ObjectiveTo investigate post-receptor mechanisms that underlie enhanced angiotensin II (Ang II)-stimulated cytosolic free Ca2+concentration ([Ca2+]i) responses in vascular smooth muscle cells from small arteries of SHR.MethodsTo determine whether Ca2+influx is altered in SHR, effects of Ca2+channel antagonists (nitrendipine and diltiazem) and depletion of extracellular Ca2+on Ang II-stimulated [Ca2+]iresponses in primary cultured unpassaged vascular smooth muscle cells from mesenteric arteries of spontaneously hypertensive rats (SHR), Wistar and Wistar-Kyoto (WKY) rats aged 17 weeks were studied. To assess whether Ca2+stores contribute to increases in Ang II-stimulated Ca2+mobilization and [Ca2+]iin SHR, cells were exposed to thapsigargin, a selective reticular Ca2+-ATPase inhibitor. [Ca2+]iwas measured by fura-2 methodology.ResultsBasal and 1 nmol/l Ang II-stimulated [Ca2+]iwere significantly greater in SHR cells (123 ± 7.1 nmol/l basal; 268 ± 7.0 nmol/l stimulated) than they were in those from WKY rats (88 ± 4.8 nmol/l basal; 221 ± 8.6 nmol/l stimulated) and Wistar rats (85 ± 3.0 nmol/l basal; 216 ± 8.3 nmol/l stimulated). In Ca2+-free medium, basal and Ang II-induced [Ca2+]iwere reduced in all groups, but Ang II-stimulated [Ca2+]iresponses were still significantly enhanced in SHR cells compared with those in Wistar and WKY rat cells (205 ± 11.2 versus 173 ± 8.0 and 161 ± 2.6 nmol/l, respectively). Administrations of 10−6mol/l diltiazem and 10−7mol/l nitrendipine decreased Ang II-elicited [Ca2+]iresponses and normalized basal [Ca2+]iin SHR cells. The inhibition induced by Ca2+channel antagonists was greater (P<0.05) in WKY and Wistar rat cells than it was in those from SHR. Administration of thapsigargin, in Ca2+-free buffer, induced a greater (P<0.05) dose-dependent [Ca2+]iincrease in SHR cells than it did in WKY rat cells. Administration of 1 nmol/l Ang II increased [Ca2+]iin thapsigargin-pretreated cells of SHR but not in those of WKY rats.ConclusionDifferent mechanisms contribute to increases in basal and Ang II-stimulated [Ca2+]iresponses in vascular smooth muscle cells from small arteries of SHR, which contribute to elevated peripheral resistance in hypertension. Increases in basal [Ca2+]imay be partly due to augmentation of Ca2+influx, whereas Ang II-induced [Ca2+]ihyper-responsiveness might depend primarily on Ca2+mobilization rather than on influx of extracellular Ca2+.