Spontaneous beating of rabbit SANC is controlled by cAMP-mediated, PKA-dependent rhythmic, local subsarcolemmal Ca2+releases (LCRs) from sarcoplasmic reticulum during late diastolic depolarization. While Ca2+influx via L-type Ca2+ channels ensures LCR occurrence, high basal PDE activity limits LCRs. The extent to which PDE regulates L-type Ca2+ current, ICa,L, however, remains enigma. We determined the extent of PDE subtype-dependent control of basal ICa,L, spontaneous SANC firing rate;and compared those to the effect of -adrenergic receptor (-AR) agonist, isoproterenol. A specific PDE4 inhibitor, rolipram, had no effect, on either ICa,L or spontaneous beating;cilostamide, a specific PDE3 inhibitor, in contrast, increased both ICa,L and spontaneous SANC firing. Simultaneous inhibition of PDE3 and PDE4 by (cilostamide+ rolipram) increased ICa,L;amplified LCR size (from 5.90.58 to 8.60.50 m);decreased the LCR period (from 309.720.6 to 214.33.9 msec);and accelerated spontaneous SANC firing rate equivalent to broad-spectrum PDE inhibitor, IBMX. These effects were even greater than those produced by -AR stimulation. Thus, concerted PDE3 and PDE4 activities control basal cAMP-PKA-dependent phosphorylation and suppress ICa,L, limiting basal LCRs and spontaneous SANC firing rate.
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