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Background— During exercise, the sympathetic nervous system is activated and blood pressure and heart rate increase. In heart failure (HF), the muscle metaboreceptor contribution to sympathetic outflow is attenuated and the mechanoreceptor contribution is accentuated. Previous studies suggest that (1) capsaicin stimulates muscle metabosensitive vanilloid receptor subtype 1 (VR1), inducing a neurally mediated pressor response, and (2) activation of ATP-sensitive P2X receptors enhances the pressor response seen when muscle mechanoreceptors are engaged by muscle stretch. Thus, we hypothesized that the pressor response to VR1 stimulation would be smaller and the sensitizing effects of P2X stimulation greater in rats with HF due to chronic myocardial infarction (MI) than in controls. Methods and Results— Eight to 14 weeks after coronary ligation, rats with infarcts >35% had an increased left ventricular end-diastolic pressure and a marked increase in heart weight. Capsaicin injected into the arterial supply of the hindlimb increased blood pressure by 39% (baseline, 93.9±9.5 mm Hg) in control animals but only by 8% (baseline, 94.8±10.1 mm Hg) in rats with large MIs ( P P Conclusions— Compared with control animals, cardiovascular responses to VR1 stimulation are blunted and P2X-mediated responses are augmented in rats with HF owing to large MIs.