Korean J Physiol Pharmacol.  2022 Mar;26(2):77-86. 10.4196/kjpp.2022.26.2.77.

Characterization of hypotensive and vasorelaxant effects of PHAR-DBH-Me a new cannabinoid receptor agonist

• López-Canales OA
• Pavón N
• Ubaldo-Reyes LM
• Juárez-Oropeza MA
• Torres-Durán PV
• Regla I
• Paredes-Carbajal MC

• KMID: 2526727
• DOI: http://doi.org/10.4196/kjpp.2022.26.2.77

Abstract

The effect of PHAR-DBH-Me, a cannabinoid receptor agonist, on different cardiovascular responses in adult male rats was analyzed. The blood pressure was measured directly and indirectly. The coronary flow was measured by Langendorff preparation, and vasomotor responses induced by PHAR-DBH-Me in aortic rings precontracted with phenylephrine (PHEN) were analyzed. The intravenous injection of the compound PHAR-DBH-Me (0.018–185 µg/kg) resulted in decreased blood pressure; maximum effect was observed at the dose of 1,850 µg/kg. A concentrationdependent increase in the coronary flow was observed in a Langendorff preparation. In the aortic rings, with and without endothelium, pre-contracted with PHEN (10^–6 M), the addition of PHAR-DBH-Me to the superfusion solution (10^–12 –10 ^–5 M), produced a vasodilator response, which depends on the concentration and presence of the endothelium. L-NAME inhibited these effects. Addition of CB 1 receptor antagonist (AM 251) did not modify the response, while CB₂ receptor antagonist (AM630) decreased the potency of relaxation elicited by PHAR-DBH-Me. Indomethacin shifted the curve concentration-response to the left and produced an increase in the magnitude of the maximum endothelium dependent response to this compound. The maximum effect of PHAR-DBH-Me was observed with the concentration of 10 ^–5 M. These results show that PHAR-DBH-Me has a concentration-dependent and endothelium-dependent vasodilator effect through CB₂ receptor. This vasodilation is probably mediated by the synthesis/release of NO. On the other hand, it is suggested that PHAR-DBH-Me also induces the release of a vasoconstrictor prostanoid.

Keyword

Cannabinoid receptor agonist; Endothelium; Hypotension; Nitric oxide; PHAR-DBH-Me; Vasodilation

Figure

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  Fig. 1 Chemical structure of PHAR-DBH-Me (IMM-59). Mol. Wt. 510.75 g/mol.

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  Fig. 2 Effect of PHAR-DBH-Me (0.018–185 µg/kg) on the mean arterial pressure (MAP), determined with the direct (A) and indirect (B) method. Control (white bars); PHAR-DBH-Me (black bars). The data represents the average of the decrease in blood pressure (mmHg). Data are reported as the mean ± SD of 5 different animals in each group. †p < 0.05 between direct groups and *p < 0.05 between indirect groups.

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  Fig. 3 Effect of PHAR-DBH-Me (10–7–10–3 M) on coronary flow with isolated heart preparation. Basal conditions (white bars); treated with PHAR-DBH-Me (black bars). The data represent the average percentage of the increase in coronary flow (ml/min) ± SD of 5 different animals in each group. *p < 0.05 vs. control (ANOVA followed by modified Newman-Keuls t-test).

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  Fig. 4 Concentration-dependent relaxation of 10–12–10–5 M PhAR-DBH-Me in 10–6 M phenylephrine pre-contracted rat aortic rings with (●) and without (○) endothelium and in presence of L-NAME (300 μM) with endothelium (▲). The data are expressed as the percentage of the maximum tension induced by phenylephrine and are shown as the mean ± SD, n = 5 rats in each group. *Denotes that the differences are significant (p < 0.05) between ● and ○. †Denotes that the differences are significant (p < 0.05) between ● and ▲.

• 

  Fig. 5 Effect of PHAR-DBH-Me (10–12–10–5 M) in aortic rings pre-contracted with phenylephrine (10–6 M) in presence of CB1 receptor antagonist (AM251) (A) and CB2 receptor antagonist (AM630) (B) (◼ and □, respectively). The data are expressed as the percentage of the maximum tension induced by phenylephrine and are shown as the mean ± SD, n = 5 rats in each group. *Denotes that the differences are significant (p < 0.05) between ○ and □.

• 

  Fig. 6 Effect of indomethacin (10–6 M) on the cumulative concentration-response curve to PHAR-DBH-Me (10–12–10–5 M) in aortic rings with (A) and without endothelium (B) pre-contracted with phenylephrine (10–6 M) (● and ○), in presence of indomethacin (▲and Δ) and L-NAME (300 μM) plus indomethacin (◼ and □). The data are expressed as the percentage of the maximum tension induced by phenylephrine and are shown as the mean ± SD, n = 5 rat in each group. *Denotes that the differences are significant (p < 0.05) between ● and ▲. †Denotes that the differences are significant (p < 0.05) between ● and ◼.

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