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).

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 (R_msa) 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