Patterns of isosorbide dinitrate and glyceryl trinitrate metabolites formed by selected segments of the rabbit gastrointestinal tract

Tam, G. S.; MacMillan, Heather; Bennett, Brian M.; Marks, Gerald S.; Brien, James F.; Nakatsu, Kanji

doi:10.1139/y88-029

Cited by 7 publications

(1 citation statement)

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“…We administered nitroglycerin acutely and not over a prolonged period of time as the drug is known to have a high gastrointestinal clearance and a low oral bioavailability in rabbits (Tam et al ., 1988). Furthermore, we did not want to risk a missed inappropriate drop in blood pressure or any further hemodynamic compromise during a long‐term oral administration of nitroglycerin.…”

Section: Methodsmentioning

confidence: 99%

Oral nicorandil recaptures the waned protection from preconditioning in vivo

Iliodromitis

Cokkinos

Ζώγα

et al. 2003

British J Pharmacology

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1 Protection from preconditioning (PC) wanes and is eventually lost when multiple bouts of short ischemia or a prolonged reperfusion interval precedes the following sustained ischemia. The activation of mitochondrial K ATP channels plays a pivotal role in the intracellular signaling of PC. We tested whether the K ATP channel opener nicorandil (nic) preserves the given protection from PC in conditions where this benefit decays and is lost. 2 Eight groups of rabbits were divided into two equal series of experiments, one without nic (placebo) and one with nic treatment. Nic was given orally for 5 consecutive days in a dose of 5 mg kg À1 d À1 . In a second step, four additional groups were treated with nic plus the K ATP channel blocker 5HD and 1 additional control group with nitroglycerin only. All the animals were anesthetized and then subjected to 30 min of myocardial ischemia and 2 h of reperfusion with one of the following interventions before the sustained ischemia: Control groups to no intervention; 3PC groups to three cycles of 5-min ischemia-10-min reperfusion; 8PC groups to eight cycles of 5-min ischemia -10-min reperfusion; and 3PC90 groups to the same interventions as the 3PC groups but with a prolonged (90 min) intervening reperfusion interval before the sustained ischemia. The infarcted and the risk areas were expressed in percent. 3 There was no significant change in infarct size between the placebo, the nic and the 5HD-nic in the control groups (41.574.7, 43.977.1 and 48.776.4%) and 3PC groups (10.373.4, 12.273.9 and 12.674.5%). However, there was a significant decrease after nic treatment in groups 8PC (47.778.8% vs 13.072.6%, Po0.01) and 3PC90 (37.376.0% vs 14.272.4%, Po0.01), which was abrogated (38.274.7 and 42.774.4%, respectively, for 8PC and 3PC90 groups). Nitroglycerin had no effect on infarct size (39.173.1%, P ¼ NS vs other controls). 4 Oral treatment with nic recaptures the waned protection of PC, both after repetitive bouts of short ischemia or after a prolonged reperfusion interval, preserving the initially obtained benefit. Nic by itself is insufficient to initiate PC in vivo.

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Section: Methodsmentioning

confidence: 99%

Oral nicorandil recaptures the waned protection from preconditioning in vivo

Iliodromitis

Cokkinos

Ζώγα

et al. 2003

British J Pharmacology

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Mechanisms of Action of Nitrates

Torfgård¹,

Ahlner²

1997

Nitrates Updated

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Glyceryl trlnitrate, isosorbide dinitrate, and isosorbide-o-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infaretion, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascnlar smooth mnscles, and the dilation of coronary vessels improves oxygen snpply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, rednces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central ne"ous system and the myoeardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth musele and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione 8-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cye ....... acts via cGMPdependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.Keg Words. organic nitrate esters, glyceryl trlnitrate, nitroglycerin, isosorbide dinitrate, isosorbide-o-mononitrate, cyclic GMP Nitroglycerin was introduced as a therapeutic agent for the treatment of angina pectoris more than a century ago [1], and since then several other nitro compounds with similar chemical properties have been introduced, for example, isosorbide dinitrate (ISDN), isosorbide-5-mononitrate (IS-5-MN), and pentaerythritol tetranitrate. An essential feature of all these compounds is a nitrate ester bond (R-O-N02). The nitrate ester group distinguishes the or-21 U. Thadani et al. (eds.), Nitrates Updated

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Mechanisms of action of nitrates

Torfgård

Ahlner

1994

Cardiovasc Drug Ther

116

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Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.

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Patterns of isosorbide dinitrate and glyceryl trinitrate metabolites formed by selected segments of the rabbit gastrointestinal tract

Cited by 7 publications

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Oral nicorandil recaptures the waned protection from preconditioning in vivo

Oral nicorandil recaptures the waned protection from preconditioning in vivo

Mechanisms of Action of Nitrates

Mechanisms of action of nitrates

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