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Cardiovascular effects of intravenous and intracoronary administration of atrial natriuretic peptide in halothane anesthetized dogs
Life Sciences, Vol. 42, pp. 1279-1286
Pergamon Press
Printed in the U.S.A.
CARDIOVASCULAR ADMINISTRATION
Ryoko
EFFECTS OF INTRAVENOUS AND INTRACORONARY OF ATRIAL NATRIURETIC PEPTIDE IN HALOTHANE ANESTHETIZED DOGS
Iwanaga
Keiichi
Fukuda'
Keigo Yoshinaga
Takao Sarut Tohru Satoh , Kenn Yamaguchi
'Department
of Medicine, School of Medicine, Keio University 5 Shinanomachi, Shinjuku-ku, Tokyo Japan !! National Cancer Center Research Institute (Received in final form February 1, 1988) Summary Cardiovascular actions of synthetic l-28 human natriuretic peptides (hANP) were examined in dogs anesthetized with halothane. In seven closed-chest dogs a Swan-Ganz catheter was inserted for measurement of increasing of cardiac output.Intravenous infusion mean doses of hANP (0.1, 0.3, O.gug/kg/min) lowered aortic pressure without affecting heart rate signifioutput and pulmonary wedge pressure cantly. Cardiac were markedly decreased while total peripheral significantly. All these resistance was increased parameters returned to control levels after lhr of recovery with an infusion to lOO-150ml of saline increase pulmonary capillary wedge pressure to the preinfusion value. Intracoronary infusion of hANP (0.05 and O.lug/kg/min) did not cause any significant changes in coronary flow and regional contraction. These results indicate that the hypotensive action of hANP is due to adecrease in cardiac output mediated reduced preload but not by negative inotropic by action.
Atria1 natriuretic peptide (ANP) has been reported to reduce arterial pressure in experimental animals (1) and in humans (2)(3)(4), however the mechanism of its depressor action has not been fully explained. Several investigators have attributed the depressor action of ANP to the reduction in cardiac output mediated through reduction in central venous
* Author for correspondence: Dr. Ryoko Iwanaga, Cardiopulmonary Division, Department of Internal Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, JAPAN 0024-3205188$3.00 + -00 Copyright (c) 1988 Pergamon Press plc
1280
Hemodynamic Effects of ANP
Vol. 42, No. 13, 1988
resistance was unchanged or pressure. In rats total peripheral increased (5)(6)(7). On the other hand, ANP has been demonstrated to relax vascular smooth muscle in vitro (8)(9)(10). In rats (11)(12), ANP was observed to reduce arterial pressure and total peripheral resistance. In conscious and in anesthetized dogs, the mechanism of the depressor action also remains obscure (13). The purpose of this study is to clarify the mechanism of the depressor action of ANP in dogs anesthetized with nitrous oxide and halothane. Firstly changes in systemic hemodynamics were induced by intravenous administration of ANP, and secondly the change in regional myocardial contraction induced by intracoronary administration was measured while systemic hemodynamics were constant. Methods Experiment 1: Intravenous Administration of ANP Seven mongrel dogs weighing IO-20kg were anesthetized with nitrous oxide and halothane, intubated, and connected to a Harvard respirator. A Swan-Ganz 7F catheter was placed in the pulmonary artery through the jugular vein for measurement of pulmonary arterial pressure, right atria1 pressure, pulmonary wedge pressure (PCWP) and cardiac output. Mean aortic pressure was measured by a catheter placed in the aorta through the femoral artery. All pressures and limb lead electrocardiogram were recorded on a polygraph (RM 6000, Nihon Kohden Co.). in the right atrium A catheter placed through the jugular vein connected to a Harvard infusion pump for infusion of was synthetic human l-28 ANP (hANP: Peptide Institute, INC.). Urine was collected through a balloon catheter inserted in the bladder. After hemodynamic stabilization was ascertained, a 20-minute control period was observed. Bolus infusions of hANP, 1.0, 3.0, and 9.0 ug/Kg, were followed by 20-minute constant infusions of respectively (FIG.l). Saline was 0.1, 0.3, and O.gug/kg/min, infused at a rate of 2ml/min throughout the experiment. At the end of an l-hour recovery period, IOO-150ml of saline was infused in order for PCWP to return to control value. Blood pressure was monitored continuously, and all other parameters were measured at Blood samples for 5-minute intervals during the experiment. measurement of plasma renin activity (PRA) and aldosterone were obtained at the end of each control, infusion and recovery PRA and aldosterone were determined by radioimmunoassay. period. Blood samples were also obtained before the induction of anesthesia and at the end of the infusion period for measurements of plasma immunoreactive ANP (irANPI. Blood samples for irANP were collected in tubes containing aprotinine, and plasma was Plasma irANP was measured by stored at -80% until assayed. on immune-affinity after extraction radioimmunoassay chromatography (14). Experiment 2: Intracoronary Administration of ANP. effects of local In the present study we studied the administration of ANP on coronary blood flow and regional Intracoronary doses of ANP produced a myocardial contraction. markedly high concentration in the coronary circulation without Five mongrel dogs weighing IOaffecting systemic hemodynamics.
Vol. 42,
No.
13,
1988
1281
Hemodynamic Effects of ANP
15kg were anesthetized with nitrous oxide and halothane, After left intubated, and connected to a Harvard respirator. thoracotomy and pericardotomy, the left anterior descending coronary artery (LAD) was dissected at the distal portion of the first diagonal branch for insertion of a bypass tube from the left subclavian artery. The bypass tube had an electromagnetic flow probe for measurement of coronary blood flow and a three way stopcock for infusion of synthetic hANP. Catheters were placed in the aorta through the femoral artery for measurement of aortic pressure and in the left ventricle to measure left ventricular pressure. A pair of microcrystals (Schuessler Co.) was implanted near the subendocardium at the center of the LAD perfusion area for measurement of regional length (FIG.l). Experiment
1 : Intravenous
Administration ANP
(pg/kg/min) 3
c 3.0pg/kg 4 ..___,,,.... _.,._.,.,___,.,.,.,.,.,.
l.O/~g/kg 4 Control
4. .._......... _.,,,....... ....,,,,“” ‘:.:.:_:.:
. . . . .
” ” ‘6;r:.:::_:,.:.:.:.:.:D 3:.:.:.:.:: ,:_:.:.:., 9.91:I:t:1:1 ::::, ;. .‘_‘_‘_‘_ Recovery1 . . . . .._ .~.~.~.~.~.~.~.‘,~,‘.‘. .,..__.,,,,._,
.1.1.1.:. I :::. . . .._.......
v---p
20 min
Experiment
9.0pg/kg
20 min
2 : lntracoronary
20 min
20 min
20 min
Administration ANP +g/kg/min)
Control
--a
20 min
‘..,‘..,b:d;s:tttttttt ;:::::::
. .._._.,. .‘,‘,‘.‘.‘.‘.‘.‘.:
1~ftf_ffff~:!,1:1:1:.:’ ._____...... 20 min
20 min
“LVP
FIG.1
The schematic representation of the experimental AOP= aortic pressure CBF= coronary blood flow LVP= left ventricular pressure The shaded area means the perfused area by LAD.
models.
Hemodynamic
1282
Effects
Vol.
of ANP
42, No.
13, 1988
As an index of regional myocardial contraction, the percent segment shortening (%SS) was calculated as follows; 100 x ((enddiastolic length) (end-systolic length)) / (end-diastolic length) (24). After hemodynamic stabilization, 20-minute control period was allowed to elapse and 20-minute constant intracoronary infusions of 0.05 and 0.1 ug/kg/min of hANP were started. Intravenous injection of the same dose of ANPdid not alter heart rate or blood pressure significantly. All hemodynamic parameters were recorded simultaneously on a polygraph every 5 minute. Data are presented as means + standard deviation and compared by paired t-test. Significance was accepted if p value was less than 0.05. Results (1)Intravenous Administration of ANP Plasma irANP concentration before the induction of anesthesia was 38 + 26 pg/ml and increased significantly at the end of infusion to 6900 + 2600 pg/ml (p
TABLE and Urinary Hemodynamic Administration of hANP -I Control
HR AOM co PCWP PAM RAM SVRx103 uv
119*12 1081t12 1.8eO.5 8+2 14+2 1*2 4.Oe1.9 1.0*0.7
O.lug
120+4 107t8 l-6+0.3 6t3 13*3 Ot2 4.6+2.0 2.9*1.0
I Responses
to
Intravenous
____--.-
0.3ug
112*11* 95+7* 1.4+0.3,, 5+2 12+3 1*2* 5.1+2.5 2.9,l.S
0.9ug
-.--___ Recovery
--108+13, 116+10 106+3, 94+4* 1.2+0.2,, l-2+0.3, 4+2 5*2 12+3 13,2 lt3 l*2** 5.7,2.3* 5.3k2.3, 2.1*1.7 3.3+1.8 ______-----
HR= heart rate: /min AOM= mean aortic pressure: mmHg CO= cardiac output: l/min/lOkg of body weight PAM= mean pulmonary arterial pressure: mmHg RAM= mean right atria1 pressure: mmHg SVR= systemic vascular resistance: dynes.sec.cm-5 UV= urine volume: ml/min * p
Saline infusion 114+2 112-~5 1.9t0.7 8+2 14*2 2+3 4.4,2.5
1283
HemodynamicEffects of ANP
Vol. 42, No. 13, 1988
Mean aortic pressure (AOM) fell significantly after 0.3 and 0.9 ug/kg/min infusion of hANP (12, 13% respectively) but returned to control levels during recovery. However heart rate did not show any significant change throughout the experiment. There was a significant decrease in cardiac output after 0.3 and 0.9 ug/kg/min infusion (22, 33% respectively). Significant decreases in PCWP were also noted after 0.3 (8 to 5mmHg, p
TABLE Hormonal hANP
Responses
to Intravenous
Control
Ald sterone' 570+228 PRA s 3.23e2.21
II
O.lug
Administration
0.3ug
0.9ug
276+49** 278+113** 281*85* 2.92il.75 2.99*3.14 1.96+1.30
'pg/ml 2ng/ml/hr * pxo.05 ** p
as mean + standard
of
Recovery
559+264 5.02+2.21
deviation.
(2)Intracoronary Administration of ANP Hemodynamic responses to intracoronary administration of hANP were summarized in Table III. A large amount of ANP was administered to the regional myocardium without changes in cardiac preload (left ventricular end-diastolic pressure and enddiastolic lengthjand afterload(aortic pressure). The estimated concentration of ANP in the coronary arterial blood was about 20 to 30 times that in systemic arterial blood obtained in experiment 1. This high concentration of ANP did not alter
1284
Hemodynamic Effects of ANP
Vol. 42, No. 13, 1988
coronary flow and regional contraction as percent segment shortening in Table III.
TABLE Hemodynamic of hANP
Effects
-in AOM mmHg LVEDP mmHg CBF ml/min/g EDL, mm %SS
%
indicated
by constant
III
of Intracoronary
Control
0.05Llg
110+8 84+2 2*1 0.8+0.3 10*0* 13+4
107*10 8Oi5 2tl
O.Bj~0.2 10,O.l 15+7
Administration
O.lug 103*1X 81+5 2*1
0.7*0.3 10,O.l
15*9
HR= heart rate AOM= mean aortic pressure LVEDP= left ventricular end-diastolic pressure CBF= coronary blood flow (values are divided by g wet weight of myocardium in the perfused area) * control values of end-diastolic length are normalized to IOmm for simplification EDL,= normalized end-diastolic length %SS= percent segment shortening
Discussion We found the depressor action of hANP in halothane anesthetized dogs to be mediated through reduction in cardiac rather than in total peripheral resistance. In fact, output, increased significantly during hANP total peripheral resistance infusion. The fall in cardiac output during hANP infusion was due to a significant reduction in pulmonary capillary wedge pressure rather than to negative inotropic action of hANP. Heart rate was not changed significantly in this experiment while mean aortic pressure decreased. Reflex tachycardia by ANP was reported in conscious sheep (15) and in humans (16). However Carson (17) reported that reflex tachycardia was not observed in conscious dogs. These data indicate that the heart rate response might be species dependent. using In previous studies dogs, infusion of synthetic ANP caused reductions in arterial pressure and cardiac output (13)(17)(18). However, the cause of reduction in cardiac output remains controversial. Burnett (18) showed that the cause was the wedge pressure. While other capillary decrease in pulmonary investigators reported that pulmonary capillary wedge pressure or central venous pressure did not change significantly (13)(17).
Vol. 42, No. 13, 1988
Hemodynamic Effects of ANP
1285
ruled out for Further, a decrease in contractility could not be a possible cause of reduction in cardiac output (13). Therefore, we examined the effects of intravenous administration of ANP on systemic hemodynamics firstly, and the effects of ANP on myocardial contractility using regional perfusion model with systemic hemodynamics. We doses which did not affect demonstrated that the preload reduction could explain the overall hemodynamic response to ANP in halothane anesthetized dogs. The preload reduction induced by ANP might be a result of either a transmembrane fluid shift (19) and diuresis with a reduction of blood volume or an increase of venous capacitance duetoa direct venodilating effect (2). ANP has been demonstrated to relax rabbit facial vein (20) or rat portal vein (21). In contrast, that in the Wangler et al. (22) reported Langendorf preparation ANP raised coronary resistance in dog, rat and guinea pig hearts. major limitations concerning The evaluations of myocardial contraction in isolated heart models are that coronary flow is high and the oxygen demand of the heart is not physiological. We used a regional myocardial perfusion model in situ so as to preserve the oxygen demand of the whole heart as possible. There were no changes in coronary blood flow and regional contraction. These data indicated that high concentration of ANP had no negative inotropic effect. During infusion of hANP, aldosterone decreased while PRA did not change, suggesting that renin-angiotensin system might not be involved in increasing vascular resistance. Lappe et al. (23) reported that chemical or surgical denervation abolished atriopeptin II-induced increases in renal vascular resistance. These results might explain the mechanism of vasoconstriction induced by ANP as an increase in sympathetic tone rather than as a direct vascular action of ANP.
References 1.
2.
3. 4.
5. 6.
7. 8.
B.L.PEGRAN, M.B.KARDON, N.C.TRIPPODO, F.E.COLE, and A.A.MacPHEE, Am.J.Physiol. 249 H265-H271 (1985). R.J.CODY, S.A.ATLAS, J.H.LARAGH, S.H.KUBO, A.B.COVIT, K.S.RYMAN, A.SHAKNOVICH, K.PONDOLFINO, M.CLARK, M.J.F.CAMARGO, R.M.SCARBOROUGH, J.A.LEWICKI, J.Clin. and Invest. 78 1362-1374 (1986). A.M.RICHARDS, M.G.NICHOLIS , H.IKRAM, M.W.I.WEBSTER, T.G.YANDLE, and E.A.ESPINER, Lancet. 2 545-549 (1985). P.WEIDMANN, L.HASLER, M.P.GNADINGER, R.E.LANG, D.E.UEHLINGER, S.SHAW,W.RASCHER, and F.C.REUBI, J.Clin.Invest. 77 734-742 (1986). R.W.LAPPE, J.F.M.SMITS, J.A.TODT, J.J.M.DEBETS, and R.L.WENDT, Circ. Res. 56 606-612 (1985). T.BAUM, E.J.SYBERTZ, -R.W.WATKINS, S.NELSON, W.COLEMAN, K.K.PULA, N.PRIOLI, M.RIVELLI, and A.GROSSMAN, J.Cardiovasc.Pharmacol. 6 898-905 (1986). R.W.LAPPE, J.A.TODT, and R.L.WENDT, Hypertension. 8 866-873 (1986). M.G.CURRIE, D.M.GELLER, B.R.COLE, J.G.BOYLAN, W.Y.SHENG, S.W.HOLMBERG, and P.NEEDLEMAN, Science. 221 71-73 (1983).
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9.
HemodynamicEffects of ANP
Vol. 42, No. 13, 1988
H.D.KLEINERT, T.MAACK, S.A.ATLAS, A.JANUSZEWICZ, J.E.SEALEY, and J.H.LARAGH, Hypertension. G(supp1 1) 143-147 (1984). 10. M.J.CAMARGO, H.D.KLEINERT, S.A.ATLAS, J.E.SEALEY, J.H.LARAGH, and T.MAACK, Am.J.Physiol. 246 F447-F456 (1984). M.ISHII, 11. Y.HIRATA, T.SUGmTO, H. MATSUOKA, T.SUGIMOTO, K.KANGAWA, and H.MATSUO, Circ. Res. 57 634-639 (1985). 12. S.FUJIOKA, T.TAMAKI, K.FUKUI, T.OKAHARA, and Y-ABE, European. J. Pharmacol. x 301-304 (1985). M.VOLPE, G.ODELL, D.MARION, S.A.ATLAS, 13. H.D.KLEINERT, M.J.CAMERGO, J.H.LARAGH, and T.MAACK, Hypertension. 8 312-316 (1986). 14. X.YOSHINAGA, ~.w+~AciucHI, K.ABE, Y.MIYAKE, K.OTSUBO, s.HORI, H.OONO, A.KANAI, K. MARUNO, Y.MISHIMA, Biomed. Rec.l 173-179 (1986). 15. B.A.BREUHAUS, H.H.SANEII, M.A.BRANDT, and J.E.CHIMOSKEY, Am.J.Physiol. 249 R776-R780, (1985). 16. P.LAROCHELLE, J.CUSSON, P.HAMET, P.DUSOUICH, J.GUTKOWSKA, E. SCHIFFRIN, J.GENEST, and M.CANTIN, J.Cardiovasc.Pharmacol. 8 1292 (1986) (Abstracts). ~~.EE.CARSON, P.F.CARLYLE, T.H.HOSTETTER, and J.N.COHN, J.Cardiovasc. Pharmacol.8 1328 (1986) (Abstracts). 18. J.TATEISHI, Y.MITANI, K.FUJITANI, and T.IWASAKI, Jpn.Circ.J. 51 296 (1987) (Abstracts) 19. J.~.BURNETT, G.M.RUBANYI, B.S.EDWARDS, T.R.SCHWAB, R.S.ZIMMERMAN, and P.M.VANHOUTTE, J.Cardiovasc.Pharmacol. 8 1323 (1986) (Abstract). 20. F.A.ALMEIDA, M.MUNEYA, and T.MAACK, J.Cardiovasc. Pharmacol. 8 1315 (1986) (Abstracts). E.P.FAISON, R.F.NUTT, European.J.Pharmacol. 102 21. R.J.WINQUIST, 169-173 (1984). 108 103-104 22. M.L.COHEN, and K.W.SCHENCK, European.J.Pharmacol. (1985). B.A.BREUHAUS, H.O.OTERO, D.A.HASTINGS, 23. R.D.WANGLER, M.D.HOLZMAN, H.H.SANEII, H.V.SPARKS, and J.E.CHIMOSKEY, Science. 230 558-561 (1985). 24. R.W.LAPPE, J.A.TODT, and R.L.WENDT, Am.J.Physiol. 249 R781R786 (1985). 25. P.THEROUX, J.ROSS, D.FRANKLIN, W.S.KEMPER, and S.SASAYAMA Circulation. -53 302-314 (1976).
Pergamon Press
Printed in the U.S.A.
CARDIOVASCULAR ADMINISTRATION
Ryoko
EFFECTS OF INTRAVENOUS AND INTRACORONARY OF ATRIAL NATRIURETIC PEPTIDE IN HALOTHANE ANESTHETIZED DOGS
Iwanaga
Keiichi
Fukuda'
Keigo Yoshinaga
Takao Sarut Tohru Satoh , Kenn Yamaguchi
'Department
of Medicine, School of Medicine, Keio University 5 Shinanomachi, Shinjuku-ku, Tokyo Japan !! National Cancer Center Research Institute (Received in final form February 1, 1988) Summary Cardiovascular actions of synthetic l-28 human natriuretic peptides (hANP) were examined in dogs anesthetized with halothane. In seven closed-chest dogs a Swan-Ganz catheter was inserted for measurement of increasing of cardiac output.Intravenous infusion mean doses of hANP (0.1, 0.3, O.gug/kg/min) lowered aortic pressure without affecting heart rate signifioutput and pulmonary wedge pressure cantly. Cardiac were markedly decreased while total peripheral significantly. All these resistance was increased parameters returned to control levels after lhr of recovery with an infusion to lOO-150ml of saline increase pulmonary capillary wedge pressure to the preinfusion value. Intracoronary infusion of hANP (0.05 and O.lug/kg/min) did not cause any significant changes in coronary flow and regional contraction. These results indicate that the hypotensive action of hANP is due to adecrease in cardiac output mediated reduced preload but not by negative inotropic by action.
Atria1 natriuretic peptide (ANP) has been reported to reduce arterial pressure in experimental animals (1) and in humans (2)(3)(4), however the mechanism of its depressor action has not been fully explained. Several investigators have attributed the depressor action of ANP to the reduction in cardiac output mediated through reduction in central venous
* Author for correspondence: Dr. Ryoko Iwanaga, Cardiopulmonary Division, Department of Internal Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, JAPAN 0024-3205188$3.00 + -00 Copyright (c) 1988 Pergamon Press plc
1280
Hemodynamic Effects of ANP
Vol. 42, No. 13, 1988
resistance was unchanged or pressure. In rats total peripheral increased (5)(6)(7). On the other hand, ANP has been demonstrated to relax vascular smooth muscle in vitro (8)(9)(10). In rats (11)(12), ANP was observed to reduce arterial pressure and total peripheral resistance. In conscious and in anesthetized dogs, the mechanism of the depressor action also remains obscure (13). The purpose of this study is to clarify the mechanism of the depressor action of ANP in dogs anesthetized with nitrous oxide and halothane. Firstly changes in systemic hemodynamics were induced by intravenous administration of ANP, and secondly the change in regional myocardial contraction induced by intracoronary administration was measured while systemic hemodynamics were constant. Methods Experiment 1: Intravenous Administration of ANP Seven mongrel dogs weighing IO-20kg were anesthetized with nitrous oxide and halothane, intubated, and connected to a Harvard respirator. A Swan-Ganz 7F catheter was placed in the pulmonary artery through the jugular vein for measurement of pulmonary arterial pressure, right atria1 pressure, pulmonary wedge pressure (PCWP) and cardiac output. Mean aortic pressure was measured by a catheter placed in the aorta through the femoral artery. All pressures and limb lead electrocardiogram were recorded on a polygraph (RM 6000, Nihon Kohden Co.). in the right atrium A catheter placed through the jugular vein connected to a Harvard infusion pump for infusion of was synthetic human l-28 ANP (hANP: Peptide Institute, INC.). Urine was collected through a balloon catheter inserted in the bladder. After hemodynamic stabilization was ascertained, a 20-minute control period was observed. Bolus infusions of hANP, 1.0, 3.0, and 9.0 ug/Kg, were followed by 20-minute constant infusions of respectively (FIG.l). Saline was 0.1, 0.3, and O.gug/kg/min, infused at a rate of 2ml/min throughout the experiment. At the end of an l-hour recovery period, IOO-150ml of saline was infused in order for PCWP to return to control value. Blood pressure was monitored continuously, and all other parameters were measured at Blood samples for 5-minute intervals during the experiment. measurement of plasma renin activity (PRA) and aldosterone were obtained at the end of each control, infusion and recovery PRA and aldosterone were determined by radioimmunoassay. period. Blood samples were also obtained before the induction of anesthesia and at the end of the infusion period for measurements of plasma immunoreactive ANP (irANPI. Blood samples for irANP were collected in tubes containing aprotinine, and plasma was Plasma irANP was measured by stored at -80% until assayed. on immune-affinity after extraction radioimmunoassay chromatography (14). Experiment 2: Intracoronary Administration of ANP. effects of local In the present study we studied the administration of ANP on coronary blood flow and regional Intracoronary doses of ANP produced a myocardial contraction. markedly high concentration in the coronary circulation without Five mongrel dogs weighing IOaffecting systemic hemodynamics.
Vol. 42,
No.
13,
1988
1281
Hemodynamic Effects of ANP
15kg were anesthetized with nitrous oxide and halothane, After left intubated, and connected to a Harvard respirator. thoracotomy and pericardotomy, the left anterior descending coronary artery (LAD) was dissected at the distal portion of the first diagonal branch for insertion of a bypass tube from the left subclavian artery. The bypass tube had an electromagnetic flow probe for measurement of coronary blood flow and a three way stopcock for infusion of synthetic hANP. Catheters were placed in the aorta through the femoral artery for measurement of aortic pressure and in the left ventricle to measure left ventricular pressure. A pair of microcrystals (Schuessler Co.) was implanted near the subendocardium at the center of the LAD perfusion area for measurement of regional length (FIG.l). Experiment
1 : Intravenous
Administration ANP
(pg/kg/min) 3
c 3.0pg/kg 4 ..___,,,.... _.,._.,.,___,.,.,.,.,.,.
l.O/~g/kg 4 Control
4. .._......... _.,,,....... ....,,,,“” ‘:.:.:_:.:
. . . . .
” ” ‘6;r:.:::_:,.:.:.:.:.:D 3:.:.:.:.:: ,:_:.:.:., 9.91:I:t:1:1 ::::, ;. .‘_‘_‘_‘_ Recovery1 . . . . .._ .~.~.~.~.~.~.~.‘,~,‘.‘. .,..__.,,,,._,
.1.1.1.:. I :::. . . .._.......
v---p
20 min
Experiment
9.0pg/kg
20 min
2 : lntracoronary
20 min
20 min
20 min
Administration ANP +g/kg/min)
Control
--a
20 min
‘..,‘..,b:d;s:tttttttt ;:::::::
. .._._.,. .‘,‘,‘.‘.‘.‘.‘.‘.:
1~ftf_ffff~:!,1:1:1:.:’ ._____...... 20 min
20 min
“LVP
FIG.1
The schematic representation of the experimental AOP= aortic pressure CBF= coronary blood flow LVP= left ventricular pressure The shaded area means the perfused area by LAD.
models.
Hemodynamic
1282
Effects
Vol.
of ANP
42, No.
13, 1988
As an index of regional myocardial contraction, the percent segment shortening (%SS) was calculated as follows; 100 x ((enddiastolic length) (end-systolic length)) / (end-diastolic length) (24). After hemodynamic stabilization, 20-minute control period was allowed to elapse and 20-minute constant intracoronary infusions of 0.05 and 0.1 ug/kg/min of hANP were started. Intravenous injection of the same dose of ANPdid not alter heart rate or blood pressure significantly. All hemodynamic parameters were recorded simultaneously on a polygraph every 5 minute. Data are presented as means + standard deviation and compared by paired t-test. Significance was accepted if p value was less than 0.05. Results (1)Intravenous Administration of ANP Plasma irANP concentration before the induction of anesthesia was 38 + 26 pg/ml and increased significantly at the end of infusion to 6900 + 2600 pg/ml (p
TABLE and Urinary Hemodynamic Administration of hANP -I Control
HR AOM co PCWP PAM RAM SVRx103 uv
119*12 1081t12 1.8eO.5 8+2 14+2 1*2 4.Oe1.9 1.0*0.7
O.lug
120+4 107t8 l-6+0.3 6t3 13*3 Ot2 4.6+2.0 2.9*1.0
I Responses
to
Intravenous
____--.-
0.3ug
112*11* 95+7* 1.4+0.3,, 5+2 12+3 1*2* 5.1+2.5 2.9,l.S
0.9ug
-.--___ Recovery
--108+13, 116+10 106+3, 94+4* 1.2+0.2,, l-2+0.3, 4+2 5*2 12+3 13,2 lt3 l*2** 5.7,2.3* 5.3k2.3, 2.1*1.7 3.3+1.8 ______-----
HR= heart rate: /min AOM= mean aortic pressure: mmHg CO= cardiac output: l/min/lOkg of body weight PAM= mean pulmonary arterial pressure: mmHg RAM= mean right atria1 pressure: mmHg SVR= systemic vascular resistance: dynes.sec.cm-5 UV= urine volume: ml/min * p
Saline infusion 114+2 112-~5 1.9t0.7 8+2 14*2 2+3 4.4,2.5
1283
HemodynamicEffects of ANP
Vol. 42, No. 13, 1988
Mean aortic pressure (AOM) fell significantly after 0.3 and 0.9 ug/kg/min infusion of hANP (12, 13% respectively) but returned to control levels during recovery. However heart rate did not show any significant change throughout the experiment. There was a significant decrease in cardiac output after 0.3 and 0.9 ug/kg/min infusion (22, 33% respectively). Significant decreases in PCWP were also noted after 0.3 (8 to 5mmHg, p
TABLE Hormonal hANP
Responses
to Intravenous
Control
Ald sterone' 570+228 PRA s 3.23e2.21
II
O.lug
Administration
0.3ug
0.9ug
276+49** 278+113** 281*85* 2.92il.75 2.99*3.14 1.96+1.30
'pg/ml 2ng/ml/hr * pxo.05 ** p
as mean + standard
of
Recovery
559+264 5.02+2.21
deviation.
(2)Intracoronary Administration of ANP Hemodynamic responses to intracoronary administration of hANP were summarized in Table III. A large amount of ANP was administered to the regional myocardium without changes in cardiac preload (left ventricular end-diastolic pressure and enddiastolic lengthjand afterload(aortic pressure). The estimated concentration of ANP in the coronary arterial blood was about 20 to 30 times that in systemic arterial blood obtained in experiment 1. This high concentration of ANP did not alter
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Vol. 42, No. 13, 1988
coronary flow and regional contraction as percent segment shortening in Table III.
TABLE Hemodynamic of hANP
Effects
-in AOM mmHg LVEDP mmHg CBF ml/min/g EDL, mm %SS
%
indicated
by constant
III
of Intracoronary
Control
0.05Llg
110+8 84+2 2*1 0.8+0.3 10*0* 13+4
107*10 8Oi5 2tl
O.Bj~0.2 10,O.l 15+7
Administration
O.lug 103*1X 81+5 2*1
0.7*0.3 10,O.l
15*9
HR= heart rate AOM= mean aortic pressure LVEDP= left ventricular end-diastolic pressure CBF= coronary blood flow (values are divided by g wet weight of myocardium in the perfused area) * control values of end-diastolic length are normalized to IOmm for simplification EDL,= normalized end-diastolic length %SS= percent segment shortening
Discussion We found the depressor action of hANP in halothane anesthetized dogs to be mediated through reduction in cardiac rather than in total peripheral resistance. In fact, output, increased significantly during hANP total peripheral resistance infusion. The fall in cardiac output during hANP infusion was due to a significant reduction in pulmonary capillary wedge pressure rather than to negative inotropic action of hANP. Heart rate was not changed significantly in this experiment while mean aortic pressure decreased. Reflex tachycardia by ANP was reported in conscious sheep (15) and in humans (16). However Carson (17) reported that reflex tachycardia was not observed in conscious dogs. These data indicate that the heart rate response might be species dependent. using In previous studies dogs, infusion of synthetic ANP caused reductions in arterial pressure and cardiac output (13)(17)(18). However, the cause of reduction in cardiac output remains controversial. Burnett (18) showed that the cause was the wedge pressure. While other capillary decrease in pulmonary investigators reported that pulmonary capillary wedge pressure or central venous pressure did not change significantly (13)(17).
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Hemodynamic Effects of ANP
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ruled out for Further, a decrease in contractility could not be a possible cause of reduction in cardiac output (13). Therefore, we examined the effects of intravenous administration of ANP on systemic hemodynamics firstly, and the effects of ANP on myocardial contractility using regional perfusion model with systemic hemodynamics. We doses which did not affect demonstrated that the preload reduction could explain the overall hemodynamic response to ANP in halothane anesthetized dogs. The preload reduction induced by ANP might be a result of either a transmembrane fluid shift (19) and diuresis with a reduction of blood volume or an increase of venous capacitance duetoa direct venodilating effect (2). ANP has been demonstrated to relax rabbit facial vein (20) or rat portal vein (21). In contrast, that in the Wangler et al. (22) reported Langendorf preparation ANP raised coronary resistance in dog, rat and guinea pig hearts. major limitations concerning The evaluations of myocardial contraction in isolated heart models are that coronary flow is high and the oxygen demand of the heart is not physiological. We used a regional myocardial perfusion model in situ so as to preserve the oxygen demand of the whole heart as possible. There were no changes in coronary blood flow and regional contraction. These data indicated that high concentration of ANP had no negative inotropic effect. During infusion of hANP, aldosterone decreased while PRA did not change, suggesting that renin-angiotensin system might not be involved in increasing vascular resistance. Lappe et al. (23) reported that chemical or surgical denervation abolished atriopeptin II-induced increases in renal vascular resistance. These results might explain the mechanism of vasoconstriction induced by ANP as an increase in sympathetic tone rather than as a direct vascular action of ANP.
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