Weak Hypotensive Effect of Chronic Administration of the Dual FAAH/MAGL Inhibitor JZL195 in Spontaneously Hypertensive Rats as Revealed by Area under the Curve Analysis

Abstract

The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes.

Function of Presynaptic Inhibitory Cannabinoid CB1 Receptors in Spontaneously Hypertensive Rats and Its Modification by Enhanced Endocannabinoid Tone

“…The present findings with MJN110, JZL195 and URB597 are in harmony with previous results in which enzyme inhibitors were administered chronically. JZL195 reduced BP in SHR but not in WKY [34], whereas URB597 failed to diminish BP in either strain ( [33]; Table 2). These findings are compatible with the view that 2-AG probably plays a more important role in the regulation of the cardiovascular system in hypertension than AEA.…”

“…However, chronic intraperitoneal URB597 administration for 2 weeks did not decrease BP in SHR [33]. By contrast, the dual FAAH/MAGL inhibitor JZL195, administered to SHR for 2 weeks revealed a weak hypotensive effect and prevented the progression of hypertension [34]. Thus, when comparing the outcomes of chronic treatment of SHR with URB597 (FAAH blockade only) and JZL195 (dual FAAH/MAGL blockade), increasing 2-AG levels by the inhibition of MAGL might become a new therapeutic option in hypertension.…”

Endocannabinoid Hydrolase Inhibitors: Potential Novel Anxiolytic Drugs

“…The newly developed AKU-005 significantly enhanced 2-AG and AEA levels and inhibited neural excitability in rat and human meninges, which is expected to be a new treatment for migraine. 230 JZL195, a classical dual MAGL/FAAH inhibitor, embodies an antidepressant activity, 231 potent neuroleptic activity, 232 weak antihypertensive effect 233 and anti-inflammatory activity. 234 Regrettably, the anxiolytic effects of JZL195 remain a subject of controversy.…”