Antagonism of Hypotensive and Bradycardic Effects. of Centrally Administered Guanfacine by. Metiamide in Anesthetized Rabbits

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1 Antagonism of Hypotensive and Bradycardic Effects of Centrally Administered Guanfacine by Metiamide in Anesthetized Rabbits Takeshi OTORII, M.D., Ph.D., Kazuhiro OHKUBO, and Kenichi SUZUKI SUMMA In anesthetized rabbits, intracerebroventricular (ICV) administration of the ƒ -adrenoceptor agonist, guanfacine, like clonidine, elicited dose-related falls in arterial blood pressure and heart rate. ICV pretreatment with the histamine H2-receptor antagonist, metiamide, significantly reduced the hypotensive and bradycardic responses caused by ICV injection of either guanfacine or clonidine. The present results seem to indicate that the antagonistic effect of metiamide against either guanfacine or clonidine is probably due to its ƒ -adrenoceptor blocking action rather than its histamine H2-receptor blocking action, suggesting that these interactions might be of central origin. Additional Indexing Words: Guanfacine Clonidine Metiamide Blood pressure Heart rate Central regulation ƒ -adrenoceptor Histamine H2-receptor HE cardiovascular effects of guanfacine, an antihypertensive phenylguanidine derivative,1),2) resemble those of clonidine in many respects.3),4) It has been reported that some of the hypotensive action of clonidine is due to a central mechanism in which cerebral pre- or postsynaptic ƒ -adrenoceptors play an important role.5)-11) Clonidine-induced activation of these central ƒ -adrenoceptors results in a reduction of the sympathetic tone and, thus, a fall in blood pressure and heart rate. On the basis of its mechanism of action, guanfacine is classified as a central ƒ -adrenoceptor stimulant like clonidine. Recently, however, it has been proposed that the hypotensive effect of clonidine is at least partly due to an activation of central histamine H2-receptors, since ICV administration of the specific histamine From the Department of Pharmacology, Yamagata University School of Medicine, Yamagata, J apan. Address for reprint: Takeshi Otorii, M.D., Department of Pharmacology, Yamagata University School of Medicine, Yamagata City , Japan. Received for publication November 14,

2 578 OTORII, OHKUBO, AND SUZUKI Jpn. Heart July 85 H2-receptor antagonist, metiamide, antagonized the hypotensive effect of clonidine in rats.12)-14) The present study was undertaken to compare the antagonistic action of metiamide against the hypotensive and bradycardic effects of guanfacine and those of clonidine in anesthetized rabbits. METHODS Albino rabbits of either sex weighing Kg, were anesthetized with urethane ( Gm/Kg, s.c.) and tracheotomized to allow spontaneous breathing. The animals were mounted in a stereotaxic apparatus and a stainless steel needle through which the drug solutions were applied intracerebroventricularly was implanted into the left ventricle according to the stereotaxic atlas of Sawyer et al.15) The arterial blood pressure was measured directly from the left carotid artery by means of a pressure transducer (Nihon Kohden MPU-0.5) and the heart rate was recorded by using the pressure pulse to trigger a cardiotachometer (Nihon Kohden RT-5). Drugs used: Guanfacine hydrochloride (Sandoz) and clonidine hydrochloride (Boehringer Ingelheim) were dissolved in 0.9% saline solution. Metiamide (Smith, Kline & French) was dissolved in 0.1N HCl and then diluted with 0.9% saline solution, as needed. The volume of drug solution to be injected was always adjusted to 0.1ml. An injection of the control solution (0.9% saline solution) had no significant effect on blood pressure and heart rate. RESULTS 1. Effects of guanfacine and clonidine on arterial blood pressure and heart rate As shown in Figs. 1 and 2, in anesthetized rabbits ICV injection of guanfacine (3-100ƒÊg/rabbit) and clonidine ( ƒêg/rabbit) elicited doserelated decreases in mean arterial blood pressure and heart rate. Timeresponse curves for the blood pressure and heart rate falls induced by guanfacine (30ƒÊg) and clonidine (3ƒÊg) are illustrated in Figs.3 and 4, respectively. Guanfacine, in a dose of 30ƒÊg, produced a fall in mean arterial blood pressure and heart rate from 5-10min after ICV injection. The maximal fall in blood pressure was observed 60-90min after injection and the hypotensive effect persisted for 2-4 hours. ICV injection of clonidine, in a dose of 3ƒÊg, produced nearly the same maximal fall in blood pressure as that of 30ƒÊg of guanfacine, although the duration of effect was shorter with clonidine

3 Vol.26 INTERACTION BETWEEN GUANFACINE AND METIAMIDE 579 No.4 Fig.1. Dose-response curves of ICV injection of guanfacine (n=7) and clonidine (n=7) on the mean arterial blood pressure (MAP) in anesthetized rabbits. Vertical bars represent the standard error of means. than with guanfacine. The bradycardic effect of guanfacine, in a dose of 30ƒÊg, was less than that of 3ƒÊg of clonidine, while nearly the same maximal fall in blood pressure was observed for the two drugs in the respective doses. 2. Effects of guanfacine and clonidine on arterial blood pressure and heart rate after pretreatment with metiamide ICV pretreatment with the histamine He-receptor antagonist, metiamide, was carried out 20min before ICV injection of either guanfacine or clonidine. The administration of metiamide (0.8mg) alone caused only a slight rise in the mean arterial blood pressure of about 10-15min duration, and at the time of administration of either guanfacine or clonidine the blood pressure was not significantly different from the pre-dose control level. The administration of metiamide (0.8mg) alone did not significantly affect the heart rate. Metiamide pretreatment caused a significant inhibition of the fall in mean arterial blood pressure and heart rate induced by either guanfacine or clonidine. As shown in Figs.1 and 2, metiamide pretreatment caused an

4 580 OTORII, OHKUBO, AND SUZUKI Jpn. Heart J. July 1985 Fig. 2. Dose-response curves of ICV injection of guanfacine (n=7) and clonidine (n=7) on the heart rate (HR) in anesthetized rabbits. Vertical bars represent the standard error of means. apparent shift to the right of the dose-response curves for the blood pressure and heart rate falls induced by both agonists. Figs.3 and 4 illustrate, respectively, the time-response curves of the hypotensive and bradycardic effects of guanfacine (30ƒÊg) and clonidine (3ƒÊg) changed by ICV pretreatment with metiamide (0.8mg). DISCUSSION We have previously reported that a fall in blood pressure and heart rate caused by ICV injection of either guanfacine or clonidine was inhibited by ICV pretreatment with the ƒ -adrenoceptor antagonist, phentolamine, in anesthetized rabbits.16) These findings suggest that presynaptic and/or postsynaptic ƒ -adrenoceptors in the central nervous system may play an important role in hypotension and bradycardia induced by guanfacine as well as by clonidine. In the present study, we demonstrated that in anesthe-

5 Vol.26 No.4 INTERACTION BETWEEN GUANFACINE AND METIAMIDE 581 Fig.3. Effects of ICV injection of guanfacine (30 ƒêg/rabbit, n=8) and clonidine (3ƒÊg/rabbit, n=8) on the mean arterial blood pressure (MAP) in the metiamide-pretreated and control rabbits. Significant difference from the control, *p<0.05, **p<0.01. Fig.4. Effects of ICV injection of guanfacine (30 ƒêg/rabbit, n=8) and (3ƒÊg/r clonidine abbit, n=8) on the heart rate (HR) in the metiamide -pretreated and control rabbits. Significant difference from the control, *p<0.05.

6 582 OTORII, OHKUBO, AND SUZUKI Jpn. Heart J uly 85 tized rabbits the hypotensive and bradycardic effects caused by ICV injection of guanfacine as well as by clonidine were reduced by ICV pretreatment with the histamine H2-receptor antagonist, metiamide. These findings are consistent with those on clonidine of other researchers, who suggested that this drug might act on several neuronal pathways containing, at least, ƒ -adrenoceptors and histamine H2-receptors in the central nervous system.12)-14) Thus, the present study gives support for the same interaction between guanfacine or clonidine and metiamide as mentioned above, suggesting that this interaction might be of central origin. There are several reports that clonidine is not only an ƒ -adrenoceptor agonist, but a histamine H2-receptor agonist with respect to the contractile response of the isolated heart17) and atria18),19) in the guinea pig and on gastric acid secretion in the anesthetized rat.18),20),21) From these reports, it is thought that the stimulation of histamine H2-receptors may be implicated in the cardiovascular effects of clonidine. However, their reports indicate that the intrinsic activity of clonidine at histamine H2-receptors mediating contractile response of heart or gastric acid secretion is much lower than that of histamine, indicating that the doses of clonidine needed to activate the histamine H2-receptors would be far larger than those needed to activate ƒ -adrenoceptors. In addition, Finch and Hicks showed that in rats ICV injection of histamine elicited a rise in blood pressure and heart rate, which might be mediated by histamine H2-receptors,22) and that in rats the administration of 4-methylhistamine, a selective histamine H2-receptor agonist, into the posterior hypothalamus did not produce a fall in blood pressure and heart rate.23) Therefore, it is probable that the hypotensive and bradycardic effects caused by ICV injection of clonidine are not involved in a stimulation of histamine H2- receptors, even if clonidine is a partial agonist of the histamine H2-receptor. On the other hand, recently, a few histamine H2-receptor antagonists have been reported to possess some ƒ -adrenoceptor antagonistic activity in various organ tissues.24)-27) From the above mentioned observations, the present results seem to indicate that the antagonistic effect of metiamide against either guanfacine or clonidine is probably due to its ƒ -adrenoceptor blocking action rather than its histamine H2-receptor blocking action. Especially, it is reasonable to claim that guanfacine-induced hypotension and bradycardia are elicited mainly via an activation of the ƒ -adrenoceptors in the central nervous system. Although in the various experiments reported by previous investigators,2)-4),18) guanfacine was found to show the same pharmacological profile as clonidine, there was no evidence suggesting that unlike clonidine this drug might activate the histamine H2-receptors. For example, Medgett

7 Vol.26 No.4 INTERACTION BETWEEN GUANFACINE AND METIAMIDE 583 and McCulloch19) have demonstrated that in anesthetized rats, although clonidine produced an increase in gastric acid secretion which was mediated by histamine H2-receptors, guanfacine did not affect the gastric acid secretion under the same experimental conditions. REFERENCES 1. Bream JB, Lauener H, Picard CW, Scholtysik G, White TG: Substituted phenylacetylguanidines: a new class antihypertensive agents. Arzncim Forsch 25: 1477, Picard CW, Bream JB: Guanfacine (BS ) and related centrally acting a-adrenoceptor stimulants. Chemistry and structure activity relationships. in Medical Chemistry, ed by Simkins MA, Cotswold Press, Oxford, p 45, Scholtysik G, Jerie P, Picard CW: Guanfacine. in Pharmacology of Antihypertensive Drugs, ed by Scriabine A, Raven Press, New York, p 79, Scholtysik G, Lauener H, Eichenberger E, Burki H, Salzmann R, Miiller-Schweinitzer E, Waite R: Pharmacological actions of the antihypertensive agent N-amidino-2-(2, 6-dichlorophenyl) acetamide hydrochloride (BS ). Arzneim Forsch 25: 1483, Haeusler G: Clonidine-induced inhibition of sympathetic nerve activity: no indication for a central presynaptic or indirect sympathomimetic mode of action. Naunyn-Schmiedeberg's Arch Pharmacol 285: 97, Hoefke W: Clonidine. in Pharmacology of Antihypertensive Drugs, ed by Scriabine A, Raven Press, New York, p 55, Isaac L: Clonidine in the central nervous system: site and mechanism of hypotensive action. J Cardiovasc Pharmacol 2(Suppl 2): 5, Kobinger W, Pichler L: Location in the CNS of adrenoceptors which facilitate a cardioinhibitory reflex. Naunyn-Schmiedeberg's Arch Pharmacol 286: 371, Schmitt H: Antihypertensive agents. in Handbook of Experimental Pharmacology, ed by Gross F, Springer-Verlag, Berlin, Heidelberg, New York, p 299, Starke K, Montel H, Gayk W, Merker R: Comparison of the effects of clonidine on preand postsynaptic adrenoceptors in the rabbit pulmonary artery. Naunyn-Schmiedeberg's Arch Pharmacol 285: 133, van Zwieten PA, Timmermans PBMWM: The role of central ƒ -adrenoceptors in the mode of action of hypotensive drugs. Trends Pharmacol Sci 1: 39, Finch L, Harvey CA, Hicks PE, Owen DAA: Clonidine-induced hypotension: further evidence for a central interaction with histamine H2-receptor antagonists in the rat. Neuropharmacology 17: 307, Karppanen H, Paakkari I, Paakkari P, Orma A-L: Possible involvement of central histamine H2-receptors in the hypertensive effect of clonidine. Nature 259: 587, Karppanen H, Paakkari I, Paakkari P: Further evidence for central histamine H 2-receptor involvement of in the hypotensive effect of clonidine in the rat. Eur J Pharmacol 42: 679, Sawyer CH, Everett JW, Green JD: The rabbit diencephalon in stereotaxic coordinates. J Comp Neurol 101: 801, Ohkubo K, Suzuki K, Oguma M, Otorii T: Central hypotensive effects of guanfacine in anaesthetized rabbits. Folia Pharmacol Japon 79: 263, 1982 (in Japanese) 17. Csongrady A, Kobinger W: Investigation into the positive inotropic effect of clonidine in isolated heart. Naunyn-Schmiedeberg's Arch Pharmacol 282: 123, Medgett IC, McCulloch MW: Effects of clonidine, guanfacine and three imidazolidine deriv - atives related to clonidine on blood pressure, heart rate and gastric acid secretion in the anaesthetized rat. Arch Int Pharmacodyn 240: 156, 1979

8 584 OTORII, OHKUBO, AND SUZUKI Jpn. Heart July Medgett IC, McCulloch MW: Receptor sites of action of clonidine: effects of clonidine and three structural isomers on prejunctional and postjunctional ƒ -adrenoceptors and histamine H2-receptors in guinea-pig isolated cardiovascular tissues. J Pharm Pharmacol 32: 137, Jennewein HM: The effect of clonidine on gastric acid secretion in rats and dogs. Naunyn- Schmiedeberg's Arch Pharmacol 297: 85, Karppanen H, Westermann E: Increased production of cyclic AMP in gastric tissue by stimulation of histamine (H2)-receptors. Naunyn-Schmiedeberg's Arch Pharmacol 279: 83, Finch L, Hicks PE: The cardiovascular effects of intraventricularly administered histamine in the anaesthetized rat. Naunyn-Schmiedeberg's Arch Pharmacol 293: 151, Finch L, Hicks PE: Involvement of hypothalamic histamine H2-receptors in the central cardiovascular actions of histamine. Neuropharmacology 16: 211, Brimblecombe EW, Duncan WAM, Owen DAA, Parson ME: The pharmacology of burimamide and metiamide, two histamine H2-receptors antagonists. Federation Proc 35: 1931, Griffith OR, Marshall I, Nasmyth PA: Blockade of pre-synaptic ƒ -adrenoceptors by metiamide. Br J Pharmacol 64: 416P, McCulloch MW, Medgett IC, Rand MJ: Effect of the histamine HZ receptor blocking drugs burimamide and cimetidine on noradrenergic transmission in the isolated aorta of the rabbit and atria of the guinea-pig. Br J Pharmacol 67: 535, Medgett IC, McCulloch MW: Effects of histamine H2-receptor antagonists on noradrenergic transmission. Proc Aust Physiol Pharmacol Soc 9: 7P, 1978