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Acetylcholine-Induced Coronary Vasoconstriction and Negative Inotropy in the Neonatal Pig Heart

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Acetylcholine-Induced Coronary Vasoconstriction and Negative Inotropy in the Neonatal Pig Heart 0031-3998/92/3202 -0236$03.00/0 PEDIATRIC RESEARCH Vol. 32, No.2, 1992 Copyright © 1992 International Pediatric Research Foundation, Inc. Printed in U.S.A. Acetylcholine-Induced Coronary Vasoconstriction and Negative Inotropy in the Neonatal Pig Heart ROBERT J. ASCUITTO, NANCY T. ROSS-ASCUITTO , DAVID RAMAGE, KATHLE EN H. McDO NOUGH , AND PHILIP J. KADOWITZ Department ofPediatrics. Section of Cardiology [R.J.A., N.T.R-A., D.R.j and Departm ent ofPharmacology [P.J.K.J, Tulane University School ofMedicine, and Department of Physiology [K.H.M.j. Louisiana State University School ofMedicine,New Orleans. Louisiana 70112 ABSTRACf. We investigated the influence of exogenously PSP, peak systolic pressure administered acetylcholine, nitric oxide, ADP, ATP, bra­ dP/dt, change in pressure per unit time dykinin, and substance P on coronary vascular tone in isolated, neonatal pig hearts (s4 d). Paced (180 bpm), isovolumically beating hearts underwent retrograde aortic perfusion, with an erythrocyte-enriched solution (hemato­ crit 0.15-0.20) at constant coronary flow mL/min/g) Some 30 years ago, Cassin et al. (I) showed that ACh dilates corresponding to a perfusion pressure of mm Hg. the normally high tone pulmonary vasculature of the fetus. More Agonists were injected into the aortic root, and the peak recently, ACh has been shown to be a potent dilator of precon­ change in coronary perfusion pressure from baseline and tracted, isolated systemic and pulmonary arteries from neonates left ventricular pressure development were assessed. Nitric of several species (2). As originally demonstrated by Furchgott oxide (3 JLL), ADP (30 nmol), ATP (30 nmol), bradykinin and Zawadzki (3), the vasorelaxation produced by ACh requires (125 ng), and substance P (50 ng) decreased the perfusion the presence of a functionally intact endothelium and involves pressure (vasodilatation) by 16.9 ± 1.2, 25.3 ± 4.4, 18.3 the production of an EDRF. ACh has also been shown to relax ± 1.2, 18.9 ± 1.4, and 7.1 ± 1.6 mm Hg, respectively. precontracted, epicardial coro nary arteries isolated from several Acetylcholine (0.5 and 1.0 nmol) produced a modest de­ species, most notably the dog (4). It has become apparent, crease in perfusion pressure (vasodilatation) of 4.2 ± 0.8 however, that these results cannot be generalized to all mammals, and 3.8 ± 0.5 mm Hg, respectively, whereas acetylcholine because large coronary arteries of adult pigs (5) and humans (6, (5, 20, and 100 nmol) increased the perfusion pressure 7) can constrict in vitro to exogenously adm inistered ACh. Re­ (vasoconstriction) by 16.7 ± 2.7, 48.2 ± 8.2, and 85.3 ± cently, Cowan and McKenzie (8) demonstrated that ACh reduces 15.1 mm Hg, respectively. Acetylcholine also decreased myocardial blood flow when injected into the left anterior de­ left ventricular peak systolic pressure from 108.7 ± 5.0 to scending coronary artery of in vivo adult pig hearts. Although 69.2 ± 4.6, 56.3 ± 6.1, and 48.2 ± 6.4 mm Hg, for the 5, this finding is consistent with the vasoconstrictor responses ob­ 20, and 100 nmol doses, respectively. Responses to acetyl­ served with ACh using isolated coronary arteries, the coronary choline were abolished by atropine (50 nmol). In a separate vascular effects of ACh in intact, functioning hearts require group of hearts, indomethacin (10- 6 M) reduced the peak additional investigation. Such information is of importance, change in perfusion pressure for the 5, 20, and 100 nmol because cholinergic mechanisms may playa role in the regulation doses of acetylcholine by 87%,66%, and 48%, respectively. of coronary blood flow. Moreover, little, if anythin g, is known In other hearts, the calcium channel antagonist, nisoldipine about the actions of ACh on the coro nary vasculature of the (10- 7 M), reduced the peak change in perfusion pressure immature heart. for the 5,20, and 100 nmol doses of acetylcholine by 87%, Therefore, the purpose of the present investigation was to 77%, and 56%, respectively. In summary, acetylcholine study the effects of ACh on mechanical function and coro nary causes predominantly coronary vasoconstrictive and nega­ vascular tone, using neonatal pig hearts. Isolated, isovolumically tive inotropic effects in neonatal pig hearts; both actions beating hearts were perfused with an erythrocyte-enriched solu­ are muscarinic receptor mediated. Our data also indicate tion under conditions of constant coronary flow. The effects of that a cyclooxygenase product may, in part, be involved in NO,ADP, ATP, BK, and sub P on the coronary vasculature this vasoconstriction, and that an extracellular source of were also examined. NO, which is believed to be EDRF, was calcium contributes to the vasoconstrictive process. studied as an example of a direct smooth muscle vasodilator (9). (Pediatr Res 32: 236-242, 1992) Th e remai ning agents were investigated because they produce endothelial-dependent coronary vasodilatation in mature hearts (10). We hypothesized that ACh would cause coronary vasocon­ Abbreviations strictio n in neon atal pig hearts, and that this vasoconstriction ACh, acetylcholine would be inhib ited by indomethacin, because ACh has also been EDRF, endothelium-derived relaxing factor shown to produce cerebrovascular constriction in piglets, which BK, brad ykinin is mediated by the release of cyclooxygenase products (11). sub P, substance P NO , nitric oxide MATERIALS AND METHODS Received October 2,1991; accepted March 18, 1992. Preparationoferythrocytesand perfusate.The perfusate (3rC) Correspondence: Robert J. Ascuitto, M.D., Ph.D ., Tulane University Medical Center, Department of Pediatrics, 1430 Tulane Ave., New Orleans, LA 70122. consisted of a crystalloid solution containing: 200 JLU jmL insu­ Supported by a grant from the Louisiana Board of Regents, LEQSF 1989-91­ lin, 118 mM NaCl, 4.7 mM KCl, 2.4 mM MgS04 , 1.2 mM RD-A-I 6. KH 2P04, 25 mM NaHC03, 2.4 mM CaCh, 5.5 mM glucose, 2­ 236 ACh IN NEONATAL PIG HEARTS 237 4 mM lactate, and 2% BSA (Cohn Fraction V; U.S. Biochemical Corp., Cleveland, OH). Outdated, saline-washed, human eryth­ rocytes (tested negative for hepatitis B and human immunode­ ficiency virus) were then suspended in this solution (hematocrits 0.15-0.20) to provide adequate oxygen delivery and buffering capacity for these large hearts (12.6 ± 1.3 g). The pH of the final solution was adjusted to 7.4-7.45 by titration with 1 N NaOH. Preparation ofsolutions. Indomethacin (Sigma Chemical Co., St. Louis, MO) was dissolved in warm NaC03 (0.08%) and protected from light. An aliquot of this solution was added to the perfusate to yield an indomethacin concentration of 10-6 M. Nisoldipine (Miles Inc., Dallas, TX) was dissolved in Cremophor EL (Sigma), Tris, and Tris-HCl (pH 7.4). The resulting suspen­ sion was warmed, and 2 mL of polyethylene glycol and 10 mL of Tris (pH 7.4) were added. This stock solution was stored frozen and protected from light. When required, this solution was thawed, diluted with saline, and infused into the aortic root at a rate equivalent to a perfusate nisoldipine concentration of 10-7 M. ACh (Sigma), ADP, and ATP (Boehringer Mannheim, Indianapolis, IN) were dissolved in saline and prepared on the day of an experiment. BK (Sigma) and sub P (Sigma) were also dissolved in saline and frozen in bottles protected from light. Stock solutions were thawed for each experiment and diluted in saline when necessary. NO was dissolved in reagent grade methanol under Os-freeconditions. The precise concentra­ tion of NO in the solution was unknown, although it was estimated to be 1-2 mM. Thus, only the volume of the NO solution injected is specified. Atropine sulfate (Abbott Labora­ Fig. 1. Perfusate in reservoir (R) was pumped through an oxygenating tories, Chicago, IL) was dissolved in perfusate solution and column (0), bubble trap (B), and heating condenser (H). Before entering injected as a bolus into the aortic root. the aorta, the perfusate passed through a constant-flow system containing Preparation ofisolatedhearts. Pigs, 12 h to 4 d of age, were a pump (P) and a pulsatile flow-damping chamber (W), which main­ used for these studies. Isolated, isovolumically beating hearts tained the coronary flow at the desired constant value. Myocardial were prepared as described previously (12, 13). Briefly, piglets temperature was kept at 3rC by enclosing the heart in a heated water were anesthetized with sodium pentobarbital (Nembutal, 25 mg/ jacket. Left ventricular isovolumic pressure was monitored by a pressure kg intraperitoneally; Abbott), anticoagulated with sodium hepa­ transducer (T,) attached to a fluid-filled balloon catheter (BC) in the left rin (heparin, 1000 U i.v.), and mechanically ventilated via a ventricular chamber. Coronary perfusion pressure was monitored with a tracheostomy. After a sternotomy, the hearts were excised rapidly pressure transducer (T2) attached to a side port above the heart. Coronary and immediately placed in ice-cold, Krebs-Henseleit solution. venous return egressed from the pulmonary artery cannula (CF). Coro­ Using the modified Langendorff system described previously nary venous return was collected separately and not returned to the (12, 13) and depicted in Figure 1, nonrecirculating, retrograde­ reservoir (R). aortic perfusion was initiated with the crystalloid solution for min (to flush the coronary arteries of debris), and then continued with respect to time (dPjdt), which were monitored via a fluid­ with the erythrocyte-enriched solution. Hearts were allowed to filled balloon catheter in the ventricular chamber. The left ven­ equilibrate while being perfused for 15 min at constant coro­ tricular end diastolic pressure was adjusted by changing the nary perfusion pressure. The enhanced oxygen-carrying capacity volume of fluid in the balloon. The end diastolic pressure was provided by the erythrocytes ensured that coronary flow rates set at 2--4 mm Hg, which is normal for a neonate.
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