--- - |2+ Abstract Aim This study determines whether the activation of olfactory calcium‐sensing receptor initiates a sympathetic activation‐dependent neurovascular reflex subsequently contributing to renal hemodynamic depression. Methods Immunohistochemistry and nose‐loading calcium‐sensitive dye were used to explore the location and function of calcium‐sensing receptor on the olfactory sensory neuron. The renal sympathetic nervous activity, renal hemodynamics and the microcirculation of kidney, liver and intestine were evaluated after liquid‐phase intranasal administrations of saline, lidocaine, calcium‐sensing receptor agonists and antagonist in sham and bilateral renal denervated rats. Real‐time renal glomerular filtration rate was measured by a magnetic resonance renography. Results Calcium‐sensing receptors were expressed on the cilia the olfactory sensory neuron and their activation depolarized olfactory sensory neuron and induced the calcium influx in the terminal side on olfactory glomeruli. Activating olfactory calcium‐sensing receptors significantly increased arterial blood pressure and renal sympathetic nervous activities and subsequently decreased renal blood flow, renal, hepatic and enteral microcirculation. Cotreatments with calcium‐sensing receptor antagonist or lidocaine inhibited these physiological alterations. The renal hemodynamic depressions by olfactory calcium‐sensing receptor activation were significantly blocked by bilateral renal denervation. The intranasal manganese administration decreased the glomerular filtration rate. Conclusion Calcium‐sensing receptor acts as a functional chemosensory receptor on olfactory sensory neuron, and its activation causes the global sympathetic enhancement contributing to systematic vasoconstriction and subsequently depresses renal blood flow and glomerular filtration rate. These data implicate a possibly clinical aspect that several environmental stimuli may activate olfactory calcium‐sensing receptors to evoke a sympathetic nervous system‐mediated neurovascular reflex to depress renal hemodynamics. - 'Acta Physiologica, EarlyView. '