Acute hyperglycemia (HG) plays a key role in the development of arterial complications. Mechanistically, Piezo1 appears to mediate shear stress-induced activation of cytosolic endothelial nitric oxide synthase (NO), through incompletely elucidated pathways. Hyperglycemia upregulates Piezo1 expression in endothelial cells. Here, we hypothesize that Piezo1 contributes to the organ-specific detrimental effects of HG on arterial myocytes vasoreactivity and excitability by activating NO signaling. We integrated our in silico model of Piezo1 channel into Morotti et al. 2017 implementation of a model of rat arterial myocytes. To simulate Piezo1-NO signaling in HG-induced simulations, we set [NO] = Piezo1 Ca2+ flux * c, where c was calculated so that the model yields ~2 fold increase in [Ca2+]i, consistent with in vitro data. We explored the influence of individual ionic currents and transporters on global cytosolic [Ca2+]i (Cai) and membrane potential (Em) in a sensitivity analysis on a virtual population of 1000 model variants, generated by introducing random perturbations to the conductances/maximal transport rates of all ion channels and transporters. Specifically, each parameter in the baseline model was independently varied with a standard deviation of 0.1, allowing for changes between -30% and +50% of the original value. Next, a regression analysis was performed to identify correlations between the parameter variations and their effects on Cai and Em. Our results suggest the intensified contribution of L-type Ca2+ channel (LTCC) on Cai in HG. Similarly, the impact of large conductance Ca2+-activated K+ channel (BKCa) on Em and Cai increased in HG, in accord with reported BKCa channel activity and sensitivity to Ca2+ in vitro. Remarkably, Piezo1 perturbations instigated opposing effects on Em and Cai in control vs. HG-induced conditions. This would imply a possible role of Piezo1-NO signaling in the heterogeneity of organ-specific vasoactive response to HG in arterial myocytes and thus a promising therapeutic avenue.