arterial baroreceptor sensitivity in calves

JOURNAL OF SURGICAL RESEARCH, 13, 235-240 (1972)

ARTERIAL BARORECEPTOR SENSITIVITY IN CALVES

J. B. PACE, PH.D., AND M. P. KAYE, M.D., M.S.

STUDIES CONCERNED WITH the evalua- tion of mechanisms controlling cardiovascular dynamics in conscious animals have primarily utilized the canine species as the experimental model. Technical advances in the development of artificial organs have necessitated the use of animal models whose body mass and surface area closely approximate that of the human. For this reason our Facility has utilized the Holstein calf as the experimental animal. The 3-mo-old calf weighs approximately 80 kg, which is close to the weight of the average adult human. In addition, values of oxygen consumption (240 ml/min STP) and cardiac output (5000 ml/min) in the calf correspond closely to values measured in adult humans [2, 41. Furthermore, the docile nature of the calf makes this animal ideal for chronic studies.

Chronic implantation of circulatory assist devices necessarily disrupts the normal inter- actions of the components responsible for physiological homeostasis ; consequently the organism will alter its physiological function so that aberrations induced by the device be- come attenuated and equilibrium is reestab- lished. The degree to which physiological control systems correct changes in function de- pends upon their sensitivity to detect these changes, together with their ability to respond and reestablish normal equilibrium. In order to make valid human applications of experimental results derived from calf experiments,

From the IIT Research Institute, Test and Evalua- tion Facility, 10 West 35 Street, Chicago, Illinois 60616.

The research upon which this publication is based was performed pursuant to Contract No. NIH- NHLI-69-2125 with the National Institutes of Health, Department of Health, Education, and Welfare.

Submitted for publication April 6, 1972.

one must establish that the sensitivity of calf control mechanisms are comparable to the human.

In mammalian species, the blood pressure is regulated within narrow limits. Artificial fluctuations in systemic pressure are immediately followed by changes in heart rate and blood flow which tend to counter the pressure rise. The sensitivity of the human heart rate response to alterations in systemic blood pressure has been determined [l], however, little information exists as to the nature of this mechanism in calves.

The following experiments were undertaken in order to evaluate heart rate changes, as well as systemic and pulmonary hemodynamics, during drug induced alterations in systemic arterial pressure in conscious calves.

METHODS

Experiments were performed on six Holstein calves ranging in weight from 69 to 90 kg. The animals were anesthetized with halothane (24% 1 and placed on positive pressure breathing. A left thoracotomy was performed in the third or fourth interspace and the pleural space entered. The brachiocephalic artery was dissected free of connective tissue at a point 4 cm above the aortic arch. Similarly, the main pulmonary artery was cleaned for 3 cm distal to the pulmonic valve ring. Electro- magnetic flow probes were placed around the arteries. Probe sizes were selected which caused a 10-200/o reduction in arterial cross section, thus insuring contact of the probe electrodes with the vessel wall. Polyethylene pressure catheters were tied into the respective arteries using a modified Seldinger technique. The catheters were placed approximately 3

Copyright B

1972 by Academic Press, Inc. AU rights o reoroduction in any form reserved.

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236 JOURNAL OF SURGICAL RESEARCH, VOL. 13, NO. 5, NOVEMBER 1972

mm proximal to the flow probe, and pressure and flow were measured at essentially the same point in the artery. The flow probe cables and the pressure catheters were led out through the dorsal limit of the incision. The ribs were closed using plastic bands and the muscle closed in anatomic layers. The skin was closed and a purse-string suture was placed in the skin at the point of exit of the catheters and cables. The animals were then given 3 million units of penicillin and the dose was repeated on each postoperative day.

Pressure and flows were recorded after the second postoperative day, while the animals were confined within their stalls. Blood flow was recorded with a Carolina Medical Elec- tronics dual channel Aowmeter (Model No. 322R). Blood pressures were recorded with Statham P37 pressure transducers. The pressure and flow pulses were recorded on a Beck- man Dynograph (Type R). The pressure transducers were connected directly to the catheters and held in place on the animal by tying elastic bands around the thorax. The flow cables were attached directly to button connectors which were exteriorized through a small skin incision above the shoulder.

In each animal, the experimental protocol was as follows. Control recordings of pressure and flow were made after the animal became accustomed to the leads and was standing quietly or resting in the prone position. Following a 5 to 10 min control period, the animal was given 1.0-0.5 mg of neosynephrine directly into the pulmonary artery. This was followed within 2-4 set by a marked rise in systemic arterial pressure with associated changes in heart rate. Following recovery from neosynephrine, 4 mg of atropine sulfate were administered in the pulmonary artery and the neosynephrine injection was repeated. The atropine paralyzed the vagal control of heart rate and therefore reductions in heart rate during hypertension induced by neosynephrine could not be attributed to the depressant action of the vagus nerves. Reductions in heart rate occurring after atropine could then be attributed to a withdrawal of sympathetic tone. In addition, acetylcholine also was administered to permit study of the influence of hypotension on heart rate and blood flow.

RESULTS

Figure 1 illustrates the hemodynamic response associated with an elevation of systemic arterial pressure in the conscious calf before and after the administration of atropine. In the control before atropine the heart rate was 76 beats/min and the brachiocephalic pressure was 112/97 mm Hg. Pulsatile pulmonary and brachiocephalic flow are shown, however the probes were uncalibrated. The intra- pulmonary injection of neosynephrine is indi- cated by the square wave pulses on the pulmonary arterial pressure trace. The second square wave represents saline wash-in. Brachioce- phalic pressure began to increase 9 set following the onset of injection and reached a peak 21 see later. At the peak of the systemic pressure response the heart rate decreased to 48 beats/see and the brachiocephalic pressure increased to 163/133 mm Hg. Hence, the administration of 1.0 mg of neosynephrine produced a reduction of 28 beats/see in heart rate and a 51 mm Hg increase in systolic pressure. Peak brachiocephalic flow was sharply reduced in association with the rise in brachiocephalic pressure and the initial sharp peak in the flow wave was markedly attenuated, tending to flatten the top of the wave. Following the administration of atropine brachiocephalic pressure was decreased to 106/69 mm Hg, and heart rate was slightly increased to 78 beats/ sec. The identical dose of neosynephrine produced a 56 mm Hg increase in systolic pressure, but unlike the response prior to atropine, heart rate was unchanged during the elevation in pressure. Peak pulmonary flow was increased while peak brachiocephalic flow was reduced as was the case prior to atropine. This experiment indicates that under these condi- tions the reduction in heart rate was entirely mediated by the vagus nerves and withdrawal of sympathetic activity was not involved in the response. Furthermore, it is apparent that fluctuations in systemic arterial pressure have a marked influence on systemic and pulmonary pulsatile blood flow.

The sensitivity of the baroreceptor reflex mechanism in the calf shown in Fig. 1 was determined in the following manner. In the control state, the cardiac cycle length was 800

PACE A&-D KAYE: BARORECEPTOR SENSITIVITY IN CALVES 237

1.0 mg NEOSYNEPHRINE

BEFORE ATROPINE-

1.0 mg NEOSYNEPWIINE

ATROPtME 0.6 mg/k@

Fig. I. Record showing alterations in systemic and pulmonary arterial pressures and flow during drug induced hypertension with neosynephrine. Prior to atropine the increased blood pressure was associated wit,h a suppres- sion in brachiocephalic peak flow and a reduction in heart rate. Following atropine administration, neosynephrine still evoked a rise in brachiocephalic blood pressure, but heart rate was unchanged.

msec and during the peak of the neosynephrine response was increased to 1250 msec. Hence, the systolic blood pressure change of 51 mm Hg was associated with a 450 msec increase in cycle length. The sensitivity of the baroreceptor system in this calf can be ex- pressed as the ratio of cycle length change to peak systolic pressure change: 450 msec/51 mm Hg = 8.82 msec/mm Hg [l].

The responses associated with fluctuations in systemic pressure in another typical experiment are shown in Fig. 2. The control heart rate was 68 beatsjmin with a brachiocephalic pressure of 153/120. The administration of neosynephrine caused a 47 mm Hg increase in systolic pressure which was associated with an 18 beat/min decrease in heart rate. Cycle length increased 316 msec and baroreceptor sensitivit(y was determined as 6.72 msec/mm Hg. The rise in brachiocephalic pressure was associated with reductions in both mean pulmonary and mean brachiocephalic flow. The straight line traces in Fig. 2 indicate mean flow determined by electrically averaging the flow pulsations. Pulmonary blood flow de-

creased 30% during the pressure response but returned to control levels 1.5 min following the injection even though systemic pressure con- tinued to be elevated. Brachiocephalic flow decreased 20%, but unlike the pulmonary flow response, it remained below control levels for the duration of elevated pressure. The pressure-flow responses occurring with acetylcholine were the inverse of those generated with neosynephrine.

Acetylcholine induced a 40 mm Hg decrease in systolic pressure with essentially no change in heart rate. The lack of cardioacceleration is probably related t.o an inadequate sympathetic effect on the pacemaker tissues in the heart. The fall in pressure was accompanied by a 50% increase in pulmonary flow together with a comparable increase in brachiocephalic flow. These results indicate that the level of systemic arterial pressure can exercise an impor- tant control on the level of blood flow in the large vessels.

Figure 3 shows the hemodynamic alterations associated with postural changes in the calf. The panel on the left shows the hemodynamic


Fig. 2. Record showing alterations in systemic and pulmonary hemodynamics induced with neosynephrine and acetylcholine. The neosynephrine hypertension was associated with reductions in pulmonary and brachiocephalic mean flow. On the other hand, acetylcholine produced a steep reduction in brachiocephalic pressure accompanied by marked increases in flow.

POST ATROPINE 0.5 mg/kg

STANDING HEAD LOWERED

Fig. 3. Record showing alterations in pulmonary and systemic hemodynamics during postural changes. Head lowering was associated with a fall in brachiocephalic pressure which accompanied a rise in peak brachiocephalic flow. These records illustrate that the inverse relationship between pressure and flow occurs in association with postural adjustments in the calf.

status with the animal standing quietly in his creased from 146/121 to 127/100 mm Hg. stall. The right hand panel shows the hemody- Heart rate remained unchanged as brachioce- namic alterations which developed as the ani- phalic pressure decreased. This fall in brachi- ma1 lowered its head in preparation to move to ocephalic pressure was accompanied by a the prone position. Systemic pressure de- marked increase in peak brachiocephalic blood

PACE AND KAYE: BARORECEPTOR SENSITIVITY IN CALVES 239

/ 0.5 mgm Neosymphrins 1

112 Sec.

Aecendieg Aorhc IFtWl

ECG

50 jgm. Acetyleholme

Fig. 4. Record showing the brachiocephalic pressure and aortic flow responses during hypo- and hypertension. Xote that heart rate did not change at the maximum fluctuations in pressure.

flow. Pulmonary blood flow was little affected by the maneuver. This experiment shows that the inverse relation between brachiocephalic pressure and flow is pertinent in a situation where arterial pressure fluctuated spontane- ously and indicat’es that these pressure-flow relationships are an integral part of the normal cardiovascular physiology of the calf.

Figure 4 illustrates an experiment in which no change in heart rate could be elicited during either acute hypertension or hypotension. The intravenous administration of neosynephrine was accompanied by a fall in peak ascending aortic blood flow, but heart rate remained essentially unchanged from control. The separation between the first and second panels represents a time lapse of 112 set, indi- cating the time interval required for pressure to decline to control levels. Panel 3 shows the hemodynamic changes resulting from the intravenous administration of acetylcholine. Acetylcholine elicited a 25 mm Hg decrease in systolic pressure which was accompanied by an increase in peak ascending aortic blood flow. As was the case with the hypertensive response, hypotension did not result in an al- teration in heart rate. Therefore, in this par- ticular calf baroreceptor control of heart rate was completely lacking.

DISCUSSION

Recent experiments in adult humans have shown that the sensitivity of the baroreceptor control of heart rate may vary between 8.0

and 12.0 msec/mm Hg [l]. These values are greater than the range of baroreceptor sensitivities determined from calves in the present report (6.7 to 8.8 msec/mm Hg), and therefore indicates that the regulatory mechanisms which control the cardiac responses in humans function at a higher level of sensitivity than in calves. From the data shown in this report, it may be inferred that the hemodynamic response of the calf to circulatory assist devices such as the intra-aortic balloon may be different from those which develop in man. Because of the lower sensitivity, the calf may not dem- onstrate changes which would ordinarily develop in man.

Recently, Dennison et al. [4] have shown that hemodynamically the 3-mo-old calf closely resembles man. Their study was concerned with obtaining mechanical measurements such as stroke volume, maximum dP/dt, mean injection rate, stroke work and stroke power. Although these measurements correlate closely with values measured in man, they give no information as to the sensitivities of the circulatory reflexes which control these parameters. The present study shows that although there may be correspondence of mechanical events, the sensitivity of the neuro- genie control systems are markedly different, and therefore application of device affected physiological data generated from calf experiments to the human should be undertaken with caution.

It is of functional importance to consider


mechanisms responsible for the lower sensitivity of the calf baroreceptor reflex system. This effect may involve the efficiency of operation of the nerve endings which reside in the cardiac tissues. In order to investigate this possi- bility, both the sympathetic and vagal nerves were electrically stimulated while recording ventricular pressures and aortic flow in calves anesthetized with halothane. Direct stimulation of the vagal nerves failed to induce cardiac slowing in three of the six animals, and in the remaining three animals the slowing was minimal (less than 20% increase in cycle length). On the other hand, direct stimulation of the vagus nerves in man induces profound slowing and cardiac arrest.

These observations indicate that the neuroeffector mechanisms in the calf heart may be poorly developed, and therefore the action effect sequence which arises from direct stimulation of a nerve fiber is greatly attenuated. Normally the baroreceptor system in man re- sponds to a decrease in aortic pressure by in- creasing heart rate [l]. Figure 2 shows that cardiac acceleration may not accompany a reduction in aortic pressure in the calf. The lack of response in this experiment is probably related to the poorly developed neuroeffector system in the sympathetic nerves. However, the anatomical studies of Getty and Mc- Kibben [3] show the existence of postgangli- onic nerves arising from paravertebral ganglia from Tr through Tg and innervating atria and ventricles.

The flow changes associated with fluctuations in aortic pressure also indicates poor intrinsic control of the calf circulation. When aortic pressure is increased, the load against which the heart must eject blood is increased, and therefore in order to pump the same volume, the heart muscle must develop greater force during contraction. The relative inability

of the calf heart to completely compensate for increases in aortic pressure is evidenced in Figs. 1 and 2. In these experiments, the reduction in brachiocephalic flow persists for the duration of elevated pressure. On the other hand, reductions in aortic pressure are accompanied by prominent increases in both brachiocephalic and pulmonary flow, which indicates that the heart muscle has not fully adjusted to the reduction in load and continues to pump with the same force as before the reduction in systemic pressure.

SUMMARY

Baroreceptor sensitivity and blood flow fluctuations were studied in normal calves during drug induced changes in systemic arterial pressure. These experiments show that the sensitivity of the baroreceptor system in calves is considerably less than in humans. Further- more, the intrinsic mechanisms by which cardiac muscle force is adjusted to changes in arterial pressure load also appear to be poorly developed in the calf. The lack of correspondence of the sensitivity of the control mechanisms between the calf and man limits the ap- plicability of results derived from calf experiments to human physiology.

REFERENCES

1. Gribbin, B., Peto, R., Pickering, T. G., and Sleight, P. Effect of age and high blood pressure on barore- flex sensitivity in man. Circ. Res. 29:4&t-431, 1971.

2. Kuida, Hiroshi, Brown, A. M., Lange, R. L., and Hecht, H. H. Cardiovascular studies on normal calves. Amer. J. Phgsiol. 200 ~247-252, 1961.

3. Getty, R., and McKibben, J. C. A study of the cardiac innervation in domestic animals : Cattle. Anat. Rec. 165:141-151, 1969.

4. Dennison, B. H., Fuqua, J. M., Hastings, F. W., Speaker, D. M., and Weber, K. T. Hemodynamic measurements in unanesthetized calves. J. Surg. Res. 11:383-389, 1971.

arterial baroreceptor sensitivity in calves

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