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THE CENTRAL EFFECTS OF ADRENALINE AND NORADRENALINE ON THE BLOOD PRESSURE IN DOG
THE
CENTRAL
ADRENALINE
EFFECTS
OF ADRENALINE
ON THE
BLOOD
PRESSURE
AND
NOR
IN DOG
SHUNJI TACHI Department of Pharmacology, Facultyof Medicine,KyotoUniversity, Kyoto Receivedfor publication,June 12, 1962
Whenever any central effects of catecholamine are studied, the possibility that the amines act indirectly by virtue of their effects upon cerebral blood vessels and flow merits some consideration. The effects of the amines upon these structures were the subjects of a number of research work since 1900's. As might be anticipated, there are many contradictory results in which adrenaline delates the cerebral vessels, constricts them, does both or does neither. Recently, Ingvar and Soderberg (1) have studied the effects of adrenaline and noradrenaline on cerebral flow in cat by measuring the rate of venous outflow of the cannulated superior sagittal sinus. They found that the intra venous adrenaline or noradrenaline produced an increase of the cerebral blood flow, ap parently secondary to the pressor response, and that noradrenaline produced less increase of the flow than adrenaline, and also that the intracarotid injection of noradrenaline caused a brief cerebral vasoconstriction before the pressor effect by the amine manifested, whereas the same procedure of adrenaline caused no initial constriction. Though there is no reason to assume that catecholamines act directly or indirectly on the specific mechanism in the brain, the present experiment was designed to elucidate the correlation between the mode of the cerebral vessels an.d the central sympathetic activity in response to the intravenously administered adrenaline or noradrenaline in the anesthetized dog following the technique of the cross circulation of their head (2). Recently, Polet and De Schaepdryver (3) have devised a modified method of the isolation of head circulation, in which the head circulation of the recipient is completely separated from that of the body with a maintenance of a normally functioning spinal cord. METHODS Dog, weighing 5 to 15 kg of body weight, was anesthetized with the intraperitoneal injection of 50 to 70 mg/kg of amytal sodium. Two dogs were prepared for one experi ment, one dog being donor and the other being recipient. By the longitudinal medico anterior incision of the skin in the neck the anterior neck muscles, trachea and eso phagus were divided with cautery ; the common carotid arteries and the vagus nerves were preserved intact. The trachea was incised in both dogs and was cannulated. The anterior surface of the seventh cervical vertebra was exposed. The soft tissues overly ing the surface of the vertebra were divided. The vertebral arteries and veins of the recipient, so far exposed, were ligated. The ascending cervical artery and vein were
exposed and were ligated bilaterally. Further attempts were tried to ligate the com municating branch between the occipital artery and the vertebral artery, and to clamp the longitudinal vertebral sinuses with a homeostat at the exposed anterior surface of the first vertebra after dissecting the sternothyreoideal, captis lon;us and rectus capitis muscles following the method devised by Kumagai et al. (4). However, due to the dif ficulty of the technique the anterior spinal artery and vein in the vertebral canal were not ligated. The common carotid arteries and the external jugular veins were separated from the connective tissues as extensively as possible. The cranial ends of the vessels of the donor and the caudal ends of the vessels of the recipient were all ligated. Poly vinylethylene tubes with diameter of 2 mm, which were filled with heparin-Ringer solu tion, were inserted into the caudal ends of the vessels of the donor and cranial ends of the vessels of the recipient, respectively. Thus the carotid arteries and jugular veins were connected bilaterally. The femoral arteries of both dogs were prepared for record ing the blood pressure by use of Hg-manometer. For the measurement of the cerebral blood flow the electromagnetic flowmeter was inserted into the carotid arteries. Both dogs were then heparinized. Accordingly, the head circulation of the recipient was supplied by the arterial blood of the donor and the venous blood of the head circulation of the recipient was forced to return to the external jugular veins of the donor. There are some technical and theoretical limitations also inherent in the cross cir culation method when it is used to assess the central action of pharmacological agents. To prevent the escape of blood from the head circulation to body circulation of the recipient all the discriminative vessels in the neck of the recipient were completely ligated. In some of the experiments 10 cc of Evan's blue was administered to the carotid arteries of the recipient, in which any trace of the dye could not be detected in blood of the body circulation. Further evidence to deny the leakage of blood will be described below in relation to the effect of acetylcholine. The drugs used were l-adrenaline hydrochloride, dl-noradrenaline hydrochloride, cocaine hydrochloride, acetylcholine chloride, atropine sulfate, hexamethonium bitartrate, tolazoline chloride and reserpine. They were all injected into the femoral vein or carotid artery. RESULTS I. Effects of Adrenaline, Noradrenaline and Acetylcholine on the Cerebral Flow of the Anesthetized Dog As the preliminary naline, noradrenaline
experiment
and acetylcholine
the effects of the intravenously on the cerebral
administered
adre
blood flow, and the systemic blood
pressure were studied in the lightly anesthetized dog, in which an electromagnetic flow meter was inserted into the common carotid artery. One to 5 ug/kg of adrenaline or noradrenaline concomitant a whole
induced
at first an increase of the cerebral
with the rise of blood pressure.
in proportion
to the rise of the blood pressure.
that at the end of the pressor
flow which
The extent of increase
response the cerebral
seemed certainly of the flow was as
But it was often observed
flow turned
to decrease and lasted
considerably long. The extent of the secondary decrease of the flow was also propor tional to the dose. Both responses of the flow of the a!-nines were not modified by the bilateral vagotomies. There could hardly be found any signi cant difference of the mode of action between adrenaline and noradrenaline. The administration of 3 to 5 mg/kg of tolazoline was enough to abolish the increased flow as well as the rise of blood pressure in response to adrenaline or noradrenaline, but the secondary decrease of the cerebral flow induced by either amine was not modified by the doses of tolazoline. From the results described above the secondary decrease of the cerebral flow seemed to derived from some central effect of adrenaline or noradrenaline, while the primary increase of the flow from the rise of blood pressure. The intracarotid injection of adrenaline or noradrenaline in doses of 1 to 3 ,J/kg produced a considerable rise of blood pressure and a decrease of the cerebral flow follow ed by a secondary increase. The latter effect of the amine on the flow lasted after the termination of the pressor response. Three to 5 mg/kg of tolazoline abolished or reversed not only the decrease but also the increase of the flow. The results show that the changes of the cerebral flow in response to intracarotidally injected amines were dependent on the vasoconstriction induced by the amine. The intravenous injection of acetylcholine caused a decrease of the cerebral flow followed by an increase. The former effect coincided with the fall of the blood pressure. To prove the results were mentioned the fact that both effects of acetylcholine on the flow were abolished by the administration of 1 m-_,/kg of atropine. The intracarotid injection of 1 to 3 p ,/k, of acetylcholine did little affect the blood pressure, while the same procedure increased the cerebral flow considerably. The increase of the cerebral flow was also abolished by the intravenous injection of 1 mg/kg of atropine. Accordingly, the increase of the cerebral flow in response to acetylcholine was regarded to derive from the vasodilation induced by the drug. Effects of the IntravenouslyAdministeredAdrenalineor Nooradrenaline to the Donor on Blood Pressureand Cerebral Flowwof the Recipient The intravenous injection of adrenaline or noradrenaline in dues of 1 to 6 ,ug/kg elicited a considerable rise of blood pressure, which was otherwise subjected to much individual variation. Following the pressor response of the donor the blood pressure of the recipient also rose with a delay of 10 to 30 seconds. Fi;. 1 illustrates the typical response of the donor and recipient to the intravenous injection of 3 gig/kg of adrenaline and 6 ,ug/kg of noradrenaline in the donor. The pressor response of the donor showed a usual pattern, sharp rise and gradual fall, while the same response of the recipient showed a gradual rise and fall, in which the peak of the rise of blood pressure was usually observed during the later half of blood pressure in the donor. The cerebral flow of the recipient showed also a usual pattern of the response to the ainines, an increased flow followed by a decrease. The former effect on the flow lasted much longer than
FIG.
1. and
The
effects
noradrenaline
of
the to the
intravenously donor
on blood
administered pressure.
adrenaline R ; recipient,
D ; donor.
the pressor response of either do. The increase of the cerebral flow and the secondary rise of blood pressure in the recipient was not modified by the bilateral vagotomies. The secondary pressor response of the recipient induced by the intravenous injection in the donor seemed not to relate with the carotid or aortic baroreceptor mechanism. Because of the almost complete separation of the head circulation of the recipient from the body circulation the secondary pressor response of the recipient was supposed to derive from the effect of the amines on some distinct mechanism of the brain or from the increase of the cerebral flow. It was further suggested that these central effects of the amines rri3ht have discharged the peripheral sympathetic amine and caused a rise of blood pressure in the body circulation of the recipient. III
Effects of the IntravenousInjection of Adrenalineor Noradrenaline to the Body Circulationof the Recipienton the Blood Pressure of the Donor The intravenous injection of 1 to 6 p7/kg of adrenaline or no,adrenaline into the body circulation of the recipient was no effect or slightly rose the blood pressure of the donor, though the same prccedure elicited a usual pressor effect in the recipient. In Fig. 2, the slight and gradual rise of blood pressure of the donor in response to the intravenous injection of 3 Sag/kg of adrenaline in the recipient is shown. In contrast to the increased cerebral flow of the recipient in response to the intravenous injection of the amines to the donor, the administration of the amines to the body circulation of the recipient decreased the cerebral flow significantly (Fig. 2). The extent of the decrease of the flow depended on the rise of blood pressure in the recipient. The effects were also not modified by the bilateral vagotomies. It was concluded that the decrease of the cerebral flow caused by the injection of the amines to body circulation of the recipient derived from some central mechanism which was activated and conducted centrally via some nervous pathway by the rise of blood pressure in the body circulation.
FIG. 2.
The to
body
cerebral
effect
of
circulation flow.
the
intravenously of
the
R ; recipient,
administered
recipient
on
blood
adrenaline pressure
and
D ; donor.
IV. Effects of the IntravenousInjectionof HypotensicsDrugs such as Acetylcholine , Hexamethonium and Atropine The intravenous injection of acetylcholine or hexamethonium in doses, which induced a fall of blood pressure about 30 to 50 mmHg in the donor , did not affect the blood pressure of the body circulation of the recipient. The same injection of the drugs to the body circulation of the recipient did not affect the blood pressure of the donor . However, the intravenous injection of 1 mg/kg of atropine in the donor , in which the fall of blood pressure about 40 to 50 mmHg was seen, elicited a slight but gradually progressive fall of blood pressure in the body circulation of the recipient (Fig. 3). The same injection of atropine to the body circulation of the recipient did not affect the blood pressure of the donor (Fig. 4). The intravenous injection of acetylcholine or hexamethonium in the donor decreased the cerebral flow, whereas the same procedure to the body circulation of the recipient
FIG. 3. The effect of intravenous injection of atropine to the donor on blood pressure. R ; recipient, D ; donor.
FIG. 4. The effect of intravenous injection of atropine to body circulation of the recipient on blood pressure. R ; recipient, D ; donor.
did not modify the flow at all. The results that the injection of acetylcholine or hexamethonium to either dog did not produce the usual hypotensive effect in the other dog were strong evidence to deny the leakage of blood between body and head circulation. The depressor response of the body circulation of the recipient to the intravenous injection of atropine in the donor also showed some central effect of atropine on the blood pressure of body circulation. V. Effects of Cocaineand Tolazolineon the PressorResponseof Body Circulationof the Recipient to the IntravenousInjection of Adrenalineto the Donor The intravenous injection of 5 to 10 mg/kg of tolazoline in the donor reversed the pressor response of the donor to adrenaline and depressed the same response to nor adrenaline. Besides, after the manifestation of the adrenolytic effect of the drug in the donor the secondary pressor response of the recipint to the intravenous injection of the amines in the donor disappeared totally. The administration of 1 mg/kg of cocaine in the donor or to the body circulation of the recipient potentiated the pressor response of the recipient to the intravenous in jection of the amines in the donor. From the results obtained above it was suggested that the pressor response of the intravenous injection of adrenaline or noradrenaline in the donor was derived from the increased release of preripheral catecholamine induced by the central effect of adrena line or noradrenaline.
1.I. Effects of the IntravenousInjection of Reserpincon the Pressor Responseof the Body Circula tion of the Recipientto the IntravenousInjection of Adrenalineor Noradrenaline to the Donor The intravenous injection of 1 m-/kg of reserpine in the donor elicited a gradually progressive rise of blood pressure not only in the donor but also to the body circula tion of the recipient. The pressor response of the donor was usually very slight and in some preparations the depressor response of donor was observed. On the other hand, the blood pressure of the body circ lation of the recipient always rose in response to the injection of the a-nines to the donor. Thou ,h the pressor response of the donor to the intravenous inject icn of adrenaline was somewhat depressed by the intravenous in jection of reserpine in the donor and the same esponse to the same procedure of nsr adrenaline was little affected, the pressor response of the recipient disappeared almost totally. However, 30 minutes or more actor the injection of reserpine the pressor response of the donor and the recipient to the intravenous injection of adrenaline or nsradrena line in the donor increased considerably. The pressor response of the body circulation of the recipient to the intravenous in jection of reserpine in the donor was supposed to relate with the release of catecholamine in the brain or with the increased concentration of catecholamines in the circulating blood of the donor. It was likely that at the early phase of reserpine action the pressor responses of the recipient and the donor were depressed by the increased level of the circulating noradrenaline and adrenaline released by reserpine or by the adrenolytic effect of reserpine, while at the later phase of reserpine action the pressor responses of either dog were sensitized by the reduction of catecholamine in the tissues. DISCUSSION The detailed distribution study of mradrenaline in the brain of dog (5) has shown that the concentration of the amine in the brain was quite uneven and the highest concentration was found in the hypothalamus, which was generally known as the site of autonomic center. Though adrenaline or ncradrenaline exhibits some vascular effect in the brain, it is believed that the amines have other pharmacological effects on the cerebral mechanism. Bonvallet et al. (6), Dell et al. (7) and Rothballer (8) showed that adrenaline or noradrenaline induced an arousal of the animal by stimulation of the ascending activating system of the reticular formation. But this effect was only seen in the non-anesthetized animal. Torii (9) in this laboratory showed that the intra venous injection of 1 mg/ka, of reserpine in urethanized rabbits abolished the pressor response of the animal to stimulation of the thalamic nuclei, but the intracarotid injec tion of 0.1 m2/kg of reserpine did not abolish the same response. He also showed that the intracarotid injection of reserpine in rabbit induced a slight motoric and sympathetic excitement in contrast to a usual sedation by reserpine given intravenously. Besides, Vogt and Holzhauer (10) postulated that the central effects of a series of central stimulants were closely related to the excitability of the sympathetic center, which was measured as the decrease of catecholamines in the innervated adrenal glands. In this experiments
the central effects of adrenaline and noradrenaline on the cerebral flow and blood pres sure were studied in the anesthetized dog, of which head circulation was supplied with the blood of other dog and consequently of which head circulation was separated from the body circulation. The reliability of the cross circulation experiment is supposed to consist mainly in the complete prevention of leakage of blood from the donor to the recipient or vice versa. In this experiment the leakage of blood was denied from the results that Evans' blue injected into the donor was not detected in the blood of body circulation of the recipient, and that the injections of acetylcholine and hexamethonium to the donor, in which marked fall of blood pressure was obtained, did not affected blood pressure of the body circulation of the recipient. The intravenous injection of adrenaline or noradrenaline in the doses, which elicited a considerable rise of blood pressure in the donor, rose the blood pressure of body cir culation of the recipient and increased the cerebral flow. The gradual rise and fall of blood pressure in the recipient were good contrast to the sharp rise and gradual fall of blood pressure in the donor. Though the pressor respronse of the -recipient to the injection of the amines in the donor was subjected to an individual variation, the extent of the rise and duration of the response depended on the dose of the amine or on the extent of the pressor response of the donor. On the other hand, the injection of the amine to the body circulation of the recipient did little affect the blood pressure of the donor. Therefore, it might be concluded that the pressor response of the recipient to the injection of amines in the donor was derived from some central effect of these catecholamines which was discharged peripherally via some nervous pathway. This conclusion was further supported by the results that the cocainization of the recipient or donor potentiated the pressor response of the recipient to the injection of the amines in the donor, and that the tolazolinization of the recipient or donor abolished the same response of the recipient. Using the head circulation praparation of 'dog Yui (11) show ed that the intracrotid injection of adrenaline in donor produced a hypotensive response of the body circulation of the recipient. He concluded that the hypotensive effect was derived from the inhibitory effect of adrenaline on the ' central structures.' Though he questioned that the pressor response of the body circulation of the recipient was definite ly derived from the leakage of blood from the head circulation to the body circulation, the intravenous injection of adrenaline to the donor in the present experiment produced not a decrease but an increase of the cerebral blood flow accompanied with the secondary pressor response of the body circulation of the recipient. The intravenous injection of the amines to the donor induced a usual pattern of the cerebral flow, an increase followed by a decrease. The same procedure of the amines to the body circulation of the recipient, on the contrary, decreased the cerebral flow relatively long. Whether the change of the cerebral flow primarily cause the peripheral discharge of the sympathetic nervous system or not was not elucidated from the present experiment.
The pressor response of body circulation of the recipient to the injection of reser pine in the donor was supposed to relate with the release of catecholamine in the brain or with the increased concentration of catecholamine in the circulating blood of the brain. During the early phase after the injection of reserpine the intravenous injection of adrenaline or noradrenaline in the donor did not increase but decrease the pressor response of the body circulation of the recipient. This result might show that some biochemical effect of reserpine on the brain prevents the manifestation of the effect of adrenaline or noradrenaline in the brain. Because 30 minutes or more after the injec tion of reserpine when the central amine was fully depleted by reserpine (12, 13) the pressor response of body circulation of the recipient to the intravenous injection of the amines increased considerably. CONCLUSION The central effects of the intravenous injection of adrenaline and noradrenaline on the blood pressure and the cerebral flow were studied in the dog, of which head cir culation was supplied with the blood of other dog. 1. The intravenous injection of adrenaline or noradrenaline increased the cerebral flow followed by a decrease, while the intracarotid injection of either amine decreased the flow followed by an increase. 2. The intravenous injection of either amine in the donor elevated the blood pressure of the body circulation of the recipient. The effect was potentiated by the cocainization of the donor or the recipient and was blocked by the tolazolinization of either animal. The intravenous injection of either amine to the body circulation of the recipient did not affect the blood pressure of the donor, but the same procedure decreased the cerebral flow significantly. 3. Though the administration of acetylcholine or hexamethonium in the donor did not affect the blood pressure of body circulation of the recipient, the same procedure of atropine in the donor induce a fall of blood pressure of the body circulation of the recipient. 4. The intravenous administration of reserpine in the donor induced a slight but prolonged elevation of blood pressure of the body circulation of the recipient. At the early phase of reserpine action the intravenous injection of either amine in the donor did not affect the blood pressure of the body circulation of the recipient, but at the late phase of reserpine action the same response was considerably potentiated. REFERENCES 1) INGVAR, D.H. ANDSODERBERG, U.: Electroenceph. din. 1Veurophysiol. 8, 403 (1956) 2) NOVAK, S.J.D.ANDSAMAAN, A. : Arch.int. Pharmacodyn. 51, 206 (1935) 3) POLET,H. ANDDE SCHAEPDRYVER, A.F.: Ibid.118, 231 (1958) 4) KUMAGAI, H., YUI,T., OGAWA, K. ANDOHGA,A. : Foliapharmacol. japon.50, 142 (1954) 5) VOGT,M. : J. Physiol.123,451 (1954)
6) BONVALLET,M., DELL, P. AND HIEBEL, G. : Electroenceph.clin. Neurophysiol.6, 119 (1954) 7) DELL, P., BONVALLET,M. AND HUGELIN, A. : Ibid. 6, 599 (1954)8 ) ROTHBALLER,A.B. : Ibid. 8, 608 (1956) 9) TOM, H. : Folia pharmacol. japon. 55, 1227 (1959) 10) VOGT, M. AND HOLZBAUER,M. : Pharmacol. Rev. 11, 483 (1959) 11) YUI, T. : Folia pharmacol. japon. 50, 602 (1954) 12) HIGUCHI, H.: THIS JOURNAL 12, 34 (1962) 13) HIGUCHI, H., MATSUO,T. AND SHIMAMOTO,K. : Ibid. 12, 48 (1962)
CENTRAL
ADRENALINE
EFFECTS
OF ADRENALINE
ON THE
BLOOD
PRESSURE
AND
NOR
IN DOG
SHUNJI TACHI Department of Pharmacology, Facultyof Medicine,KyotoUniversity, Kyoto Receivedfor publication,June 12, 1962
Whenever any central effects of catecholamine are studied, the possibility that the amines act indirectly by virtue of their effects upon cerebral blood vessels and flow merits some consideration. The effects of the amines upon these structures were the subjects of a number of research work since 1900's. As might be anticipated, there are many contradictory results in which adrenaline delates the cerebral vessels, constricts them, does both or does neither. Recently, Ingvar and Soderberg (1) have studied the effects of adrenaline and noradrenaline on cerebral flow in cat by measuring the rate of venous outflow of the cannulated superior sagittal sinus. They found that the intra venous adrenaline or noradrenaline produced an increase of the cerebral blood flow, ap parently secondary to the pressor response, and that noradrenaline produced less increase of the flow than adrenaline, and also that the intracarotid injection of noradrenaline caused a brief cerebral vasoconstriction before the pressor effect by the amine manifested, whereas the same procedure of adrenaline caused no initial constriction. Though there is no reason to assume that catecholamines act directly or indirectly on the specific mechanism in the brain, the present experiment was designed to elucidate the correlation between the mode of the cerebral vessels an.d the central sympathetic activity in response to the intravenously administered adrenaline or noradrenaline in the anesthetized dog following the technique of the cross circulation of their head (2). Recently, Polet and De Schaepdryver (3) have devised a modified method of the isolation of head circulation, in which the head circulation of the recipient is completely separated from that of the body with a maintenance of a normally functioning spinal cord. METHODS Dog, weighing 5 to 15 kg of body weight, was anesthetized with the intraperitoneal injection of 50 to 70 mg/kg of amytal sodium. Two dogs were prepared for one experi ment, one dog being donor and the other being recipient. By the longitudinal medico anterior incision of the skin in the neck the anterior neck muscles, trachea and eso phagus were divided with cautery ; the common carotid arteries and the vagus nerves were preserved intact. The trachea was incised in both dogs and was cannulated. The anterior surface of the seventh cervical vertebra was exposed. The soft tissues overly ing the surface of the vertebra were divided. The vertebral arteries and veins of the recipient, so far exposed, were ligated. The ascending cervical artery and vein were
exposed and were ligated bilaterally. Further attempts were tried to ligate the com municating branch between the occipital artery and the vertebral artery, and to clamp the longitudinal vertebral sinuses with a homeostat at the exposed anterior surface of the first vertebra after dissecting the sternothyreoideal, captis lon;us and rectus capitis muscles following the method devised by Kumagai et al. (4). However, due to the dif ficulty of the technique the anterior spinal artery and vein in the vertebral canal were not ligated. The common carotid arteries and the external jugular veins were separated from the connective tissues as extensively as possible. The cranial ends of the vessels of the donor and the caudal ends of the vessels of the recipient were all ligated. Poly vinylethylene tubes with diameter of 2 mm, which were filled with heparin-Ringer solu tion, were inserted into the caudal ends of the vessels of the donor and cranial ends of the vessels of the recipient, respectively. Thus the carotid arteries and jugular veins were connected bilaterally. The femoral arteries of both dogs were prepared for record ing the blood pressure by use of Hg-manometer. For the measurement of the cerebral blood flow the electromagnetic flowmeter was inserted into the carotid arteries. Both dogs were then heparinized. Accordingly, the head circulation of the recipient was supplied by the arterial blood of the donor and the venous blood of the head circulation of the recipient was forced to return to the external jugular veins of the donor. There are some technical and theoretical limitations also inherent in the cross cir culation method when it is used to assess the central action of pharmacological agents. To prevent the escape of blood from the head circulation to body circulation of the recipient all the discriminative vessels in the neck of the recipient were completely ligated. In some of the experiments 10 cc of Evan's blue was administered to the carotid arteries of the recipient, in which any trace of the dye could not be detected in blood of the body circulation. Further evidence to deny the leakage of blood will be described below in relation to the effect of acetylcholine. The drugs used were l-adrenaline hydrochloride, dl-noradrenaline hydrochloride, cocaine hydrochloride, acetylcholine chloride, atropine sulfate, hexamethonium bitartrate, tolazoline chloride and reserpine. They were all injected into the femoral vein or carotid artery. RESULTS I. Effects of Adrenaline, Noradrenaline and Acetylcholine on the Cerebral Flow of the Anesthetized Dog As the preliminary naline, noradrenaline
experiment
and acetylcholine
the effects of the intravenously on the cerebral
administered
adre
blood flow, and the systemic blood
pressure were studied in the lightly anesthetized dog, in which an electromagnetic flow meter was inserted into the common carotid artery. One to 5 ug/kg of adrenaline or noradrenaline concomitant a whole
induced
at first an increase of the cerebral
with the rise of blood pressure.
in proportion
to the rise of the blood pressure.
that at the end of the pressor
flow which
The extent of increase
response the cerebral
seemed certainly of the flow was as
But it was often observed
flow turned
to decrease and lasted
considerably long. The extent of the secondary decrease of the flow was also propor tional to the dose. Both responses of the flow of the a!-nines were not modified by the bilateral vagotomies. There could hardly be found any signi cant difference of the mode of action between adrenaline and noradrenaline. The administration of 3 to 5 mg/kg of tolazoline was enough to abolish the increased flow as well as the rise of blood pressure in response to adrenaline or noradrenaline, but the secondary decrease of the cerebral flow induced by either amine was not modified by the doses of tolazoline. From the results described above the secondary decrease of the cerebral flow seemed to derived from some central effect of adrenaline or noradrenaline, while the primary increase of the flow from the rise of blood pressure. The intracarotid injection of adrenaline or noradrenaline in doses of 1 to 3 ,J/kg produced a considerable rise of blood pressure and a decrease of the cerebral flow follow ed by a secondary increase. The latter effect of the amine on the flow lasted after the termination of the pressor response. Three to 5 mg/kg of tolazoline abolished or reversed not only the decrease but also the increase of the flow. The results show that the changes of the cerebral flow in response to intracarotidally injected amines were dependent on the vasoconstriction induced by the amine. The intravenous injection of acetylcholine caused a decrease of the cerebral flow followed by an increase. The former effect coincided with the fall of the blood pressure. To prove the results were mentioned the fact that both effects of acetylcholine on the flow were abolished by the administration of 1 m-_,/kg of atropine. The intracarotid injection of 1 to 3 p ,/k, of acetylcholine did little affect the blood pressure, while the same procedure increased the cerebral flow considerably. The increase of the cerebral flow was also abolished by the intravenous injection of 1 mg/kg of atropine. Accordingly, the increase of the cerebral flow in response to acetylcholine was regarded to derive from the vasodilation induced by the drug. Effects of the IntravenouslyAdministeredAdrenalineor Nooradrenaline to the Donor on Blood Pressureand Cerebral Flowwof the Recipient The intravenous injection of adrenaline or noradrenaline in dues of 1 to 6 ,ug/kg elicited a considerable rise of blood pressure, which was otherwise subjected to much individual variation. Following the pressor response of the donor the blood pressure of the recipient also rose with a delay of 10 to 30 seconds. Fi;. 1 illustrates the typical response of the donor and recipient to the intravenous injection of 3 gig/kg of adrenaline and 6 ,ug/kg of noradrenaline in the donor. The pressor response of the donor showed a usual pattern, sharp rise and gradual fall, while the same response of the recipient showed a gradual rise and fall, in which the peak of the rise of blood pressure was usually observed during the later half of blood pressure in the donor. The cerebral flow of the recipient showed also a usual pattern of the response to the ainines, an increased flow followed by a decrease. The former effect on the flow lasted much longer than
FIG.
1. and
The
effects
noradrenaline
of
the to the
intravenously donor
on blood
administered pressure.
adrenaline R ; recipient,
D ; donor.
the pressor response of either do. The increase of the cerebral flow and the secondary rise of blood pressure in the recipient was not modified by the bilateral vagotomies. The secondary pressor response of the recipient induced by the intravenous injection in the donor seemed not to relate with the carotid or aortic baroreceptor mechanism. Because of the almost complete separation of the head circulation of the recipient from the body circulation the secondary pressor response of the recipient was supposed to derive from the effect of the amines on some distinct mechanism of the brain or from the increase of the cerebral flow. It was further suggested that these central effects of the amines rri3ht have discharged the peripheral sympathetic amine and caused a rise of blood pressure in the body circulation of the recipient. III
Effects of the IntravenousInjection of Adrenalineor Noradrenaline to the Body Circulationof the Recipienton the Blood Pressure of the Donor The intravenous injection of 1 to 6 p7/kg of adrenaline or no,adrenaline into the body circulation of the recipient was no effect or slightly rose the blood pressure of the donor, though the same prccedure elicited a usual pressor effect in the recipient. In Fig. 2, the slight and gradual rise of blood pressure of the donor in response to the intravenous injection of 3 Sag/kg of adrenaline in the recipient is shown. In contrast to the increased cerebral flow of the recipient in response to the intravenous injection of the amines to the donor, the administration of the amines to the body circulation of the recipient decreased the cerebral flow significantly (Fig. 2). The extent of the decrease of the flow depended on the rise of blood pressure in the recipient. The effects were also not modified by the bilateral vagotomies. It was concluded that the decrease of the cerebral flow caused by the injection of the amines to body circulation of the recipient derived from some central mechanism which was activated and conducted centrally via some nervous pathway by the rise of blood pressure in the body circulation.
FIG. 2.
The to
body
cerebral
effect
of
circulation flow.
the
intravenously of
the
R ; recipient,
administered
recipient
on
blood
adrenaline pressure
and
D ; donor.
IV. Effects of the IntravenousInjectionof HypotensicsDrugs such as Acetylcholine , Hexamethonium and Atropine The intravenous injection of acetylcholine or hexamethonium in doses, which induced a fall of blood pressure about 30 to 50 mmHg in the donor , did not affect the blood pressure of the body circulation of the recipient. The same injection of the drugs to the body circulation of the recipient did not affect the blood pressure of the donor . However, the intravenous injection of 1 mg/kg of atropine in the donor , in which the fall of blood pressure about 40 to 50 mmHg was seen, elicited a slight but gradually progressive fall of blood pressure in the body circulation of the recipient (Fig. 3). The same injection of atropine to the body circulation of the recipient did not affect the blood pressure of the donor (Fig. 4). The intravenous injection of acetylcholine or hexamethonium in the donor decreased the cerebral flow, whereas the same procedure to the body circulation of the recipient
FIG. 3. The effect of intravenous injection of atropine to the donor on blood pressure. R ; recipient, D ; donor.
FIG. 4. The effect of intravenous injection of atropine to body circulation of the recipient on blood pressure. R ; recipient, D ; donor.
did not modify the flow at all. The results that the injection of acetylcholine or hexamethonium to either dog did not produce the usual hypotensive effect in the other dog were strong evidence to deny the leakage of blood between body and head circulation. The depressor response of the body circulation of the recipient to the intravenous injection of atropine in the donor also showed some central effect of atropine on the blood pressure of body circulation. V. Effects of Cocaineand Tolazolineon the PressorResponseof Body Circulationof the Recipient to the IntravenousInjection of Adrenalineto the Donor The intravenous injection of 5 to 10 mg/kg of tolazoline in the donor reversed the pressor response of the donor to adrenaline and depressed the same response to nor adrenaline. Besides, after the manifestation of the adrenolytic effect of the drug in the donor the secondary pressor response of the recipint to the intravenous injection of the amines in the donor disappeared totally. The administration of 1 mg/kg of cocaine in the donor or to the body circulation of the recipient potentiated the pressor response of the recipient to the intravenous in jection of the amines in the donor. From the results obtained above it was suggested that the pressor response of the intravenous injection of adrenaline or noradrenaline in the donor was derived from the increased release of preripheral catecholamine induced by the central effect of adrena line or noradrenaline.
1.I. Effects of the IntravenousInjection of Reserpincon the Pressor Responseof the Body Circula tion of the Recipientto the IntravenousInjection of Adrenalineor Noradrenaline to the Donor The intravenous injection of 1 m-/kg of reserpine in the donor elicited a gradually progressive rise of blood pressure not only in the donor but also to the body circula tion of the recipient. The pressor response of the donor was usually very slight and in some preparations the depressor response of donor was observed. On the other hand, the blood pressure of the body circ lation of the recipient always rose in response to the injection of the a-nines to the donor. Thou ,h the pressor response of the donor to the intravenous inject icn of adrenaline was somewhat depressed by the intravenous in jection of reserpine in the donor and the same esponse to the same procedure of nsr adrenaline was little affected, the pressor response of the recipient disappeared almost totally. However, 30 minutes or more actor the injection of reserpine the pressor response of the donor and the recipient to the intravenous injection of adrenaline or nsradrena line in the donor increased considerably. The pressor response of the body circulation of the recipient to the intravenous in jection of reserpine in the donor was supposed to relate with the release of catecholamine in the brain or with the increased concentration of catecholamines in the circulating blood of the donor. It was likely that at the early phase of reserpine action the pressor responses of the recipient and the donor were depressed by the increased level of the circulating noradrenaline and adrenaline released by reserpine or by the adrenolytic effect of reserpine, while at the later phase of reserpine action the pressor responses of either dog were sensitized by the reduction of catecholamine in the tissues. DISCUSSION The detailed distribution study of mradrenaline in the brain of dog (5) has shown that the concentration of the amine in the brain was quite uneven and the highest concentration was found in the hypothalamus, which was generally known as the site of autonomic center. Though adrenaline or ncradrenaline exhibits some vascular effect in the brain, it is believed that the amines have other pharmacological effects on the cerebral mechanism. Bonvallet et al. (6), Dell et al. (7) and Rothballer (8) showed that adrenaline or noradrenaline induced an arousal of the animal by stimulation of the ascending activating system of the reticular formation. But this effect was only seen in the non-anesthetized animal. Torii (9) in this laboratory showed that the intra venous injection of 1 mg/ka, of reserpine in urethanized rabbits abolished the pressor response of the animal to stimulation of the thalamic nuclei, but the intracarotid injec tion of 0.1 m2/kg of reserpine did not abolish the same response. He also showed that the intracarotid injection of reserpine in rabbit induced a slight motoric and sympathetic excitement in contrast to a usual sedation by reserpine given intravenously. Besides, Vogt and Holzhauer (10) postulated that the central effects of a series of central stimulants were closely related to the excitability of the sympathetic center, which was measured as the decrease of catecholamines in the innervated adrenal glands. In this experiments
the central effects of adrenaline and noradrenaline on the cerebral flow and blood pres sure were studied in the anesthetized dog, of which head circulation was supplied with the blood of other dog and consequently of which head circulation was separated from the body circulation. The reliability of the cross circulation experiment is supposed to consist mainly in the complete prevention of leakage of blood from the donor to the recipient or vice versa. In this experiment the leakage of blood was denied from the results that Evans' blue injected into the donor was not detected in the blood of body circulation of the recipient, and that the injections of acetylcholine and hexamethonium to the donor, in which marked fall of blood pressure was obtained, did not affected blood pressure of the body circulation of the recipient. The intravenous injection of adrenaline or noradrenaline in the doses, which elicited a considerable rise of blood pressure in the donor, rose the blood pressure of body cir culation of the recipient and increased the cerebral flow. The gradual rise and fall of blood pressure in the recipient were good contrast to the sharp rise and gradual fall of blood pressure in the donor. Though the pressor respronse of the -recipient to the injection of the amines in the donor was subjected to an individual variation, the extent of the rise and duration of the response depended on the dose of the amine or on the extent of the pressor response of the donor. On the other hand, the injection of the amine to the body circulation of the recipient did little affect the blood pressure of the donor. Therefore, it might be concluded that the pressor response of the recipient to the injection of amines in the donor was derived from some central effect of these catecholamines which was discharged peripherally via some nervous pathway. This conclusion was further supported by the results that the cocainization of the recipient or donor potentiated the pressor response of the recipient to the injection of the amines in the donor, and that the tolazolinization of the recipient or donor abolished the same response of the recipient. Using the head circulation praparation of 'dog Yui (11) show ed that the intracrotid injection of adrenaline in donor produced a hypotensive response of the body circulation of the recipient. He concluded that the hypotensive effect was derived from the inhibitory effect of adrenaline on the ' central structures.' Though he questioned that the pressor response of the body circulation of the recipient was definite ly derived from the leakage of blood from the head circulation to the body circulation, the intravenous injection of adrenaline to the donor in the present experiment produced not a decrease but an increase of the cerebral blood flow accompanied with the secondary pressor response of the body circulation of the recipient. The intravenous injection of the amines to the donor induced a usual pattern of the cerebral flow, an increase followed by a decrease. The same procedure of the amines to the body circulation of the recipient, on the contrary, decreased the cerebral flow relatively long. Whether the change of the cerebral flow primarily cause the peripheral discharge of the sympathetic nervous system or not was not elucidated from the present experiment.
The pressor response of body circulation of the recipient to the injection of reser pine in the donor was supposed to relate with the release of catecholamine in the brain or with the increased concentration of catecholamine in the circulating blood of the brain. During the early phase after the injection of reserpine the intravenous injection of adrenaline or noradrenaline in the donor did not increase but decrease the pressor response of the body circulation of the recipient. This result might show that some biochemical effect of reserpine on the brain prevents the manifestation of the effect of adrenaline or noradrenaline in the brain. Because 30 minutes or more after the injec tion of reserpine when the central amine was fully depleted by reserpine (12, 13) the pressor response of body circulation of the recipient to the intravenous injection of the amines increased considerably. CONCLUSION The central effects of the intravenous injection of adrenaline and noradrenaline on the blood pressure and the cerebral flow were studied in the dog, of which head cir culation was supplied with the blood of other dog. 1. The intravenous injection of adrenaline or noradrenaline increased the cerebral flow followed by a decrease, while the intracarotid injection of either amine decreased the flow followed by an increase. 2. The intravenous injection of either amine in the donor elevated the blood pressure of the body circulation of the recipient. The effect was potentiated by the cocainization of the donor or the recipient and was blocked by the tolazolinization of either animal. The intravenous injection of either amine to the body circulation of the recipient did not affect the blood pressure of the donor, but the same procedure decreased the cerebral flow significantly. 3. Though the administration of acetylcholine or hexamethonium in the donor did not affect the blood pressure of body circulation of the recipient, the same procedure of atropine in the donor induce a fall of blood pressure of the body circulation of the recipient. 4. The intravenous administration of reserpine in the donor induced a slight but prolonged elevation of blood pressure of the body circulation of the recipient. At the early phase of reserpine action the intravenous injection of either amine in the donor did not affect the blood pressure of the body circulation of the recipient, but at the late phase of reserpine action the same response was considerably potentiated. REFERENCES 1) INGVAR, D.H. ANDSODERBERG, U.: Electroenceph. din. 1Veurophysiol. 8, 403 (1956) 2) NOVAK, S.J.D.ANDSAMAAN, A. : Arch.int. Pharmacodyn. 51, 206 (1935) 3) POLET,H. ANDDE SCHAEPDRYVER, A.F.: Ibid.118, 231 (1958) 4) KUMAGAI, H., YUI,T., OGAWA, K. ANDOHGA,A. : Foliapharmacol. japon.50, 142 (1954) 5) VOGT,M. : J. Physiol.123,451 (1954)
6) BONVALLET,M., DELL, P. AND HIEBEL, G. : Electroenceph.clin. Neurophysiol.6, 119 (1954) 7) DELL, P., BONVALLET,M. AND HUGELIN, A. : Ibid. 6, 599 (1954)8 ) ROTHBALLER,A.B. : Ibid. 8, 608 (1956) 9) TOM, H. : Folia pharmacol. japon. 55, 1227 (1959) 10) VOGT, M. AND HOLZBAUER,M. : Pharmacol. Rev. 11, 483 (1959) 11) YUI, T. : Folia pharmacol. japon. 50, 602 (1954) 12) HIGUCHI, H.: THIS JOURNAL 12, 34 (1962) 13) HIGUCHI, H., MATSUO,T. AND SHIMAMOTO,K. : Ibid. 12, 48 (1962)