In Vivo Induction and Reversal of Nitroglycerin Tolerance in Human Coronary Arteries

May, David C.; Popma, Jeffrey J.; Black, William H.; Schaefer, Susan M.; Lee, H. R.; Levine, Benjamin D.; Hillis, L. David

doi:10.1056/nejm198709243171305

Cited by 159 publications

(23 citation statements)

References 30 publications

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“…Several mechanisms have been described as possibly contributing to nitrovasodilator resistance or tolerance. One of the more widely studied is that depletion of thiol moieties may be responsible for nitrovasodilator tolerance (i.e., [38][39][40][41][42]. Formation of low molecular weight S-nitroso-thiols, such as N-acetylcysteine, facilitates NO entrance to the SMC of the vascular media (43).…”

Section: Discussionmentioning

confidence: 99%

Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP.

Soff¹,

Cornwell²,

Cundiff³

et al. 1997

J. Clin. Invest.

104

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A key component of the nitric oxide-cyclic guanosine monophosphate (cGMP) pathway in smooth muscle cells (SMC) is the type I GMP-dependent protein kinase (PK-G I). Activation of PK-G I mediates the reduction of cytoplasmic calcium concentrations and vasorelaxation. In this manuscript, we demonstrate that continuous exposure of SMC in culture to the nitrovasodilators S -nitroso-N -acetylpenicillamine (SNAP) or sodium nitroprusside (SNP) results in ‫ف‬ 75% suppression of PK-G I mRNA by 48 h. PK-G I mRNA and protein were also suppressed by continuous exposure to cGMP analogues 8-bromo-and 8-(4-chlorophenylthio) guanosine-3,5-monophosphate or the cAMP analogue dibutyryl cAMP. These results suggest that activation of one or both of the cyclic nucleotide-dependent protein kinases mediates PK-G I mRNA suppression. Using isoform-specific cDNA probes, only the PK-G I ␣ was detected in SMC, either at baseline or after suppression, while PK-G I ␤ was not detected, indicating that isoform switch was not contributing to the gene regulation. Using the transcription inhibitor actinomycin D, the PK-G I mRNA half-life in bovine SMC was observed to be 5 h. The half-life was not affected by the addition of SNAP to actinomycin D, indicating no effect on PK-G I mRNA stability. Nuclear runoff studies indicated a suppression of PK-G I gene transcription by SNAP. PK-G I suppression was also observed in vivo in rats given isosorbide dinitrate in the drinking water, with a dose-dependent suppression of PK-G I protein in the aorta. PK-G I antigen in whole rat lung extract was also suppressed by administration of isosorbide or theophylline in the drinking water. These data may contribute to our understanding of nitrovasodilator resistance, a phenomenon resulting from continuous exposure to nitroglycerin or other nitrovasodilators. ( J.

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Section: Discussionmentioning

confidence: 99%

Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP.

Soff¹,

Cornwell²,

Cundiff³

et al. 1997

J. Clin. Invest.

104

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“…Studies in patients made tolerant by intravenous GTN administration have documented that there is partial loss of the effect of intracoronary GTN to increase coronary sinus blood flow. During this tolerant state, the infusion of NAC (100 mg kg-1) restored the response to intracoronary GTN to that seen in the non-tolerant state (May et al, 1987). These data must, however, be interpreted with caution as intracoronary GTN in these doses may result in coronary arteriolar dilatation not coronary arterial dilatation.…”

mentioning

confidence: 78%

Update on nitrate tolerance.

Parker¹

1992

Brit J Clinical Pharma

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1. It is now recognised that nitrate therapy designed to provide effects throughout 24 h each day induces tolerance. Such tolerance may be partial or complete and is associated with diminished haemodynamic and clinical effects. 2. The mechanism of tolerance is not completely understood but it seems to be related to the depletion of reduced sulphydryl groups in vascular smooth muscle and to the activation of counter‐regulatory forces. These include elevated plasma catecholamines, arginine vasopressin and plasma renin activity. Activity of the renin‐angiotensin system is associated with sodium and water retention and plasma volume expansion. The increase in vasoconstrictor influences and augmented plasma volume could modulate the effect of nitrate‐induced vasodilatation.

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“…2,5,10,11) Treatment with SH donor may reverse the nitrate tolerance; in fact, N-acetyl cysteine showed partial release of this tolerance. 13,14) On the other hand, there are other reports in which thiol supplementation does not prevent the tolerance to nitrates. [15][16][17] ISMN is one of the active metabolites of isosorbide dinitrate 4,5) and has been widely used as a prophylactic drug for ischemic or coronary heart disease.…”

Section: Discussionmentioning

confidence: 99%

Tolerance to Nitroglycerin Induced by Isosorbide-5-Mononitrate Infusion in Vivo.

Manabe

Yamamoto

Satoh

et al. 2001

Biological & Pharmaceutical Bulletin

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Nitrates are still important drugs for clinical therapy of the patient with ischemic heart disease and for relief of anginal attack. Treatments with nitrates, however, develop vascular tolerance associated with attenuation of hemodynamic and antianginal effects.2,3) When a therapeutic plasma level of nitrates is maintained over 24 h, it may cause a tolerance to nitrates.2,3) Isosorbide-5-mononitrate (ISMN) is one of the active metabolites of isosorbide dinitrate and has been clinically used. 4,5) Because this agent is hard to metabolize further by the hepatic metabolic system, its therapeutic plasma level can be sustained for a longer period. 4,5) ISMN is clinically used for treatment of patients with hypertension or angina pectoris.6-8) Sublingual dosing of nitroglycerin (glyceryl trinitrate; GTN) is used for relief of the anginal pain of patients treated chronically with ISMN. Many clinical reports show lack of development of tolerance to ISMN. 7,9) However, we failed to find a report on whether the tolerance to GTN occurs when there has been chronical treatment with ISMN. In the present study, we compared tolerance to GTN in the rat infused continuously with ISMN to the rat infused continuously with GTN. MATERIALS AND METHODSThe investigation conformed to the Guiding Principles for the Care and Use of Experimental Animals in Hokkaido College of Pharmacy (published in 2001).Materials ISMN and GTN were supplied by Toa Eiyo Ltd., Fukushima, Japan. Osmotic pumps (Alzet Animal Preparation Male Sprague Dawley rats weighing 250-300 g were anesthetized with sodium pentobarbital (60 mg/kg, i.p.). Under artificial respiration, the left common carotid artery and the right external jugular vein were dissected free, and cannulated. A cannula introduced into the carotid artery was filled with saline solution containing heparin (100 units/ml), and connected to a pressure transducer. Heart rate was monitored from the ECG limb lead II. Mean arterial blood pressure and heart rate were recorded on a polygraph via a blood pressure amplifier (San-Ei 2238) and a bioelectric amplifier (San-Ei 1253A), respectively. ISMN and GTN dissolved in 99% ethanol were diluted with 5% glucose to prepare the solution at the concentration of 0.25-250 mg/kg and 0.25 mg/kg-2.5 mg/kg, respectively. Therefore, the final concentrations of ethanol and glucose were 5% and 5%, respectively. ISMN (0.25-250 mg/kg) or GTN (0.25 mg/kg-2.5 mg/kg) was injected through the right external jugular vein. Some rats were chronically infused with ISMN or GTN using an osmotic pump (ALZET ® Model 2001 and 2ML1) embedded subcutaneously in their back. The osmotic pump was filled with either 99% ethanol as vehicle, 250 mg/ml ISMN, 13 mg/ml GTN, or 20 mg/ml GTN, dissolved in 99% ethanol, and the solution was pumped out at 10 ml/h. ISMN was infused at the dose of 2.5 mg/h/rat for 3 or 7 d, whereas GTN was infused at 1.3 mg/h/rat for 7 d or 0.2 mg/h/rat for 3 d.Statistics The results are expressed as meansϮS.E.M. The significance of differences between groups was evaluated b...

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In Vivo Induction and Reversal of Nitroglycerin Tolerance in Human Coronary Arteries

Cited by 159 publications

References 30 publications

Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP.

Smooth muscle cell expression of type I cyclic GMP-dependent protein kinase is suppressed by continuous exposure to nitrovasodilators, theophylline, cyclic GMP, and cyclic AMP.

Update on nitrate tolerance.

Tolerance to Nitroglycerin Induced by Isosorbide-5-Mononitrate Infusion in Vivo.

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