The present work aimed to elucidate the influence of thyroid functional status on the ₁-adrenoreceptor-induced activation of hepatic metabolic functions. The experiments were performed in either a nonrecirculating liver perfusion system featuring continuous monitoring of portal pressure, PO₂, pCa, and pH, or isolated hepatocytes from euthyroid, hyperthyroid, and hypothyroid rats. Hypothyroidism decreased the ₁-adrenergic stimulation of respiration, glycogen breakdown, and gluconeogenesis. These effects were accompanied by a decreased intracellular Ca²⁺ mobilization corroborating that those processes are regulated by the Ca²⁺-dependent branch of the ₁-adrenoreceptor signaling pathway. Moreover, in hyperthyroid rats the ₁-adrenergic-induced increase in cytosolic Ca²⁺ was enhanced, and glucose synthesis or mobilization was not altered. The thyroid status influenced neither the ₁-adrenergic stimulation of vascular smooth muscle contraction nor the ₁-agonist-induced intracellular alkalinization and protein kinase C (PKC) activation. Thus the distinct impairment of the Ca²⁺-dependent branch of the ₁-adrenoreceptor signaling pathway by thyroid status provides a useful tool to investigate the role played by each signaling pathway, Ca²⁺ or PKC, in controlling hepatic functions.