The 5-hydroxytryptamine transporter (5-HTT) is thought to play a key role in the development of primary pulmonary arterial hypertension (PAH) and secondary hypoxia-related PAH. Attenuated hypoxic PAH has been reported in mice lacking the 5-HT transporter gene (Eddahibi et al., 2000). It was also shown that the selective 5-HTT inhibitors fluoxetine and citalopram protect against chronic hypoxia-induced pulmonary hypertension (CHPHT) in mice (Marcos et al, 2003) and hence, 5-HTT inhibitors are being considered as a novel therapeutic approach to PAH. Their effect on contractile responses to 5-HT have, however, not been examined. The fawn-hooded (FH) rat strain exhibits a congenital predisposition to primary PAH (Sato et al., 1992) displaying increased circulating levels of 5-HT and alterations in the serotonin transporter (Aulakh et al., 1994; Tschopp & Zucker, 1972)

Hence, we studied the acute effects of citalopram and fluoxetine on responses to 5-HT in pulmonary resistance arteries (PRAs) from normoxic and CHPHT male FH rats (45 days old, ~200g). The rats were subjected to 2 weeks chronic hypoxia (10% O₂) and subsequently developed PAH as described previously (Keegan et al., 2001). PRAs (~200µm i.d.) from all rats were mounted (Krebs solution; 37^oC;16%O₂/5%CO₂) on wire myographs (tensions: normoxics ~15mmHg and hypoxics ~ 33mmHg) and cumulative concentration responses to 5-HT (1nM-0.1mM) obtained in the absence or presence of citalopram (0.1µM & 1.0µM) or fluoxetine (0.1µM & 1.0µM). Inhibitor pre-incubation time was 45 minutes. Maximum contractile responses (Emax, % response to 50mM KCl ± sem) and potency (pEC₅₀) values were obtained. Statistical comparisons were made by one-way analysis of variance. When significance was obtained (P<0.05), the differences were established using the Newman-Keuls multiple comparison test. In PRAs from normoxic rats, 5-HT induced a contractile response (pEC₅₀ = 5.5 ± 0.1; Emax = 31.5 ± 0.1%; n = 8). In CHPHT rats, the PRAs exhibited a significant increase (P<0.01) in sensitivity (pEC₅₀ = 6.2 ± 0.1) and maximum response (Emax = 132 ± 10%; n = 10; P<0.001) when compared with normoxic controls. In normoxic rats 1µM citalopram caused a 10 fold increase (P<0.01) in the sensitivity of 5-HT ( pEC₅₀ = 6.3 ± 0.1; n=8); and at 0.1 µM it further increased (P<0.001) the potency ( pEC₅₀ = 6.9 ± 0.3; n=7) and also increased the maximum response (Emax = 50 ± 9%; P<0.05; n=7) Fluoxetine at 0.1µM increased (P<0.05) the potency of 5-HT (pEC₅₀ = 6.2 ± 0.1; n=6); without affecting the maximum response to 5-HT (Emax = 35 ± 2%; n=6); but was without any effect at 1µM (pEC₅₀ = 5.7 ± 0.2; Emax = 45 ± 14%; n=8). In chronic hypoxic FH rats, citalopram at 0.1µM and 1µM significantly increased (P<0.05) the potency of 5-HT (pEC₅₀ = 6.9 ± 0.2, n=4 and 7.0 ± 0.2; n=6, respectively) whilst fluoxetine(1mM) decreased (P<0.5) the potency (pEC₅₀ = 6.0 ± 0.1; n=6 and maximum response (Emax = 90 ± 10%; n=6).

In conclusion, the selective 5-HTT inhibitor citalopram increases the sensitivity to 5-HT in PRAs from both the normoxic and CHPHT FH rat. Fluoxetine has differing effects dependent on the absence/presence of chronic hypoxia-induced PAH. These differences require further investigation.

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Sato, K., et al., (1992) Am. J. Med, 99, 249-254.
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