pA2 online
Copyright 2004 The British Pharmacological Society

059P University of Bath
Summer Meeting July 2004

1-adrenoceptor affinity of antipsychotic drugs

Zahra Nourian, Jørgen Matz1 & Michael J. Mulvany. Department of Pharmacology, University of Aarhus, Aarhus, and 1H. Lundbeck A/S, Copenhagen, Denmark

Print abstract

Search PubMed for:


Nourian Z
Matz J
Mulvany MJ

The therapeutic action of antipsychotic drugs in the treatment of schizophrenia is attributed to their central dopamine antagonist effect (Strange, 2001), but they also have effects on other receptors such as
1-adrenoceptors in the blood vessels (Buckley et al, 2000). Therefore, a common side effect is orthostatic hypotension, which is probably correlated to their peripheral vascular actions. Here we have determined the 1-adrenoceptor affinity of some antipsychotic drugs (sertindole, risperidone, clozapine, and ziprasidone) in rat small mesenteric arteries (mainly 1A-adrenoceptors) and rat aorta (mainly
1D-adrenoceptors) as well as prazosin as a positive control.

Male Wistar rats (300-350 g) were killed by cervical dislocation. Small mesenteric arteries
(l100=200–300 µm) and thoracic aorta (approx. 2 mm) were mounted as ring preparation on a wire myograph containing physiological salt solution aerated with 5% CO2 in air at 37 ° C. After checking viability of vessels, endothelial integrity was assessed using acetylcholine (10-5 M, mesenteric; 3*10-6 M, aorta). The endothelium was removed and viability rechecked. Cumulative concentration response curves were constructed to phenylephrine (PE: 0.02 µM to 640 µM, mesenteric; 3 nM to 30 µM, aorta) in absence and presence of the antipsychotics (30 min incubation). Appropriate vehicle controls and blockers of neuronal and extraneuronal uptake of noradrenaline,
ß and 2-adrenoceptors (cocaine, corticosterone 21-acetate, propranolol and yohimbine, respectively) were used throughout. The EC50 values in the presence and absence of antipsychotics were used to determine the concentration-ratio (CR). pA2 values were calculated by Schild analysis .

Table 1 shows the results. For prazosin, risperidone and clozapine pA2-values were similar for mesenteric arteries and aorta, suggesting antagonism of both 1A- and 1D-adrenoceptors. Sertindole had high affinity for 1A-adrenoceptors, but little affinity for a 1D-adrenoceptors. Ziprasidone had lower affinity for 1A-adrenoceptors, and little affinity for 1D-adrenoceptors (for aorta, CR 1.0 for ziprasidone 1 µ M to 10 µM).

Rmsa

Raorta

compound

pA2

slope

n

pA2

slope

n

prazosin

9.52

0.85±0.13

21

10.1

0.82±0.14

12

sertindole

8.78

1.24±0.14

12

6.31

1.99±0.21 ٭

12

risperidone

8.92

0.86±0.13

12

8.36

0.99±0.21

16

clozapine

7.64

1.22±0.1

12

7.39

1.09±0.17

12

ziprasidone

7.98

1.08±0.18

12

nc

0.19±0.14 ٭

13

Table 1. Schild analysis of the effect of prazosin, sertindole, risperidone, clozapine, and ziprasidone on phenylephrine concentration-response curves in endothelium-denuded rat small mesentric artery (Rmsa) and rat aorta. ٭ Slope significantly different from unity; nc, not calculated.

In summary, these results suggest that sertindole and ziprasidone have low affinity for 1D and selectivity for 1A-adrencoceptors.

Buckley, N.A. et al. (2000) Drug Safety, 23, 215-228
Strange, P.G. (2001) Pharmacol. Rev., 53, 119-133