Relationship between myoglobin contents and increases in cyclic GMP produced by glyceryl trinitrate and nitric oxide in rabbit aorta, right atrium and papillary muscle

It has previously been shown that the vasodilatory response to glyceryl trinitrate (GTN) was decreased during hypothermic cardiopulmonary bypass. The purpose of these experiments was to determine the effect of temperature on GTN-induced relaxation and on GTN biotransformation in rabbit aorta. It was determined that the EC50 of GTN on rabbit aortic rings (RARs) was increased significantly from 1.8 × 10−8 M at 37 °C to 3.4 × 10−8 M at 27 °C (p < 0.05). The production of NO by rabbit aortic strips (RASs) was significantly less at 27 °C compared with 37 °C after 80 min, being 9.62 × 10−11 ± 13.2 × 10−11 mol NO/g wet wt. RASs compared with 5.71 × 10−10 ± 9.43 × 10−11 mol NO/g wet wt. RASs, respectively (p < 0.05), after 80 min incubation. There was no difference in the amount of glyceryl-1,2-dinitrate (1,2-GDN) produced from GTN at the two temperatures. The ED20 for NO-induced relaxation of RARs increased from 3.46 × 10−10 ± 2.24 × 10−10 mol at 37 °C to 1.01 × 10−9 ± 4.51 × 10−10 mol at 27 °C (p < 0.05). These data indicate that the biotransformation of GTN and the release of NO were impaired by hypothermia, and that this, as well as a decrease in the tissue response to NO at 27 °C, explains the decrease in GTN activity at reduced body temperatures.Key words: glyceryl trinitrate, nitric oxide, temperature, rabbit aorta, vasodilation.

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Mechanism of glyceryl trinitrate-induced vasodilation. I. Relationship between drug biotransfor mation, tissue cyclic GMP elevation, and relaxation of rabbit aorta

Journal of Cardiothoracic Anesthesia ◽

10.1016/0888-6296(88)90250-5 ◽

1988 ◽

Vol 2 (4) ◽

pp. 578

Keyword(s):

Glyceryl Trinitrate ◽

Cyclic Gmp ◽

Rabbit Aorta

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Inhibition of nitrovasodilator- and acetylcholine-induced relaxation and cyclic GMP accumulation by the cytochrome P-450 substrate, 7-ethoxyresorufin

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y92-181 ◽

1992 ◽

Vol 70 (9) ◽

pp. 1297-1303 ◽

Cited By ~ 30

Author(s):

Brian M. Bennett ◽

Bernard J. McDonald ◽

Rita Nigam ◽

Patrick G. Long ◽

W. Craig Simon

Keyword(s):

Nitric Oxide ◽

Glyceryl Trinitrate ◽

Cyclic Gmp ◽

Guanylyl Cyclase ◽

Competitive Inhibition ◽

Direct Interaction ◽

Inhibitory Effect ◽

Rat Aorta ◽

Endothelial Nitric Oxide ◽

Cytochrome P 450

We examined the effect of the cytochrome P-450 substrate, 7-ethoxyresorufin (7-ER), and its corresponding product, resorufin, on nitrovasodilator- and endothelium-dependent relaxation of isolated rat aorta. The EC50 value for glyceryl trinitrate (GTN) induced relaxation was increased over 100-fold by 7-ER and less than 3-fold by resorufin. The EC50 value for sodium nitroprusside (SNP) induced relaxation was increased approximately 12-fold by 7-ER, acetylcholine (ACh) induced relaxation was abolished, and relaxation induced by isopropylnorepinephrine was not significantly affected. GTN-, SNP-, and ACh-induced increases in cyclic GMP accumulation were inhibited by 7-ER, as were basal cyclic GMP levels in endothelium-intact, but not endothelium-denuded tissues. 7-ER decreased GTN biotransformation in intact aorta and decreased the regioselective formation of glyceryl-1,2-dinitrate. The activation by GTN and SNP of aortic guanylyl cyclase in broken cell preparations was not affected by 7-ER, indicating that the inhibitory effect of 7-ER is probably not due to a direct interaction with guanylyl cyclase. The inhibitory effect of 7-ER on GTN-induced relaxation was not altered by the addition of superoxide dismutase, suggesting that 7-ER does not act by increasing superoxide anion concentration (which would serve to increase the degradation of nitric oxide (NO) formed during vascular GTN biotransformation). Our data provide further evidence for the role of the cytochrome P-450 – cytochrome P-450 reductase system in the biotransformation of GTN to an activator (presumably nitric oxide) of guanylyl cyclase. The data are consistent with a mode of action of 7-ER involving either competitive inhibition of vascular cytochrome P-450 or uncoupling of vascular cytochrome P-450 reductase from cytochrome P-450. The data also suggest that the cytochrome P-450 system facilitates NO release from SNP and that 7-ER has an inhibitory effect on endothelial nitric oxide synthase.Key words: glyceryl trinitrate, nitrovasodilators, cytochrome P-450, vascular smooth muscle, 7-ethoxyresorufin, endothelium, cyclic GMP.

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Nitric oxide-induced vasodilation of organic nitrate-tolerant rabbit aorta

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y88-220 ◽

1988 ◽

Vol 66 (10) ◽

pp. 1344-1346 ◽

Cited By ~ 15

Author(s):

Christopher J. Slack ◽

Brian E. McLaughlin ◽

Kanji Nakatsu ◽

Gerald S. Marks ◽

James F. Brien

Keyword(s):

Nitric Oxide ◽

Glyceryl Trinitrate ◽

Isosorbide Dinitrate ◽

Vascular Tissue ◽

Rabbit Aorta ◽

Nitrate Tolerance ◽

Organic Nitrate ◽

Vasodilator Agents ◽

Vasodilator Drugs ◽

Before And After

It is postulated that the organic nitrate vasodilator agents, including glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN), are prodrugs, such that biotransformation to the active inorganic metabolite, nitric oxide (NO), occurs prior to the onset of vasodilation. Furthermore, it is proposed that organic nitrate tolerance in vascular tissue involves decreased formation of NO. To test this latter hypothesis, we examined vasodilation induced by NO, GTN, and ISDN in non-tolerant, GTN-tolerant, and ISDN-tolerant rabbit aortic rings (RARs). Isolated RARs were contracted submaximally with phenylephrine; the time of onset of relaxation and percent relaxation of tissue were determined in response to NO (0.3 μM), GTN (0.03 μM), and ISDN (0.12 μM) before and after a 1-h treatment with 500 μM GTN, 500 μM ISDN, or buffer only. The data demonstrated that the response to NO was not changed in GTN-tolerant and ISDN-tolerant tissues, in which there was virtually no GTN-induced or ISDN-induced relaxation. These results are consistent with the postulate that organic nitrate vasodilator drugs must undergo biotransformation to NO before vasodilation can occur and that the mechanism of organic nitrate tolerance involves decreased formation of NO.

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