Difference in the potency of α₂‐adrenoceptor agonists and antagonists between the pithed rabbit and rat

Abstract

1 The subtypes ofa-adrenoceptors which mediate pressor responses to sympathomimetic agonists or to nerve stimulation in pithed rabbits have been classified according to the effects of 'selective' antagonists and a comparison has been made, for the xt2-subtype, with corresponding responses in the rat.2 In the rabbit the dose-response curve for phenylephrine was shifted to the right in parallel by prazosin (1 mg kg-') and was unaffected by rauwolscine (1 mg kg '). The dose-response curve for noradrenaline was shifted to the right by prazosin (I mg kg -') and was shifted to a smaller extent by rauwolscine (1 mg kg -') or imiloxan (1Omg kg-'). After rauwolscine, prazosin produced a rightward shift larger than when given alone. After prazosin, rauwolscine produced a rightward shift larger than when given alone. 3 The responses to pressor nerve stimulation at low frequencies (< 1 Hz) could be reduced by prazosin, rauwolscine or imiloxan but those at a higher frequency could be reduced only by prazosin. 4 These results indicate that the responses to noradrenaline or to nerve stimulation are mediated by both a,-and a2-adrenoceptors. Low doses or frequencies have a proportionately greater component which is M2 5 Responses to noradrenaline after prazosin (1 mg kg -'), were sufficiently sensitive to rauwolscine to be considered as predominantly a2. A comparison was therefore made of such responses in the rat and rabbit. They were produced by a lower dose per unit body weight in the rat whereas this was less marked for the M2-adrenoceptor agonist guanabenz. In the rabbit they were more susceptible to blockade by rauwolscine but were less sensitive to Wy 26703 than in the rat. This demonstrates that the ;c2-adrenoceptors mediating pressor responses in vivo, like those in other tissues in vitro, are different in rat and rabbit, with regard to antagonists.

Pharmacological profile of the clonidine‐induced inhibition of vasodepressor sensory outflow in pithed rats: correlation with α2A/2C‐adrenoceptors

“…Figure 4 shows that clonidine‐ (10 μg kg −1 min −1 ) induced inhibition of electrically induced vasodepressor responses (as compared to those during 15 μg kg −1 min −1 methoxamine; control responses), which remained unaltered in animals pretreated with 1 ml kg −1 saline (Figure 4a), was: (i) antagonized in animals pretreated with 300 μg kg −1 rauwolscine (Figure 4b), 300 and 1000 μg kg −1 BRL44408 (Figures 4d and e) or 10 and 30 μg kg −1 MK912 (Figures 4i and j); and (ii) resistant to blockade in animals pretreated with 100 μg kg −1 BRL44408 (Figure 4c), 3000 and 10000 μg kg −1 imiloxan (Figures 4f and g) or 3 μg kg −1 MK912 (Figure 4h). It must be emphasized that the doses of the above antagonists were high enough to completely block their respective α 2 ‐adrenoceptor subtypes in the cardiovascular system ( Bulloch et al ., 1987 ; Gavin and Docherty, 1996 ; Willems et al ., 2001 ; Cobos‐Puc et al ., 2007 ).…”

“…Admittedly, clonidine can also interact with imidazoline receptors ( Eglen et al ., 1998 ), but rauwolscine does not block them at concentrations that completely antagonize α 2 ‐adrenoceptors ( Göthert et al ., 1999 ). On this basis, we investigated the role of the α 2A , α 2B and α 2C subtypes by using the antagonists BRL44408 (α 2A ), imiloxan (α 2B ) and MK912 (α 2C ) (Table 1) at doses high enough to completely antagonize their respective receptor subtypes ( Bulloch et al ., 1987 ; Gavin and Docherty, 1996 ; Willems et al ., 2001 ; Cobos‐Puc et al ., 2007 ). As BRL44408 (300 and 1000 μg kg −1 ) or MK912 (10 and 30 μg kg −1 ), but not imiloxan (3000 and 10000 μg kg −1 ), antagonized clonidine‐induced inhibition (Figure 4), the simplest interpretation of these findings is that α 2A (blocked by BRL44408) and α 2C (blocked by MK912), rather than α 2B , adrenoceptors could be involved.…”

Presynaptic α2‐autoinhibition in a vascular neuroeffector junction where ATP and noradrenaline act as co‐transmitters

“…This study also highlighted the difficulties encountered when analysing prejunctional effects of an antagonist like yohimbine, which is also active at postjunctional a2-adrenoceptors. It has been proposed that postjunctional a2-adrenoceptors occur in the vicinity of the postganglionic sympathetic varicosities in the vasculature in the pithed rabbit (McGrath et al, 1982;Bulloch et al, 1987) and the pithed rat . Vasoconstrictor responses of the rabbit ileocolic artery to exogenous NA are mediated exclusively by a1-adrenoceptors, since they are abolished by relatively low concentrations of prazosin but not attenuated by yohimbine (von Kugelgen & Starke, 1985;and present study).…”