Increasing evidence supports a role for the adipokine, apelin, and its receptor (APJ), in the regulation of cardiovascular function. Activation of apelin/APJ receptor signaling pathways causes vasodilation in most peripheral arteries studied thus far. Apelin-induced vasodilation may be mediated, at least in part, by nitric oxide (NO) or by prostanoids derived from cyclooxygenase metabolism of arachidonic acid. The effects of apelin on cerebral arteries are presently unknown, and although apelin increases blood flow in the coronary circulation, the underlying mechanism(s) have not been elucidated. Here, we investigated the vasorelaxant effects of apelin in coronary and middle cerebral arteries isolated from rats (Sprague-Dawley, male, 275-325 g). Immunoblot analysis established that APJ receptor protein was present in both arteries and immunofluorescence studies using confocal microscopy demonstrated APJ receptor expression on endothelial cells (n=4). In isolated arteries suspended in myographs for isometric tension recording, concentration-response curves to apelin (10-8 – 10-6 M) were obtained in arterial rings contracted with 5-HT (10-7 M). Values are means ± SEM, compared by ANOVA. In cerebral arteries, apelin had no effect on vascular tone in rings with or without endothelium; however, the endothelium-dependent vasodilator, bradykinin (10-9 – 10-6 M) caused relaxations (pD2=8.02 ± 0.3; Emax=83 ± 4% relaxation; n=5) that confirmed the presence of functional endothelium in these preparations. In contrast to cerebral arteries, apelin caused relaxation in endothelium-intact coronary arteries (pD2=6.91 ± 0.1; Emax=45 ± 6% relaxation; n=9), but had no effect in those without endothelium. The endothelium-dependent response to apelin was completely abolished by the nitric oxide synthase inhibitor, nitro-l-arginine (3 x 10-5 M; P<0.05, n=6) but was unaffected by the cyclooxygenase inhibitor, indomethacin (10-5 M) (pD2=6.72 ± 0.3 vs 6.85 ± 0.5; Emax=38 ± 5 vs 40 ± 9% relaxation, in the absence and presence of indomethacin, respectively; P>0.05, n=6). Apelin-induced relaxation was also abolished by the large conductance, calcium-activated K channel (BKCa) blocker, iberiotoxin (10-7 M; P<0.05, n=6). Thus, APJ receptors are expressed on endothelial cells in both coronary and cerebral arteries; however, apelin causes endothelium-dependent relaxation of coronary arteries but has no vasorelaxant effect in cerebral arteries. Apelin-induced relaxation of coronary arteries is likely mediated by NO rather than prostanoids and requires activation of BKCa channels. The findings also suggest that the putative beneficial vasodilator effect of apelin in the coronary circulation may not occur in cerebral arteries, despite the presence of APJ receptors in the cerebrovascular endothelium.