We herein describe the regulation of cardiac receptors in a typical high-altitude native animal. Heart rate response to isoproterenol (HR(ISO)) (beats · min-1 · mg ISO · kg-1) and atropine, the density of β- adrenergic (β(AR) and muscarinic (M2) receptors, and the ventricular content of norepinephrine (NE) and dopamine (DA) were studied in guinea pigs (Cavia porcellus). Animals native to Lima, Peru (150 m) were studied at sea level (SL) and after 5 wk at 4,300-m altitude (SL-HA). Animals native to Rancas [Pasco, Peru (4,300 m)] were studied at high altitude (HA) and after 5 wk at SL (HA-SL). HA animals had a lower HR(ISO), maximum number of β(AR) binding sites (B(max)), β(AR) dissociation constant (K(d)), NE, and DA (P < 0.05) and a higher M2 B(max) (P < 0.001) when compared with the SL group HA- SL showed an increase of the HR(ISO), β(AR) K(d), and NE (P < 0.05) and a decrease of the M2 B(max) and K(d) (P < 0.0001) when compared with the HA group. The present study demonstrates the differential regulation and reversibility of the autonomic control in the guinea pig heart.