In vivo cardiovascular actions of caffeine have been reported in some animals (Ilback et al; 2007) but not in rabbits. This study investigated the effects of caffeine on cardiovascular activities of rabbits in vivo and also examined the mechanism(s) involved in caffeine action. The study was carried out on adult male anaesthetised New Zealand rabbits (weighing 1.8-2.2Kg) divided into 3 groups (n=5). Group I rabbits were given 0.2ml/Kg of normal saline and served as control while groups II and III rabbits were administered with 2mg/Kg and 6mg/kg caffeine respectively for 28 days. Following anaeshesia, arterial pressure (AP) was measured using non-invasive oscillometric blood pressure device (Contec Medicals, China) and Lead II ECG and heart rate (HR) were recorded using veterinary ECG machine by Edan Instruments. Anaesthesia was induced by i.v. injection of sodium pentobarbitone (30 mg/kg). Blood samples (3.0ml/rabbit) were collected by retro orbital puncture to determine plasma cathecholamines. The animals were sacrificed by cervical dislocation and cardiac tissue biopsies were collected on dry ice for biochemical and immunohistochemical analyses. Cardiac tissue cAMP concentrations, adenyl cyclase 9 and beta1 receptor expression were determined by immunohistochemistry and colorimetry techniques respectively, with assay kits obtained from Biovision inc. Plasma catecholamines were determined by the use of ELISA kit (LDN Lab.). The results showed that caffeine at 2mg/kg and 6mg/kg significantly increased AP from 69.6 ± 2.46 mmHg to 72.9 ± 4.28 and 81.8 ± 2.0 mmHg respectively. HR decreased from 258.6 ± 3.9 beats/min to 234.0 ± 2.5 beats/min for 2 mg/kg caffeine and increased to 290.2 ± 5.79 beats/min for 6 mg/kg caffeine. Caffeine at 6 mg/kg only significantly reduced the QT interval from 164.0 ± 8.7 milisecs to 133.0 ± 1.23 milisecs. Caffeine also significantly increased the plasma levels of dopamine, adrenaline and noradrenaline. Caffeine at the two doses significantly increased cardiac immunoreactivity for adenyl cyclase 9. Also caffeine at 2mg/kg and 6mg/kg increased cardiac tissue cAMP concentrations from 5.097±0.29 to 6.840±0.26 and 6.36±0.14 pmol/well. Using immunohistochemical analysis, percentage beta1 receptor expression was significantly high in response to the two doses of caffeine administered. The study therefore showed that caffeine increased cardiovascular activities of the rabbit most probably by increasing plasma catecholamines and activation of beta1 adrenergic receptors in the heart tissue.