Vascular tone, a key determinant of arterial pressure, is set by the contractile state of vascular smooth muscle cells (VSMCs). There is a variety of mechanisms that regulate VSMC contractility and can represent possible targets for antihypertensive therapy. Among these mechanisms, membrane potential and [Ca2+]i are of paramount importance, and changes in the way VSMCs control them are at the core of the development of arterial hypertension. Using a hypertensive mouse strain (BPH) and its corresponding normotensive control (BPN), we have previously identified changes in the expression and function of ion channels (voltage-dependent  Ca2+ and K+ channels and TRPC channels) contributing to the increased vascular tone of the hypertensive vessels. However, changes in the contribution of different G-protein coupled receptors (GPCRs) could also be relevant. Therefore, here we explored if changes in some of the molecular constituents of several GPCRs pathways could contribute to increased vascular tone in BPH mice. Mice were anesthesized by isoflurane inhalation (5% O2 at 2.5 Lmin-1) and sacrificed by cervical dislocation, following the EC guiding principles regarding 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 of several components of the contractile machinery, including receptors (purinergic and α1-adrenergic), second messengers and ion channels and pumps. Their functional contribution was analyzed by exploring the contractile responses to Phenylephrine (Phe) and Uridine triphosphate (UTP) using pressure and wire myography. The involvement of primary effectors of Gq11 and G12-13 pathways in agonist-induced contractions was evaluated with specific blockers of Phospholipase C (PLCβ), Protein Kinase C (PKC) and Rho-associated protein kinase (ROCK). Dose-response curves for Phe showed a larger vasoconstrictor effects in BPH arteries (maximal tension (Tmax) of 2.85±0.06 mN in BPN and 8.56±0.06 mN in BPH, p<0.001) with increased affinity (EC50 of 1.74±0.15 µM in BPN and 0.58±0.02 µM in BPH, p<0.05). In the case of UTP, there was also a significant increase in Tmax in BPH (2.63±0.45 mN in BPN and 5.65±0.33 mN in BPH, p<0.001) together with a large leftward shift of the dose-response curve. While the EC50 for UTP in BPN was of 424.05±137.09 µM, UTP dose response curves in BPH were best fitted to a two-binding site model with EC50 of 1.79±0.43 and 126.70±141 µM respectively. These data suggested a different functional expression of P2Y receptors in the hypertensive animal, confirmed by expression studies and pharmacological characterization of the responses. We have also found a larger contribution of ROCK and PLC to Phe and UTP responses in BPN arteries, as well as a differential role of Ca2+-activated Cl- channels to Phe and UTP effects in both preparations. Our results demonstrate not only a greater reactivity of the arteries from hypertensive mice, but also a significant change in the relative contribution of the different effectors involved in each signaling pathways. These data evidence how the marked non-linear character of the contractile responses hinders the prediction of the global effects produced from changes in individual elements.