Selective inhibition of heme oxygenase, without inhibition of nitric oxidesynthase or soluble guanylyl cyclase, by metalloporphyrins at low concentrations

Studies on the physiological role of heme oxygenase (HO) require an inhibit or that will selectively inhibit HO activity without inhibiting the activit y of either nitric oxide synthase (NOS) or soluble guanylyl cyclase (sGC). The objective of this study was to test a series of metalloporphyrins that have previously been shown to inhibit HO activity, for their ability to inh ibit HO without inhibiting NOS or sGC activities. Measurement of activity o f HO in rat brain microsomes and NOS in rat brain cytosol was made for samp les incubated with metalloporphyrins (0.15-50 mu M), including zinc protopo rphyrin IX, zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG), chromi um mesoporphyrin IX (CrMP), tin protoporphyrin IX, and zinc N-methylprotopo rphyrin IX. CrMP and ZnBG were found to be the most selective inhibitors of HO activity (i.e., caused the greatest inhibition of HO activity, 89 and 8 0%, respectively, without inhibition of NOS activity). Based on these resul ts, sGC activity in rat lung cytosol incubated with CrMP or ZnBG (0.15-15 m u M) was measured. ZnBG did not affect basal sGC activity but did potentiat e S-nitroso-N-acetylpenicillamine (SNAP)-induced sGC activity. CrMP did not affect either basal or SNAP-induced activity. It was concluded that of the five metalloporphyrins studied, CrMP, at a concentration of 5 mu M, was a selective inhibitor of HO activity and was the most useful metalloporphyrin for the conditions tested. Thus, CrMP would appear to be a valuable chemic al probe in elucidating the physiological role of HO.