| pA2 online © Copyright 2004 The British Pharmacological Society |
017P
University of Bath Summer Meeting July 2004 |
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Role of central nicotinic receptors in cardiovascular regulation |
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Print abstract Two neuronal nicotinic acetylcholine receptors subtypes have been clearly identified in the brain, a heteromeric receptor ( 
4β 2 ) and a homomeric receptor ( 7 ). Experiments were preformed to investigate the role of these two subtypes in central cardiovascular regulation by comparing the effects of nicotine administered intracerebroventricularly (i.c.v.) with those of a selective agonist for the 4β 2 receptor, TC-2559 (Chen et al., 2003), and the 7 receptor, Astra IV ((R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(5-(2-pyridyl)thiophene-2-carboxamide; De Filippi et al., 2002).
Experiments were performed on Sprague Dawley male rats (250-350g) anaesthetized with α -chloralose (100 mg kg-1 ), artificially ventilated and neuromuscular blocked (3 mg kg-1; decamethonium). Recordings were made of mean blood pressure (MAP), heart rate (HR) and renal nerve activity (RNA; see Anderson et al., 1992). Test drugs were given by i.c.v. injections (5 µl). Changes were compared with saline by two-way ANOVA and the least significant difference test. All values (n=5) are means ± s.e. mean.
Nicotine (0.3 & 1 µmol kg-1) produced significant (P<0.05) increases in MAP (11 ± 2 & 25 ± 9 mmHg) associated with renal sympathoinhibition. Astra IV (3 & 10 µmol kg-1) caused a significant increase in MAP (22 ± 5 & 32 ± 9 mmHg) associated with increases in RNA (106 ± 20% & 227 ± 56%). 1 m mol kg-1 caused a significantly increased RNA but no changes in MAP. TC-2559 (1 & 3 µmol kg-1) caused a significant rise in RNA (79 ± 21% & 259 ± 52%). At 3 µmol kg-1 this was associated with a significant rise in MAP. In the presence of dihydro- β -erythroidine (DH β E, 10 m mol kg -1), nicotine (0.3 m mol kg-1) had no effect on MAP or HR but now caused a significantly rise in RNA (39 ± 6%). For Astra IV and TC-2559 (3 µmol kg-1) the rise in MAP was no longer significant. This was still associated, for Astra IV with a similar increase in RNA but for TC-2559 the rise in RNA was significantly reduced.
This study indicates that activation of 4β 2 or 7 can cause renal sympathoexcitation. The overall effects on MAP are difficult to interpret. Nicotine is known to release vasopressin (Ota et al., 1992), which would be expected to cause a rise in MAP associated with reflex sympathoinhibition. As observed with nicotine in the present study, and as this is blocked by DH β E, this suggests that activation of 4β 2 receptors causes the release of vasopressin. However, TC-2559 causes sympathoexcitation not sympathoinhibition and that this is also reduced by DH β E, is not consistent with such interpretation.
Anderson, I.K. et al., (1992). Br. J. Pharmacol., 107, 1020-1028
Chen, Y. et al., (2003). Neuropharmacology, 45, 434-444
De Fillipi, G. et al., (2002). Neurosci. Abstr., 28, 137.5
Ota, M. et al., (1992). Proc. Soc. Exp. Biol. Med., 201, 208-214
Christopher Moore is in receipt of BBSRC PhD collaborative award with Eli Lilly