Gen. Pharmac. Vol. 27, No. 2, pp. 299-304, 1996 Elsevier Science Inc. Printed in the USA.

ELSEVIER

ISSN 0306-3623/96 0306-3623(95)02006-Y

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Brain al-Adrenoceptor in the Cardiovascular Responses to BHT-920 and Phenylephrine

Daniel Ricci* and Carlos Alberto Taira CATEDRA DE FARMACOLOGfA, FACULTAD DE FARMAClA ¥ BIOQUIMICA, UNIVERSIDAD DE BUENOS AIRES,

JUNIN 956 PISO 5TO, 1113 BUENOS AIRES, AROENTINA

ABSTRACT. 1. It is well known that alA-adrenoceptors have binding sites for imidazolic and for phenylethylaminic drugs. A study was made relating alA-adrenoceptor involvement in cardiovascular responses to intracerebroventricular (ICV) injection of BHT-920, an imidazoliclike drug, and phenyleph- rine, a phenylethylaminic drug, in conscious sham-operated and sinoaortically-denervated rats.

2. In sham-operated rats, cardiovascular responses to BHT-920 (30 ~tg, ICY) were increase of blood pressure and bradycardia but in sinoaortically denervated rats, after the pressor response, a decrease of blood pressure was also seen. The pressor and bradycardic responses to agonist were greater in sinoaorti- cally denervated rats than in sham-operated rats. Phenylephrine (90 Itg, ICY) showed a biphasic effect on blood pressure: an increase followed by a decrease, and bradycardia. The cardiovascular responses to phenylephr ine in sinoaortic-denervated rats were greater than in sham-operated rats.

3. In sinoaortically denervated and sham-operated rats subchronicaUy treated with the Ql-adrenoceptor antagonist prazosin (0.5 mg kg- 1, intraperitoneaUy twice daily, for 6 days), an increase of cardiovascular responses tO ICY administrat ion of BHT-920 and phenylephrine was seen.

4. Baroreceptor deafferentation by sinoaortic denervation enhances the cardiovascular responses to BHT-920 and phenylephrine. The effects of BHT-920 could be mediated by brain ~tlA adrenoceptors because this agonist has an imidazoliclike structure; phenylephrine could also be activating central ~hA-adrenoceptors. T h e enhanced cardiovascular responses after prazosin treatment could also be due to a supersensitivity of brain ~qA.adrenoceptors. OEN PHARMAC 27;2:299-304, 1996.

KEY WORDS. otl-adrenoceptor, BHT-920, phenylephrine, prazosin, sinoaortic denervation

I N T R O D U C T I O N

Deafferentation of the cardiovascular baroreflex system by means of sinoaortic denervation induces an increase of blood pressure variability in the rat, cat, dog, and human (Cowley et al., 1973; Chalmers et al., 1979; Norman et al., 1981; Ramirez et al., 1985; Mancia et al., 1985; Aksamit et al., 1987) and also induces changes in brain catecholaminer- gic pathways in the activities of the corresponding enzymes of biosynthe- sis (Nakamura and Nakamura, 1981; Taira et al., 1983; Ricci et al., 1992). Moreover, cardiovascular responses to intracerebroventricular (ICV) administration of a-adrenoceptor agonists are increased in this denervated animal model also (Ricci et al., 1992).

The ctl-adrenoceptors were classified into atA-, alB-, arc-, and a,D- subtypes (Bylu nd et al., 1994~ Goetz et al., 1994). Both imidazolic drugs and phenylethylaminic derivatives have affinity with the al^-adreno- ceptor (Wilson et al., 1991). Furthermore, phenylethylaminic drugs, at high doses, also show affinity with ctm-adrenoceptors (Wilson et al., 1991). On the other hand, t12-adrenoceptors were classified into a2A-, a2~-, am-, and a2D-subtypes as well (Bylund et al., 1994).

Because sinoaortic denervation modifies the cardiovascular response to ICV injection of a-adrenoceptor agonists, it was of interest to study the involvement of the different a-adrenoceptor subtypes in the changes induced by the baroreceptor deafferentation and suhchronic treatment with prazosin, an az-adrenoCeptor antagonist.

Thus, cardiovascular responses to central administration of BHT-920, an a2-adrenoceptor agonist and imidazoliclike drug, and phenylephrine, an a,-adrenoceptor agonist and phenylethylaminic derivate, were mea-

*To whom correspondence should be addressed. Received 11 April 1995.

sured in conscious sham-operated and sinoaortically-denervated rats. These responses to both agonists were measured in subchronically prazosin-treated and -untreated groups of rats.

MATERIALS AND METHODS

Wistar male rats (200-300 g) were used. The rats were anesthetized with chloral hydrate (200 mg/kg- 1 intraperitoneally [IP]) and lidocaine (0.5 %) was injected subcutaneously in the midline of the neck. Sinoaortic denervation was performed according to the method of Krieger (1964). A sham operation was also carried out. The experiments were performed on conscious rats 7 days after the corresponding operation.

Two days before the experiments, a stainless-steel guide cannula (22G) was implanted in the left lateral ventricle of the rats, under chloral hydrate anesthesia, at coordinate point A 5.8 mm, L 1.5 mm, and H 4.5 mm (De Grout, 1959). Dye was injected ICV under ether anesthesia at the end of each experiment and brain was removed and examined to verify the correct positioning of the guide cannula.

Twenty-four hours before the experiments, the rats were anesthetized with ether and the right femoral artery and vein were cannulated with a polyethylene cannulas (PE 50) filled with heparinized saline solution (25 U/ml-1). The cannulas were then passed under the skin to emerge at the back of the neck.

On the day of the experiment, the arterial cannula was connected to a Sthatam Gould P23ID pressure transducer (Sthatam, Hato Rey, Puerto Rico) coupled to a Grass 79D polygraph (Grass Instruments, Quincy, MA).

The ICV injection of drugs was carried out by inserting an injection needle (28G) through the guide cannula, and this needle was connected

300 D. Ricci and C. A. Taira

TABLE 1. Baroreflex sensitivity is shown as the ratio AHRIAMBP (Coleman 1980; Fuxe e t aL, 1983)

Basal values Saline solution

HR MBP (mmHg) (bpm) AMBP AHR

Ratio

AHR/AMBP

sham(n = 7) 107 _+ 4 357 _+ 16 1 _+ 2 4 _+ 5 SAD (n = 7) 108 _+ 7 390 _+ 17 4 _+ 3 4 _+ 4

Phenylephrine 4 gg.kg -~ sham(n = 7) 106 _+ 4 364 _+ 15 47 _+ 3 -95 _+ 13 SAD(n = 7) 107 _+ 7 378 _+ 16 48 _+ 7 -10 _+ 9*

D

2.1 _+0.3 0.2 _+ 0.2*

* P < 0.0005 versus the corresponding values of sham-operated rats.

to a 5-~tl Hamilton syringe with a polyethylene cannula (PE 50). BHT-920 and phenylephrine were dissolved in saline solution and prazosin was dissolved in a solution of glucose (5%) and drops of acetic acid (3%). The drugs were injected ICV in a volume of 2 ~tl on 1 min.

For brain a~-adrenoceptor blockade, groups of rats were treated with prazosin (0.5 mg/kg -1 IP, twice daily), according to the procedure to Cavero and Roach (1978) modified by Gutkind et al. (1986), for 6 days after sinoaortic denervation of sham operation. The last dose was given 24 h before the study.

The following drugs were used: prazosin hydrochloride (Pfizer, Argen- tina); phenylephrine hydrochloride (Poen Labs, Argentina); and BHT- 920 hydrochloride (Biberach and Der Reiss, France).

Data are expressed as the means _+ SEM. Analysis of variance (AN- OVA) and the Student t test were used for statistical evaluation of the data (Bruning and Kintz, 1977).

RESULTS

Seven days after the operation, mean blood pressure, heart rate, and baroreflex sensitivity were evaluated in both groups of rats (Table 1). Basal values of mean blood pressure and heart rate measured in con- scious animals were similar in denervated and in sham-operated rats. The intravenous (IV) bolus injection of phenylephrine (4 ~tg/kg -I) elicited a pressor response of similar magnitude in both groups of ani- mals, which was reflexly compensated for by bradycardia only in sham- operated rats. The lack of baroreflex compensatory cardiac response in denervated animals was reflected in a decreased baroreflex sensitivity (Table 1).

The subchronic treatment with prazosin did not modify the basal values in either group of rats (Table 2).

The ICV administration of BHT-920 (10-60 ttg) induced an increase in mean blood pressure associated with bradycardia in the conscious sham-operated rats. However, in sinoaortically denervated rats, the drug produced a rise in blood pressure followed by a fall, which was associated with bradycardia. These actions of BHT-920 were dose- dependent in both groups of experimental animals and significantly greater in sinoaortically denervated rats (Fig. 1).

Phenylephrine (3-60 ~tg) administered ICV, induced an increase in mean blood pressure and a fall in heart rate. A dose of 90 ~tg induced a biphasic response: an increase of mean blood pressure followed by a decrease. In sinoaorticaUy denervated rats, phenylephrine showed similar effects, but the responses were significantly greater than in sham-operated rats. All these actions of phenylephrine were dose- dependent and significantly greater in sinoaortically denervated rats (Fig. 2).

Figure 3 shows the time course of the changes in blood pressure and heart rate after the ICV administration of the BHT-920 (30 ~tg) in prazosin-treated and -untreated sharrvoperated rats. In the untreated sham-operated rats, bradycardia and a pressor response to the agonist were seen. Prazosin subchronic treatment increased systolic and dia- stolic pressure responses to the BHT-920 by 100% and 60%, respectively, in sham-operated rats. An increase in the bradycardic effect after treat- ment was also seen in these animals.

Figure 4 shows the time course of changes in blood pressure and heart rate after central injection of BHT-920 (30 ~tg, ICV) in prazosin- treated and -untreated sinoaortically-denervated rats. In untreated si- noaortically denervated rats, the agonist showed a biphasic effect of blood pressure, a pressor and hypotensive action, and bradycardia. The prazosin treatment increased the effects of BHT-920 in sinoaortically denervated rats and increased the systolic pressor response by 62% and the diastolic pressor response by 34%.

The time course of the changes in blood pressure and heart rate induced by ICV injection of phenylephrine (90 ~tg) in prazosin-treated and -untreated sham-operated rats are shown in Figure 5. In untreated sham-operated rats, phenylephrine had a biphasic pressor and hypoten- sive action and also induced bradycardia. Prazosin treatment increased these effects of phenylephrine, then the systolic pressor response was increased by 110% and the diastolic pressor response by 40%.

In untreated sinoaortically denervated rats, phenylephrine (90 ~tg ICV) induced biphasic pressor-hypotensive response and fall of heart rate (Fig. 6). Once again, prazosin treatment increased the systolic (22%) and diastolic (15%) pressor responses and the hypotensive response and the bradycardia.

TABLE 2. Basal mean blood pressure (MBP) and heart rate (HR) of prazosin (Pra)-treated and .untreated sham.operated (SO) and sinoaorticall¥ denervated (SAD) rats

MBP (mmHg) HR (bpm)

E r a Era untreated treated untreated treated

SO (n = 7) 107 _+ 3 109_+ 3 366 _+ 14 375 -+ 10 SAD(n = 7) I10 _+ 7 118_+6 393 _+ 12 417 _+ 12

DISCUSSION

It is well known that sinoaortic denervation induces a loss of baroreflex cardiovascular regulatory mechanisms and further blood pressure vari- ability (Cowley et al., 1973; Mancia et al., 1985; Aksamit et al., 1987). In this work, the loss of baroreflex function was reflected in the lack of reflex bradycardia induced by a pressor dose of phenylephrine and in a diminished baroreflex sensitivity (Coleman 1980; Fuxe et al., 1983). Changes in the cardiovascular responses to brain a-adrenoceptor stimu- lation were also seen in these denervated rats (Ricci et al., 1992). More-

Brain al-Adrenoceptor in Cardiovascular Responses to BHT-920 301

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over, sinoaortically denervated rats are sensitive to the hypotensive action of central-acting a-adrenergic antihypertensive drugs such as clonidine and a-methyldopa (Taira et al., 1983; Ricci et al., 1992).

Brain a-adrenoceptors and imidazolic receptors are involved in cen- tral cardiovascular regulatory mechanisms (Van Zwieten, 1975; Olmos eta/., 1992). The al-adrenoCeptors were classified into al^-, als-, ale, and air-subtypes (Bylund eta/., 1994; Goetz et al., 1994). Furthermore, the al^-adrenoceptor could be stimulated by both phenylethylamines and imidazolic drugs (Wilson et al., 1991).

In this work, because sinoaortic denervation induces changes in the responsiveness of brain a-adrenoceptor in rats and rabbits (Korner et al., 1984; Ricci et al., 1992), we have studied the subtypes of a-adrenoceptor involved in these changes.

The direct and reflex components were assessed from the differences in responses between intact and sinoaortically denervated rats. In intact rats, it is not possible to differentiate the direct from the reflex compo- nents of the circulatory response, either during central release of trans- mitter or following central administration of drugs. Surprisingly, there has been a tendency under these circumstances to ignore the reflex effects and there have been few attempts to assess the magnitude of

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FIGURE 2. Changes in mean blood pressure (MBP) and heart rate (HR) induced by phenylephrine (Phe 3-90 pg, ICV) in sham- operated (SO) and sinoaortically denervated (SAD) rats. Open bars represent the sham-operated values and black bars the sinoaorti- cally denervated values. Each value is the mean_+ SEM of 7 animals. *At least P<O.05 versus the corresponding sham-operated group.

the two components. In this work, the responses in sinoaortically dener- vated rats were assumed to approximate to the direct central nervous system stimulation (Korner et al., 1984).

Moreover, we have also studied the alterations induced by the sub- chronic treatment with prazosin, an al-adrenoceptor antagonist, in the cardiovascular responses to ICV administration of a-adrenoceptor agonists in animals with intact baroreflex mechanisms and in sinoaorti- cally denervated rats.

Cardiovascular responses to ICV injection of BHT-920 in sham- operated rats included an increase of arterial blood pressure and brady- cardia, similar effects were observed by Kawasaki and Takasaki (1986), in normotensive rats, but in sinoaortically denervated rats the pressor response was followed by a decrease. Similar responses were also seen with imidazolic drugs such as clonidine and guanabenz in sinoaortically denervated rats (Bonham et al., 1984; Ricci et al., 1992).

The pressor response and bradycardia to the central administration of this agonist were greater in sinoaortically-denervated rats than in sham-operated rats.

It is well known that BHT-920 expresses an affinity with the a2-adreno- ceptor (Kawasaki and Takasaki, 1986) and because of its imidazoliclike structure (Van Zwieten, 1975), for al^-adrenoceptor also (Wilson et al.,

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FIGURE 3. Time courses of changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and heart rate (HR), after BHT-920 (30 lag, ICV) administration in sham-operated (SO) rats with and without prazosin treatment. Open circles represent values o f untreated sham-operated rats; black circles represent values of prazosin.treated sham-operated rats. Each value is the mean_+SEM of 7 animals. *At least P*~0.05 versus the corresponding untreated values.

1991): Thus, these cardiovascular effects of BHT-920 could be due to brain a2- and a~wadrenoceptor stimulation.

Phenylephrine, a phenylethylamine, has dose-dependent pressor and bradycardic effects, but at doses of 90 lag ICV showed a biphasic effect on blood pressure: pressor action followed by a decrease of blood pres- sure and bradycardia. These cardiovascular responses were greater in sinoaortically denervated rats than in sham-operated rats. In normoten-

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FIGURE 4. T ime courses of changes in systolic blood preuure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and heart rate (HR), after BHT.920 (30 lag, ICV) administration in sinoaortically denervated (SAD) rats with and without prazosin treatment. Open circles represent values of untreated sinoaortically denervated rats; black circles represent values of prazosin-treated sinoaorticaUy-denervated rats. Each value is the mean_+SEM of 7 animals. *At least P<0.05 versus the corresponding untreated values.

sive rats, Hiwatari and Johnston (1985) observed an increase in blood pressure and bradycardia after the ICV injection of the al-adrenoceptor agonist phenylephrine.

In our experiments, increases in the cardiovascular responses to brain a-adrenoceptor stimulation with BHT-920 and phenylephrine were seen in both sham-operated and sinoaortically-denervated rats after

Brain avAdrenoceptor in Cardiovascular Responses to BHT-920 303

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FIGURE 5. Time course of changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and heart rate (FIR), after phenylephrine (Phe: 90 pg, ICV), in sham-operated (SO) rats With and without prazosin treatment. Open circles represent values of untreated sham-operated rats; black circles represent values of prazosin.treated sham.operated rats. Each value is the mean_+SEM of 7 animals. *At least P<0.05 versus the corresponding untreated values.

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FIGURE 6. Time course of changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), and heart rate (HR), after phenylephrine (Phe: 90 pg, ICV), in sinoaorticaUy denervated (SAD) rats with and without prazosin treatment. Open circles represent values of untreated sinoaortically denervated rats; black circles represent values of prazosin-treated sinoaortically denervated rats. Each value is the mean_+SEM of 7 animals. *At least P<0.05 versus the corresponding untreated rats values.

subchronic prazosin treatment. These changes could be due to an increase in the concentration of the binding site by means of an upregula- don mechanism. Chronic blockade with antagonists induces an increase of binding site concentration and a supersensibility to stimulation by agonists. For example, subchronic idazoxan treatment induces an in- crease in imidazolic binding site concentration through the upregulation

mechanism in adipocytes, brain cortex, and so forth (Portillo et al., 1991; Olmos, 1992).

It is well known that prazosin crosses the blood-brain barrier (Cavero and Roach, 1978); therefore, in our experiments, the subchronic pra- zosin treatment could be inducing an increase in these responses medi- ated by brain al-adrenoceptors.

304 D. Ricci and C. A. Taira

In this work, agonists such as BHT-920, an imidazolidike drug, and phenylephrine, a phenylethylamine, were used. Phenylephrine has af- finity with the al^-adrenoceptor and, at high doses, for the alB-adreno- ceptor (Wilson et al., 1991).

The cardiovascular responses to BHT-920 could be mediated by the a2-adrenoceptor. However, because the al^-adrenoceptor may be stimulated by imidazolic drugs, the increasing effects of BHT-920 could also be mediated by alA-adrenoceptor.

In normotensive rats the effects of phenylephrine are blocked by 5-methylurapidil, and ch^-adrenoceptor antagonist, but not by chloro- ethyldonidine, an a~B-adrenoceptor antagonist (Ricci and Taira, 1994).

These results suggest that the increase in the responses to the central injection of phenylephrine and BHT-920, after subchronic prazosin treatment, could be mediated by a supersensibility of ct~^-adrenoceptor.

It is interesting to point out that the extent of increase in systolic pressor responses to BHT-920 and phenylephrine is greater than in diastolic pressor responses in both groups ofprazosin-treated rats. Estan et al. (1990) reported, a significant increase in systolic pressor response to clonidine after reserpine treatment. It is well known that cardiac output is involved in systolic blood pressure and contractile responses mediated by al-adrenoceptor stimulation in the heart (Skomedal et al., 1985); thus, prazosin treatment could also affect peripherial al-adreno- ceptors. Therefore, an enhanced cardiac contractility mediated by car- diac al-adrenoceptor supersensibility could be involved in the increase of systolic blood pressure response seen in this work.

Cardiovascular responses to BHT-920 and phenylephrine could be due by the stimulation of al^-adrenoceptor through either the imida- zolic site or the phenylethylaminic site. It is possible that subchronic prazosin treatment would induce an increase of brain concentration of a~A-adrenoceptor by means of upregulation mechanisms, since this antagonist expresses affinity with both cq^- and a~a-adrenoceptors. Therefore, the increase in alA-adrenoceptor concentration would en- hance the cardiovascular responses to BHT-920 and phenylephrine in both groups of rats.

In conclusion, sinoaortic denervation modifies the cardiovascular responses to ICV administration of phenylephrine and BHT-920. Therefore, reflexes mediated through the arterial baroreceptor in rats substantially modify the nature and/or magnitude of the centrally produced cardiovascular responses to the agonists studied.

The brain ctt^-adrenoceptor could be involved in the cardiovascular responses to ICV injection of BHT-920 and phenylephrine, and the supersensibility to these agonists in both groups of rats, after the sub- chronic prazosin treatment, could be due to an increase in the concentra- tion of this adrenoceptor.

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