Effects of Nicardipine and Prostaglandin E1 on Coronary Hemodynamics in Dogs with Coronary Artery Stenosis.

Acta Med. Nagasaki 38:232 - 236

Effects of Nicardipine and Prostaglandin E1 on Coronary Hemodynamics in Dogs with Coronary Artery Stenosis.

Masahiko Miyako

Department of Anesthesiology, Nagasaki University School of Medicine, 1-7-1, Sakamoto, Nagasaki 852, Japan

Summary: This study was undertaken in dogs to investigate the effects of nicardipine (NCR)- and prostaglandin E1 (PGE1)- induced hypotension on left ventricular myocardial function, and on coronary hemodynamics in the presence of a partially obstructed left coronary artery. A stenosis of left circumflex coronary artery (LCX) was induced to reduce LCX blood flow by 20%. Mean arterial pressure (MAP) was lowered by infusion of NCR or PGE1 to 80% and 60% of the control. Heart rate, cardiac index, left ventricular dp/dt max, myocardial oxygen extraction ratio, inner/outer blood flow ratio and myocardial lactate extraction ratio showed no significant change at either 80%- or 60%-MAP during infusion of either drug. PGE1 -induced hypotension reduced left ventricular end-diastolic pressure at both 80%- and 60%-MAP. The results indicate that the moderate hypotension induced by NCR or PGE1 does not exert either myocardial depression or adverse effects on the myocardial oxygen supply-demand relationship in the presence of a critical coronary stenosis.

Introduction

Deliberate hypotension is an anesthetic technique to de- crease blood loss during surgery and to provide a dry field for the surgeon."'-" Intravenous nicardipine (NCR)4.5' 6) and prostaglandin E, (PGE,)''8.9' have been introduced in recent years to control blood pressure during clinical anesthesia, and have proved to be useful for deliberate hypotension.

NCR lowers blood pressure resulting from vasodilation due to inhibition of calcium influx into the vascular smooth muscle. NCR mainly dilates resistance vesseles and also has an effect to increase coronary blood flow.'°' PGE, exerts direct relaxing action on the vascular smooth muscle and causes hypotension. PGE, also has been shown to cause coronary vasodilation and reduction of both preload and afterload of the left ventricle.". 12. 13)

The blood flow to ischemic myocardium depends on coronary perfusion pressure, and it is risky to lower arterial pressure in the patients with ischemic heart disease."' Although NCR and PGE, are considered to be beneficial for the ischemic heart, it is not clear how these compounds affect the heart with critical coronary-artery stenosis14' when administered to lower arterial blood pressure rapidly during general anesthesia.

The present study was designed to investigate the effects of NCR- and PGE,-induced hypotension on left ventricular myocardial function, and on coronary hemodynamics in the presence of partially obstructed left coronary circulation.

Materials and Methods.

Surgical preparation

Sixteen mongrel dogs of either sex, weighing 11.4 to 15.6 (mean 13.1) kg were used in this study. Anesthesia was induced with 30mg/kg of sodium pentobarbital i. v., and maintained with continuous infusion of sodium pentobar- bital, 1 mg/kg/min, pancuronium chloride, i. v. appropri- ately, and inhalation of 50% N2O in O2. The animals were intubated with a cuffed endotracheal tube and ventilated mechanically with air at a tidal volume of 15ml/kg. End- tidal CO, concentration was measured continuously with an infrared CO2 analyzer (Datex, Helsinki) and maintained at levels of 35-40mmHg by adjusting the respiratory rate. An infrared heating lamp and a circulating water blanket were used to maintain the esophageal temperature between 37-38.5C. Arterial blood gas analysis and measurement of serum electrolytes were carried out frequently to maintain pH of 7.35 to 7.45, serum Na of 135 to 155mEq/1 and serum K of 3.7 to 5.3mEq/1. Active intervention was not necessary to maintain these ranges except for adjusting pH with 7% NaHCO3 solution in some animals.

In all dogs, catheters were inserted into the femoral vein, into the abdominal aorta via the left femoral artery (Fig. 1).

Normal saline was administered at a rate of 4-6ml/kg/hr

into the femoral vein into which NCR and PGE, were also

administered. Intraarterial pressure was monitored via the

abdominal aorta. The chest was opened through the sixth

left intercostal space, and the heart was suspended in a

pericardial cradle. Precalibrated electromagnetic flow

probes (Nihon Kohden, Japan) of appropriate sizes to

ensure a snug fit were placed around the ascending aorta,

the left circumflex coronary artery (LCX) approximately

1-2cm distal to its origin, and the left anterior descending

coronary artery (LAD) distal to its first large diagonal

Fig. 1. Schematic diagram of the experimental preparation

branch. The flow probes were connected to flowmeters (Nihon Kohden, Japan). A catheter was inserted into the left ventricle via the cardiac apex to measure the left ventricular pressure. A damping device (Accudynamics Sorenson Research, Salt Lake City) was used to get an appropriate damping of the pressure wave. Myocardial blood flow was measured with the hydrogen gas clearance method using platinum tissue electrodes (200um in diam- eter) at both the outer layers (2-3mm in depth) and the inner layers (8-9mm in depth).

Experimental protocol

At the end of the surgical preparation, at least 30min were allowed for stabilization. After control readings (presten- osis value) had been obtained, a stenosis of LCX was induced using a stainless steel screw type mechanical occluder placed immediately distal to the flow probes. The stenosis was defined as the constriction necessary to reduce LCX blood flow by 20%. About 30min was allowed after inducing stenosis for the reactive hyperemia to disappear and for hemodynamic stabilization, and the second readings (basal value) were obtained.

Then the dogs were randomly divided into two groups to recieve NCR or PGE,. Both NCR and PGE, were dissolved in normal saline, and NCR was used as a 0.02% solution, PGE, as a 0.0025% solution. NCR and PGE, was infused at a dose which caused decrease in MAP to 80% of the basal value. After maintenance of stable MAP for 30min, the third readings (80% MAP value) were obtained. The dose of NCR or PGE, was then increased to cause decrease in MAP to 60% of the basal value. After maintenance of

stable MAP for 30min, the fourth readings (60% MAP value) were obtained. The hemodynamic data were calcu- lated by the formula shown in Table 1.

Table 1. Hemodynamic Formulas

-CI = CO/BSA

•TPR = MAP x 79.92/CO

•I/O RATIO = MBFI/MBFO

•OER = (Ca02-CcsO2)/Ca02 x 100

•LER = (LaA-LaCS)/LaA x 100 ABBREVIATIONS

CI: cardiac index CO: cardiac output

BSA: = body surface area 0.112 x (weight:kg)' TPR: total peripheral resistance

MBFI: myocardial blood flow through the inner layer MBFO: myocardial blood flow through the outer layer OER: myocardial oxygen extraction ratio

Ca02: arterial oxygen content CcsO2: coronary sinus oxygen content LER: myocardial lactate extraction ratio LaA: arterial lactate content

LaCS: coronary sinus lactate content

Statistics

For statistical analysis, paired t-test was used for compar- ison between the basal value and the pre-stenosis value and between 80%-MAP or 60%-MAP value and the basal value. Non-paired t-test was used for comparison between groups of NCR and PGE,. All results are expressed as mean ± SEM. A P value less than 0.05 was considered statistically significant.

Results

The mean doses to maintain 80%- and 60%-MAP were 5.2

± 0.54 and 15.6 ± 1.58,ug/kg/min for NCR, and 0.63 ± 0.04 and 1.90 ± 0n l3,ug/kg/min for PGE,.

Heart rate, cardiac index, left ventricular dp/dt max showed no significant change at 80%- or 60%-MAP in either drug (Table 2 and 3). Total peripheral resistance exhibited significant decrease dose-dependently at 80%- and 60%-MAP in both drugs. Left ventricular end-diastolic pressure showed a significant decrease at 80%- and 60%- MAP in PGE,, but showed no change in NCR. The blood flow in the left anterior descending coronary artery (LADF), which was a non-stenosed vessel, showed no significant change at 80%- or 60%-MAP in either drug. Myocardial blood flow at the inner (MBFI) and outer layers (MBFO) of the left circumflex coronary artery stenosis region showed no significant change at 80%- or 60%-MAP in either drug.

There was a significant increase in inner/outer blood flow

(I/0) ratio at 60%-MAP in NCR (Fig. 2). Myocardial

oxygen extraction ratio (OER) and Myocardial lactate

extraction ratio (LER) showed no significant change at

80%- or 60%-MAP in either drug (Fig. 3 and 4).

Table 2. Effects of Nicardipine-Induced Hypotension on Systemic and Coronary Hemodynamics (Mean ± SEM; N = 8) Stenosis

Variables Prestenosis

Basal 80%-MAP 60%-MAP

HR (bpm) 143 ± 3 141 ± 2 140±4 136±5

MAP (mmHg) 134 ± 4 128 ± 5* 106 ± 6*,** 80 ± 6*,**

CI (1/min/m2) 2.57 ± 0.16 2.53 ± 0.15 2.74 ± 0.20 2.78 ± 0.13

LVdp/dtmax (mmHg/sec) 3600 ± 133 3314 ± 175* 3371 ± 175 2951 ± 305

LVEDP (mmHg) 3.38 ± 0.45 3.88 ± 0.55 3.50 ± 0.64 3.75 ± 0.69

TPR (dynes-sec/em') 7055 ± 470 6840 ± 476 5306 ± 505*,** 3854 ± 348*,**

LCXF (ml/min) 44.0 ± 2.9 33.8 ± 3.1* 33.0 ± 2.7* 31.8 ± 2.9*

LADF (ml/min) 11.6 ± 1.1 13.6 ± 1.0* 13.1 ± 1.5 13.6 ± 2.0

MBFI (ml/100g/min) 86.2 ± 2.6 78.2 ± 3.9* 83.7 ± 5.7 80.6 ± 10.4

MBFO (ml/100g/min) 70.5 ± 3.9 58.6 ± 5.0* 61.1 ± 6.7 55.0 ± 9.1

I/O ratio 1.23 ± 0.04 1.37 ± 0.07* 1.41 ± 0.05* 1.51 ± 0.05*

OER (%) 63.3 ± 6.5 63.0 ± 4.4 56.2 ± 5.3 55.1 ± 6.9

LER (%) 34.6 ± 7.2 25.7 ± 5.9 27.4 ± 4.1 23.7 ± 5.1

* P < 0.05 vs pre-stenosis value, * * P < 0.05 vs basal value

Table 3. Effects of Prostaglandin E,-Induced Hypotension on Systemic and Coronary Hemodynamics (Mean ± SEM; N = 8) Stenosis

Variables Prestenosis

Basal 80%-MAP 60%-MAP

HR (bpm) 141 ± 2 141 ±2 144 ± 4 144 ± 4

MAP (mmHg) 141 ± 6 130 ± 7* 111 ± 6*,** 87 ± 4*,**

CI (1/min/m2) 2.51 ± 0.16 2.53 ± 0.17 2.77 ± 0.17* 2.72 ± 0.23

LVdp/dtmax (mmHg/see) 3656 ± 93 3456 ± 170 3455 ± 98 3279 ± 150*

LVEDP (mmHg) 3.38 ± 0.67 4.25 ± 0.85* 3.38 ± 0.83** 3.25 ± 0.69**

TPR (dynes-sec/em') 7264 ± 209 6664 ± 297* 5208 ± 246*,** 4264 ± 345*,**

LCXF (ml/min) 42.9 ± 2.9 34.0 ± 2.5* 32.5 ± 2.2* 29.0 ± 2.0*,**

LADF (ml/min) 10.5 ± 1.1 12.9 ± 1.1 13.8 ± 0.9* 12.4 ± 1.0*

MBFI (ml/lOOg/min) 86.9 ± 2.0 86.4 ± 4.9 89.2 ± 2.8 83.7 ± 4.6

MBFO (ml/100g/min) 67.3 ± 2.7 66.0 ± 4.0 65.5 ± 2.3 63.1 ± 2.3

I/O ratio 1.30 ± 0.07 1.32 ± 0.05 1.37 ± 0.04 1.33 ± 0.06

OER (%) 66.1 ± 2.7 69.0 ± 4.9 65.1 ± 1.7 65.3 ± 3.8

LER (%) 36.8 ± 4.1 25.1 ± 4.6* 22.8±3.5* 25.6 ± 5.2*

* P < 0.05 vs pre-stenosis value, ** P < 0.05 vs basal value

Fig. 2. Effects of nicardipine- and prostaglandin E,-induced hypotension on the inner/outer layer (I/O) ratio of myocardial blood flow (mean ± SEM; n = 8 for each value)

*P < 0.05 VS Pre-stenosis value, ***P < 0.05 between the groups

Fig. 3. Effects of nicardipine- and prostaglandin E,-induced

hypotension on the myocardial oxygen extraction ratio (OER)

(mean ± SEM; n = 8 for each value)

Fig. 4. Effects of nicardipine- and prostaglandin E,-induced hypotension on the myocardial lactate extraction ratio (LER) (mean ± SEM; n = 8 for each value)

* P < 0.05 VS Pre-stenosis value

Discussion

A model of critical coronary artery stenosis'°' was made in the present experiment. Under this condition, the coronary artery distal to stenosis was dilated maximally and the autoregulation was lost. Thus, the coronary blood flow would depend on the coronary perfusion pressure."' In- deed, in the present experiment, the blood flow of the stenosed artery decreased in proportion as the arterial pressure lowered. It is known that the aggravation of myocardial oxygen demand-supply relationship develops initially at the inner leyers and that the cellular necrosis during ischemia begins from the inner layers."' In the normal heart, the inner layers of the ventricle have a higher

blood flow per unit weight than the outer layers, and the oxygen consumption of the inner layers is also higher than that of the outer layers."' In the heart with coronary artery stenosis, the myocardial blood flow at the inner layers is characteristically underperfused due to the low coronary pressure caused by stenosis.'a' In the present experiment, there was no significant difference in the myocardial blood flow at the inner layers and myocardial blood flow at the outer layers at the stenosed area at 80%- or 60%-MAP in either NCR or PGE,. It has been reported that the I/O ratio in the left ventricle of dogs are between 1.0 to 1.3 in the absence of narrowed coronary artery."' in the persent results, the I/O ratio was more than 1.0 at 80%- and 60%-MAP during both drugs, suggesting that there would be no insufficient perfusion in the inner layers of the ventricle.

It is known that when myocardial oxygen demand in- creases, the coronary artery blood flow also increases to cope with it, but myocardial oxygen extraction ratio does not change. In the present study, the myocardial oxygen extraction ratio did not change at 80%- or 60%-MAP during either drug, indicating that there might be coronary artery dilation, which were not due to an increase in the myocardial oxygen consumption. Myocardial lactate ex- traction ratio is considered as an index for myocardial ischemia.20' It has been reported that the myocardial lactate extraction ratio less than 10% would indicate myocardial ischemia.21' In the present results, the myocardial lactate extraction ratio was more than 10% at both 80%- and 60%-MAP during both drugs, and there was no significant difference between the two drugs.

Heart rate is an important factor to determine myocardial ischemic disorder,") and the local myocardial contractility might be effected when heart rate increases. In the present study, heart rate remained almost constant, and seemed not to play a role in the change of myocardial oxygen demand- supply relationship. CI and LVdp/dt max showed no signif- icant change at 80%- and 60%-MAP in either drug, indi- cating that there was no myocardial depression during the each drug-induced hypotension.

In conclusion, the moderate hypotension induced by NCR or PGE, does not exert either myocardial depression or adverse effects on the myocardial oxygen supply- demand relationship in the presence of a critical coronary stenosis.

Acknowledgement

I would like to appreciate for kindness of animal supply from the Laboratory Animal Center and extend my sincere appreciation to Pre-Prof. Yutaka Gotoh and Prof. Koji Sumikawa who kindly instructed and advised me. I would also like to extend my gratitude to Assistant Professor Fujigaki and Mr. Ureshino for technical assistance. A part of this study was reported at 37th Congress of the Japan Society of Anesthesiology, at Nagano, in May 11, 1990.

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