It promotes the release of calcium from the sarcoplasmic reticulum and also may allow influx of external calcium into the smooth muscle cells, causing contraction of the vessel walls. Accumulation of catecholamines caused by prevention of reuptake may result in smooth muscle contraction by an effect on several receptors in the vessel walls. This latter mechanism is supported by dopamine antagonist

(haloperidol) and calcium channel blocker (verapamil) prevention of vasospasm in cocaine-exposed smooth Inhibitors,research,lifescience,medical muscle cells (He et al. 1994). Endothelin-1, an endogenous vasoactive peptide, has been implicated in the development of atherosclerosis and vasoconstriction. Endothelin-1 has been detected in the urine and serum of cocaine users. An endothelin-1 antagonist reversed cocaine-induced vasospasm in animal models Inhibitors,research,lifescience,medical (Fandino et al. 2003). Vasoconstriction may play a role in cocaine-related stroke even days after last cocaine use. Metabolized by the liver, cocaine has a half-life of approximately 1 hour, but major provasoconstrictive metabolites can last for days. There is also large variation among individuals, with metabolites lingering in chronic Inhibitors,research,lifescience,medical users for up to 3 weeks (Enevoldson 2004). Vasospasm may cause endothelial injury, resulting in intimal hyperplasia and platelet

activation and aggregation, ultimately occluding vessels (Treadwell and Robinson 2007). This may be why microvascular white matter changes are found on MRI in chronic cocaine users (Volkow et al. 1988; Goforth et al. 2010). Inhibitors,research,lifescience,medical Cocaine administration activates platelets resulting in α-granule release and the formation of platelet-rich microaggregates (Heesch et al. 2000). It also increases platelet responsiveness to arachidonic acid, and causes the release of thromboxane β2 and plasminogen activating factor-1 inhibitor (PAI-1). All of these factors promote platelet aggregation (Togna et al. 1985; Kolodgie et al. 1995) and facilitation of thrombus formation. Very few cases of biopsy-proven vasculitis associated with cocaine exposure have been reported. These cases describe a hypersensitivity-type

vasculitic morphology that differs from Inhibitors,research,lifescience,medical the typical inflammatory central nervous system vasculitis. Supporting this is the fact that in cases of presumed cocaine-induced Phosphatidylinositol diacylglycerol-lyase vasculitis, steroids failed to improve the PDE inhibitor mouse patient’s symptoms in the short term (Merkel et al. 1995). Most studies have failed to demonstrate these findings on autopsy (Brust 2002; Enevoldson 2004). Cocaine may promote accelerated atherosclerosis, leading to longer term increased risk for AIS in cocaine users. Rabbits with high cholesterol that were exposed to cocaine demonstrated a greater extent of cholesterol plaque in the proximal thoracic aorta than control rabbits (Kolodgie et al. 1993). In the presence of cocaine, cell membranes are more permeable to atherogenic lipoproteins (Kolodgie et al. 1993, 1995, 1999). Cardioembolism is a well-known cause of cocaine-related stroke.