CB1 receptor activation in the rat paraventricular nucleus induces bi-directional cardiovascular effects via modification of glutamatergic and GABAergic neurotransmission

Abstract

We have shown previously that the cannabinoid receptor agonist CP55940 microinjected into the paraventricular nucleus of the hypothalamus (PVN) of urethane-anaesthetized rats induces depressor and pressor cardiovascular effects in the absence and presence of the CB1 antagonist AM251, respectively. The aim of our study was to examine whether the hypotension and/or hypertension induced by CP55940 given into the PVN results from its influence on glutamatergic and GABAergic neurotransmission. CP55940 was microinjected into the PVN of urethane-anaesthetized rats twice (S1 and S2, 20 min apart). Antagonists of the following receptors, NMDA (MK801), β2-adrenergic (ICI118551), thromboxane A2–TP (SQ29548), angiotensin II–AT1 (losartan) or GABAA (bicuculline), or the NO synthase inhibitor L-NAME were administered intravenously 5 min before S2 alone or together with AM251. The CP55940-induced hypotension was reversed into a pressor response by AM251, bicuculline and L-NAME, but not by the other antagonists. The CP55940-induced pressor effect examined in the presence of AM251 was completely reversed by losartan, reduced by about 50–60 % by MK801, ICI118551 and SQ29548, prevented by bilateral adrenalectomy but not modified by bicuculline and L-NAME. Parallel, but smaller, changes in heart rate accompanied the changes in blood pressure. The bi-directional CB1 receptor-mediated cardiovascular effects of cannabinoids microinjected into the PVN of anaesthetized rats depend on stimulatory glutamatergic and inhibitory GABAergic inputs to the sympathetic tone; the glutamatergic input is related to AT1, TP and β2-adrenergic receptors and catecholamine release from the adrenal medulla whereas the GABAergic input is reinforced by NO.

Why Do Marijuana and Synthetic Cannabimimetics Induce Acute Myocardial Infarction in Healthy Young People?

“…In our own studies on the paraventricular nucleus of the hypothalamus (PVN; [ 220 , 221 ]; Table 5 ), cannabinoids led to brady- or tachycardia, dependent on the experimental conditions. Microinjection of the cannabinoid CP55940 into this brain region led to bradycardia, which was antagonized by the CB 1 -R antagonist AM251 given into the PVN.…”

Infusion of Melatonin Into the Paraventricular Nucleus Ameliorates Myocardial Ischemia–Reperfusion Injury by Regulating Oxidative Stress and Inflammatory Cytokines

“…Bilateral PVN cannulae were implanted, as described previously. 29,30 After induction of anesthesia with 3% pentobarbital sodium (30 mg/kg, intraperitoneal injection), the rats were placed in a stereotaxic apparatus (Stoelting WPI, Wood Dale, IL), and a stainless steel cannula was implanted bilaterally into the PVN. The stereotaxic coordinates for PVN were as follows: 1.8 mm caudal from bregma, 0.4 mm lateral to the midline, and 7.9 mm ventral to the dorsal surface.…”

Cannabinoids in arterial, pulmonary and portal hypertension – mechanisms of action and potential therapeutic significance

“…Expression of CB 1 receptors was higher in the RVLM of SHR, but levels of AEA and 2‐AG were similar when compared with control rats (Wang et al ., ). In our own studies (Grzęda et al ., and unpublished) on anaesthetized rats, a CB 1 receptor‐mediated depressor response could be evoked by microinjection of CP55940 into the PVN, which was reversed into a pressor response by i.v. AM251.…”

“…Sympathetic tone is mediated centrally by the rostral ventrolateral medulla (RVLM) and the paraventricular nucleus of the hypothalamus (PVN) (see Grzęda et al ., ; Wang et al ., ), two CNS nuclei, the function of which in hypertension is modified by cannabinoid ligands (Figure ). Thus, it has been shown that microinjection of the CB 1 receptor agonist arachidonyl‐2‐chloroethylamide (ACEA) into the RVLM increased BP, HR and renal sympathetic nerve activity (RSNA).…”