Investigation of the effects of central blockade of α7 and α4β2 nAChRs on blood pressure and renal sympathetic nerve activity in the anaesthetized rat

Christopher Moore , Yun Wang2, Andrew G Ramage Department of Pharmacology, UCL, London NW3 2PF, 2Lilly Research Centre, Eli Lilly Co. & Ltd, Windlesham, Surrey, UK

Ganglionic nAChRs play an important physiological role in the maintenance of blood pressure, however little is known about their physiological role in the central control of blood pressure. In the present experiments the effects of i.c. dihydro-β-erythroidine (DhβE), an α4β2 receptor antagonist, methyllycaconitine (MLA), an α7 receptor antagonist, and α-bungarotoxin (α-BgT), a homomeric (α7- α10) antagonist, on baseline blood pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RNA) were examined.

Male Sprague Dawley rats (250-350g) were anaesthetized (i.v.) with α -chloralose (100 mg kg-1 and maintained with 15 mg kg-1 when necessary), artificially ventilated and neuromuscular blocked (3 mg kg-1; decamethonium). Recordings were made of MAP, HR and renal nerve activity. Depth of anaesthesia was assessed by the stability of MAP, HR and RNA following a noxious stimulus. Changes were compared with control, saline (5 μl; i.c.) by two-way ANOVA and the least significant difference test. All values are means ± S.E.M. At the end of the experiment animals were killed by an overdose of pentobarbitone

DhβE (10 µmol kg-1; n=5) caused a significant and transient rise in MAP after 1 min of 12 ± 2 mmHg associated with a significant and transient increase in RNA of 105 ± 24% and no change in HR. MLA at both doses (0.5; 1.0 µmol kg-1; n=5) had similar effects causing a significant delayed increase in MAP reaching 41±8 and 39 ± 12 mmHg by 5 min, however this was only associated with an increase in RNA of 110 ± 43% for the highest dose. Neither dose had any significant effect on HR. However a low dose (0.1 µmol kg -1; n=5) by 10 min caused a fall in MAP of 15 ± 4 mmHg, HR of 58 ± 13 and RNA of -58 ± 9%. α-BgT (0.01 µmol kg-1; n=5) had no effect on MAP, HR or RNA, however it did block the rise in MAP evoked by the α7 agonist PSAB-OFP (Broad et al., 2002; Astra IV; 3 µmol kg-1) given i.c.

These data imply that central cholinergic pathways, via nAChRs at the level of brainstem, are involved in blood pressure regulation. However, the lack of a dose response curve with MLA and the fact that these antagonists can cause a rise in MAP as seen with the agonists (Moore, this meeting) make these data difficult to interpret.

Broad et al., (2002). Eur. J. Pharmacol, 452, 137-144

CM was supported by a BBSRC collaborative studentship.
Y.W. present address is Central Research Institute of the Shanghai Pharmaceutical Group, Shanghai, China.