Studies on the Carotid Body and the Carotid Sinus Circulatory Effects Of

Studies on the Carotid Body and the Carotid Sinus

Circulatory Effects of the Carotid Chemoreflex

Takashi SASAKI, M.D.

SUMMARY Previously, carotid chemoreflex and baroreflex have been reported, although for the most part of these mechanisms have not been clarified. In this experiments, circulatory effects of the carotid chemoreflex were investigated in the anesthetized dogs. Chemoreflex was performed with Lobeline (0.02mg, 1ml) and potassium cyanide (KCN, 1%, 1ml) through the catheter inserted to the carotid sinus. Continuously, during experiments, systolic blood pressure (S.P), diastolic blood pressure (D.P), systolic pulmonary blood pressure (SPaP), diastolic pulmonary blood pressure (DPaP), respiration and pulse rate were recorded simultaneously in the closed chest dogs. Cardiac output, pulmonary blood flow, coronary blood flow, S.P, D.P, SPaP, DPaP, and pulse rate were examined in the controlled breathing of the open chest dogs. In each experiment, during and after reflex, blood gas, HCO3-, and pH were measured. However, none of them were changed by these reflexes. In the case of the closed chest dogs, chemoreflex by Lobeline did not change S.P and D.P, but SPaP was increased by 22.54%, significantly. DPaP was increased by 18.14%. Respiration rate was increased by 26.46% significantly. Heart rate was decreased by 9.15%. In the open chest dogs, chemoreflex by Lobeline increased S.P and D.P by 13.05% and 14.58% significantly . SPaP and DPaP were increased by 22.19% and 21.97% significantly . Pulmonary resistance was increased by 28.57% significantly . Pulmonary blood flow was decreased by 9.7% significantly. In the open chest dogs, chemoreflex with KCN increased S.P, D.P, and SPaP by 21.59%, 21.39%, and 41.02% significantly. Pulmonary resistance was increased by 20% significantly . Pulmonary blood flow was decreased by 10.43%. Cardiac output was not changed but coronary blood flow was increased by 6.50% significantly. It should be noted here that the carotid chemoreflex caused the hyperrespiration, the changes of pulmonary arterial blood pressure , pulmonary resistance, and pulmonary blood flow significantly, but these

From the Second Department of Internal Medicine , Nihon University School of Medicine (De- partment of Cardiovasology, Surugadai Nihon University Hospital) , Tokyo.Thi s report was made according to the statement at th e 36th Annual Meeting of Japanese Cir- culation Society, April, 1972. Received for publication August 13, 1973. 539 Jap Heart J. 540 SASAKI November, 1973

hemodynamic changes are capable of being separated from the effects of hyperrespiration through the chemoreflex mechanism.

Additional Indexing Words: Carotid chemoreflex Carotid chemoreceptor stimulation Sponta- neous breathing Controlled breathing Lobeline KCN

EYMANS and Heymans demonstrated the presence of chemically sen- sitive nerve receptors in the region of the aortic arch in 1927.1) De Castro was the first to suggest that the carotid body subserved a chemosensory function.2) Briefly, it was shown that perfusion of the vascu- larly isolated, innervated, carotid body by blood of abnormal chemical com- position provoked reflex responses of respiration and blood pressure. Hypoxic hypoxia, hypercapnia or acidity of the perfusion fluid were found to cause reflex hyperpnea and hypertension which were abolished by section of the corresponding sinus nerve.3) As a series, studies on the carotid bodies and the sinus reflexes were started by this clinic 9 years ago.4)-9) Hemodynamic changes of the carotid chemoreceptor stimulation on cardiovascular systems are not yet clarified, and this time circulatory effects of the carotid chemoreceptor stimulation were investigated in the closed chest dogs and in the open chest dogs.

METHODSAND MATERIALS Experiments were performed on 20 dogs weighing 10 to 15Kg, of either sex. Anesthesia was induced with sodium pentobarbital 0.5mg/Kg intravenously. The common carotid arteries were exposed and both right external and internal carotid arteries were also revealed. Catheter was inserted through the external carotid artery and positioned in the common carotid artery. Another catheter was inserted from the external carotid vein, through the right atrium and the ventricle to the left pulmonary artery. Pulmonary arterial pressure and right ventricular pressure were recorded through the catheter. Systemic arterial pressure was recorded through the catheter inserted to the femoral artery. Electro-cardiogram was also recorded. Lobeline (0.02mg), potassium cyanide (KCN, 1%) were infused into the sinus through the catheter. Closed chest experiments were performed by measuring systemic arterial blood pressure (S.P and D.P), pulmonary arterial blood pressure (SPaP and DPaP), respiration and pulse rate continuously before and after the infusion of drugs. Under controlled breathing by tracheal intubation, the chest was opened. The respirator was kept at the rate of 22 breaths/min, tidal volume was 200-250ml of air. Left lateral thoracotomy was performed in the fourth intercostal space. The heart was exposed and electromagnetic flow probes (Nihon Koden, MP-5 type) were placed around the thoracic aorta, left pulmonary artery and left circumflex Vol.14 CAROTID CHEMOREFLEX 541 No.6

Fig. 1. Schema for setting of the carotid chemoreflex, non-cannulating probes of cardiac output, pulmonary blood flow and coronary blood flow. Catheter for systemic blood pressure, pulmonary blood pressure and right ventricular pressure. coronary artery. Cardiac output, pulmonary blood flow and coronary blood flow were induced into the recorder by these probes. Systemic arterial pressure, right ventricular pressure and pulmonary blood pressure were measured through the catheter connected to the pressure transducers (Nihon Koden, MPF type). The isometric time tension index (dp/dt/IIT) was calculated by using the electrocardiogram, right ventricular pressure and right ventricular dp/dt. Blood gases and pH were determined by the I.L meter (Instrumentation Laboratory Inc, model 113 and 127). Pulmonary vascular resistance was calculated as the quotient of the mean pulmonary arterial pressure (mmHg) and the mean pulmonary blood flow (ml/min), and was shown in mmHg/ml/min. Systemic vascular resistance was calculated from the mean aortic pressure (mmHg) and cardiac output (ml/min), and was shown in mmHg/ml/min. The standard II lead electrocardiogram was used for measurements of the heart rate. Just before the experiments, 1ml of normal saline was rapidly infused into the carotid sinus through the catheter, and it was confirmed that no changes took place. 542 SASAKI Jap. Heart J. November, 1973 Then, Lobeline and KCN were infused into the catheter . After 0.5-1.0sec from the onset of the pulmonary circulatory changes due to the carotid sinus infusion of drugs, systemic arterial pressure began to rise. The changes were shown at the time of maximal effects by the carotid chemoreceptor stimulation as determined by the highest point in aortic pressure, which occurred about 5-6sec after the onset of the carotid chemoreceptor stimulation. Results of each experiment were revealed by the percentage at the level of of the baseline values before the carotid chemoreceptor stimulation. Systemic blood pressure, pulmonary blood pressure, pulmonary blood flow, heart rate, cardiac output, coronary blood flow, right ventricular pressure and RVPdp/dt were recorded by the multiple channel recorder (Nihon Kohden, WI- 180) simultaneously. The data were statistically examined by Student's T-test.

RESULTS

Carotid chemoreceptorstimulation by Lobeline in the closed chest dogs The changes of the mean values, the standard deviation, and the statis- tical significance of changes are shown in Table I. Systolic blood pressure and diastolic blood pressure were changed not significantly. Systolic pulmonary blood pressure increased by the difference

Table I. Effects of the Carotid Chemoreflex by Lobeline in the Closed Chest Dogs

S.P: Systolic pressure (mmHg), D.P: Diastolic pressure (mmHg), S-PaP: Systolic pulmonary pressure (mmHg), D-PaP: Diastolic pulmonary pressure (mmHg), H.R: Heart rate (beats/min), Breathing: Breathing rate/min, R.V.P: Right ventricular pressure (mmHg), dp/dt/IIT: Isome- tricti me tension index, P.C: Percent change, P: P-value, P-values were calculated using Student's T-test, N: Number of experiments, n.s: not significant, S.D: Standard deviation, Lobeline: 0.02mg, 1ml. Vol.14 CAROTID CHEMOREFLEX 543 No.6 of 7.16•}4.67mmHg (percent change: 22.54%) from 31.76•}18.25mmHg, significantly. Diastolic pulmonary blood pressure increased (P.C: 18.14%), but not significantly. Heart rate decreased (P.C: 9.15%), but not significantly. Breathing rate increased by the difference of 2.69•}2.58 rate/min (P.C:

26.46%) from 10.17•}8.56 rate/min, significantly. Right ventricular pressure and isometric time tension index (dp/dt/IIT) were not changed.

Carotid chemoreceptor stimulation by Lobeline in the open chest dogs

The changes are shown in Table II.

The control systolic blood pressure was 128.26•}27.38mmHg and control diastolic blood pressure was 80.35•}4.02mmHg. After carotid chemoreceptor stimulation, systolic blood pressure increased by 16.74•}23.32mmHg

(P.C: 13.05%) and diastolic blood pressure increased by 11.72•}11.54mmHg

Table II. Effects of the Carotid Chemoreflex by Lobeline in the Open Chest Dogs

S.P: Systolic pressure (mmHg), D.P: Diastolic pressure (mmHg), S-PaP: Systolic pulmonary pressure (mmHg), DPaP: Diastolic pulmonary pressure (mmHg), P.B.F: Pulmonary blood flow (ml/min), H.R: Heart rate (beats/min), C.O: Cardiac output (ml/min), C.B.F: Coronary blood flow (ml/min), P.R: Pulmonary vascular resistance (mmHg/ml/min), S.R: Systemic vascular resistance (mmHg/ml/min), R.V.P: Right ventricular pressure (mmHg), dp/dt/IIT: Isometric time tension index, P.C: percent changes, P: P-value, P-values were calculated using Student's T-test, N: Number of experiment, n.s: not significant, S.D: Standard deviation , Lobeline: 0.02mg, 1ml. Jap. Heart J. 544 SASAKI November, 1973

(P.C: 14.58%), significantly. The control systolic pulmonary blood pressure was 28.58•}8.74mmHg and diastolic pulmonary blood pressure was 10.92•}

7.60mmHg. Systolic pulmonary blood pressure increased by 6.34•}5.89 mmHg (P.C: 22.19%) and diastolic pulmonary blood pressure also increased by 2.40•}2.30mmHg (P.C: 21.97%), significantly. Pulmonary blood flow decreased by 32.50•}88.68mm/min (P.C: 9.70%) from 334.79•}417.59ml/ min, P less than 0.05, with carotid chemoreceptor stimulation. Heart rate, cardiac output and coronary blood flow were not changed. Pulmonary vascular resistance increased by 0.02•}0.09mmHg/ml/min (P.C: 28.57%) from 0.07•}0.16mmHg/ml/min, significantly. Systemic vascular resistance

was also increased by 0.03•}0.11mmHg/ml/min (P.C: 11.38%) from 0.25•}

0.13mmHg/ml/min, significantly. Right ventricular pressure and the iso-

Table III. Effects of the Carotid Chemoreflex by KCN in the Open Chest Dogs

S.P: Systolic pressure (mmHg), D.P: Diastolic pressure (mmHg), S-PaP: Systolic pulmonary pressure (mmHg), D-PaP: Diastolic pulmonary pressure (mmHg), P.B.F: Pulmonary blood flow (ml/min), H.R: Heart rate (beats/min), C.O: Cardiac output (ml/min), C.B.F: Coronary blood flow (ml/min), P.R: Pulmonary vascular resistance (mmHg/ml/min), S.R: Systemic vascular resistance (mmHg/ml/min), R.V.P: Right ventricular pressure (mmHg), dp/dt/IIT: Isometric time tension index, P.C: Percent changes, P: P-value, P-values were calculated using Student's T-test, N: Number of experiment, n.s: not significant, S.D: Standard deviation, KCN: 1%, 1ml. Vol.14 CAROTID CHEMOREFLEX 545 No.6 metric time tension index were not changed significantly.

Carotid chemoreceptor stimulation by KCN in the open chest dogs

The changes are shown in Table III.

The control systolic pressure was 122.88•}41.13mmHg and control

diastolic pressure was 77.31•}20.69mmHg. After carotid chemoreflex by

KCN, systolic pressure increased by 26.54•}16.95mmHg (P.C: 21.59%)

and diastolic pressure increased by 16.54•}8.69mmHg (P.C: 21.39%), sig-

nificantly. Systolic pulmonary pressure increased by 9.46•}7.97mmHg

(P.C: 41.02%) from the control level, significantly. But diastolic pulmonary

pressure was not changed significantly. Pulmonary blood flow decreased significantly. Heart rate and cardiac output were not changed. Coronary

blood flow increased (P.C: 6.5%), significantly. Pulmonary vascular re-

sistance increased (P.C: 20%) and systemic vascular resistance also increased

(P.C: 11.11%), significantly. Right ventricular pressure increased (P.C: 7.31%) significantly. But, the isometric time tension index was not changed.

Before and after the carotid chemoreceptor stimulation, blood gas,

HCO3- and pH were measured and are shown in Table IV. But none of them

were changed by these reflexes.

Table IV. Blood Gas and pH Changes before and after the Carotid Chemoreflex Closed Chest

P.C: Percent change, P: P-value, P-values were calculated using Student's T-test , N: Number of experiments, n.s: not significant, S.D: Standard deviation. Jap. Heart J. 546 SASAKI November, 1973

DISCUSSION

The results indicate that the carotid chemoreceptor stimulation increased pulmonary blood pressure, decreased pulmonary blood flow and increased pulmonary vascular resistance, significantly. Heart rate decreased, but not significantly, by the reflex. Breathing rate increased, significantly by the carotid chemoreflex. Systemic aortic pressure was not changed by the carotid chemoreflex, in the closed chest. Systemic aortic pressure, however, increased and systemic vascular resistance increased, in the open chest. It is natural to consider that the carotid chemoreflex causes hyperrespiration and pulmonary circulatory changes follow, but in our experiments, the carotid chemoreflex caused similar changes about pulmonary circulation both in spontaneous breathing and in artificial ventilation. Above all, we confirmed in the observations that the carotid chemoreflex caused 2 kinds of phenomena such as pulmonary vascular constriction and respiratory changes, because, in both conditions of controlled and uncon- trolled breathing, pulmonary vasoconstriction occurred, with and without respiratory changes. Still more, systemic blood pressure began to rise 0.5-1 sec after the pulmonary circulatory changes. The present observation shows that pulmonary circulatory reflex and systemic circulatory reflex were caused by 2 kinds of reflactory circuits. Numerous investigators have asserted that the carotid chemoreflex makes changes in systemic circulation.10)-12) Comroe and Mortimer showed that stimulation of the carotid bodies characteristically produced bradycardia and hypotension in dogs with controlled breathing, and stimulation of the aortic bodies produced hypertension.13) Bernthal reported that anoxic stimulation of the carotid body causes an extensive peripheral vasoconstriction in limb vasculature in artificially ventilated dogs.14) Present study showed that the carotid chemoreflex caused hyperrespiration and made the changes in systemic arterial pressure but we can not find out any definite changes in dogs spontaneously breathing. Elevation of blood pressure and increases in systemic arterial resistance were caused by the carotid chemoreflex in artificially ventilated dogs. Increases in aortic pressure in the open chest animals suggest secondary effects of the carotid chemoreceptor stimulation and may be influenced by the catecholamine release from the adrenal medulla. Differences of blood catecholamine levels between closed chest animals and open chest animals were examined in previous preexperi- Vol.14 No.6 CAROTID CHEMOREFLEX 547 ments by Weil-Malhelbe and Bone's modified method.7)-9) Aviado et al reported their anoxic stimulation of chemoreceptors in the carotid and aortic bodies. They observed that anoxic stimulation of both chemoreceptors causes pulmonary vasoconstriction but they did not determine whether the observed pulmonary vasoconstriction arose from anoxic stimulation of the carotid body or aortic body.15) Daly and Daly concluded that the carotid chemoreceptor stimulation with their complex perfusion preparation causes pulmonary vasoconstriction.16) Shlomo Stern et al emphasized that in the stimulation of chemoreceptors by nicotine, pulmonary vasoconstriction was caused by the aortic body stimulation but not by the carotid body stimulation,17) as was stressed by Comroe.18) Having not examined the aortic body, we have not much knowledge of the differences between the cardiovascular effects of the aortic body stimulation and those of the carotid body,13),19),20)but the present study shows that the carotid body stimulation can possibly produce pulmonary circulatory changes.

ACKNOWLEDGEMENTS The author thanks Professor M. Hatano and Professor K. Oshima, Nihon University, School of Medicine, for advice and suggestions; Dr. N. Kajiwara and Dr. A. Hayashi for their valuable instructions.

REFERENCES

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