Table 3.

Cardiac effects of acute cannabinoid administration in experimental animals in vivo.

Species	Anesthesia	Agonist	Dose (mg/kg) and Route of Administration 1	Effects	Mechanisms and Involvement of CB1-Rs/CB2-Rs/Others if Determined	References
rhesus monkeys	conscious	THC	0.5 i.v.	↑HR	antagonists not used	[133]
rhesus monkeys	conscious	THC	0.75–4 i.p.	↓HR	antagonists not used	[134]
rhesus monkeys	conscious	THC WIN-2	0.1–10 i.m. 0.1–10 i.m.	↓HR	bradycardia is mediated viaCB1-Rs (prevented by RIM)	[135]
rhesus monkeys	conscious	RIM	3.2 i.v.	↑HR	CB1-Rs responsible for bradycardia are activated via endocannabinoids	[136]
mongrel dogs	conscious	THC	1 and 2.5 i.v.	↓HR and CO dose-dependent; ↑RVSW	antagonists not used	[137]
beagle dogs	conscious	Sativex® (CBD: THC)	spray; max. plasma levels 10.5:18.5 ng/mL	↔HR	antagonists not used	[138]
rabbits	conscious	WIN-2	0.005 and 0.05 i.v. 0.5 i.v.	↓HR ↑HR	both bradycardia and tachycardia are mediated by CB1-Rs, since RIM reduced bradycardia and reversed tachycardia	[139]
rabbits	conscious	CP WIN-2 WIN-3	each 0.0001, 0.001, 0.01 i.c.	↓HR; dose-dependent ↓HR; dose-dependent ↔HR	bradycardia related to an increase in cardiac vagal activity and CB1-Rs (prevented/diminished by i.v. atropine and RIM)	[140,141]
Wistar rats	conscious	THC	4, 6, 8 i.p.	↓HR	antagonists not used	[142]
Sprague Dawley rats	conscious	WIN-2	0.005, 0.05 0.25 i.v.	↔HR ↓HR	since WIN-2 increased BP authors suggested that the clear dissociation between the effects of WIN-2 on BP and HR are consistent with the bradycardia being mediated centrally	[143]
Sprague Dawley rats	conscious	THC JWH-018 AM2201 XLR-11 CP	0.3–3.0 s.c. 0.18–0.56 0.1–0.3 0.1–3.0 0.01–0.1	↔HR ↔HR ↔HR ↔HR ↔HR	THC, CP and the synthetic cannabinoids JWH-018, AM2201 and XLR-11 increase BP only	[144]
Wistar rats	conscious	O-1602	0.25 i.a.	↔HR	antagonists not used	[145]
CB1+/+ and CB1−/− mice	conscious	AEA WIN-2	0.25 2 i.v.	↓HR but only in CB1+/+ but not in CB1−/−	bradycardia is mediated via CB1-Rs	[146]
CB1+/+ and CB1−/− mice	conscious	deletion of CB1-R	-	basal HR was higher in CB1−/− than in CB1+/+ but only during active period	eCBs induce bradycardia via the activation of CB1-Rs but only during active period	[147]
mice GPR55+/+ GPR55−/−	conscious or isoflurane	deletion of GPR55	-	in GPR55−/−: ↓basal HR ↑LVEDV, LV mass, heart weight, ↔LVID, CO, EF	GPR55 affects preload and chronotropy	[85]
mice	conscious	THC SDB-001 JWH-018	1–10 i.p. 0.3–3 1–10	↓HR ↓HR ↓HR	the effect of THC on HR is shared by another two CB-R agonists (antagonists not used)	[25]
mice	conscious	cannabis THC (10–14%) and CBD (0–2%)	cigarettes via Smoke Inhalation System	↑serum COHb modulation of the proportionality of innate immune-cell populations in the lungs	increase in serum COHb level and modification of immunological system	[148]
mongrel dogs	morphine, chloralose	THC	1 and 2.5 i.v.	↑HR (dose-dependent) ↓RVSW	antagonists not used	[137]
mongrel dogs	pentobarbital	THC	2.5 i.v	↓HR	the maximal THC-induced bradycardia occurred only when both sympathetic and parasympathetic innervation to the heart was intact	[149]
mongrel dogs	pentobarbital	THC	2.5 i.v	HR was constant by electrical pacing; ↓CO, ↓SV, ↓LVP ↓LVEDP, ↓+dp/dt	↓CO mainly due to diminished venous return to the heart and not to impaired contractile force of the myocardium (experiments in which CO was constant by a right heart-bypass procedure)	[150]
cats	chloralose	THC THC	2 i.v. 2 i.c.v.	↓HR ↓HR	bradycardia induced by a central mechanism was diminished by cervical cardiac denervation but not by vagotomy	[151]
cats	pentobarbital	THC	0.2 i.v	↓HR	bradycardia antagonists not used	[152]
mice	isoflurane	THC	0.002 i.p.	↔HR, LVESD, LVEDD, FS	antagonists not used; lack of effect not surprising since a very low dose was chosen	[153]
Wistar rats	urethane	THC	1, 2, 5 i.v.	↓HR	bradycardia due to alteration of efferent vagal activity (blocked by vagotomy and atropine i.v.)	[142]
Sprague Dawley rats	urethane	THC ∆8-THC	0.5 i.v. 0.5 i.v.	↓HR ↓HR	bradycardia	[152]
Sprague Dawley rats	pentobarbital	RIM AM251	3 i.v. 3 i.v.	prevention (by RIM but not AM251) of the LPS-induced ↓cardiac contractility (+dp/dt and LVSP) but not of ↑HR	a cardiac receptor distinct from CB1-R or CB2-R mediates negative inotropy	[154]
Sprague Dawley rats	diethyl ether + urethane	THC THC HU-210 CP WIN-2 JWH-015 AEA	0.03–10 i.v. 30 i.v. 0.003–0.3 i.v. 0.001–0.3 i.v. 0.01–10 i.v. 3–30 i.v. 4 i.v.	↓HR dose-dependent ↑HR ↓HR dose-dependent ↓HR dose-dependent ↓HR dose-dependent ↓HR dose-dependent initial and delayed ↓HR	bradycardia induced by all compounds mediated by CB1-Rs (blocked by RIM); in the case of AEA, only the delayed ↓HR was diminished by RIM	[155]
Sprague Dawley rats	pentobarbital + isoflurane	JWH-030	0.1 i.v. 0.5 i.v.	↔ QT interval ↑ QT interval, ↔RR interval	prolongation of the QT interval may be associated with adverse cardiovascular effects in abusers of synthetic cannabinoids	[156]
Wistar rats	chloralose	HU-210 AEA MethAEA ACPA	0.1 i.v. 2.5 i.v. 2.5 i.v. 0.125 i.v.	↓HR, ↔ECG ↓HR, ↑duration QRS ↓HR ↔ ECG ↓HR ↔ ECG	bradycardia mediated by CB1-Rs (inhibited by RIM but not by SR144528)	[157]
mice TRPV1+/+ TRPV1−/−	pentobarbital	AEA	20 i.v.	brief (Phase I) and profound (Phase II) ↓HR, LVSP, LVEDP, +dp/dt, −dp/dt	brief (Phase I) and profound (Phase II) bradycardia and ↓cardiac contractility due to AEA mediated via TRPV1- and CB1-Rs, respectively (absent/present in TRPV1−/− and not modified/blocked by RIM, respectively); basal LVSP, LVEDP, +dp/dt, −dp/dt and HR did not differ between TRPV1+/+ and TRPV1−/−	[158]
Wistar rats	urethane	WIN-2 CP	0.03–1 i.v. 0.03–1 i.v.	↓HR and plasma [NA] less pronounced in ventilated than in spontaneously breathing rats	depressive action of CBs depends on the respiratory state of the animals and CB1-Rs inhibiting sympathetic and intensifying cardiac vagal tone, since ↓HR and plasma [NA] were diminished by RIM and methylatropine	[159]
	urethane plus pancuronium	WIN-2	0.03–1 i.v.
mice GPR55+/+ GPR55−/−	ketamine/ xylazine	deletion of GPR55	-	GPR55−/−: young: ↑HR, ↔ most other cardiac functions; mature: cardiac dysfunction (↑LVESV, ↑LVEDV, ↓EF) and ventricular remodeling (↓LV free wall thickness, ↓heart weight/body weight ratio); young and mature: ↓cardiostimulatory responses to α1/β1-AR agonist dobutamine	GPR55 involved in the control of adrenergic signalling	[87]
mongrel dogs (spinal)	pentobarbital	THC	2.5 i.v	↔ HR; ↔ increases in HR induced by ES or by ISO	THC is devoid of any ganglionic or β-adrenergic blocking properties	[149]
Wistar rats (pithed) 2	Pentobarbital 3	WIN-2 CP MethAEA WIN-3	0.0005–0.5 i.v. 0.0004–0.4 i.v. 1.1, 3.6 i.v. 0.0005–0.5 i.v.	↔HR, ↓increases in HR induced by ES 5 and NIC ↔increases in HR induced by ISO ↔ ES 5 increases in HR	↓neurogenic sympathetic neuroeffector transmission in the heart via CB1-Rs located prejunctionally on the postganglionic rather than on the preganglionic sympathetic nerve fibers innervating the heart (blocked by RIM and/or AM251) and not on the chromaffin cells of the adrenal medulla (inhibitory effect of MethAEA on NIC-induced increase in HR not modified by AM251)	[40,160]
Wistar rats (pithed, adrenalectomized) 2	Pentobarbital 3	WIN-2 CP	0.0005–0.5 i.v. 0.0004–0.4 i.v.	↔HR, ↓increases in HR induced by ES 5 and NIC		[40]
Wistar rats (pithed) 2	pentobarbital or urethane 3	CP	0.4 i.v.	↔HR, ↓increases in HR induced by ES 5	stronger inhibitory effect of CP on the neurogenic tachycardic response in pentobarbitone- than in urethane-anaesthetized rats	[161]
Wistar rats (pithed) 3	Pentobarbital 2	WIN-2 CP WIN-3	0.0005–0.5 i.v. 0.0004–0.4 i.v. 0.0005-0.5 i.v.	↔ HR, ↓decreases in HR induced by ES of n. vagus ↔decreases in HR induced by methacholine	presynaptic CB1-Rs located on the post- and/or preganglionic cardiac vagal nerve fibers did not modify the vagal bradycardia	[40]
rabbits (pithed) 4	pentobarbital	WIN-2 CP	0.005–1.5 i.v. 0.003–1 i.v.	both: ↓increase in HR induced by ES 5 WIN-2: ↔increase in HR induced by ISO	↓neurogenic sympathetic and vagal neuroeffector transmission in the heart (via CB1-Rs on pre- or postganglionic neurons; blocked by RIM)	[139]
		WIN-2 CP	0.005–0.5 i.v. 0.003–0.3 i.v.	↓ES decreases in HR elicited by ES of n. vagus
Wistar rats (pithed) 2	Urethane 3	AEA CP	1 i.v. 0.4 i.v.	↔HR; ↓increases in HR induced by ES 5	↓neurogenic sympathetic tachycardia due to the presynaptic CB1-R but not GPR18 (blocked by AM251 but not O-1918, respectively)	[162]
Sprague Dawley rats (pithed)	ether	THC	1 i.v.	↔HR; ↔alterations in HR induced by ISO and propranolol	β-adrenoceptors not involved in the cardiac action of THC	[163]
hairless mice	ketamine and xylazine	AEA CBD WIN-2	5 i.p. 5 i.p. 5 i.p.	AEA (unlike CBD and WIN-2) ↓venular thrombus formation in ear venules	↓thrombus formation evoked by AEA was dependent on cyclooxygenase metabolites (it was reduced by INDO i.p.)	[164]

We have focused on cardiac (but not blood pressure) responses induced by CB-R agonists; CB-R antagonists were mentioned only if their cardiac effects were determined independent of CB-R agonists. If not stated otherwise, antagonists did not modify cardiac parameters by themselves. ¹ If not stated otherwise, doses are given in mg/kg; ² vagotomized and pretreated with atropine 1.5–2 μmol/kg i.p. and pancuronium 0.8 μmol/kg i.v; ³ vagotomized and pretreated with propranolol 3 μmol/kg i.v.; ⁴ pretreated with i.v. methylatropine (1 mg/kg bolus plus an infusion of 2 mg/kg/h) and gallamine triethiodide (5 mg/kg) or succinylcholine (1 mg/kg); ⁵ electrical stimulation of preganglionic sympathetic nerves. ↑increase; ↓decrease; ↔no effect; +dp/dt, maximum rates of contraction; −dp/dt, maximum rates of relaxation; [NA], noradrenaline concentration; α₁/β₁ AR, α₁/β₁-adrenergic receptors; ∆⁸-THC, Δ⁸-tetrahydrocannabinol (previous nomenclature Δ⁶-THC); ACPA, arachidonoylcyclopropylamide; Adr, adrenaline; AEA, anandamide; BP, blood pressure; CB₁-R_, cannabinoid CB₁ receptor; CB_2, cannabinoid CB₂ receptor; CBD, cannabidiol; CBs, cannabinoids; CO, cardiac output; COHb, carboxyhemoglobin; CP, CP55940; eCBs, endocannabinoids; ECG, electrocardiogram;LEF, ejection fraction; ES, electrically stimulated; FS, fractional shortening; GPR55, G protein-coupled receptor 55; HR, heart rate; i.a., intraarterially; i.c., intracisternally; i.c.v., intracerebroventricularly; i.m., intramuscularly; INDO, indomethacin; i.p., intraperitoneally; ISO, isoprenaline; i.v., intravenously; LPS, lipopolysaccharide; LV, left ventricle; LVEDD, left ventricular end-diastolic diameter; LVEDP, left ventricular end-diastolic pressure; LVEDV, left ventricular end-diastolic volume; LVESD, left ventricular end-systolic diameter; LVESV, left ventricular end-systolic volume; LVID, left ventricular internal diameter; LVP, left ventricular peak; LVSP, left ventricular systolic pressure; MethAEA, methanandamide; n., nerve; NIC, nicotine; RIM, rimonabant; RVSW, right ventricular stroke work; s.c., subcutaneously; SV, stroke volume; THC, Δ⁹-tetrahydrocannabinol (previous nomenclature Δ¹-THC); TRPV1, transient receptor-potential cation-channel subfamily V member 1; WIN-2, WIN55212-2; WIN-3, WIN55212-3.