The extracellular calcium-sensing receptor, CaSR, is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative (wild-type, WT) and Cre-positive (SM22α)CaSR(∆flox/∆flox) (knock-out, KO) mice showed and endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared to WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca(2+)) concentrations (1-5 mM) evoked contraction in WT, but only relaxation in KO aortae. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared to WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either NO-synthase inhibition with L-NAME or by a high salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca(2+) concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.