Chronic inhibition of fatty acid amide hydrolase by URB597 produces differential effects on cardiac performance in normotensive and hypertensive rats.

BACKGROUND AND
PURPOSE: Fatty acid amide hydrolase (FAAH) inhibitors are postulated to possess anti-hypertensive potential, because their acute injection decreases BP in spontaneously hypertensive rats (SHR), partly through normalization of cardiac contractile function. Here, we examined whether the potential hypotensive effect of chronic FAAH inhibition by URB597 in hypertensive rats correlated with changes in cardiac performance. EXPERIMENTAL APPROACH: Experiments were performed using perfused hearts and left atria isolated from 8- to 10-week-old SHR, age-matched deoxycorticosterone acetate (DOCA)-salt rats and normotensive controls chronically treated with URB597 (1 mg·kg-1 ) or vehicle. KEY
RESULTS: URB597 decreased BP only in the DOCA-salt rats, along with a reduction of ventricular hypertrophy and diastolic stiffness, determined in hypertension. We also observed normalization of the negative inotropic atrial response to the cannabinoid receptor agonist CP55940. In the SHR model, URB597 normalized (atria) and enhanced (hearts) the positive ino- and chronotropic effects of the β-adrenoceptor agonist isoprenaline respectively. Ventricular CB1 and CB2 receptor expression was decreased only in the DOCA-salt model, whereas FAAH expression was reduced in both models. URB597 caused translocation of CB1 receptor immunoreactivity to the intercalated discs in the hearts of SHR. URB597 increased cardiac diastolic stiffness and modified the ino- and lusitropic effects of isoprenaline in normotensive rats. CONCLUSION AND IMPLICATIONS: Hypotensive effect of chronic FAAH inhibition depend on the model of hypertension and partly correlate with improved cardiac performance. In normotensive rats, chronic FAAH inhibition produced several side-effects. Thus, the therapeutic potential of these agents should be interpreted cautiously.