to Regulation of the Brain Vessels

Short Communication Japanese Journal of Physiology, 34,193-197,1984 The Relevance of Cardio-pulmonary-vascular Reflex to Regulation of the Brain Vessels Masatsugu NAKAI and Koichi OGINO Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, Suita, Osaka, 565 Japan Summary In 11 cordotomized (C2) rats with the vagi cut, monopolar electrical stimulation at a current intensity of 73+21 (S.E.) ua (n=6) to the intermediate region of the solitary nucleus elicited an increase (p<0.05) in regional blood flow (iodoantipyrine technique) of 71 % and 43 % in the frontal cortex and caudate nucleus, respectively. The findings suggest that some of the cardio-pulmonary and Cardio-vascular reflex mechanisms are involved in the regulation of the blood vessels of the brain. Key Words: neurogenic control, vasopressin-induced pressor response. Purves and his colleagues (JAMES et al., 1969; PONTE and PURVES, 1974; JAMES and MACDONELL, 1975) first claimed that the cardio-vascular reflexes regulate the blood vessels of the brain. Activation of the baroreceptor and chemoreceptor could thus enhance autoregulatory vasoconstriction induced by increased arterial blood pressure and myogenic vasodilatation elicited by hypoxemia, respectively. Their results, however, have not been widely accepted by other investigators. The investigations reported to date were carried out more or less with physiological stimulation or inhibition of afferent apparatuses of the reflex, i.e., the baro- or chemoreceptor, or their afferent nerves. We thus attempted to demonstrate such regulation of the brain circulation by producing rather unspecific as well as forced activation of the reflex arcs. This activation was carried out by electrical stimulation of the medullary relay station of the reflex arcs, i.e., the intermediate region of the solitary nucleus (SOL). A preliminary account of the present work has been presented at the 60th Annual Meeting of the Physiological Society of Japan (NAKAI and OGINO, 1983). Experiments were conducted on a total of 11 male Wistar rats weighing 306± 7 (S.E.) g. The animals were anesthetized (2% halothane), immobilized (d-tubocurarine, 0.5 mg/kg body weight, i.m.) and artificially ventilated. The cervical Received for publication September 22, 1983 193

194 M. NAKAI and K. OGINO vago-sympathetic trunk was cut bilaterally and the head fixed in a stereotaxic frame. The cervical spinal cord was dissected at C2. Continuous infusion of phenylephrine (407+52 ng/(min 100 g), n=11) through a cannula inserted into the femoral vein served to combat hypotension. On termination of the operative procedures, the anesthetic was switched to a mixture of 60 % N20 and 40 % 02. A time lapse of 1 hr was then allowed as a settling period. The animal's body temperature was maintained at between 37 and 38 C by a heating pad. A monopolar electrode consists of stainless steel wire of 0.1 mm diameter which is insulated with only the cut surface exposed. In the stimulation study, the electrode was introduced into the intermediate region of the SOL. It is difficult in rats to observe moment-to-moment responses of cerebral blood flow. For exploration of the most sensitive site in the SOL, we instead observed the pressor response which is entirely attributable to increased vasopressin release on stimulation in cordotomized rats with cut vagi (NAKAI et al., 1982b). The regional threshold current of the stimulus, which increased the mean arterial blood pressure by 10 mmhg, was determined in the SOL. Intermittent trains (1 sec on/1 sec off) of negative square waves (0.5 msec width; 50 Hz) were then delivered at a current intensity of 2.5 times the threshold to a point within the SOL at which the threshold current was the lowest. One to 2 min after the start of stimulation, the cerebral blood flow was determined. Both in the control and stimulation studies, an antagonist of vasopressin at a dose of 600 ng/100 g i.v. was administered (NAKAI et al., 1982b) prior to the determination of blood flow, since a marked increase in arterial pressure would otherwise be elicited by increased vasopressin release on stimulation of the SOL (NAKAI et al., 1982b). Iodoantipyrine was used to determine the regional blood flow of the brain. Details of the technique have been described elsewhere (NAKAI et al., 1982a). The frontal and occipital cerebral cortices are referred to in the present study as the rostral and caudal cortices, respectively. We sampled the bilateral superior and inferior colliculi as a single mass. The stimulated site in the SOL was later confirmed histologically as described elsewhere (NAKAI et al., 1982a). Table 1 lists the mean arterial pressure and blood gas values monitored shortly before the time of determination of cerebral blood flow. It was found Table 1. Results for mean arterial blood pressure (ABP), carbon dioxide (Paco2) and oxygen (Pao2) tensions, and ph of the arterial blood at the time of determination of cerebral blood flow. Japanese Journal of Physiology

REFLEXOGENIC VASODILATATION OF BRAIN 195 Fig. 1. Vasodilatory effect of electrical stimulation of the intermediate region of the SOL on the brain circulation in cordotomized rats with cut vagi. Rostral and caudal cortices are abbreviated to R, cortex and C. cortex, respectively. Open bars indicate the regional cerebral blood flow (rcbf) in the control study (n=5), and closed bars, that in the stimulation study (n=6). The vertical lines at the tops of the bars indicate the S.E. In the latter study, the stimulus was delivered to the SOL at a current intensity of 73+21 1iA. that there were no statistically significant differences in these parameters between the control and stimulation studies. Figure 1 demonstrates the regional blood flow of the brain in the control and stimulation studies. The stimulus was delivered to the intermediate region of the SOL at a current intensity of 73±21(S.E.),uA (n=6). We previously found that current spread of the stimulus to other structures, which are at least 0.3 mm apart from the SOL, is negligible when the stimulus intensity is less than 200 ua (Yamane et al., 1984; in preparation for publication). In response to the stimulation, the rostral and caudal cortices, colliculi, caudate nucleus, and white matter significantly increased their flow. The cortices responded most sensitively. In other regions of the brain, the regional blood flow showed a slight increase without being statistically significant. Purves and his colleagues (JAMES et al., 1969; PoNTE and PURVES, 1974; JAMES and MACDoNELL,1975) were the first to demonstrate that the cardio-vascular reflexes regulate the blood vessels of the brain. They concluded that inhibition Vol. 34, No. 1, 1984 + indicates statistical significance (p <0.05, unpaired t-test). GT

196 M. NAKAI and K. OGINO of the arterial baroreflex and activation of the chemoreflex lead to an increase in cerebral blood flow. Results obtained by other investigators, however, do not favor this observation (e.g., HEISTAD et al., 1976; HEISTAD and MARCUS, 1976). We consider that these inconsistent results for the effect of reflexes on the brain circulation may reflect the adoption of physiological activation or inhibition of the reflex arcs. Changes in cerebrovascular tone yielded by a change in the functional state of some reflex arcs could be muffled to maintain the brain environment in an unchanged state by possible reciprocal effects of other neural mechanisms which might operate simultaneously. We therefore designed our experiment with a rather unphysiological stimulation of the reflex arc to observe the response in the cerebral blood flow. As a result, the brain, especially the cerebral cortex, increased its blood flow in response to electrical stimulation of the intermediate region of the SOL. This region is known to receive the terminals of afferents of the carotid sinus nerve (CRILL and REIS, 1968; MIURA and REIS, 1969; PANNETON and LOEWY, 1980), and of the aortic nerves (CRILL and REIS, 1968; KUMADA and NAKAJIMA, 1972; WALLACH and LOEWY, 1980). The sensory afferents, which run from the heart or lung and ascend the vagus nerve, also exclusively terminate there (KALIA and MESULAM, 1980). The electrical stimulation of this intermediate region of the SOL in the present study may thus have activated neural integrations which are the ascending efferent limbs of the cardio-vascular and cardio-pulmonary reflex arcs. We speculate, therefore, that some of the reflex arcs regulate the blood vessels of the brain by vasodilatation. Since our study employed electrical stimulation, further work is necessary to eliminate the possibility of antidromic activation of regions other than the SOL. REFERENCES CRILL, W. E. and REIS, D. J. (1968) Distribution of carotid sinus and depressor nerves in cat brain stem. Am. J. Physiol., 214: 269-276. HEISTAD, D. D, and MARCUS, M. L. (1976) Total and regional cerebral blood flow during stimulation of carotid baroreceptors. Stroke, 7: 239-243. HEISTAD, D. D., MARCUS, M. L., EHRHARDT, J. C., and ABBOUD, F. M. (1976) Effect of stimulation of carotid chemoreceptors on total and regional cerebral blood flow. Circ. Res., 38: 20-25. JAMES, I. M. and MACDoNELL, L. A. (1975) The role of baroreceptors and chemoreceptors in the regulation of the cerebral circulation. Clin. Sci. Mol. Med., 49: 465-471. JAMES, I. M., MILLAR, R. A., and PURVES, M. J. (1969) Observations on the extrinsic neuronal control of cerebral blood flow in the baboon. Circ. Res., 25: 77-93. KALIA, M. and MESULAM, M.-M. (1980) Brain stem projections of sensory and motor components of the vagus complex in the cat. II. Laryngeal, tracheobronchial, pulmonary, cardiac, and gastrointestinal branches. J. Comp. Neurol.,193: 467-508. KUMADA, M. and NAKAJIMA, H. (1972) Field potentials evoked in rabbit brainstem by stimulation of the aortic nerve. Am. J. Physiol., 223: 575-582. MIURA, M. and REIS, D. J. (1969) Termination and secondary projections of carotid sinus nerve Japanese Journal of Physiology

REFLEXOGENIC VASODILATATION OF BRAIN 197 in the cat brain stem. Am. J. Physiol., 217; 142-153. NAKAI, M., IADECOLA, C., and REIS, D. J. (1982a) Global cerebral vasodilation by stimulation of rat fastigial cerebellar nucleus. Am. J. Physiol., 243: H226-H235. NAKAI, M. and OGINO, K. (1983) Evidence for cerebrovasodilatory effect of cardiovascular reflex arc as evidenced by electrical stimulation of nucleus tractus solitarius. J. Physiol. Soc. Jpn., 45: 546 (in Japanese with English abstract). NAKAI, M., YAMANE, Y., UMEDA, Y., and OGINO, K. (1982b) Vasopressin-induced pressor response elicited by electrical stimulation of solitary nucleus and dorsal motor nucleus of vagus of rat. Brain Res., 251: 164-168. PANNETON, W. M. and LOEWY, A. D. (1980) Projections of the carotid sinus nerve to the nucleus of the solitary tract in the cat. Brain Res., 191: 239-244. PONTE, J. and PuxvEs, M. J. (1974) The role of the carotid body chemoreceptors and carotid sinus baroreceptors in the control of cerebral blood vessels. J. Physiol. (Land.), 237: 315-340. WALLACH, J. H. and LoEWY, A. D. (1980) Projections of the aortic nerve to the nucleus tractus solitaries in the rabbit. Brain Res., 188: 247-251. Vol. 34, No. 1, 1984