Tolerance to Nitroglycerin in Vascular Smooth Muscle Cells

Treatment with nitric oxide (NO)-producing vasodilators such as nitroglycerin (NTG) and sodium nitroprusside (SNP) causes tolerance. Both NTG and SNP relax blood vessels by increasing guanosine 3',5'-cyclic monophosphate (cGMP) in vascular smooth muscle. We determined the effect of treatment with NTG on cGMP production in cultured pig coronary smooth muscle cells (CSM). Cells incubated for 1 h with 10 microM NTG were desensitized to the effect of NTG on cGMP, but 100 microM NTG was required to induce cross-tolerance to SNP. Acute concentration-response curves of cGMP to NTG and to SNP were determined in cells pretreated for 1 h with 100 microM NTG and compared to response curves in untreated cells. In untreated cells, both NTG and SNP increased cGMP concentration dependently. SNP (1 mM) increased cGMP to 575 +/- 22 pmol/mg vs 55 +/- 4 pmol/mg for 1 mM NTG (P < 0.01, n = 8). Pretreated cells were unresponsive to acutely applied NTG but remained responsive to SNP, although the concentration-response curve to SNP was significantly depressed by approximately 60%. After washout of the NTG pretreatment, the cGMP response to SNP returned to control within 48 h while response to NTG required 72 h. These results show that smooth muscle cells exposed to NTG become tolerant to the effect of NTG on cGMP, and that cross-tolerance to SNP required a 10-fold higher concentration of NTG. The cGMP concentration-response curves of these tolerant cells to rechallenge with NTG or SNP were different.(ABSTRACT TRUNCATED AT 250 WORDS)