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Response to dopamine in rats with acute and chronic pulmonary hypertension
ABSTRACTS
EFFECTS OF INDOMETHACIN, PROSTACYCLIN AND PROSTAGLANDIN E2 ON THE FETAL CARDIAC OUTPUT AND ITS DISTRIBUTION
EXPERIMENTAL NEONATAL CARDIAC CYANOSIS: CREATION OF ANIMAL MODEL AND ITS USE TO EVALUATE CELLULAR METABOLIC FUNCTION Michael H. Gewitz, MD; William J. Rashkind, MD; Angela Sharkey, BS; Mari Ragni, MS; Henry R. Wagner, MO, University of Pennsylvania School of Medicine, Philadelphia,Pa.
Eleftherios B. Sideris, M.D., Kazuoki Yokochi, M.D., Tomas Van helder, Flavio Coceani, M.D., Peter M. Olley, M.D.,F.A.C.C. Hospital for Sick Children,Toronto, Canada
In order to assess in viva cellular metabolic function in neonatal cyanotic heart disease, we developed a closed chest animal model of intracardiac right-to-left shunting (R-L)’ in newborn lambs. At cardiac catheterization (cath.) after collection of control data, 25 lambs, age 2 to 7 underwent balloon atria1 septostomy and restriction days, of tricuspid valve flow via transcatheter delivered prostheses resulting in atria1 R-L and systemic arterial (SA) desaturation in 14 of 24 (m control=gO%+3.8; m post cath. =75%+8.2,p<0.01). Pulmonary artery (PA) and SA pressures and pulmonary venous (PV) satubations were equivalent pre and post cath. Arterial blood gas data revealed alveolar hyperventilation post cath. (iii pC02=24, iii pH=7.49, iii pO2=40). In 5 of these lambs transpulmonary extraction of endogenous norepinephrine (NE), an index of endothelial cell metabolic function was evaluated pre and post R-L. No change in extraction (PANE-PVNE/PANE) was seen imnediately after R-L creation. At 5 to 7 days of cyanosis, however, extraction fell significantly (m extraction control=29%+8.6; m extraction cyanotics=5%+1.4, ~~0.05). These experiments indicate that a closed chest animal model of intracardiac R-L can be created which enables metabolic evaluation, and that pulmonary endothelial NE extraction is reduced in the presence of chronic right to left intracardiac shunting. The reduction in catecholamine extraction cannot be attributed solely to reduced pulmonary blood flow and suggests that endothelial functional alteration results from the chronic hypoxemia.
Fbqer N. FXuchan, FD, FAOZ; Glenn C. merquist, MD, FpM3: Deborah RadsMker. BA: Children's Hosoital Nati&-& Medical Center; Wkngton, D.C. * Chick embryos atths stageof active cardiogenesis-e subjectedtogr~hypxiaandtheresultantchangein ventricularfunctionmeasuredover6hoursusingcinephotoanalysis. lWqos at 84 hours gestation were incugas mixture. A 16 bated in a hunidified nitrcgenwgen ntn nuke cank-ara systemwas used to filmthe embryonic heartin~.~ieframes,obtainedhwrly,andedited/ enlarged to showpeakdiastole andpeak systolewere analyzed for hsart rate (HR), tims for ejection, er&diastolic andend-systilic~ions, and shortening fracin 6% tion (SF). Ebur groups of 15 gnbryos were exam&ed 02, 11% 02, 16% 02, androanair. E&hel&cyoservedas its own control. All en&yos wre sacrificed after 6 hours of filming and examixd histolcgically. Intergroup
statistical aqarisions revealed ths folloxing: 1) withinlhour,O concentrations below roan air prcdti significant dila h tion of the primitive ventricle. In 6% 02 an asscciated tachycatdia and loss of contracti~ lity (&SF) was observed; p<.OOOl; 2) within 3 hours of hypoxic stress the akove charqes indinrensionandcontractility were rx&zd with even mild hypoxia (16% 02); p <.OOOl; 3) &art rate response was not significantly altered except with Imderately severe hypxia (6% 02); as evaluated by light micrus~, was not although noted in &ately severe hypaxia. In conclusion, the use of cinepti* analysis adds sensitivity tn sm techniques (change in HR, light microscopy) ti derons~ates that there is rio “latent” period for injury of the developing heart 4)
Cell
dianage,
observed in mild hypxia
withhypoxic stress.FuW evaluationof subtlealterations of cardiac fur&ion andassociated flawpatduring critical phases of embryogenesismayprovideclues to the etiology of congenital kart disease.
The effects of Indomethacin (INDO) Prostaglandin (PC)12 and PGE2 on the fetal cardiac output (CO) and its distribution were studied in 19 fetal lambs. A triple thermodilution method (TH) was used in all animals c&pled with radionuclide microspheres estimations (MICS) in 9. Two hundred ug/kg of INDO induced a main pulmonary artery to aorta gradient (G) maximal within 45 min to 1 hour, an effect which lasted 2 - 3 hours. PGE had a threshold of .05 pg/kg/min, to abolish (G) an 2 its effect lasted 30 min after D/C the infusion. PG12 in doses up to 0.1 ug/kg/min increased (G) significantly (p < .05). Ductal constriction by INDO did not affect the CO but altered its distribution (+RVCO, 4LVCO) while the percentage of RVCO to the lungs and to the duct did not change. PGI in doses of 0.05 ug/kg/min or higher caused redis Eribution of RVCO by decreasing ductal flow and increasing the pulmonary flow. PGE, normalized the distribution of CO. In conclusion, --9 inLvivo PGE2 was more effective on the duct than on the uulmonarv circulation and PGI was ineffective on the duct but a very potent pulmonagy vasodilator. Both PG's and INDO did not alter CO but changed its distribution. This study confirms our -in vitro observations on the relative potencies of the two PG's on the ductus arteriosus and the fetal pulmonary Circulation.
RESPONSE TO MlPAMINE IN RATS WITH ACUTE AND CHRONIC PULMONARY HYPERTENSION. Gerald R. Marx, MD; Marlene Rabinovitch,MD,FACC; Walter Gamble, MD: Lynne Reid,MD, Children's Hospital Medical Center, Boston, MA. Our clinical experience that dopamine(D) may be less effective in increasing cardiac output(C0) postoperatively in children with congenital heart defects and pulmonary hypertension(PH) seemed to relate more to pulmonary vascular disease than to left ventricular dysfunction. Since these two factors are difficult to separate in a clinical setting, the following experiment was carried out. In 15 adult male Sprague-Dawley rats, pressures(P) were monitored in the PA, LV, A0 and SVC; measurement of oxygen consumption permitted calculation of CO, pulmonary and systemic resistance(Rp,Rs). Intravenous D at 15 and 25 ug/kg/min(D15,D25) was given to 6 normal(N) rats(Fpa =21.8+4.5,Rp=.O4+0.12) and to six with chronic PH(CHrats), (Pppa=31.4+6.2,G=.O8+.025), induced by two weekhypobaric hypoxia and associated with known pulmonary vascular changes. These rats were studied in random order both in room air and during exposure to acute hypoxia(H) i.e.lO% FIO2 for 2 hours; Fppa rose in N to 26.8+4.6 and in CH to 43.6+10.9(p
March 1982
The Amerkan
Journal of CARDIOLOGY
Volume 49
939
EFFECTS OF INDOMETHACIN, PROSTACYCLIN AND PROSTAGLANDIN E2 ON THE FETAL CARDIAC OUTPUT AND ITS DISTRIBUTION
EXPERIMENTAL NEONATAL CARDIAC CYANOSIS: CREATION OF ANIMAL MODEL AND ITS USE TO EVALUATE CELLULAR METABOLIC FUNCTION Michael H. Gewitz, MD; William J. Rashkind, MD; Angela Sharkey, BS; Mari Ragni, MS; Henry R. Wagner, MO, University of Pennsylvania School of Medicine, Philadelphia,Pa.
Eleftherios B. Sideris, M.D., Kazuoki Yokochi, M.D., Tomas Van helder, Flavio Coceani, M.D., Peter M. Olley, M.D.,F.A.C.C. Hospital for Sick Children,Toronto, Canada
In order to assess in viva cellular metabolic function in neonatal cyanotic heart disease, we developed a closed chest animal model of intracardiac right-to-left shunting (R-L)’ in newborn lambs. At cardiac catheterization (cath.) after collection of control data, 25 lambs, age 2 to 7 underwent balloon atria1 septostomy and restriction days, of tricuspid valve flow via transcatheter delivered prostheses resulting in atria1 R-L and systemic arterial (SA) desaturation in 14 of 24 (m control=gO%+3.8; m post cath. =75%+8.2,p<0.01). Pulmonary artery (PA) and SA pressures and pulmonary venous (PV) satubations were equivalent pre and post cath. Arterial blood gas data revealed alveolar hyperventilation post cath. (iii pC02=24, iii pH=7.49, iii pO2=40). In 5 of these lambs transpulmonary extraction of endogenous norepinephrine (NE), an index of endothelial cell metabolic function was evaluated pre and post R-L. No change in extraction (PANE-PVNE/PANE) was seen imnediately after R-L creation. At 5 to 7 days of cyanosis, however, extraction fell significantly (m extraction control=29%+8.6; m extraction cyanotics=5%+1.4, ~~0.05). These experiments indicate that a closed chest animal model of intracardiac R-L can be created which enables metabolic evaluation, and that pulmonary endothelial NE extraction is reduced in the presence of chronic right to left intracardiac shunting. The reduction in catecholamine extraction cannot be attributed solely to reduced pulmonary blood flow and suggests that endothelial functional alteration results from the chronic hypoxemia.
Fbqer N. FXuchan, FD, FAOZ; Glenn C. merquist, MD, FpM3: Deborah RadsMker. BA: Children's Hosoital Nati&-& Medical Center; Wkngton, D.C. * Chick embryos atths stageof active cardiogenesis-e subjectedtogr~hypxiaandtheresultantchangein ventricularfunctionmeasuredover6hoursusingcinephotoanalysis. lWqos at 84 hours gestation were incugas mixture. A 16 bated in a hunidified nitrcgenwgen ntn nuke cank-ara systemwas used to filmthe embryonic heartin~.~ieframes,obtainedhwrly,andedited/ enlarged to showpeakdiastole andpeak systolewere analyzed for hsart rate (HR), tims for ejection, er&diastolic andend-systilic~ions, and shortening fracin 6% tion (SF). Ebur groups of 15 gnbryos were exam&ed 02, 11% 02, 16% 02, androanair. E&hel&cyoservedas its own control. All en&yos wre sacrificed after 6 hours of filming and examixd histolcgically. Intergroup
statistical aqarisions revealed ths folloxing: 1) withinlhour,O concentrations below roan air prcdti significant dila h tion of the primitive ventricle. In 6% 02 an asscciated tachycatdia and loss of contracti~ lity (&SF) was observed; p<.OOOl; 2) within 3 hours of hypoxic stress the akove charqes indinrensionandcontractility were rx&zd with even mild hypoxia (16% 02); p <.OOOl; 3) &art rate response was not significantly altered except with Imderately severe hypxia (6% 02); as evaluated by light micrus~, was not although noted in &ately severe hypaxia. In conclusion, the use of cinepti* analysis adds sensitivity tn sm techniques (change in HR, light microscopy) ti derons~ates that there is rio “latent” period for injury of the developing heart 4)
Cell
dianage,
observed in mild hypxia
withhypoxic stress.FuW evaluationof subtlealterations of cardiac fur&ion andassociated flawpatduring critical phases of embryogenesismayprovideclues to the etiology of congenital kart disease.
The effects of Indomethacin (INDO) Prostaglandin (PC)12 and PGE2 on the fetal cardiac output (CO) and its distribution were studied in 19 fetal lambs. A triple thermodilution method (TH) was used in all animals c&pled with radionuclide microspheres estimations (MICS) in 9. Two hundred ug/kg of INDO induced a main pulmonary artery to aorta gradient (G) maximal within 45 min to 1 hour, an effect which lasted 2 - 3 hours. PGE had a threshold of .05 pg/kg/min, to abolish (G) an 2 its effect lasted 30 min after D/C the infusion. PG12 in doses up to 0.1 ug/kg/min increased (G) significantly (p < .05). Ductal constriction by INDO did not affect the CO but altered its distribution (+RVCO, 4LVCO) while the percentage of RVCO to the lungs and to the duct did not change. PGI in doses of 0.05 ug/kg/min or higher caused redis Eribution of RVCO by decreasing ductal flow and increasing the pulmonary flow. PGE, normalized the distribution of CO. In conclusion, --9 inLvivo PGE2 was more effective on the duct than on the uulmonarv circulation and PGI was ineffective on the duct but a very potent pulmonagy vasodilator. Both PG's and INDO did not alter CO but changed its distribution. This study confirms our -in vitro observations on the relative potencies of the two PG's on the ductus arteriosus and the fetal pulmonary Circulation.
RESPONSE TO MlPAMINE IN RATS WITH ACUTE AND CHRONIC PULMONARY HYPERTENSION. Gerald R. Marx, MD; Marlene Rabinovitch,MD,FACC; Walter Gamble, MD: Lynne Reid,MD, Children's Hospital Medical Center, Boston, MA. Our clinical experience that dopamine(D) may be less effective in increasing cardiac output(C0) postoperatively in children with congenital heart defects and pulmonary hypertension(PH) seemed to relate more to pulmonary vascular disease than to left ventricular dysfunction. Since these two factors are difficult to separate in a clinical setting, the following experiment was carried out. In 15 adult male Sprague-Dawley rats, pressures(P) were monitored in the PA, LV, A0 and SVC; measurement of oxygen consumption permitted calculation of CO, pulmonary and systemic resistance(Rp,Rs). Intravenous D at 15 and 25 ug/kg/min(D15,D25) was given to 6 normal(N) rats(Fpa =21.8+4.5,Rp=.O4+0.12) and to six with chronic PH(CHrats), (Pppa=31.4+6.2,G=.O8+.025), induced by two weekhypobaric hypoxia and associated with known pulmonary vascular changes. These rats were studied in random order both in room air and during exposure to acute hypoxia(H) i.e.lO% FIO2 for 2 hours; Fppa rose in N to 26.8+4.6 and in CH to 43.6+10.9(p
March 1982
The Amerkan
Journal of CARDIOLOGY
Volume 49
939