Several β-adrenoceptor blocking drugs at high concentrations cause cardiostimulation.Such non-conventional partial agonists (eg. pindolol) have been contra-indicated in the treatment of heart disease (Podrid and Lown, 1982).Freestone et al (1999) have shown that CGP12177, structurally similar to pindolol, causes smaller increases in intracellular calcium concentration, but is 40 times more pro-arrhythmic than isoprenaline (ISO) in mouse ventricular myocytes.Cardiostimulatory effects of CGP12177 are propranolol-insensitive but are blocked by bupranolol.These, and other observations, have led to the designation of a new receptor – the low affinity β1-adrenoceptor separate to the high affinity β1-adrenoceptor.Myocyte contraction is caused by CICR through RyR of the sarcoplasmic reticulum.We determine whether CGP12177 caused the spontaneous release of calcium from the SR thus providing a mechanism for its reported arrhythmogenic effects.Atrial cells were isolated from WKY rats by a method developed in our laboratories (Freestone et al, 2000).Images of calcium events were obtained by the Zeiss LSM510 Meta confocal microscope.Cells were perfused with propranolol (200nM) alone, ISO alone (100nM), CGP12177 (1μM) in the presence of propranolol, 2-APB (5μM) and propranolol in the presence of CGP12177 and nifedipine (10μM) and propranolol in the presence of CGP12177 and the frequency of calcium events recorded.When perfused with propranolol there were 0.05 ± 0.03 s-1 whole cell calcium waves, 0.4 ± 0.1 s-1 large but localised calcium release events (wavelets) and 41 ± 6.7 s-1 calcium sparks observed (n =12).CGP12177 in presence of propranolol (200nM) significantly increased the incidence of wavelets to, 0.86 ± 0.17s-1 at 1µM CGP12177 (p < 0.005; n=12).Addition of ISO resulted in an increase (p < 0.01) in spark frequency from 26.7 ± 4.5 s-1 to 38.7 ± 7.9 s-1 from basal (n=5) but did not increase the frequency of whole cell calcium waves or wavelets.2-APB and propranolol perfusion resulted in 0.4 ± 0.2 wavelets s-1 and 30.4 ± 4.3 calcium sparks s-1 (n=7 cells from 3 animals).CGP12177 with 2-APB and propranolol increased the incidence of wavelets to 1.9 ± 0.4 wavelets s-1 (p < 0.005) but did not alter the frequency of calcium sparks.Addition of CGP12177 with nifedipine in the presence of propranolol resulted in an increase in calcium wavelets from 0.6 ± 0.2 to 1.1 ± 0.4 s-1 (n=9) but no calcium waves were observed.Nifedipine and CGP12177 in the presence of propranolol caused a decrease in the calcium events in rat atrial myocytes.However, CGP12177 in the presence of propranolol is associated with more potent arrhythmogenic effects.Experiments with 2-APB show that arrhythmogenic effects coming from low affinity β1-adrenoceptor are not via IP3R calcium release and therefore a different mechanism must exist.