Desensitization of guanylyl cyclases in cultured human airway smooth-muscle cells

We previously showed that cultured human airway smooth-muscle cells (HASMC) contain soluble and particulate guanylyl cyclases (GCs). We studied the de sensitization of soluble and particulate GCs in HASMC. Homologous desensiti zation of soluble GC occurred after incubation with S-nitroso-N-acetyl penc illamine (SNAP). SNAP-dependent desensitization was blocked by hemoglobin, a nitric oxide (NO) scavenger, suggesting that it was due to NO release. Cr oss-desensitization between SNAP and sodium nitroprusside (SNP) and the lac k of thiol reduction after SNAP or SNP treatment suggested that thiol deple tion was not involved. Assays for soluble GC activity and experiments using protein synthesis inhibitors suggested that SNAP-dependent desensitization was due to reduced soluble GC. Homologous desensitization of particulate G C occurred after pretreatment with atrial natriuretic peptide (ANP) accompa nied by reduced particulate GC activity. Recovery required protein synthesi s, suggesting that it was due to reduction in particulate GC. Homologous de sensitization to either SNAP or ANP was not altered by phosphodiesterase (P DE) inhibitors, suggesting that increased PDE activity was not involved. Cr oss-desensitization experiments using SNAP and ANP and experiments using za prinast to elevate cyclic guanosine monophosphate showed no evidence of het erologous desensitization. Our results suggest that pretreatment of HASMC w ith SNAP or ANP causes homologous, but not heterologous, desensitization of soluble and particulate GCs, respectively.