Spontaneous beating of rabbit SANC is controlled by rhythmic, local subsarcolemmal Ca2+releases (LCRs) from sarcoplasmic reticulum which occur during diastolic depolarization. Spontaneous, rhythmic LCRs activate inward Na+/Ca2+ exchange current, imparting an exponential increase to the later part of the diastolic depolarization to fire an action potential. LCRs are critically dependent on Ca2+ influx via L-type Ca2+ channels which are regulated by high basal PDE and PKC activities. The extent to which either PDE or PKC regulate basal L-type Ca2+ current, ICa,L, however, remains enigma. We determined the extent of PKC and PDE subtype-dependent control of basal ICa,L, spontaneous SANC firing rate. Specific PKC inhibitors either GF109203X or calphostin C markedly suppressed both spontaneous SANC firing and ICa,L amplitude, strongly suggesting that ICa,L could be a major target of basal PKC activity in SANC. 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 5.9 to 8.6 mkm);decreased the LCR period (from 309.7 to 214.3 msec);and accelerated spontaneous SANC firing rate equivalent to broad-spectrum PDE inhibitor, IBMX. Thus, concerted PKC and combination of PDE3 and PDE4 activities control basal phosphorylation of L-type Ca2+ channels in SANC regulating ICa,L amplitude, thus modulating basal LCRs and spontaneous SANC firing rate.
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