Background and purpose: Resistance blood vessels are innervated by sympathetic and primary sensory nerves, which modulate vascular tone through the release of noradrenaline and calcitonin gene-related peptide (CGRP), respectively. Moreover, electrical stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses which are mainly mediated by CGRP release. The present study has investigated the role of a 2 -adrenoceptors in the inhibition of these vasodepressor responses. Experimental approach: 144 pithed male Wistar rats were pretreated with hexamethonium (2 mg kg À1 min À1 ) followed by i.v. continuous infusions of either methoxamine (15 and 30 mg kg À1 min À1 ) or clonidine (3, 10 and 30 mg kg À1 min À1 ). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T 9 -T 12 ) resulted in frequencydependent decreases in diastolic blood pressure. Key results: The infusion of clonidine (10 mg kg À1 min À1 ), as compared to those of methoxamine (15 or 30 mg kg À1 min À1 ), inhibited the vasodepressor responses to electrical stimulation without affecting those to i.v. bolus injections of a-CGRP (0.1-1 mg kg À1 ). This inhibition by clonidine was: (i) antagonized by 300 mg kg À1 rauwolscine (a 2A/2B/2C ), 300 and 1000 mg kg À1 BRL44408 (a 2A ), or 10 and 30 mg kg À1 MK912 (a 2C ); and (ii) unaffected by 1 ml kg À1 saline, 100 mg kg À1 BRL44408, 3000 and 10000 mg kg À1 imiloxan (a 2B ) or 3 mg kg À1 MK912. Conclusions and implications:The inhibition produced by 10 mg kg À1 min À1 clonidine on the vasodepressor (perivascular) sensory outflow in rats may be mainly mediated by prejunctional a 2A /a 2C -adrenoceptors.

British Journal of Pharmacology (2008) 154, 1160; doi:

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This study has characterised the pharmacological profile of some dopaminergic agents of the ergoline family including the antiparkinsonian drug 8S-lisuride at native guinea pig histamine H(1) receptors and recombinant human and guinea pig H(1) receptors. We used segments of guinea pig ileum to study contractile responses, Sf9 insect cell membranes expressing the guinea pig H(1) receptor (gpH(1)R) and the human H(1) receptor (hH(1)R) to analyse GTPase activity of G(q)-proteins and we conducted [(3)H]mepyramine binding studies using recombinant gpH(1)Rs and hH(1)Rs. 8S-Lisuride acted as a potent partial agonist at H(1)Rs of guinea pig ileum (pD(2) 7.6, E (max) 28% of histamine-induced maximum response) and as a silent antagonist at recombinant gpH(1)Rs (pA(2) 7.5) and hH(1)Rs (pA(2) 7.7) in GTPase studies. In contrast, its epimeric counterpart, 8R-lisuride, lacked efficacy and showed much lower affinity for H(1)Rs of both species than 8S-lisuride. High affinity of 8S-lisuride and low affinity of 8R-lisuride was also estimated for gpH(1)Rs and hH(1)Rs in radioligand binding studies. The 1-allylated derivative of 8S-lisuride, 1-allyl-8S-lisuride, was equipotent with its parent compound (pD(2) 7.7) and showed enhanced efficacy in guinea pig ileum and at recombinant gpH(1)Rs in GTPase studies (E (max) 53%, 32%). Other antiparkinsionian drugs such as 8S-terguride, pergolide, cabergoline and bromocriptine displayed lower affinities for H(1)Rs than 8S-lisuride. In conclusion, our results show that the antiparkinsonian drug 8S-lisuride is dramatically more potent than its epimeric counterpart 8R-lisuride in all assays used. 8S-Lisuride behaved as a partial agonist at gpH(1)Rs and as a silent antagonist at hH(1)Rs. Thus 8S-lisuride may act as an antagonist in vivo. This may be of potential importance since H(1)Rs modulate dopaminergic transmission in the brain.