Abstract—The effects of alterations in calcium in the perfusion media were studied on &bgr;-adrenergic coupling in isolated hearts from 3 different transgenic mice: cardiac-specific overexpressed &agr;1subunit of L-type calcium channel, overexpressed G&agr;q, and phospholamban knockout. Isolated hearts from all 3 models, when studied at [Ca2+] of 2 mmol/L in the perfusate, showed the usual blunted or no response to &bgr;-adrenergic stimulation. Lowering [Ca2+] to 0.75 to 1.5 mmol/L unloaded the hearts of calcium and restored to nearly normal the responsiveness to &bgr;-agonist stimulation.