New Developments in Nitrosovasodilator Therapy

Leopold, Jane A.; Loscalzo, Joseph

doi:10.1177/1358863x9700200305

Cited by 7 publications

(6 citation statements)

References 128 publications

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“…22 ± 24 Therapeutically, vasodilatory agents such as nitroprusside, linsidomine (SIN-1), and nitroglycerin (glyceryl trinitrate) which activate soluble guanylate cyclase after conversion to NO have shown ef®cacy in limited clinical trials in humans for the treatment of erectile dysfunction by intracavernous injection. 4 However, since these agents relax the peripheral vasculature via a similar mechanism and are prone to systemic side-effects, 5 they must be administered locally by intracavernosal injection or topical application.…”

Section: Discussionmentioning

confidence: 99%

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Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone

et al. 2001

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The potential of ATP-sensitive potassium channel openers (KCOs) for the treatment of male erectile dysfunction has recently been suggested based on positive clinical outcomes following intra-cavernosal administration of pinacidil. Agents that increase the levels of cGMP via elevation of nitric oxide (NO) nitroglycerin, for example, are also effective in improving erectile function preclinically and clinically. The aim of the present study was to determine the effects and mechanism of the action of nicorandil on rabbit corpus cavernosum. The in vitro regulation of smooth muscle tone was assessed in isolated cavernosal tissues pre-contracted with phenylephrine. Nicorandil, but not its major metabolite, relaxed phenylephrine-precontracted cavernosum smooth muscle with an EC 50 of 15 m m mM. The effects of nicorandil were only partially reversed by the K ATP channel blocker glyburide (10 m m mM) or by a soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one (ODQ, 3 m m mM). However, a combination of ODQ and glyburide completely blocked the relaxant effects of nicorandil. The results of the present study indicate that nicorandil can relax rabbit cavernosal tissue in vitro via a mechanism that involves activation of K ATP channels and stimulation of soluble guanylate cyclase.

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Section: Discussionmentioning

confidence: 99%

“…Nitrovasodilators (organic nitrates and NO donors) have shown limited ef®cacy in clinical trials for male erectile dysfunction. 4 However, since these agents relax the peripheral vasculature via a similar mechanism and are prone to systemic side-effects, 5 they must be administered locally by intracavernosal injection or topically.…”

Section: Introductionmentioning

confidence: 99%

Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone

et al. 2001

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“…Treatment with conventional nitrate preparations is limited by potential hemodynamic effects (hypotension) (7), poor antithrombotic properties (8), and drug tolerance (9). To overcome these limitations, development of novel NO donors with antithrombotic/anti-ischemic properties and negligible hemodynamic effects has been a challenge for the correct treatment of patients with ischemic heart disease.…”

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confidence: 99%

A novel anti-ischemic nitric oxide donor inhibits thrombosis without modifying haemodynamic parameters

Vilahur¹,

Segales²,

Casaní³

et al. 2004

Thromb Haemost

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Platelets are involved in the clinical presentations of ischemic heart disease. Our objective was to study the antithrombotic effects of a new nitric oxide donor (LA419), a neutral sugar organic nitrate with a protected thiol group in its molecular structure. Animals were randomly distributed in three groups: I) oral administration of LA419 (0.9-1.8-3.6-5 mg/kg/d, 10 days); II) oral administration of standard IS-5-MN (0.9-1.8 mg/kg/d, 10 days); III) non-treated group (control). In catheterized pigs, thrombosis was studied under controlled rheological conditions by radioisotopic evaluation of deposited platelets on damaged vessel wall, placed in an extracorporeal perfusion chamber. Changes in blood pressure, heart rate, and platelet aggregation were evaluated. Results have shown that LA419 significantly decreased thrombus formation according to the degree of vascular damage, and shear rate conditions in a dose-dependent manner (p<0.005), without significant modifications on blood pressure and/or elevation of liver enzymes. In contrast, IS-5-MN only showed a significant reduction on platelet deposition at the high dose, that was associated to hypotension and elevation of liver enzymes. Therefore, we conclude that this new anti-ischemic NO-donor (NOd) LA419 that inhibits platelet function without modifying blood pressure may be a highly efficacious strategy to passivate platelet activation induced by a damaged vessel wall.

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“…4 Endothelial synthesis of NO plays a fundamental role both in the regulation of platelet reactivity and in the control of vascular tone. 5 However, the effects of high-dose heparin on NO-mediated vasoreactivity in vivo have never been addressed. This effect would be clinically relevant in procedures such as PTCA and cardiopulmonary bypass, in which an activated partial thromboplastin time Ͼ100 seconds is currently used.…”

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confidence: 99%

High-Dose Heparin Impairs Nitric Oxide Pathway and Vasomotion in Rats

et al. 1999

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Background-Platelet-activating effects have been reported with high-dose heparin in acute thrombotic disorders. Recent studies have shown that increased platelet aggregation is due to reduced nitric oxide (NO) production in endothelial cells cultured in the presence of high-dose heparin. The aim of this study was to determine whether heparin can affect the NO pathway and the regulation of the vascular tone in vivo. Methods and Results-Anesthetized and mechanically ventilated Sprague-Dawley rats were treated with high-dose heparin. After 4 hours, the endothelial constitutive NO synthase (ecNOS) protein content in the aorta decreased (36% reduction, PϽ0.05), as detected by immunoblotting, and NO-dependent vascular reactivity was impaired. In fact, the increase in mean arterial blood pressure after inhibition of ecNOS with N G -nitro-L-arginine methyl ester (30 mg/kg) was smaller in heparin-treated animals than in controls (ϩ26.9Ϯ4.8 versus ϩ48.3Ϯ9.1 mm Hg, PϽ0.05), and further infusion of the biological ecNOS substrate L-arginine (0.5 g/kg) was ineffective in reversing systemic vasoconstriction (Ϫ1% versus 28% vasodilatation, PϽ0.001 eparin is the most widely used anticoagulant in current clinical practice. However, there is growing evidence that heparin can induce platelet activation. Recent studies report that therapeutic doses of heparin increase spontaneous and stimulated platelet aggregation when administered during acute coronary syndromes or unstable angina, but also in healthy subjects. [1][2][3] This effect is associated with impaired endothelial nitric oxide (NO) synthesis in bovine aortic endothelial cells exposed to high-dose heparin. 4 Endothelial synthesis of NO plays a fundamental role both in the regulation of platelet reactivity and in the control of vascular tone. 5 However, the effects of high-dose heparin on NO-mediated vasoreactivity in vivo have never been addressed. This effect would be clinically relevant in procedures such as PTCA and cardiopulmonary bypass, in which an activated partial thromboplastin time Ͼ100 seconds is currently used.The present study investigated the effects of heparin on systemic vascular tone of anesthetized rats after either inhibition or activation of the NO pathway by N G -nitro-L-arginine methyl ester (L-NAME) or L-arginine, respectively. Endothelial constitutive NO synthase (ecNOS) protein expression after heparin administration was also measured. Methods Animal PreparationThe investigation was conducted according to the Guide for the Care and Use of Laboratory Animals (US National Institutes of Health). Twenty-one Sprague-Dawley rats, maintained on a standard diet (mean body weight, 250Ϯ50 g), were anesthetized with sodium pentobarbital (30 mg/kg IP). A tracheostomy was performed, and the animals were mechanically ventilated to ensure physiological levels of arterial blood gases (PO 2 , 70 to 80 mm Hg; PCO 2 , 27 to 35 mm Hg). A single-lumen catheter was placed in the right carotid artery for blood pressure recording, and a second catheter was placed in the ri...

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New Developments in Nitrosovasodilator Therapy

Cited by 7 publications

References 128 publications

Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone

Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone

A novel anti-ischemic nitric oxide donor inhibits thrombosis without modifying haemodynamic parameters

High-Dose Heparin Impairs Nitric Oxide Pathway and Vasomotion in Rats

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