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On the mechanism of central hypotensive action of clonidine* R.C. SRIMAL,K. GULATI,AND B. N. DHAWAN Divisiorz o f Pharnracology, Central Drug Research Institute., E u c k n o ~ v - I Pndia , Received December 3, 1976 SRIMAI,R. C., GUI.ATI,K., and BHAWAN, B. N. 1977. On the mechanism of central hypotensive action of clonidine. Can. J. Physiol. Pharmacol. 55, 1007-101 4. The hypotensive effect of clonidine in anaesthetised (pentobarbitone) cat has been analysed with the help of pharniacological tools. Application of clonidine (0.1% ) to the exposed ventral surface of medulla oblongata produced hypotension (28.6%) and bradycardia ( 1 8% ) . Similar application of glycine ( 5 % ) and GABA ( 10% ) also lowered the blood pressure of cat by 20.3% and 29.3%, respectively. The hypotension as well as the bradycardia owing to clonidine were significantly (p < 0.01 ) biocked by similar prior application of atropine methylnitrate ( I 76 ) and heniicholinium-3 (PIC.$,1 % ). whereas HCs pretreatment only insignificantly blocked the hypotension produced by glycine (p > 0.80) and S A R A ( p > 0.70). Topical application of atropine (1% ) also blocked ( g 0.05) the hypotensive effect of clonidine. Intravenous administration of clonidine (50pg/kg) produced hypotension (34.6%) after an intial hypertensive response and bradycardia (38.8%). The hypotension was significantly ( p 0.01 ) blocked by pretreatment of the cat with intracerebroventricular atropine (4 mg) or HCa (0.5 rng). Topical application of atropine ( 1 % ) to the ventral surface of medulla also significantly ( p < 0.05) reduced the hypotension and bradycardia resulting from intravenous administration of clonidine. I t is concluded that an intact cholinergic link in the brainstem is essential for the hypotenqive effect of clonidine.


0.3) between the hypo- cats produced immediate sharp hypotension tensive effect of first and second application but which recovered soon after removal of the swab. a significant ( p < 0.01 ) reduction was ob- This was significantly reduced after pretreatserved in the bradycardia. ment of the animal with topical atropine (see A similar application of glycine (5.0% for Fig. 3 ) . 3 min ) produced hypotension of 20.3 -t 9.6% . In five cats 50 pg/kg clonidine was adminGamma-aminobutyric acid (10% for 3 min) , istered intravenously after topical application of

*

1010

CAN. .T-

PHYSIOL. PHARMACBL.

b e a t s /min

2v

-

Can. J. Physiol. Pharmacol. Downloaded from www.nrcresearchpress.com by SAVANNAHRIVNATLABBF on 11/13/14 For personal use only.

ACH tO%

-

C-0.1%

beats/ min

.

u

I min

FIG.3. Ventral surface of medulla of a pentsbarbitone anaesthetised cat has been exposed and the record of the heart rate (beatsimin) and blood pressure (mmHg) have been taken. Topical application of acetylcholine (ACh, 1.8% ) for 30 s produced a marked and transient depressor response. Similar application of clonidine (@, 0.1 Ci'o ) for 45 s produced the usual hypotension and bradycardia. Lower panel shows the effect of ACk and C after a topical application sf atropine ( 1.0%) for 60 min. Note that the hypotensive responses of ACh as well as C are significantly reduced.

1 % atropine solution to the ventral surface of medulla for 60 min. Clonidine produced much less hypotension (4.2 -t- 6.6% ) and bradycardia ( 16.1 5 4.296 ) in these animals and the reduction was statistically significant (Table 2). Records from a typical experiment have been shown in Fig. 4. Intravenous administration of clonidine (PO pg/kg) 60 min after pretreatment of the animals with atropine (4 mg, icv) failed to produce any hypstension and the initial lmypertensisn

VBL. 55, 1977

was also more marked. Bradycardia was, however, observed but it was about half sf the usual magnitude. Summary of results of all the experiments has been given in Table 2. Eflect of HC, Pretreatment on the Action of Ckoazidine Application of HC3 ( I % ) for 60 min over the ventral surface of medulla completely prevented the hypotensive effect sf subsequent topical application of clonidine (Fig. 2 ) . There was no significant change in the hypotensive effect of topically applied glycine as well as GABA after HC, pretreatment, as is evident from the summary of results in Table 3. Similarly an injection of HC:! (0.5 rng icv) 120 min before the intravenous injection of cIonidine (50 pg/kg) completely blocked the hypotensive effect of the latter and significantly reduced the effect on the heart rate (see Fig. 1 and Table 2). Noradrenaline (0.19% for 5 min) when agplied topically to the ventral surface of medulla produced hypertension and tachycardia. This remained unaffected by pretreatment of the animal with HC3 administered either intracerebroventricularly or applied topically.

Discussion A variety of substances when applied topically to the ventral sudace of medulla have been shown to produce a depressor or pressor effect (Guertzenstein 1973) which is not the result of their systemic absorption. Several cholinomimetic agents like physastigmine and carbachol were found to produce a depressor response (Guertzenstein 1973) like clonidine (Bousquet and Guertzenstein I973 ) . Atropine, on the other hand, had a definite pressor effect.

TABLE I. Effect of topical application of clonidine (8.17qj for 45 s) on blood pressure and heart rate of cats Heart rate, beats/min

Blood pressure, mmHg Pretreatment Nil Atropine, 1 % Atropine methylnitrate, 17: HC& lYo

No. animals

At peak

o10/

Initial

effect

hypotension

Initial

At peak effect

11 5

12325.8 14Tk1'7.9

88k6 125218.3

28.653.6 15.7k4.3"

158f 11.3 125f 9.8

131 k12.7 111 f 7 . 5

1823.3 9.9k2.7

3

127k2'7 94512.4

117k23.7 99k13.5

137541.4 120k41.2

129539.4 16656.7

6+2.1** 1.8+2.1**

4

$.3_+4.2** 0**

(#