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. 2023 Apr 19;24(8):7515.
doi: 10.3390/ijms24087515.

Acute Cardiovascular and Cardiorespiratory Effects of JWH-018 in Awake and Freely Moving Mice: Mechanism of Action and Possible Antidotal Interventions?

Beatrice Marchetti  1 , Sabrine Bilel  1 , Micaela Tirri  1 , Giorgia Corli  1 , Elisa Roda  2 , Carlo Alessandro Locatelli  2 , Elena Cavarretta  3   4 , Fabio De-Giorgio  5   6 , Matteo Marti  1   7
Affiliations

Acute Cardiovascular and Cardiorespiratory Effects of JWH-018 in Awake and Freely Moving Mice: Mechanism of Action and Possible Antidotal Interventions?

Beatrice Marchetti et al. Int J Mol Sci. .

Abstract

JWH-018 is the most known compound among synthetic cannabinoids (SCs) used for their psychoactive effects. SCs-based products are responsible for several intoxications in humans. Cardiac toxicity is among the main side effects observed in emergency departments: SCs intake induces harmful effects such as hypertension, tachycardia, chest pain, arrhythmias, myocardial infarction, breathing impairment, and dyspnea. This study aims to investigate how cardio-respiratory and vascular JWH-018 (6 mg/kg) responses can be modulated by antidotes already in clinical use. The tested antidotes are amiodarone (5 mg/kg), atropine (5 mg/kg), nifedipine (1 mg/kg), and propranolol (2 mg/kg). The detection of heart rate, breath rate, arterial oxygen saturation (SpO2), and pulse distention are provided by a non-invasive apparatus (Mouse Ox Plus) in awake and freely moving CD-1 male mice. Tachyarrhythmia events are also evaluated. Results show that while all tested antidotes reduce tachycardia and tachyarrhythmic events and improve breathing functions, only atropine completely reverts the heart rate and pulse distension. These data may suggest that cardiorespiratory mechanisms of JWH-018-induced tachyarrhythmia involve sympathetic, cholinergic, and ion channel modulation. Current findings also provide valuable impetus to identify potential antidotal intervention to support physicians in the treatment of intoxicated patients in emergency clinical settings.

Keywords: JWH-018; amiodarone; atropine; cardiovascular; nifedipine; propranolol; respiratory; synthetic cannabinoid.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effect of systemic administration of JWH-018 (6 mg/kg), amiodarone (5 mg/kg), and JWH-018 followed by amiodarone on heart rate (A), pulse distention (B), breath rate (C), and arterial oxygen saturation (D). Data are expressed as percentage of basal values in the form mean ± SEM of eight different evaluations for each group. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons. ** p < 0.01, *** p < 0.001, JWH-018 versus vehicle. # p < 0.05, ## p< 0.01, ### p< 0.001, JWH-018 versus JWH-018 + amiodarone. ° p < 0.05, °° p < 0.01, °°° p < 0.001, amiodarone versus vehicle.
Figure 2
Figure 2
Frequency of tachyarrhythmia episodes between 0–60 (A), 60–120 (B), 120–180 (C), 180–240 (D), 240–300 (E), and 300–360 (F) minutes after administration of JWH-018 (6 mg/kg) or JWH-018 followed by amiodarone (5 mg/kg), expressed as number of events per mean heart rate value. Mean ± SEM of eight different evaluations for each group. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons. ### p < 0.001 versus JWH-018 + amiodarone.
Figure 3
Figure 3
Effect of systemic administration of JWH-018 (6 mg/kg), atropine (5 mg/kg), or JWH-018 followed by atropine on heart rate (A), pulse distention (B), breath rate (C), and arterial oxygen saturation (D). Data are expressed as percentage of basal values in the form mean ± SEM of eight different evaluations for each group. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons. * p < 0.05, *** p < 0.001, JWH-018 versus vehicle. ## p < 0.01, ### p< 0.001 versus JWH-018 + atropine. ° p < 0.05, atropine versus vehicle.
Figure 4
Figure 4
Frequency of tachyarrhythmia episodes between 0–60 (A), 60–120 (B), 120–180 (C), 180–240 (D), 240–300 (E), and 300–360 (F) minutes after administration of JWH-018 (6 mg/kg) or JWH-018 followed by atropine (5 mg/kg), expressed as number of events per mean heart rate value. Mean ± SEM of eight different evaluations for each group. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons. # p < 0.05, ### p< 0.001 versus JWH-018 + atropine.
Figure 5
Figure 5
Effect of systemic administration of JWH-018 (6 mg/kg), nifedipine (1 mg/kg), or JWH-018 followed by nifedipine on heart rate (A), pulse distention (B), breath rate (C), and arterial saturation (D). Data are expressed as percentage of basal values in the form Mean ± SEM of eight different evaluations for each group. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons. ** p < 0.01, *** p < 0.001, JWH-018 versus vehicle. ## p < 0.01, JWH-018 versus JWH-018 + nifedipine. ° p < 0.05, °° p < 0.01, °°° p < 0.001, JWH-018 nifedipine versus vehicle. Changes in systolic and diastolic blood pressure (E). Data are expressed as absolute values (mmHg) of average effect. Statistical analysis was performed by one-way ANOVA followed by Bonferroni’s test for multiple comparisons. *** p < 0.001 versus vehicle. ## p < 0.01 JWH-018, ### p < 0.001 versus JWH-018 + nifedipine.
Figure 6
Figure 6
Frequency of tachyarrhythmia episodes between 0–60 (A), 60–120 (B), 120–180 (C), 180–240 (D), 240–300 (E), and 300–360 (F) minutes after administration of JWH-018 (6 mg/kg) or JWH-018 followed by nifedipine (5 mg/kg), expressed as number of events per mean heart rate value. Mean ± SEM of eight different evaluations for each group. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons. # p < 0.05, ### p < 0.001 versus JWH-018 + nifedipine.
Figure 7
Figure 7
Effect of systemic administration of JWH-018 (6 mg/kg), propranolol (2 mg/kg), or JWH-018 followed by propranolol on heart rate (A), pulse distention (B), breath rate (C), and oxygen blood saturation (D). Data are expressed as percentage of basal values in the form mean ± SEM of four different evaluations for each group. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons. ** p < 0.01, *** p < 0.001, JWH-018 versus vehicle. ## p < 0.01, ### p< 0.001, JWH-018 versus JWH-018 + propranolol. ° p < 0.05, propranolol versus vehicle.
Figure 8
Figure 8
Frequency of tachyarrhythmia episodes between 0–60 (A), 60–120 (B), 120–180 (C), 180–240 (D), 240–300 (E), and 300–360 (F) minutes after administration of JWH-018 (6 mg/kg) or JWH-018 followed by propranolol (2 mg/kg), expressed as number of events per mean heart rate value. Mean ± SEM of eight different evaluations for each group. Statistical analysis was performed by two-way ANOVA followed by Bonferroni’s test for multiple comparisons. # p < 0.05, ## p < 0.01, ### p < 0.001 versus JWH-018 + propranolol.
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