Effect of binge cocaine treatment on hindlimb vascular function

Abstract

Chronic cocaine abuse is known to cause endothelial dysfunction and atherosclerosis. The present study investigated the effect of binge cocaine treatment, a model for chronic cocaine abuse, on the blood flow responses to the adrenergic agonists norepinephrine, phenylephrine and isoproterenol, the endothelium-dependent vasodilator acetylcholine, and the endothelium independent vasodilator sodium nitroprusside (SNP) in the hindlimb vascular bed of male Sprague Dawley rats. Rats received either single binge or double binge treatment. Each binge treatment consisted of three doses of cocaine (30 mg kg(-1) i.p.) for 3 days. For double binge treatment, there was a 4 day recovery period between the binges. At the end of the treatment the rats were anesthetized and agonists were administered into the right hindlimb circulation through a catheter in the left iliac artery and blood flow responses were measured with a flow probe around the right iliac artery. Rats receiving double cocaine binges showed a significant decrease in the magnitude and duration of the blood flow response to norepinephrine and a decrease in the duration of the blood flow response to phenylephrine, isoproterenol and acetylcholine when compared with saline controls. The blood flow response to SNP was not changed. Total plasma nitrate-nitrite levels were significantly reduced and big endothelin levels were significantly increased in rats receiving double cocaine binges. This study demonstrates that binge cocaine treatment can alter endothelial function, while not changing smooth muscle function, and impairs the adrenergic pathway.

Molecular Analysis of Cocaine-Induced Endothelial Dysfunction: Role of Endothelin-1 and Nitric Oxide

“…A number of previous studies have also shown that cocaine increases ET-1 release from endothelial cells [21,23]. In addition, previous work from our group have also demonstrated that chronic administration of cocaine in rats significantly increases big ET-1 levels in the rat plasma [6]. In the present study, cocaine treatment of HAECs significantly increased ET-1 levels within 6-12 h and this increase in ET-1 came back to basal levels after 24 h. Although the in vitro findings on acute effects of cocaine on endothelial cells may not directly correlate with the effects of chronic exposure in vivo, the current studies implicate a molecular mechanism which may result in the increased plasma ET-1 levels observed in the in vivo models.…”

“…In long-term cocaine users, change in the forearm blood flow elicited by infusion of the endothelium-dependent vasodilator acetylcholine is significantly decreased, suggesting that cocaine may cause vascular dysfunction by impairing pathways that lead to NO release from ECs [4]. Previous in vivo studies from this laboratory using rats have shown that chronic, but not acute, exposure to cocaine leads to changes in endothelial function [5,6]. In the present in vitro study, HAECs are used in an attempt to delineate the molecular effects of both acute and chronic cocaine exposure on EC activation, a predisposing condition that initiates atherosclerosis [7][8][9][10].…”

“…Our previous study using a rat model demonstrated that chronic binge cocaine treatment increases plasma levels of big-ET-1 which is the precursor of ET-1 [6]. In rabbit basilar artery, cocaine has been shown to induce vasospasm via ET-1 [24] directly implicating ET-1 in cocaine-induced vascular dysfunction.…”

Diazepam Protects Against the Enhanced Toxicity of Cocaine Adulterated With Atropine

“…Binge treatment was carried out according to Pradhan et al (25) and consisted of three injections of cocaine (40 mg / kg) or cocatropine (40 + 20 and 40 + 60 mg / kg) 3-h apart on each of three consecutive days. After a four-day recovery period, the animals again received cocaine or cocatropine according to the same schedule.…”

Cocaine Constriction of Rat Basilar Artery in situ: Roles of Nitric Oxide and Endothelin-1

“…It was further suggested that the ET-1 release by cocaine was mediated by σ-1 receptor [10]. Also in general support of the involvement of ET-1 in cocaine constriction are the increased plasma/urine levels of ET-1 or big ET-1 in rats following binge cocaine [12], in cocaine-intoxicated patients [10], and in pregnant women with cocaine-related complications [13]. …”