Tolerance to nitroglycerin in vascular smooth muscle cells

Recovery and cross-tolerance to sodium nitroprusside

L. M. Zhang, Manuel R Castresana, W. H. Newman

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 μM NTG were desensitized to the effect of NTG on cGMP, but 100 μM 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 μM 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. Also, in cells tolerant to NTG the cGMP response to SNP recovered while the response to NTG was still depressed. These differences suggest that although both drugs act by releasing NO, the mechanism of tolerance to the vasodilator response is not the same.

Original languageEnglish (US)
Pages (from-to)1053-1059
Number of pages7
JournalAnesthesia and Analgesia
Volume78
Issue number6
StatePublished - Jan 1 1994
Externally publishedYes

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Nitroglycerin
Nitroprusside
Vascular Smooth Muscle
Smooth Muscle Myocytes
Vasodilator Agents
Nitric Oxide
Cyclic GMP

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

Cite this

Tolerance to nitroglycerin in vascular smooth muscle cells : Recovery and cross-tolerance to sodium nitroprusside. / Zhang, L. M.; Castresana, Manuel R; Newman, W. H.

In: Anesthesia and Analgesia, Vol. 78, No. 6, 01.01.1994, p. 1053-1059.

Research output: Contribution to journalArticle

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abstract = "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 μM NTG were desensitized to the effect of NTG on cGMP, but 100 μM 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 μM 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. Also, in cells tolerant to NTG the cGMP response to SNP recovered while the response to NTG was still depressed. These differences suggest that although both drugs act by releasing NO, the mechanism of tolerance to the vasodilator response is not the same.",
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