Vascular smooth muscle cells (VSMCs) from hypertensive mice (BPH mice) have a depolarized membrane potential and an increased vascular tone when compared with myocytes from their normotensive controls (BPN mice). We have previously shown an increased functional expression of a member of the DAG-activated TRPC family of non-selective cation channels, namely TRPC3, in mesenteric VSMC of hypertensive mice which could contribute to the increased vascular tone by favoring depolarization (Alvarez-Miguel et al. 2017). However, changes in the functional expression of some G-protein coupled receptors (GPCRs) could also contribute to the altered vascular tone by modulating the TRPC3 channels or Ca2+ activated Cl- currents (CaCl). Therefore, here we explored if changes in the molecular constituents of the purinergic signaling cascades could contribute to the hypertensive phenotype of the BPN/BPH model. BPN and BPN mice were anesthesized by isoflurane inhalation (5% O2 at 2.5 Lmin-1) and sacrificed by cervical dislocation, according to the European Community guiding principles with respect to the care and use of animals (Directive 2010/63/UE). Endothelial-denuded mesenteric arteries and isolated VSMC from BPN and BPH mice were used to analyze the expression and association pattern of GCPRs and TRPC and CaCl channels by qPCR and PLA assays. Their functional contribution was explored using electrophysiology and myography studies. Pressurized mesenteric arteries showed larger, dose-dependent, vasoconstrictor effects to UTP and UDP in BPH compared to BPN. Both the pharmacological profile of these responses and qPCR data indicated an increased expression of P2Y6 receptors in BPH. Patch-clamp studies showed a significantly larger UTP-induced depolarization in BPH VSMCs which could be abolished by niflumic acid and by Tmem16A inhibitor. Moreover, these blockers induced a significantly higher hyperpolarization in BPH VSMC, pointing to a relevant contribution of CaCl channels to determine VSMC resting Vm. These effects agreed with the higher mRNA expression of Cl- channels obtained in BPH cells by qPCR. Surprisingly, voltage-clamp studies showed no differences in UTP-activated whole-cell currents between BPH and BPN VSMC even though a fraction of these currents could be blocked by niflumic acid, Tmem16A inhibitor or Pyr10 (a TRPC blocker). In this context, we propose that differences between BPN and BPH UTP-mediated responses are the result of a combination of changes in the expression of P2Y6 receptors, TRPC and CaCl channels, together with some variation in their functional coupling. Altogether, these findings could be relevant to explain the increased vascular tone in the hypertensive phenotype.