occurred in the ischemic zone, followed by a sustained Ro 23-6152 (R) was infused intravenously for dyskinesis (0% of pre ligation levels). Post-ischemic %SS improved to 76, 100 min, starting 10 min before the LAD ligation. 87, and 98% of pre ligation levels following 30, GO, and 100 ug/kg/min doses. R, at decreased the incidence of ventricular fibrilladoses of 10, 30, and 60 ug/kg/min, Similar anti-ischemic, tion from 6/11 (S) to Z/7, O/5, and l/6, respectively. anti-arrhythmic, and hemodynamic effects were observed with diltiazem at 30 These results demonstrate that calcium channel blockers of the diltiazem w/ Wmi n. class are beneficial in maintaining post-ischemic function and reducing lethal arrhythmias. It is not known if these effects are due to direct cardioprotective activity or to changes in coronary perfusion and energy demand.
DILTIAZEM
S.146
Cell
Cardiol
21 (Supplement
II) (1989)
436mcr
OF DSCO GNEQKDE~A~~ RWEXWSDRABBITiWKARDlUM: A!Ei3l3TRATIoN. R. Fewari, G.M. E'offa, C. Cexni, S. Cwello, Chair ofCardiologyandChe%nistzy, UniversityofBrescia, Brescia, Intbis studywekwe inv&cigatedthepossibility thatD6c0,
REJ.ATICN!NIW TIMING AND Iv'EDAL,ITY A. Ekxaso, A. Caqxni and A. Albertini. Italy. aphenylalkylamines calciunantagonst,
OF
protects theisolatedrabbit hearts againstischaemic andreperfusicsl (R) induced damage. n-603 was either subcutaneoxly injected (2 r&kg, twice daily for 5 to 6 days) to the rabbit before the isolation of the hearts or delivered to the isolated hearts in the perfizate (lcr6 M) either at the cnset of iscbaemia (I) and dwiq R or onlydwingpost-ischaemicR. I (1 ml/min) wds for 90 min followed by 30 min of R. Myccardial danage wss de-4 interms ofmechanical fimcticn, releaseof cpI( and noradrenaline, isolated mitxxkoxkial of L!-KO to the
faction, calcim hcmmtasis andendqenxs stores ofATP and CP. A&ninistration rabbits or to the isolated hearts at the time of I exerted protection: -1) 'Ihe rise in diastolic pressdurjng Iwas diminshedwithgreaterrecoveryofdevelopedpressure duringR; -2) CPK andnoradrenalinerelease duringRwerereduced; 3) the oxygenccns~ticnarx3ATPgener&ing capacities of mitochcndrial werebetternxxintained; 4) calciunl-smeostasis andofendcgenous ATF and CP storeswere near d. The two differentmodalities ofadninistition did not ptice stitantially different results. When adninistiM totheisolatedhearts after theischaemicpericd, D-&X failedto improve mechanical recovery and releaseofendogenous substances. However, it reduced mitozhondrial calcium overloadand irr@rovedATPproducticm.
437
?HEDFECrSOFL-PRGPI~INECN~ R. Ferrari, A. Cargnoni, E. Pasini, G.M. University of Brescia, Brescia, Italy. To assess whether the adninistraticn
3XXWMl'CANDREPERFUSEDW~IUM:A~~~~Y. Boffa, C. Ceconi, S. Cwello, 0.
Visioli.
Chair
of
Cardi.ology,
of L-prcpionyl-carni tine protects the heart against the causedbyischaemia (I) andrqerfusion (R) ;old to es'c&lishifI.+~ionyl~&tine effwts df?pmdent, iso$ated-pbit sm were inf&wl with three different concentsations of L.p~ionyl-c.arnitine: 10 , 10 and10 M. &ring control, nomvxic perfUsicn and6omi.n of 1o.v flop I (37OC) followed by 30 min of R, diastolic and developed pressures were roni'cored, colonary effluent was collectedandassayedforlactateandfor~atinephosphokinase (CFK),m?tcch~driawere harvested and deterioration are dose
assayed forrespiraixryactivity, ATPpnxlucticn andcalciun content and tissue concentration of ATP andCP were determined. Lpropiorgrl-carni' kne reduced the ischaanic induced detesicratia of mitcchcnclrisl fxxtion and the depsoq3wation of tissue stores of A'IP. On R, hearts treated with Lprcpionyl~tine recover4better than theunlreatedhearts with respect to left ventricular perfcamanc e,Epleniskmentof A'IPandCP s'coresandmitokcndr ial fwtion. Ihe R-inticed mitcchondrial calcium overload and release of m$ers (10 A fm
436
also reduced. lhe effect of Lpmpioqylxarni M) failed tomodify ixhaanic ti4reperfwion increase of the dosage to10 Mdidnotresultti
tine was dose dependent. damage. 'Ihebestprckective ftierprotection.
PRESERVATION
The lmer ccncentra$i~ effectfound at10
M.
OF CONTRACTILE FUNCTION IN THE POST-ISCHEMIC CANINE MYOCARDIUM WITH THE ANALOG, RO 23-6152. P. Dahlen, R. Vergona, and A.J. Higgins. Department of Pharmacology and Chemotherapy, Hoffmann-La Roche Inc., Nutley, New Jersey, USA. The left anterior descending coronary artery (LAD) in anesthetized dogs was ligated for 30 min, followed by 120 min reperfusion. Subendocardial segment shortening (%SS) in ischemic and non-ischemic zones of the heart was measured with ultrasonic transducers. In saline-treated (S) dogs, %SS in the ischemic zone ceased Reciprocal increases and was replaced by systolic bulging during the LAD ligation. in %SS in the non-ischemic zone accompanied these changes. On reperfusion, a transien-t recovery of %SS occurred in the ischemic zone, followed by a sustained Ro 23-6152 (R) was infused intravenously for dyskinesis (0% of pre ligation levels). Post-ischemic %SS improved to 76, 100 min, starting 10 min before the LAD ligation. 87, and 98% of pre ligation levels following 30, GO, and 100 ug/kg/min doses. R, at decreased the incidence of ventricular fibrilladoses of 10, 30, and 60 ug/kg/min, Similar anti-ischemic, tion from 6/11 (S) to Z/7, O/5, and l/6, respectively. anti-arrhythmic, and hemodynamic effects were observed with diltiazem at 30 These results demonstrate that calcium channel blockers of the diltiazem w/ Wmi n. class are beneficial in maintaining post-ischemic function and reducing lethal arrhythmias. It is not known if these effects are due to direct cardioprotective activity or to changes in coronary perfusion and energy demand.
DILTIAZEM
S.146