Abstract
There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ETA receptor antagonist ZD2574 to determine whether chronic ETA receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 ± 1.2-fold increase in the EC50value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg−1 t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ETA receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ETB receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 ± 0.4-fold and a 2.2 ± 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.
Footnotes
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Send reprint requests to: Dr. Brian M. Bennett, Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario K7L 3N6, Canada. E-mail: bennett{at}post.queensu.ca
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↵1 This work was supported by Grant T3319 from the Heart and Stroke Foundation of Ontario.
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↵2 Recipient of an Ontario Graduate Student scholarship and a Queen's Graduate Award.
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↵3 Recipient of a Queen's Graduate Award.
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↵4 Recipient of a Career Investigator Award from the Heart and Stroke Foundation of Canada.
- Abbreviations:
- GTN
- glyceryl trinitrate
- NO
- nitric oxide
- ET-1
- endothelin-1
- PKC
- protein kinase C
- Ang II
- angiotensin II
- 1,2-GDN
- glyceryl-1,2-dinitrate
- 1,3-GDN
- glyceryl-1,3-dinitrate
- ZD2574
- 2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-pyridine-3-sulfonamide
- AUC
- area under the curve
- MAP
- mean arterial pressure
- Received May 16, 2000.
- Accepted July 17, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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