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Effects of drugs interfering with the metabolism of octopamine on blood pressure of rats
Cony. Biochem. Physiol. Vol. 72C, No. 1. pp. 153-157, 1982 Printed in Great Britain
0306492/82!030153-05~3.00/0 0 1982 Pcrgamon Press Ltd
SHORT COMMUNICATION EFFECTS OF DRUGS INTERFERING WITH THE METABOLISM OF OCTOPAMINE ON BLOOD PRESSURE OF RATS BERNARD DELBARRE,
GIS~LEDELBARRE,DANIELLECASSET-SENON and PATRICIASESTILLANGE
Chir. Exp. Lab.. Faculte de MCdecine. 37032 Tours Cedex, France (Received 7 June 1981)
Abstract-l. pOctopamine injected in lateral ventricle of conscious spontaneously hypertensive rats decreased systolic blood pressure @BP). 2. Precursors of octopamine-tyrosine. tyramine and phenylethanolamine (PEAkhad the same effect. The administration of pargyline. a MAO inhibitor, which increased brain octopamine, resulted in a reduction of systolic blood pressure; and this decrease was ereater after administration of octonamine _ precursors and PEA. 3. Similarly, drugs known to inhibit activity of phenylethanolamine N-methyl-transferase (PNMT) and to increase brain octonamine level such as SKF 64139 and DCMB decreased SBP. 4. p-Octopamine hypot&sion was not antagonized by piperoxan, yohimbine and prazosin, a relatively selective antagonist of post-synaptic K adrenoceptors. 5. These results suggest that octopamine may be involved in central blood pressure regulation, and the receptors sensitive to octopamine appeared to be distinct from those receptive to the catecholamines.
INTRODUCTION Recently, p-octopamine, m-octopamine and phenylethanolamine had been found to have higher levels in brain of spontaneously hypertensive rats (SHR) than in those of normotensive rats (David, 1978). In our previous work, we have shown that. injected in the lateral ventricle and the cistema magna of SHR, p-octopamine induces dose-dependent falls of blood pressure (BP), (Delbarre et al., 1980). In the present study, we have investigated the cardiovascular actions of the precursors of octopamine, tyrosine, tyramine in conscious SHR, and in conscious experimental hypertensive rats. Moreover, an increase of rat brain octopamine had
been reported after pargyline administration (Brandau & Axelrod. 1972), and after phenylethanolamineN-methyl-transferase (PNMT) inhibition by SKF 64139 (Da Prada er al., 1979). This finding prompted us to study, in conscious SHR, the cardiovascular responses of pargyline, a monoamineoxidase(MAO)inhibitor,andoftwoPNMT inhibitors such as SKF 64139 (7,8 dichloro1,2,3,4-tetrahydroisoquinoline hydrochloride) and DCMB (23-dichloro-a-methyl-benzylamine hydrochloride), interfering with the metabolism of this amine. The high rate of turnover of octopamine in spite of low tissue concentrations prompted us to compare the cardiovascular effects of p-octopamine, m-octopamine and phe-nylethanolamine (PEA) with noradrenaline when these amines were administered at the same dose in lateral ventricle of conscious SHR. Moreover, Jagiello-Wojtowicz (1979) had found ihat the stimulatory effect of octopamine is realized 153
through catecholaminergic neurones. So it seemed interesting to determine if the effects of octopamine were abolished by adrenoceptor-blocking drugs. Previous work, in conscious cats, had shown that presynaptic a-adrenoceptor blocking agents such as yohimbine and piperoxan did not antagonize the octopamine-induced hypotension (Casset-Senon et a!., 1980). In this study, we have investigated the modification of central cardiovascular effects of poctopamine by using prazosin, a relatively selective antagonist of post-synaptic a-adrenoceptors, in conscious SHR. MATERIALSAND METHODS Male SHR, supplied by the Centre d’Elevage du C.N.R.S. (Orleans) and male rats of Wistar strain were used. Renal hypertension was induced in Wistar rats by applying a solid silver clip with an i.d. of 0.20mm on the left renal artery, leaving the right kidney untouched (Leencn & de Jong, 1971). Blood pressure increased. A month later, the rats were tested, and only animals exhibiting hypertension were used for experiment. Systolic blood pressure (SBP) of unanesthetized rats were measured by two types of methods. In the first time, we have determined SBP with an indirect pneumatic pulse pressure transducer (Narco-Biosystem. Houston) in which the rats were heated at 32°C for measurement. In a second time of experiment, SBP .was measuring with a photoelectric system using tail pulsations at temperatures such as 25-28°C (IITC. Inc. Mod. 59. NJ). This new method had been reported to be better, because it does not require the heating of animals and avoids the effect of heating on SBP of SHR. Indeed, we have observed that drugs like phenylethanolamine (PEA), which increases body temperature, induced
154
Short Communication
Short Communication mortality in rats after heating for SBP measurement; these effects were not so pronounced with SBP photoelectric system. A mean value from at least six consecutive readings for each animal were used for computation. The drugs were: SKF 64139 (7,8-dichloro-1,2.3.4-tetrahydroisoquinoline hydrochloride) Smith-Kline & French: DCMB (2,3-dichloro-a-methyl-benzylamine hydrochloride) Lilly Research Lab; pargyline (Abbott); tyramine HCl, DLphenylethanolamine, t-tyrosine methyl ester HCI (Sigma), p-octopamine (Sigma), m-octopamine (Sigma), noradrenaline (Sigma) and prazosin (Pfizer). Drugs were administered intraperitoneally. but p-octopamine. m-octopamine, phenylethanolamine and noradrenaline were also injected in lateral ventricle (constant volume of IOpt). Statistical analysis of the data presented in this paper was based upon Student’s r-test for paired samples. Differences for which P was co.05 were considered significant.
of precursors alone
Eflects qfphen!,let/ta,lolamine i.p. and p-octopamiue i.p.
By using heated method, other
biogenic
amine.
we found that PEA, and at the dose of 25 mg:kg i.p..
induced a significant decrease of SBP in SHR. The use of this amine in association with pargyline induced mortality of rats. But with the photoelectric measure system. phenylethanolamine. at the dose of 5 mg,kg i.p.. was found to have more potent hypotensive effect. 1 hr after administration. After pretreatment with pargyline. this amine induced a long-lasting hypotensive action (more than 4 hr). As we have shown in previous work. p-octopamine (I 5 mg:kg i.p.l caused a decrease of BP in conscious SHR. Eflects of PSM 7 inhibitors
The administration of SKF 64139 (25 mg kg i.p.) and DCMB (50mg/kg i.p.) resulted in reductions of SBP in SHR. SKF 64139 seemed more potent than DCMB. but its hypotensive effect was short (2 hr).
RESULTS Eficts ment
155
or with pargyline pretreatEflects qf amines in lateral ventricle
In SHR. Tyramine (5 mgikg i.p.) and tyrosine (30mg/kg i.p.) decreased significantly SBP in SHR.
Two hours after administration, BP was returned to initial values. Pargyline alone (20mg/kg i.p.) induced a short-lasting hypotension. But if we gave pargyline 20min before tyramine or tyrosine, the hypotension was potentiated, and this effect lasted more than 3 hr (Table 1). In experimental hypertensive rats. It was observed that pargyhne-induced hypotension was long-lasting of SBP at 2hr + SEM (maximal decrease P < 0.05) while tyramine -1Ok3mmHg (Tmgjkg i.p.) was without effect on blood pressure. If we gave pargyline (20mg/kg i.p.) 20min before tyramine. the hypotension was potentiated (maximal decrease of SBP at 2 hr k SEM = -37 i 4.mm Hg, P < 0.001); this effect lasted 4 hr.
-50 20
In SHR. injection of p-octopamine (5 pg:rat) in lateral ventricle induced a significant decrease of SBP followed by an increase 1 hr after. The cardiovascular action of m-octopamine was less potent for the same dose, while phenylethanolamine. introduced intracerebrally. also produced a significant hypotension 20 min after. Noradrenaline (5 pgirat) strongly decreased SBP which returned to initial values 2 hr after administration in lateral ventricle of SHR (Fig. 1). Eflects of prazosin on poctopamine-induced sion
hypoten-
Rats were given prazosin (50-75 or lOO&kg per OS) 1 hr 40 min before p-octopamine (5 ygsrat ICV). Results showed that the octopamine induced hypotension observed at 20min persisted, but the hyper-
L 60
120
Time , min Fig. 1. Comparison of hypertensive effects of amines when injected into lateral ventricle of conscious spontaneous hypertensive rats. Doses of drugs were 5 pg/rat: M norepinephrine (N = 6). +O phenylethanolamine (N = 6). a---a m-octopamine (N = 8), A-A p-octopamine (N = 17). SBP were obtained by photoelectric heatless system. ** P c 0.01. *** P c 0.001.
156
Short Communication
Table 2. Changes in systolic blood pressure of conscious SHR Basal Treatment
Change in systolic blood pressure (mean k SEM) (mm Hg)
N
SBP value
7 17
192 k 6 203 + 2
-2 + Z(NS)(l) -33 f 4***(l)
-2 k l(NS)(l) + 15 f 38” (1)
- 1 F 1(NS)(l) + 1 + l(NS)(l) + 1 k 3(NS) (2)
20 min
1 hr
2 hr
Saline p-Octopamine p-Octopamine after prazosin
10 jll ICV 5 pg,/rat ICV 5 fig/rat ICV 50 pg/kg P.O.
,
195 f 5
-27 i: 7(NS)(2)
- 3 * 3*** (2)
p-Octopitmine after prazosin
5 pg/rat ICV 75 /(g/kg P.O.
7
192 + 6
-22 + 2(NS)(2)
-2 + 2***(2)
+O.l + l(NS)(2)
p-Octopamine after prazosin
5fig;rat ICV 100 pg:kg P.O.
7
190 + 7
-35 t lO(NS)(2)
-26 & 6***(2)
-4 & 2’ (2)
IV: animals. SBP measurement was obtained with pneumatic heated method. Student’s r-test: P in comparison to initial values: (1) P in comparison *P < 0.05. **p < 0.01. +**p < 0.001. NS: not significant.
tension at 1 hr was abolished by each dose of prazosin (Table 2). DISCUSSION
The hypotensive activity of p-octopamine and of the precursors of this amine may be considered to be central in origin, since systematically administered these amines produced increases of blood pressure.
The increase in brain octopamine concentrations found after the administration of IMAO (Brandau & Axelrod. 1972: David, 1978) may explain the decrease of blood pressure following injection of this drug. in SHR. The potentiation of this effect by precursors of octopamine may be explained by the fact that the rise of brain octopamine is greatly increased after both administration of IMAO and precursors of this amine such as tyrosine and tyramine (Brandau & Axelrod, 1972). Similarly, drugs known to inhibit activity of PNMT (Saavedra, 1979: Pendleton rr ul., 1976) and to increase brain octopamine (da Prada et al.. 1979) induce decreases of blood pressure in adult SHR. The more important hypotensive activity obtained with SKF 64139 may be related to the fact that SKF 64139 possesses an x-adrenergic blocking activity (Pendleton et ul.. 1976) while no r-adrenergic blocking effects have been observed after administration of DCMB (Saavedra, 1979). The decrease of blood pressure in SHR after the
administration of pargyline and PNMT inhibitors may be the consequence of amine accumulation. Fuentes er (II., (1979) suggest that pargyline reduced blood pressure in SHR by causing norepinephrine accumulation. However, it may also be due to an enhancement of phenylethanolamine and octopamine levels. Further investigations showing the levels of these three amines in the brain following pargyline administration should be necessary to explain this hypotensive effect. Piperoxan, yohimbine and prazosin were without effect on octopamine hypotension. Moreover, p- and m-octopamine had only a weak effect on [‘HI-p-amino clonidine binding which labels x2 receptors (IC 50 = 5000 and 2200 nM. respectively)
to octopamine
values: (2).
and on C3H]prazosin binding which labels r, receptors (IC50 > 10,000 nM) in the rat brain cortex (Uzan & le Fur. personal communication). Our results were in general accord with those of Hicks & McLennan (1978), who reported that octopamine elicited excitations of single cortical neurons were not correlated with dopamine- or noradrenalineelicited effects. In summary, our data suggest that the lack of activity of piperoxan, yohimbine and prazosin in preventing octopamine hypotension in SHR might indicate that the receptors responsible for evoking this antihypertensive effect might be different from preand postsynaptic x-adrenoceptors. These results offer experimental support for the existence of receptors sensitive to octopamine which are independent of those receptive to the catecholamines and for their role in central blood pressure regulation in rats and cats. Acknowledgrrnenr-We thank Dr W. de Jong (Rudolf Magnus Institute for Pharmacology, Utrecht) for the manufactured method of the clips used in this work. REFERENCES
BRANDAUK. & AXELRODJ. (1972) The biosynthesis of octopamine. ,V[IrtnL’n-Schmiedeberg’sArch. Phurmuc. 273, 123-133. CASSET-SENON D.. DELBARREB. & DELBARREG. (1980) Effects of drugs interfering with metabolism of octopamine in spontaneous hypertensive rats. Sot. ,Veurosci. .Ibsrr. 6, 162. DA PRADA M., Krss D. & KELLERH. H. (1979) Elevation of rat brain normethanephrine (NM) and p-octopamine after PNMT inhibition. 7th Meeting Int. Sot. .Veurothem., p. 287. DAVIDJ. C. (1978) Augmentation des taux de phenylethanolamine, m-octopamine et p-octopamine au niveau de I’hypothalamus et de la tige ceribrale de rats genetiquement hypertendus (SHR Kyoto).. C.r. hebd. Shone. Acod. Sci., Paris 287, 1293-1295. DELBARREB., CASSET-SENON D. & DELBARREG. (1980) Octopamine in central blood pressure regulation. ARCS, Med.
Sci.. Pharmac.
8, 23.
FUENTESJ. A.. ORDAZ A. & HEFF N. H. (1979) Central mediation of the antihypertensive effect of pargyline in
Short Communication spontaneously hypertensive rats. Eur. J. Pharmac. 57, 21-27. HICKS T. P. & MCLENNANH. (1978) Comparison of the actions of octopamine and catecholamines on single neurons of the rat cerebral cortex. Br. J. Pharmac. 64, 485-491. JAGIELLO-WOJTOWICZ E. (1979) Mechanism of central action of octopamine. Pd. J. P/tarmac. Phartn. 31, 509-5 16.
1.57
LEENENF. M. & DE JONG W. (1971) A solid silver clip for induction of predictable levels of renal hypertension in the rat. J. appl. Physiol. 31, 142-144. PENDLETON R. G., KAISERC. 8: GESSNERG. (1976) Studies on adrenal phenylethanolamine A’-methyl-transferase (PNMT) with SKF 64139, a selective inhibitor. J. Pharmat. esp. Ther. 197, 623-632. SAAVEDRA J. M. (19791 Adrenaline levels in brain stem nuclei and effects of a PNMT inhibitor on spontaneously hypertensive rats. Brain Res. 166. 283-292.
0306492/82!030153-05~3.00/0 0 1982 Pcrgamon Press Ltd
SHORT COMMUNICATION EFFECTS OF DRUGS INTERFERING WITH THE METABOLISM OF OCTOPAMINE ON BLOOD PRESSURE OF RATS BERNARD DELBARRE,
GIS~LEDELBARRE,DANIELLECASSET-SENON and PATRICIASESTILLANGE
Chir. Exp. Lab.. Faculte de MCdecine. 37032 Tours Cedex, France (Received 7 June 1981)
Abstract-l. pOctopamine injected in lateral ventricle of conscious spontaneously hypertensive rats decreased systolic blood pressure @BP). 2. Precursors of octopamine-tyrosine. tyramine and phenylethanolamine (PEAkhad the same effect. The administration of pargyline. a MAO inhibitor, which increased brain octopamine, resulted in a reduction of systolic blood pressure; and this decrease was ereater after administration of octonamine _ precursors and PEA. 3. Similarly, drugs known to inhibit activity of phenylethanolamine N-methyl-transferase (PNMT) and to increase brain octonamine level such as SKF 64139 and DCMB decreased SBP. 4. p-Octopamine hypot&sion was not antagonized by piperoxan, yohimbine and prazosin, a relatively selective antagonist of post-synaptic K adrenoceptors. 5. These results suggest that octopamine may be involved in central blood pressure regulation, and the receptors sensitive to octopamine appeared to be distinct from those receptive to the catecholamines.
INTRODUCTION Recently, p-octopamine, m-octopamine and phenylethanolamine had been found to have higher levels in brain of spontaneously hypertensive rats (SHR) than in those of normotensive rats (David, 1978). In our previous work, we have shown that. injected in the lateral ventricle and the cistema magna of SHR, p-octopamine induces dose-dependent falls of blood pressure (BP), (Delbarre et al., 1980). In the present study, we have investigated the cardiovascular actions of the precursors of octopamine, tyrosine, tyramine in conscious SHR, and in conscious experimental hypertensive rats. Moreover, an increase of rat brain octopamine had
been reported after pargyline administration (Brandau & Axelrod. 1972), and after phenylethanolamineN-methyl-transferase (PNMT) inhibition by SKF 64139 (Da Prada er al., 1979). This finding prompted us to study, in conscious SHR, the cardiovascular responses of pargyline, a monoamineoxidase(MAO)inhibitor,andoftwoPNMT inhibitors such as SKF 64139 (7,8 dichloro1,2,3,4-tetrahydroisoquinoline hydrochloride) and DCMB (23-dichloro-a-methyl-benzylamine hydrochloride), interfering with the metabolism of this amine. The high rate of turnover of octopamine in spite of low tissue concentrations prompted us to compare the cardiovascular effects of p-octopamine, m-octopamine and phe-nylethanolamine (PEA) with noradrenaline when these amines were administered at the same dose in lateral ventricle of conscious SHR. Moreover, Jagiello-Wojtowicz (1979) had found ihat the stimulatory effect of octopamine is realized 153
through catecholaminergic neurones. So it seemed interesting to determine if the effects of octopamine were abolished by adrenoceptor-blocking drugs. Previous work, in conscious cats, had shown that presynaptic a-adrenoceptor blocking agents such as yohimbine and piperoxan did not antagonize the octopamine-induced hypotension (Casset-Senon et a!., 1980). In this study, we have investigated the modification of central cardiovascular effects of poctopamine by using prazosin, a relatively selective antagonist of post-synaptic a-adrenoceptors, in conscious SHR. MATERIALSAND METHODS Male SHR, supplied by the Centre d’Elevage du C.N.R.S. (Orleans) and male rats of Wistar strain were used. Renal hypertension was induced in Wistar rats by applying a solid silver clip with an i.d. of 0.20mm on the left renal artery, leaving the right kidney untouched (Leencn & de Jong, 1971). Blood pressure increased. A month later, the rats were tested, and only animals exhibiting hypertension were used for experiment. Systolic blood pressure (SBP) of unanesthetized rats were measured by two types of methods. In the first time, we have determined SBP with an indirect pneumatic pulse pressure transducer (Narco-Biosystem. Houston) in which the rats were heated at 32°C for measurement. In a second time of experiment, SBP .was measuring with a photoelectric system using tail pulsations at temperatures such as 25-28°C (IITC. Inc. Mod. 59. NJ). This new method had been reported to be better, because it does not require the heating of animals and avoids the effect of heating on SBP of SHR. Indeed, we have observed that drugs like phenylethanolamine (PEA), which increases body temperature, induced
154
Short Communication
Short Communication mortality in rats after heating for SBP measurement; these effects were not so pronounced with SBP photoelectric system. A mean value from at least six consecutive readings for each animal were used for computation. The drugs were: SKF 64139 (7,8-dichloro-1,2.3.4-tetrahydroisoquinoline hydrochloride) Smith-Kline & French: DCMB (2,3-dichloro-a-methyl-benzylamine hydrochloride) Lilly Research Lab; pargyline (Abbott); tyramine HCl, DLphenylethanolamine, t-tyrosine methyl ester HCI (Sigma), p-octopamine (Sigma), m-octopamine (Sigma), noradrenaline (Sigma) and prazosin (Pfizer). Drugs were administered intraperitoneally. but p-octopamine. m-octopamine, phenylethanolamine and noradrenaline were also injected in lateral ventricle (constant volume of IOpt). Statistical analysis of the data presented in this paper was based upon Student’s r-test for paired samples. Differences for which P was co.05 were considered significant.
of precursors alone
Eflects qfphen!,let/ta,lolamine i.p. and p-octopamiue i.p.
By using heated method, other
biogenic
amine.
we found that PEA, and at the dose of 25 mg:kg i.p..
induced a significant decrease of SBP in SHR. The use of this amine in association with pargyline induced mortality of rats. But with the photoelectric measure system. phenylethanolamine. at the dose of 5 mg,kg i.p.. was found to have more potent hypotensive effect. 1 hr after administration. After pretreatment with pargyline. this amine induced a long-lasting hypotensive action (more than 4 hr). As we have shown in previous work. p-octopamine (I 5 mg:kg i.p.l caused a decrease of BP in conscious SHR. Eflects of PSM 7 inhibitors
The administration of SKF 64139 (25 mg kg i.p.) and DCMB (50mg/kg i.p.) resulted in reductions of SBP in SHR. SKF 64139 seemed more potent than DCMB. but its hypotensive effect was short (2 hr).
RESULTS Eficts ment
155
or with pargyline pretreatEflects qf amines in lateral ventricle
In SHR. Tyramine (5 mgikg i.p.) and tyrosine (30mg/kg i.p.) decreased significantly SBP in SHR.
Two hours after administration, BP was returned to initial values. Pargyline alone (20mg/kg i.p.) induced a short-lasting hypotension. But if we gave pargyline 20min before tyramine or tyrosine, the hypotension was potentiated, and this effect lasted more than 3 hr (Table 1). In experimental hypertensive rats. It was observed that pargyhne-induced hypotension was long-lasting of SBP at 2hr + SEM (maximal decrease P < 0.05) while tyramine -1Ok3mmHg (Tmgjkg i.p.) was without effect on blood pressure. If we gave pargyline (20mg/kg i.p.) 20min before tyramine. the hypotension was potentiated (maximal decrease of SBP at 2 hr k SEM = -37 i 4.mm Hg, P < 0.001); this effect lasted 4 hr.
-50 20
In SHR. injection of p-octopamine (5 pg:rat) in lateral ventricle induced a significant decrease of SBP followed by an increase 1 hr after. The cardiovascular action of m-octopamine was less potent for the same dose, while phenylethanolamine. introduced intracerebrally. also produced a significant hypotension 20 min after. Noradrenaline (5 pgirat) strongly decreased SBP which returned to initial values 2 hr after administration in lateral ventricle of SHR (Fig. 1). Eflects of prazosin on poctopamine-induced sion
hypoten-
Rats were given prazosin (50-75 or lOO&kg per OS) 1 hr 40 min before p-octopamine (5 ygsrat ICV). Results showed that the octopamine induced hypotension observed at 20min persisted, but the hyper-
L 60
120
Time , min Fig. 1. Comparison of hypertensive effects of amines when injected into lateral ventricle of conscious spontaneous hypertensive rats. Doses of drugs were 5 pg/rat: M norepinephrine (N = 6). +O phenylethanolamine (N = 6). a---a m-octopamine (N = 8), A-A p-octopamine (N = 17). SBP were obtained by photoelectric heatless system. ** P c 0.01. *** P c 0.001.
156
Short Communication
Table 2. Changes in systolic blood pressure of conscious SHR Basal Treatment
Change in systolic blood pressure (mean k SEM) (mm Hg)
N
SBP value
7 17
192 k 6 203 + 2
-2 + Z(NS)(l) -33 f 4***(l)
-2 k l(NS)(l) + 15 f 38” (1)
- 1 F 1(NS)(l) + 1 + l(NS)(l) + 1 k 3(NS) (2)
20 min
1 hr
2 hr
Saline p-Octopamine p-Octopamine after prazosin
10 jll ICV 5 pg,/rat ICV 5 fig/rat ICV 50 pg/kg P.O.
,
195 f 5
-27 i: 7(NS)(2)
- 3 * 3*** (2)
p-Octopitmine after prazosin
5 pg/rat ICV 75 /(g/kg P.O.
7
192 + 6
-22 + 2(NS)(2)
-2 + 2***(2)
+O.l + l(NS)(2)
p-Octopamine after prazosin
5fig;rat ICV 100 pg:kg P.O.
7
190 + 7
-35 t lO(NS)(2)
-26 & 6***(2)
-4 & 2’ (2)
IV: animals. SBP measurement was obtained with pneumatic heated method. Student’s r-test: P in comparison to initial values: (1) P in comparison *P < 0.05. **p < 0.01. +**p < 0.001. NS: not significant.
tension at 1 hr was abolished by each dose of prazosin (Table 2). DISCUSSION
The hypotensive activity of p-octopamine and of the precursors of this amine may be considered to be central in origin, since systematically administered these amines produced increases of blood pressure.
The increase in brain octopamine concentrations found after the administration of IMAO (Brandau & Axelrod. 1972: David, 1978) may explain the decrease of blood pressure following injection of this drug. in SHR. The potentiation of this effect by precursors of octopamine may be explained by the fact that the rise of brain octopamine is greatly increased after both administration of IMAO and precursors of this amine such as tyrosine and tyramine (Brandau & Axelrod, 1972). Similarly, drugs known to inhibit activity of PNMT (Saavedra, 1979: Pendleton rr ul., 1976) and to increase brain octopamine (da Prada et al.. 1979) induce decreases of blood pressure in adult SHR. The more important hypotensive activity obtained with SKF 64139 may be related to the fact that SKF 64139 possesses an x-adrenergic blocking activity (Pendleton et ul.. 1976) while no r-adrenergic blocking effects have been observed after administration of DCMB (Saavedra, 1979). The decrease of blood pressure in SHR after the
administration of pargyline and PNMT inhibitors may be the consequence of amine accumulation. Fuentes er (II., (1979) suggest that pargyline reduced blood pressure in SHR by causing norepinephrine accumulation. However, it may also be due to an enhancement of phenylethanolamine and octopamine levels. Further investigations showing the levels of these three amines in the brain following pargyline administration should be necessary to explain this hypotensive effect. Piperoxan, yohimbine and prazosin were without effect on octopamine hypotension. Moreover, p- and m-octopamine had only a weak effect on [‘HI-p-amino clonidine binding which labels x2 receptors (IC 50 = 5000 and 2200 nM. respectively)
to octopamine
values: (2).
and on C3H]prazosin binding which labels r, receptors (IC50 > 10,000 nM) in the rat brain cortex (Uzan & le Fur. personal communication). Our results were in general accord with those of Hicks & McLennan (1978), who reported that octopamine elicited excitations of single cortical neurons were not correlated with dopamine- or noradrenalineelicited effects. In summary, our data suggest that the lack of activity of piperoxan, yohimbine and prazosin in preventing octopamine hypotension in SHR might indicate that the receptors responsible for evoking this antihypertensive effect might be different from preand postsynaptic x-adrenoceptors. These results offer experimental support for the existence of receptors sensitive to octopamine which are independent of those receptive to the catecholamines and for their role in central blood pressure regulation in rats and cats. Acknowledgrrnenr-We thank Dr W. de Jong (Rudolf Magnus Institute for Pharmacology, Utrecht) for the manufactured method of the clips used in this work. REFERENCES
BRANDAUK. & AXELRODJ. (1972) The biosynthesis of octopamine. ,V[IrtnL’n-Schmiedeberg’sArch. Phurmuc. 273, 123-133. CASSET-SENON D.. DELBARREB. & DELBARREG. (1980) Effects of drugs interfering with metabolism of octopamine in spontaneous hypertensive rats. Sot. ,Veurosci. .Ibsrr. 6, 162. DA PRADA M., Krss D. & KELLERH. H. (1979) Elevation of rat brain normethanephrine (NM) and p-octopamine after PNMT inhibition. 7th Meeting Int. Sot. .Veurothem., p. 287. DAVIDJ. C. (1978) Augmentation des taux de phenylethanolamine, m-octopamine et p-octopamine au niveau de I’hypothalamus et de la tige ceribrale de rats genetiquement hypertendus (SHR Kyoto).. C.r. hebd. Shone. Acod. Sci., Paris 287, 1293-1295. DELBARREB., CASSET-SENON D. & DELBARREG. (1980) Octopamine in central blood pressure regulation. ARCS, Med.
Sci.. Pharmac.
8, 23.
FUENTESJ. A.. ORDAZ A. & HEFF N. H. (1979) Central mediation of the antihypertensive effect of pargyline in
Short Communication spontaneously hypertensive rats. Eur. J. Pharmac. 57, 21-27. HICKS T. P. & MCLENNANH. (1978) Comparison of the actions of octopamine and catecholamines on single neurons of the rat cerebral cortex. Br. J. Pharmac. 64, 485-491. JAGIELLO-WOJTOWICZ E. (1979) Mechanism of central action of octopamine. Pd. J. P/tarmac. Phartn. 31, 509-5 16.
1.57
LEENENF. M. & DE JONG W. (1971) A solid silver clip for induction of predictable levels of renal hypertension in the rat. J. appl. Physiol. 31, 142-144. PENDLETON R. G., KAISERC. 8: GESSNERG. (1976) Studies on adrenal phenylethanolamine A’-methyl-transferase (PNMT) with SKF 64139, a selective inhibitor. J. Pharmat. esp. Ther. 197, 623-632. SAAVEDRA J. M. (19791 Adrenaline levels in brain stem nuclei and effects of a PNMT inhibitor on spontaneously hypertensive rats. Brain Res. 166. 283-292.