Studies Of Clonidine And Moxonidine On Arterial Baroreflex And Transient Pressor Response

Arterial baroreflex （ABR） is one of the most important mechanisms in the regulation ofcardiovascular activities. Baroreflex function, expressed as baroreflex sensitivity （BRS）, is animportant determinant for many cardiovascular diseases. Recent studies performed instroke-prone spontaneously hypertensive rats （SHR-SP） indicated that BRS is an independentpredictor for stroke; restoration of BRS may be a new strategy for the prevention of stroke. Inthis study, SHR-SP were used to examine effects of clonidine, moxonidine, folic acid andmecobalamine on ABR function, and to study further the possible site of action. The aim of thepresent study was to find drugs potentially improving impaired ABR function and to provideexperimental evidence for their applications in clinic.To investigate effects of clonidine, moxonidine, folic acid and mecobalamine on ABR function,a single dose of drug was administered intragastdcally. The results indicated that SBP and DBPwere significantly decreased （16±3 mm Hg and 12±3 mm Hg） and HP was prolongeddramatically by clonidine 10.0μg/kg. DBP was significantly decreased by clonidine1.0μg/kgwhile SBP and HP were not affected obviously. BRS was enhanced markedly by both doses ofclonidine. SBP and DBP were significantly decreased and BRS was significantly improved byboth doses of moxonidine （i.g., 0.1 mg/kg and 1.0 mg/kg）. BRS was significantly increased butSBP, DBP and HP were not affected by moxonidine 0.05 mg/kg. SBP, DBP and HP were notinfluenced by intragastric folic acid （1.0 mg/kg） or mecobalamine（1.0 mg/kg）, but BRS wassignificantly increased by both drugs.To investigate the possible mechanisms involved in the BRS improving effect of clonidine,moxonidine and mecobalamine, intracerebroventricular （i.c.v.） injections of these drugs wereconducted in conscious SHR-SP. The results indicated that SBP, DBP were significantlydecreased and BRS was significantly increased by i.c.v, injection of clonidine （4μg） ormoxonidine （5μg）, while SBP, DBP and BRS were not affected by i.c.v, injection ofmecobalamine （20μg）. These results demonstrated that clonidine and moxonidine improvedABR function through central mechanisms, While mecobalamine increased BRS throughperipheral mechanisms. In conclision, clonidine, moxonidine, folic acid and mecobalamine improve impaired ABRfunction in SHR-SP. The BRS improving effects of clonidine and moxonidine were notsecondary to a decrease of blood pressure. Central mechanisms were involved in the BRSimproving effect of either clonidine or moxonidine, while mecobalamine improves ABRfunction through peripheral mechanisms. Clonidine and moxonidine are centrally acting antihypertensive drugs applied in clinic fora long time. They mediate peripheral sympathoinhibition and reductions in blood pressure byacting on central I₁-imidazoline receptors. It was reported that clonidine, by activation ofperipheralα-adrenoceptors, produced transient pressor response after intravenous （i.v.） injectionin anesthetized animals. Moxonidine, with at least 40-fold higher affinity to I₁-imidazolinereceptors overα₂-adrenoceptors, caused also a transient pressor response. This work wasdesigned to compare the features ofpressor response between moxonidine and clonidine, and toinvestigate differences in receptors involved in their pressor responses in anesthetizedspontaneously hypertensive rats.The results indicated that i.v. clonidine （3, 10, 30μg/kg） and moxonidine （0.1, 0.3, 1.0mg/kg） produced dose-dependent pressor responses and significant blood pressure reductionsand heart period （HP） prolongations. Moxonidine produced greater pressor response thanclonidine at the doses to produce a similar reduction of blood pressure. The pressor areas ofmoxonidine were about 3～17 times of those induced by clonidine.Clonidine 10μg/kg and moxonidine0.3mg/kg were selected for further studies. Effects ofdifferent receptor blockers （i.v.） on transient pressor responses to clonidine and moxonidinewere investingated to find receptors involved. It was found that transient pressor response toclonidine was not affected by prior injection of selectiveα₁-antagonist prazosin （10μg/kg）, butcompletely blocked by prior injection of selectiveα₂-antagonist yohimbine （2 mg/kg）,indicating thatα₁-adrenoceptors were not involved in the transient pressor response of clonidineand it was mediated byα₂-adrenoceptors. Transient pressor response to moxonidine was notaffected by prior injection of prazosin （10μg/kg） but attenuated by yohimbine （2 mg/kg）,phentolamine （0.2 mg/kg） or idazoxan （1 mg/kg）, indicating that it was notα₁-adrenoceptorsbutα₂-adrenoceptors that involved in the trasient pressor response to moxonidine, and theremight be the involvement of I₁-imidazoline receptors. Transient pressor response to moxonidinewas attenuated by prior injection of yohimbine （4 mg/kg）, but completely abolished by priorinjection of combination ofyohimbine （2 mg/kg） and idazoxan （1 mg/kg）, or by prior injection of idazoxan （2 mg/kg）, indicating that bothα₂-adrenoceptors and I₁-imidazoline receptors wereinvolved in the transient pressor response of i.v. moxonidine.Further studies revealed that blood pressure was significantly reduced and HP wassignificantly prolonged after clonidine or moxonidine was administered into lateral cerebralventricle of SHR, but no transient pressor responses appeared in both cases. These resultsdemonstrated that peripheral mechanisms but not central mechanisms were involved in thetransient pressor responses of i.v. clonidine and moxonidine.In conclusion, transient pressor response of i.v. clonidine was mediated by peripheralα₂-adrenoceptors, while this response of i.v. moxonidine was mediated by both peripheralI₁-imidazoline receptors andα₂-adrenoceptors.