Pulmonary vascular remodeling due to overgrowth of PASMC is a major cause for the elevated PVR in patients with idiopathic pulmonary arterial hypertension (IPAH). Increased [Ca²⁺]_cyt, resulting from enhanced capacitative Ca²⁺ entry (CCE) and upregulated transient receptor potential (TRP) channel expression, is involved in stimulating PASMC proliferation. Short-term (30 min) pretreatment with forskolin (FSK, 10 µM), a direct activator of adenylyl cyclase, in combination with the cyclic nucleotide phosphodiesterase inhibitor isobutylmethylxanthine (IBMX, 200 µM), attenuated CCE in PASMC from normal subjects, normotensive patients (NPH) and IPAH patients. The FSK-mediated CCE inhibition was independent of PKA as H89 negligibly affected the decrease in CCE produced by cAMP. By contrast, longer (4 h) treatment with FSK (with IBMX) attenuated CCE in normal and NPH PASMC, but enhanced CCE in IPAH PASMC. This enhancement of CCE was abolished by PKA inhibition and associated with an upregulaton of TRPC3. In addition, cAMP increased TRPC1 mRNA expression in IPAH PASMC, an effect blunted by H89. Furthermore, iloprost down-regulated TRPC3 expression in IPAH PASMC and FSK-mediated cAMP increase inhibited IPAH PASMC proliferation. Although a rapid rise in cellular cAMP decreases CCE by a PKA-independent mechanism, a sustained cAMP increase inhibits CCE in normal and NPH PASMC but increases CCE via a PKA-dependent pathway in IPAH PASMC. The divergent effect of cAMP on CCE parallels effects on TRPC expression. The results suggest that the combined use of a PKA inhibitor and cAMP-elevating drugs may provide a novel approach for treatment of IPAH.