Orthostatic hypotensive effect of antipsychotic drugs in Wistar rats by in vivo and in vitro studies of alpha1-adrenoceptor function.
BACKGROUND
Many antipsychotics cause orthostatic hypotension possibly due to antagonist action on resistance vessel alpha1A-adrenoceptors (alpha1A-AR).


OBJECTIVE
We have tested this possibility by determining in Wistar rats how the orthostatic hypotensive effect of several antipsychotic drugs compares with their affinity for adrenoceptors in mesenteric small arteries (MSA with mainly alpha1A-AR) and aorta (mainly alpha1D-AR).


METHODS
Using a tilt setup, orthostatic hypotension was measured in anaesthetized rats for prazosin and the antipsychotics haloperidol, sertindole, risperidone, clozapine, ziprasidone, domperidone, olanzapine, and aripiprazole. For in vitro studies, segments of MSA and aorta were mounted on a wire myograph for isometric tension recording. Cumulative concentration-response curves were constructed to phenylephrine (PE) in the absence and presence of the drugs. Apparent affinity (pA2) was calculated by Schild analysis.


RESULTS
Prazosin antagonized tilt-induced and PE responses in both studies (threshold 4 ng/ml, pA2 9.52 MSA, 10.1 aorta). The rank order of the potency of the antipsychotics in the tilt experiments correlated (r2 = 0.69, P = 0.01) with the pA2-values in MSA: Risperidone and sertindole had the highest potency in the tilt test (threshold 159 and 97 ng/ml) and the highest apparent affinity in MSA (pA2 8.92 and 8.78), in contrast with aripiprazole and domperidone, which had the lowest in each case (threshold 4.1 and 3.0 microg/ml, pA2 7.17 and 6.99). In aorta, the pA2 values did not correlate with the in vivo potencies; in particular, sertindole had no functional affinity in aorta.


CONCLUSIONS
We conclude that the orthostatic hypotensive effect in rats of the antipsychotic drugs investigated is mediated through alpha1A-ARs.
Department of Pharmacology, University of Aarhus, University Park 1240, 8000, Aarhus C, Denmark.
Z
Z
Nourian
T
T
Mow
D
D
Muftic
S
S
Burek
M L
ML
Pedersen
J
J
Matz
M J
MJ
Mulvany
D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D001011:Aorta / Q000294:innervation; D004305:Dose-Response Relationship, Drug; D007024:Hypotension, Orthostatic / Q000139:chemically induced*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000294:innervation; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects
D014150:Antipsychotic Agents; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D011224:Prazosin