Gen. Pharmac. Vol. 32, No. 1, pp. 29–34, 1999 ISSN 0306-3623/99 $–see front matterCopyright 1998 Elsevier Science Inc. PII S0306-3623(98)00018-4Printed in the USA. All rights reserved

Adrenoceptor Involvement in the CardiovascularResponses to B-HT 920 in Sinoaortic Denervated Rats

Daniel Ricci* and Carlos Alberto TairaCatedra de Farmacologıa,

Facultad de Farmacia y Bioquımica, Universidad de Buenos Aires,Junın 956 piso 5to., 1113, Buenos Aires, Argentina [Tel: (541) 964-8265; Fax: (541) 962-5341]

ABSTRACT. 1. A study was made relating the involvement of a-adrenoceptors in the cardiovascularresponses to intracerebroventricular (ICV) injection of B-HT 920, a clonidine-type drug, in conscioussham-operated and sinoaortic-denervated rats.

2. Wistar rats were used, 7 days after the sham operation or sinoaortic denervation. For ICV injec-tion of drugs, a guide cannula had been previously implanted in the left lateral ventricle.

3. In sham-operated rats, cardiovascular responses to B-HT 920 (10–60 mg) were increased bloodpressure and bradycardia; but, in sinoaortic-denervated rats, after the pressor response, a decrease inblood pressure also was seen. The responses to this agent were greater in sinoaortic-denervated ratsthan in sham-operated animals. Treatment with the a2-adrenoceptor antagonist yohimbine (30 mg), theimidazoline receptor antagonist idazoxan (15 mg) and the a1A-adrenoceptor antagonist 5-methylurapidil(15 mg) blocked the responses to B-HT 920 (30 mg). The a1-adrenoceptor antagonist prazosin (15mg) and the a1B-adrenoceptor antagonist chloroethylclonidine (100 mg) did not modify the responsesto agonist.

4. Sinoaortic denervation enhances the cardiovascular responses to B-HT 920. Moreover, the ef-fects of ICV administration of B-HT 920 could be mediated by several types of brain receptors: imida-zoline receptors and a1A- and a2-adrenoceptors. gen pharmac 32;1:29–34, 1999. 1998 ElsevierScience Inc.

KEY WORDS. a-Adrenoceptor, B-HT 920, blood pressure, imidazoline receptor, sinoaortic denervation

INTRODUCTION cal activity, in spite of its different molecular structure (Kobingerand Pichler, 1977; Van Zwieten, 1975), injected ICV in consciousDeafferentation of the cardiovascular baroreflex system by means ofsham-operated and sinoaortic-denervated rats.sinoaortic denervation induces an increase in blood pressure variability

in several species (Aksamit et al., 1987; Mancia et al., 1985; Normanet al., 1981; Ramirez et al., 1985). Moreover, cardiovascular re- MATERIALS AND METHODSsponses to intracerebroventricular (ICV) administration of a-adre-

Wistar male rats (200–230 g) were used. The rats were anesthetizednoceptor agonists are increased in this denervated animal model,with chloral hydrate (200 mg/kg IP), and lidocaine (0.5%) was in-too (Ricci et al., 1992; Taira et al., 1983).jected subcutaneously in the midline of the neck. Sinoaortic dener-The a-adrenoceptors and imidazoline receptors of the central ner-vation was performed according to the method of Krieger (1964). Avous system have a role in the central cardiovascular regulationsham operation also was carried out. The experiments were per-(Bousquet et al., 1984, 1992; Buccafusco et al., 1995; Ricci et al.,formed on conscious rats 7 days after the corresponding operation.1992). Studies by several authors showed the existence of several

Seven days after the operation, the effectiveness of sinoaortic de-types of a1-adrenoceptors in central and peripheral tissues. Re-nervation was tested in all rats and was shown by the absence ofcently, the a1-adrenoceptors were classified into a1A-, a1B-, a1C- andbradycardia after intravenous injection of phenylephrine (4 mg/kg).

a1D-subtypes (Bylund et al., 1994). On the other side, several sub-The magnitude pressor of response to the vasoconstriction agent was

types of a2-adrenoceptors also were seen and classified into a2A, a2B, similar in both groups but only reflexively compensated by bradycar-a2C and a2D (Bylund et al., 1994).

dia in sham-operated rats.Because sinoaortic denervation modifies the cardiovascular responses Two days before the experiments, a stainless steel guide cannula

to the ICV injection of a-adrenoceptor agonists, it was interesting (22G) was implanted in the rat left lateral ventricle under chloralto study the involvement of the different a-adrenoceptor subtypes hydrate anesthesia (200 mg/kg IP), at coordinate points A (5.8 mm),in the changes induced by the baroreceptor deafferentation. Thus, L (1.5 mm) and H (4.5 mm) from stereotaxic zero (De Groot, 1959).this work studies involvement of the central imidazoline receptors Dye was injected intracerebroventricularly under ether anesthesia atand a-adrenoceptor subtypes in the cardiovascular responses to B-HT the end of each experiment, and the brain was removed and exam-920 (2-amino-6-ethyl-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepin ined to verify the correct positioning of the guide cannula.dihydrochloride), an a2-adrenoceptor agonist and an experimental Twenty-four hours before the experiments, the rats were anesthe-antihypertensive compound with a clonidine-type of pharmacologi- tized with ether, and right femoral artery and vein were cannulated

with polyethylene cannulas (PE 50) filled with heparinized salinesolution (25 U/ml). The cannulas were then passed under the skin*To whom correspondence should be addressed.

Received 4 November 1997; accepted 15 December 1997. to emerge at the back of the neck.

30 D. Ricci and C. A. Taira

TABLE 1. Basal values of blood pressure and heart rate in sham-operated and sinoaortic-denervated rats

MBP HR

Sham-operated 104 6 2 mmHg 378 6 6 bpmSinoaortic-denervated 111 6 8 mmHg 387 6 9 bpm

Values of mean blood pressure (MBP) and heart rate (HR), bpm (beats perminute), of 45 rats for each group.

On the day of the experiment, the arterial cannula was connectedto a Sthatam Gould P23ID pressure transducer (Sthatam Inst., HatoRey, Puerto Rico) coupled to a Grass 79 D polygraph (Grass Inst.,Quincy, MA, USA).

Blood pressure was measured in conscious, freely moving animals,and the mean blood pressure was calculated from the following for-mula: diastolic pressure1(systolic pressure2diastolic pressure)/3.

Blood pressure was recorded before the start of the experiment forat least 30 min or until a stable tracing had been obtained.

The ICV injection of drugs was carried out by inserting an injec-tion needle (28G) through the guide cannula, and this needle wasconnected to a 5-ml Hamilton syringe with a polyethylene cannula(PE 50).

B-HT 920, idazoxan and chloroethylclonidine were dissolved insaline solution, and prazosin, yohimbine and 5-methylurapidil weredissolved in a solution of glucose (5%) and drops of acetic acid(3%). The drugs were injected intracerebroventricularly in a vol-ume of 2–5 ml/min.

All doses are expressed in terms of their free bases. The follow-ing drugs were used: prazosin hydrochloride (Pfizer, Argentina),5-methylurapidil, chloroethylclonidine dihydrochloride and idaz-oxan hydrochloride (RBI, USA), yohimbine hydrochloride (Sigma, FIGURE 1. Time course of the changes in mean blood pressureUSA) and B-HT 920 hydrochloride (Biberach and Der Reiss, France). (MBP) and in heart rate (HR) after B-HT 920 (30 mg, ICV).

Sham-operated (s) and sinoaortic-denervated rats (d); n55 inData are expressed as the means6SEM. One-way or two-wayeach group. *At least P,0.05 versus the corresponding sham-analysis of variance followed by Student’s t-test was used for statisti-operated group.cal evaluation of data (Bruning and Kintz, 1977).

RESULTSFigure 3 shows the peak pressor and bradycardiac responses after

Conscious rats with intact baroreceptors (sham-operated) and si- B-HT 920 (30 mg) in untreated and treated sham-operated rats, andnoaortic-denervated animals were used 7 days after operation. Basal Figure 4 shows the peak hypotensive and bradycardiac responsescardiovascular parameters determined in the two groups did not after B-HT 920 (30 mg) in untreated and treated sinoaortic-dener-show significant differences (Table 1). vated rats. In both groups of rats, the experiments with the antago-

B-HT 920 (30 mg, ICV) induced an increase in mean blood pres- nists reduced the responses to B-HT 920 with idazoxan (imidazo-sure immediately after injection (30 sec), and the maximum re- line), yohimbine (a2) and 5-methylurapidil (a1A). On the othersponse occurred at approximately 2 min in conscious normal rats. In hand, prazosin (a1) and chloroethylclonidine (a1B) did not modifycontrast, in sinoaortic-denervated rats, the drug produced a rise in the responses to B-HT 920 (Figs. 3 and 4).blood pressure (10 min) followed by a fall, which was maximal atapproximately 17 min (Fig. 1).

DISCUSSIONIn both sham-operated and sinoaortic-denervated rats, B-HT 920induced a bradycardia that was significantly greater in sinoaortic- It is well known that brain a-adrenoceptors and imidazoline recep-

tors take part in the central cardiovascular regulatory mechanismsdenervated rats (Fig. 1).These actions of B-HT 920 were dose-dependent in both groups (Bousquet et al., 1984, 1992; Buccafusco et al., 1995; Ricci and

Taira, 1994, 1995; Ricci et al., 1992).of rats and pressor and bradycardic effects were significantly greaterin sinoaortic-denervated rats (Fig. 2). Sinoaortic denervation induces a loss of baroreflex cardiovascular

regulatory mechanisms, an increase in blood pressure variabilityThe following antagonists were injected intracerebroventricularlybefore B-HT 920: prazosin (a1), yohimbine (a2), idazoxan (imidazo- (Aksamit et al., 1987; Mancia et al., 1985; Ramirez et al., 1985)

changes in the responsiveness of brain a-adrenoceptor (Ricci andline), chloroethylclonidine (a1B) and 5-methylurapidil (a1A). B-HT920 (30 mg) was injected 15 min after 15 mg of prazosin or idazoxan, Taira, 1995; Ricci et al., 1992) and hypersensibility to the hypoten-

sive action of central-acting a-adrenergic antihypertensive drugs15 min after 30 mg of yohimbine, 105 min after 100 mg of chloroeth-ylclonidine and 30 min after 100 mg of 5-methylurapidil, when a such as clonidine and a-methyldopa (Ricci et al., 1992; Taira et al.,

1983). In this work , we studied the subtypes of a-adrenoceptor tak-stabilization of baseline values was reached (data not shown).

Cardiovascular Responses to B-HT 920 31

FIGURE 2. (Top) The maximum increases in mean blood pres-sure (MBP) in sham-operated (SO) rats; (middle) the maximumincreases and decreases in mean blood pressure in sinoaortic-denervated (SAD) rats; and (bottom) the maximum decrease inheart rate (HR) in sham-operated and sinoaortic-denervated rats FIGURE 3. Effects of antagonists on the cardiovascular responsesinduced by B-HT 920 (10–60 mg, ICV). Open columns represent to B-HT 920 (30 mg) in sham-operated rats: Changes in mean bloodthe SO rat values and black the SAD rat values; n55 in each pressure (MBP) and heart rate (HR). Prazosin (PRA, 15 mg)1group. *At least P,0.05 versus the corresponding SO group. BHT; yohimbine (YOH, 30 mg)1BHT; idazoxan (IDA, 15 mg)1

BHT; chloroethylclonidine (CEC, 100 mg)1BHT; 5-methyl-urapidil (5 MU, 100 mg)1BHT; n56 in each group. *At leastP,0.05 versus the corresponding control group.ing part in these changes. Thus, cardiovascular responses to central

administration of B-HT 920, an a2-adrenoceptor agonist and cloni-dine-type drug, were measured in sham-operated and in sinoaortic-

tions of imidazolines. In our study, the potential complicating factordenervated conscious rats. A “clonidine type” of pharmacologicalof peripheral actions was avoided by use of ICV injection. In addi-activity has hitherto been described for chemical structures containingtion, interference or potentiation of clonidine-type-drug effects byan imidazoline ring or similar systems, including the sequence ofanesthesia (Kawasaki and Takasaki, 1986; Sannajust et al., 1992)was prevented by using conscious rats.2 NH 2 C 5 N,

\Y Cardiovascular responses to ICV injection of B-HT 920 in sham-

operated rats were an increase in arterial blood pressure and brady-where Y is N or O;cardia, similar results were obtained in normotensive rats byKawasaki and Takasaki (1986) and King and Pang (1988) after in-therefore B-HT 920 may be considered a clonidine-type drug (Vantracisterna magna administration of B-HT 920.Zwieten, 1975).

Trolin (1975) postulated from transection experiments that clon-Direct central injection is an important component of the study,idine increases blood pressure by an action in the forebrain on thebecause it is likely that there are marked differences in bioavailabil-suprabulbar a-adrenoceptors. Administration of central antihyper-ity among the agents when the drugs are administered peripherally.tensive agents into the lateral ventricle elicits elevation rather thanMoreover, at the doses employed, the cardiovascular responses tofall in blood pressure in conscious rats (Sannajust et al., 1992), prob-B-HT 920 are mediated by central a-adrenoceptors (Kawasaki andably mediated by activation of a2-adrenoceptors in the paraventricularTakasaki, 1986; Ricci and Taira, 1996).hypothalamus that mediate a pressor response (Ebihara et al., 1993).Antagonists of GABA, serotonin and muscarinic receptors all in-Effects of B-HT 920, a clonidine-type agent, injected intracerebro-terfere with the action of clonidine-type drugs (Buccafusco, 1992),

implicating a multitransmitter pathway in the cardiovascular ac- ventricularly, could be mediated by these a-adrenoceptors as well.

32 D. Ricci and C. A. Taira

the arterial baroreceptors by measuring the responses of B-HT 920in sham-operated and in sinoaortic-denervated rats.

Several treatments with selective antagonists were made for studiesof the involvement of the subtypes of a-adrenoceptors. Doses usedby us were taken from the literature (Kawasaki and Takasaki, 1986;Piascik et al., 1992; Ricci and Taira, 1994, 1995; Ricci et al., 1992).

Idazoxan is an antagonist with affinity for both a2-adrenoceptorsand imidazoline receptors (Hamilton et al., 1988; Senard et al.,1990); it has been widely employed for the characterization andidentification of a-adrenoceptors because it displays greater affinityand a2/a1 selectivity than do other antagonists (Doxey et al., 1984).The identification of more selective imidazoline receptor antago-nists with low affinity for a2-adrenoceptors will be required for fur-ther investigations.

Morrow and Creese (1986) demonstrated the existence of twoseparate populations of a1-adrenoceptor-binding sites in the rat cen-tral nervous system. The a1A-adrenoceptor has a high affinity for5-methylurapidil and is not inactivated by chloroethylclonidine,whereas the a1B-adrenoceptor has a low affinity for this compoundand is inactivated by chloroethylclonidine (Hanft and Gross, 1989;Minneman, 1988).

Chloroethylclonidine irreversibly inactivates a1B-adrenoceptorsin rat tissues (Terman et al., 1989) and, because it is an alkylatingagent, the time for baseline stabilization is 105 min, according toseveral authors (Piascik et al., 1992; Ricci and Taira, 1994). Withthe other blockades, agonists were injected after a stabilization ofbasal values was reached.

In both groups of rats, the experiments with antagonists showedthe blockade of the cardiovascular responses to B-HT 920 with ida-zoxan (imidazoline and a2), yohimbine (a2) and 5-methylurapidil(a1A). On the other hand, prazosin (a1) and chloroethylclonidine(a1B) did not modify these responses to B-HT 920. The results sug-gest that cardiovascular responses to centrally injected B-HT 920could be mediated by brain a1A- and a2-adrenoceptors and imidazo-line receptors in both groups of rats. Similar results were obtainedFIGURE 4. Effects of antagonists on the cardiovascular responses

to B-HT 920 (30 mg) in sinoaortic-denervated rats. Changes in by clonidine in our laboratory (Ricci and Taira, 1994, 1995).mean blood pressure (MBP) and heart rate (HR). Prazosin (PRA, There is evidence that B-HT 920, when injected centrally, in-15 mg)1BHT, yohimbine (YOH, 30 mg)1BHT; idazoxan (IDA, duces a decrease in arterial pressure in anesthetized rats (Kawasaki15 mg)1BHT, chloroethylclonidine (CEC, 100 mg)1BHT, 5-meth- and Takasaki, 1986; Trolin, 1975) that is blocked by a-adrenocep-ylurapidil (5MU, 100 mg)1BHT; n56 in each group. *At least

tor antagonists (Kobinger, 1978; Bousquet and Schwartz, 1983).P,0.05 versus the corresponding control group.Moreover, the postjunctional a2-adrenoceptor antagonist potencyof idazoxan has been reported; studies by Doxey et al. (1983) inpithed rats show that imidazoline is slightly more potent than yo-In sinoaortic-denervated rats, the pressor response was followedhimbine in blocking clonidine-induced pressor responses.by a decrease. The pressor response and bradycardia to the central

B-HT 920 is believed to exert its hypotensive effect through acti-administration of this agonist were greater in sinoaortic-denervatedvation of central a2-adrenoceptors within the central nervous sys-rats than in sham-operated rats.tem, mainly at structures in the medulla oblongata, where they in-Several authors reported that centrally administered clonidineduce an inhibition of sympathetic outflow from the brain (Kobinger,produces no hypotensive effect in conscious animals, whereas the1978). The nucleus tractus solitarius is the site of a potent depressordrug becomes strongly hypotensive when administered centrally toresponse to locally administered a2-agonists (Kubo and Misu, 1981;conscious animals with sinoaortic denervation (Brody et al., 1984;Sved et al., 1992).Ricci et al., 1992). Therefore, lack of hypotensive response to cloni-

The hypotensive effect of clonidine-type drugs is mediated by im-dine or B-HT 920 in conscious animals may be due to the ability ofidazoline receptors localized in the rostral ventrolateral medulla ob-baroreceptor reflexes to offset the potential for producing the inhibi-longata (Buccafusco et al., 1995; Ernsberger et al., 1990; Reis et al.,tion of central sympathetic outflow.1992). However, because the a1A-adrenoceptor may be stimulatedThe direct and reflex components were assessed from the differ-by imidazoline drugs, the effects of B-HT 920 could be mediated byences in responses between intact and sinoaortic-denervated rats. Inthe a1A-adrenoceptor, too (Wilson et al., 1991). Evidence showsthe intact animal, it is not possible to differentiate the direct fromthat imidazoline-like compounds may interact with the a1-adreno-the reflex components of the circulatory response, either duringceptor (Ruffolo et al., 1977).central release of transmitter or after central administration of drugs

(Korner et al., 1984). In the present study, we assessed the role of Timmermans et al. (1984) and Kawasaki and Takasaki (1986) re-

Cardiovascular Responses to B-HT 920 33

a selective, potent and specific antagonist of alpha2-adrenoceptors. Br. J.ported that prazosin has an apparent inhibitory effect on pressor re-Pharmac. 78, 489–505.sponse to B-HT 920. Moreover, subchronic prazosin treatment in the

Doxey J. C., Lane A. C., Roach A. G. and Virdee N. K. (1984) Comparisonsham-operated and sinoaortic-denervated rats induced an increase in of the a-adrenoceptor antagonist profiles of idazoxan (RX 781094), yo-the cardiovascular responses mediated by the brain a1-adrenoceptor himbine, rawolscine and corynanthine. Naunyn Schmiedeberg’s Arch.

Pharmac. 325, 136–144.(Ricci and Taira, 1996). In previous work in our laboratory, in-Ebihara H., Kawasaki H., Nakamura S., Takasaki K. and Wada A. (1993)creases in the cardiovascular responses to B-HT 920 were seen in

Pressor response to microinjection of clonidine into the hypothalamicsham-operated and sinoaortic-denervated rats after subchronic pra- paraventricular nucleus in conscious rats. Brain Res. 624, 44–52.zosin treatment, and these previous results suggested a brain a1-adre- Ernsberger P., Giuliano R., Willette R. and Reis D. J. (1990) Role of imidaz-noceptor involvement in the responses to B-HT 920 (Ricci and ole receptors in the vasodepressor response to clonidine analogs in the

rostral ventrolateral medulla. J. Pharmac. Exp. Ther. 253, 408–418.Taira, 1996).Hamilton A. A., Reid J. L. and Yakubu M. A. (1988) [3H] yohimbine andImidazolines interact with high affinity at the a1A-adrenoceptor

[3H] idazoxan bind to different sites on rabbit forebrain and kidney mem-subtype and with low affinity at the a1B-subtype (Wilson et al., branes. Eur. J. Pharmac. 146, 345–348.1991). Chloroethylclonidine, an antagonist of a1B-adrenoceptors, Hanft G. and Gross G. (1989) Subclassification of a1-adrenoceptor recogni-

tion sites by urapidil derivatives and other selective antagonists. Br. J.did not significantly affect the pressor response to B-HT 920 in con-Pharmac. 97, 691–700.scious rats (Piascik et al., 1992).

Kawasaki H. and Takasaki K. (1986) Central alpha-2 adrenoceptor-medi-The biphasic nature of the dose–response curves may indicate ated hypertensive response to clonidine in conscious, normotensive rats.involvement of more than one receptor or more than one brain re- J. Pharmac. Exp. Ther. 236, 810–818.gion. Inasmuch as this characteristic dose–response profile existed King K. A. and Pang C. C. Y. (1988) Differential cardiovascular effects of

central clonidine and B-HT 920 in conscious rats. Can. J. Physiol. Phar-for both the imidazoline and the nonimidazoline compounds, themac. 66, 1455–1460.simple dichotomy of imidazoline receptor and a2-adrenoceptor se-

Kobinger W. (1978) Central a-adrenergic systems as targets for hypotensivelectivity may yet prove incorrect, and a more complex model may drugs. Rev. Physiol. Biochem. Pharmac. 81, 40–100.be required. In conclusion, reflexes mediated through the arterial Kobinger W. and Pichler L. (1977) Pharmacological characterization of BH-T

933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d]-azepin dihydro-baroreceptor in rats are involved in the nature and magnitude of thechloride) as a hypotensive agent of the clonidine-type. Naunyn-Schmie-centrally induced cardiovascular responses to B-HT 920.deberg’s Arch. Pharmac. 300, 39–46.On the other hand, several types of receptors, including a1A- Korner P. I., Head G. A. and Badoer E. (1984) Effects of sinoaortic denerva-

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511–521.This work was supported by a grant from Secretaria de Ciencia y Tecnica, Uni-Kubo T. and Misu Y. (1981) Pharmacological characterization of the a-adre-versidad de Buenos Aires.

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