The nitroxyl anion (HNO) is a potent dilator of rat coronary vasculature (original) (raw)
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British Journal of Pharmacology, 2014
The NO redox sibling nitroxyl (HNO) elicits soluble guanylyl cyclase (sGC)-dependent vasodilatation. HNO has high reactivity with thiols, which is attributed with HNO-enhanced left ventricular (LV) function. Here, we tested the hypothesis that the concomitant vasodilatation and inotropic actions induced by a HNO donor, Angeli's salt (sodium trioxodinitrate), were sGC-dependent and sGC-independent respectively. Haemodynamic responses to Angeli's salt (10 pmol-10 μmol), alone and in the presence of scavengers of HNO (L-cysteine, 4 mM) or of NO [hydroxocobalamin (HXC), 100 μM] or a selective inhibitor of sGC [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), 10 μM], a CGRP receptor antagonist (CGRP8-37 , 0.1 μM) or a blocker of voltage-dependent potassium channels [4-aminopyridine (4-AP), 1 mM] were determined in isolated hearts from male rats. Angeli's salt elicited concomitant, dose-dependent increases in coronary flow and LV systolic and diastolic function. Both L-cysteine and ODQ shifted (but did not abolish) the dose-response curve of each of these effects to the right, implying contributions from HNO and sGC in both the vasodilator and inotropic actions. In contrast, neither HXC, CGRP8-37 nor 4-AP affected these actions. Both vasodilator and inotropic actions of the HNO donor Angeli's salt were mediated in part by sGC-dependent mechanisms, representing the first evidence that sGC contributes to the inotropic and lusitropic action of HNO in the intact heart. Thus, HNO acutely enhances LV contraction and relaxation, while concomitantly unloading the heart, potentially beneficial actions in failing hearts.
British Journal of Pharmacology, 2001
Vasorelaxant properties of three nitric oxide (NO) donor drugs (glyceryl trinitrate, sodium nitroprusside and spermine NONOate) in mouse aorta (phenylephrine pre-contracted) were compared with those of endothelium-derived NO (generated with acetylcholine), NO free radical (NO´; NO gas solution) and nitroxyl ion (NO 7 ; from Angeli's salt). 2 The soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4-)oxadiazolo(4,3-a)-quinoxalin-1-one; 0.3, 1 and 10 mM), concentration-dependently inhibited responses to all agents. 10 mM ODQ abolished responses to acetylcholine and glyceryl trinitrate, almost abolished responses to sodium nitroprusside but produced parallel shifts (to a higher concentration range; no depression in maxima) in the concentration-response curves for NO gas solution, Angeli's salt and spermine NONOate. 3 The NO´scavengers, carboxy-PTIO, (2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide; 100 mM) and hydroxocobalamin (100 mM), both inhibited responses to NO gas solution and to the three NO donor drugs, but not Angeli's salt. Hydroxocobalamin, but not carboxy-PTIO, also inhibited responses to acetylcholine. 4 The NO 7 inhibitor, L-cysteine (3 mM), inhibited responses to Angeli's salt, acetylcholine and the three NO donor drugs, but not NO gas solution. 5 The data suggest that, in mouse aorta, responses to all three NO donors involve (i) activation of soluble guanylate cyclase, but to diering degrees and (ii) generation of both NO´and NO 7. Glyceryl trinitrate and sodium nitroprusside, which generate NO following tissue bioactivation, have pro®les resembling the pro®le of endothelium-derived NO more than that of exogenous NO. Spermine NONOate, which generates NO spontaneously outside the tissue, was the drug that most closely resembled (but was not identical to) exogenous NO.
British Journal of Pharmacology, 1992
on vasodilatation induced by ATP, substance P, 5-hydroxytryptamine (5-HT), bradykinin and sodium nitroprusside (SNP) were examined in the guinea-pig coronary bed, by use of a Langendorff technique. The effects of these inhibitors of nitric oxide synthesis were assessed on their ability to inhibit both the amplitude and the area of the vasodilator response. 2 The vasodilator responses evoked by low doses of 5-HT (5 x 10`-'°5 x 10 mol) were almost abolished by L-NAME and L-NOARG (both at 10-5, 3 x 10-5 and 1O-4M), although L-NOARG (3 x 10-s M) was significantly less potent than L-NAME (3 x 10-5 M) as an inhibitor of vasodilator responses to 5-HT (5 x 10-8 mol). 3 The vasodilator responses evoked by substance P (5 x 102-5 X I0-mol) were reduced in the presence of L-NAME and L-NOARG (both at 10-5 and 3 x 10-5 M). The response to substance P was almost abolished by L-NAME and L-NOARG (both at 10-4 M). 4 The amplitude of the vasodilator responses to ATP (5 x 10-" and 5 x 10-9-5 x 10-mol) was little affected by either L-NAME or L-NOARG (both at 10-5, 3 x 10-5 and 10-4 M). However, the area of the response to ATP (5 x 10-`o-5 x 10-7 mol) was inhibited by L-NAME (10-5, 3 x 10-5 and 10-4M) and to a lesser extent by L-NOARG (10-5 and 10-M). 5 The amplitude and area of the vasodilator responses to bradykinin (5 x 10-12-5 x 10-11 mol) were reduced, but not abolished, by L-NOARG and L-NAME. 6 Neither the amplitude nor area of the responses to sodium nitroprusside (5 x 10-'°-5 x 10-7 mol) were inhibited by either L-NAME or L-NOARG (both at 10-5 and 3 x 10-5 M). 7 It is concluded that in the guinea-pig coronary vasculature, the vasodilatation evoked by substance P and low doses of 5-HT is mediated almost exclusively via nitric oxide, whereas the vasodilatations evoked by ATP and bradykinin appear to involve other mechanisms in addition to the release of nitric oxide. L-NAME was a more effective agent than L-NOARG in inhibiting the vasodilator actions of 5-HT and ATP in this preparation.
Naunyn-Schmiedeberg’s Archives of Pharmacology, 1994
We investigated the relative contribution of basal and agonist stimulated EDRF/NO release to the adjustment of coronary tone and myocardial perfusion in conscious dogs by inhibiting coronary endothelial NO formation with NG-nitro-L-arginine methyl ester (L-NAME). Chronically instrumented conscious dogs (n = 9) were prepared for measurement of mean arterial blood pressure (MAP), heart rate (HR), coronary blood flow (CF) and diameter of the left circumflex (CDLc) and left anterior descending (CDLAD) coronary artery, respectively. Intracoronary infusions of L-NAME (30.3 mM; 0.25 ml x min-1) caused significant increases in MAP and decreases in HR. CDLc decreased by 3.8°70 from 3.01_+0.04 to 2.90+0.04 mm and CF decreases by 30% from 12.9_+0.2 to 9.1 +0.2 (aU). Peak reactive hyperemia (CFmax) evoked by 20-s-lasting occlusions of the left circumflex coronary artery decreased from 29.9+0.8 to 25.8_+ 1.0 aU and maximal flow-dependent coronary dilation were reduced from 2.04_+0.08 to 0.91 _+0.12% after inhibition of NO-synthesis. Intracoronary infusions of acetylcholine (ACh), adenosine (Ado), bradykinin (Bk), and papaverine (Pap) caused dose-dependent increases in CDLc and CE Infusion of L-NAME nearly abolished the dilator effect of Ado on CDLc and reduced those to ACh, Bk and Pap. Increases in CF to ACh, Ado and Bk but not to Pap were reduced by L-NAME. Subsequent intracoronary infusions of L-arginine (303 mM; 0.25 ml x min-1) reduced L-NAME-induced CF-changes partly, but did not reverse coronary constriction. These results suggest that inhibition of the continuous release of nitric oxide markedly reduces myocardial perfusion in vivo. Endogenous dilator mechanisms are likewise impaired. Thus, in the heart, nitric oxide deficiency probably cannot be fully compensated for by counterregulating mechanisms.
Proceedings of the National Academy of Sciences, 2003
Nitroxyl anion (HNO͞NO ؊ ), the one-electron reduced form of nitric oxide (NO), induces positive cardiac inotropy and selective venodilation in the normal in vivo circulation. Here we tested whether HNO͞NO ؊ augments systolic and diastolic function of failing hearts, and whether contrary to NO͞nitrates such modulation enhances rather than blunts -adrenergic stimulation and is accompanied by increased plasma calcitonin gene-related peptide (CGRP). HNO͞NO ؊ generated by Angelis' salt (AS) was infused (10 g͞kg per min, i.v.) to conscious dogs with cardiac failure induced by chronic tachycardia pacing. AS nearly doubled contractility, enhanced relaxation, and lowered cardiac preload and afterload (all P < 0.001) without altering plasma cGMP. This contrasted to modest systolic depression induced by an NO donor diethylamine-(DEA)͞NO or nitroglycerin (NTG). Cardiotropic changes from AS were similar in failing hearts as in controls despite depressed -adrenergic and calcium signaling in the former. Inotropic effects of AS were additive to dobutamine, whereas DEA͞NO blunted -stimulation and NTG was neutral. Administration of propranolol to nonfailing hearts fully blocked isoproterenol stimulation but had minimal effect on AS inotropy and enhanced lusitropy. Arterial plasma CGRP rose 3-fold with AS but was unaltered by DEA͞NO or NTG, supporting a proposed role of this peptide to HNO͞NO ؊ cardiotropic action. Thus, HNO͞NO ؊ has positive inotropic and lusitropic action, which unlike NO͞nitrates is independent and additive to -adrenergic stimulation and stimulates CGRP release. This suggests potential of HNO͞NO ؊ donors for the treatment of heart failure.
Biochemical and Biophysical Research Communications, 2010
Contractile dysfunction and diminished response to b-adrenergic agonists are characteristics for failing hearts. Chemically donated nitroxyl (HNO) improves contractility in failing hearts and thus may have therapeutic potential. Yet, there is a need for pharmacologically suitable donors. In this study we tested whether the pure and long acting HNO donor, 1-nitrosocyclohexyl acetate (NCA), affects contractile force in normal and pathological ventricular myocytes (VMs) as well as in isolated hearts. VMs were isolated from mice either subjected to isoprenaline-infusion (ISO; 30 lg/g per day) or to vehicle (0.9% NaCl) for 5 days. Sarcomere shortening and Ca 2+ transients were simultaneously measured using the IonOptix system. Force of contraction of isolated hearts was measured by a Langendorff-perfusion system. NCA increased peak sarcomere shortening by + 40-200% in a concentration-dependent manner (EC 50 55lM).EfficacyandpotencydidnotdifferbetweennormalandchronicISOVMs,despitethefactthatthelatterdisplayedamarkedlydiminishedinotropicresponsetoacuteb−adrenergicstimulationwithISO(1lM).NCA(60lM)increasedpeaksarcomereshorteningandCa2+transientamplitudeby55 lM). Efficacy and potency did not differ between normal and chronic ISO VMs, despite the fact that the latter displayed a markedly diminished inotropic response to acute b-adrenergic stimulation with ISO (1 lM). NCA (60 lM) increased peak sarcomere shortening and Ca 2+ transient amplitude by 55lM).EfficacyandpotencydidnotdifferbetweennormalandchronicISOVMs,despitethefactthatthelatterdisplayedamarkedlydiminishedinotropicresponsetoacuteb−adrenergicstimulationwithISO(1lM).NCA(60lM)increasedpeaksarcomereshorteningandCa2+transientamplitudeby200% and $120%, respectively, suggesting effects on both myofilament Ca 2+ sensitivity and sarcoplasmic reticulum (SR) Ca 2+ cycling. Importantly, NCA did not affect diastolic Ca 2+ or SR Ca 2+ content, as assessed by rapid caffeine application. NCA (45 lM) increased force of contraction by 30% in isolated hearts. In conclusion, NCA increased contractile force in normal and b-adrenergically desensitized VMs as well as in isolated mouse hearts. This profile warrants further investigations of this HNO donor in the context of heart failure.
British Journal of Pharmacology, 1988
Acetylcholine (ACh, 0.03-3.0 pM) induced a dose-dependent vasodilatation in the isolated Langendorff-perfused heart of the rabbit. The vasodilatation was mimicked by exogenous nitric oxide (NO, 0.045-4.5 nmol). 2 There was no detectable vascular relaxing activity in the cardiac effluent when these concentrations of ACh or NO were injected through the heart, even in the presence of an infusion of superoxide dismutase (SOD). 3 Acetylcholine (0.03-3.0 uM), however, induced the release into the cardiac effluent of a material which produced a chemiluminescent signal when reacted with ozone, a response which could be mimicked with exogenous NO (0.045-4.5 nmol) injected through the heart. 4 The effects of ACh, but not those of NO, were antagonized by atropine (2pM). Prostacyclin (1 yM) injected through the heart induced vasodilatation without the release of a biologically active or chemiluminescent material. 5 During passage through the heart, >99% of the biological activity of exogenous NO disappeared, whereas there was approximately 50% reduction of its chemiluminescent response. This indicates complete transformation into a mixture containing approximately 50% NO2-and 50% of other non-chemiluminescent material(s), presumably NO3-. 6 This study suggests that ACh induces endothelium-dependent vasodilatation in the coronary circulation through the release of the endogenous nitrovasodilator, NO, which is rapidly converted to N02 and N03.
Proceedings of the National Academy of Sciences, 2001
The physiologic activity and mechanism of action of NO ؊ in vivo remains unknown. The NO ؊ generator Angeli's salt (AS, Na2N2O3) was administered to conscious chronically instrumented dogs, and pressure-dimension analysis was used to discriminate contractile from peripheral vascular responses. AS rapidly enhanced left ventricular contractility and concomitantly lowered cardiac preload volume and diastolic pressure (venodilation) without a change in arterial resistance. There were no associated changes in arterial or venous plasma cGMP. The inotropic response was similar despite reflex blockade with hexamethonium or volume reexpansion, indicating its independence from baroreflex stimulation. However, reflex activation did play a major role in the selective venodilation observed under basal conditions. These data contrasted with the pure NO donor diethylamine͞NO, which induced a negligible inotropic response and a more balanced veno͞arterial dilation. AS-induced positive inotropy, but not systemic vasodilatation, was highly redox-sensitive, being virtually inhibited by coinfusion of N-acetyl-L-cysteine. Cardiac inotropic signaling by NO ؊ was mediated by calcitonin gene-related peptide (CGRP), as treatment with the selective CGRP-receptor antagonist CGRP-(8 -37) prevented this effect but not systemic vasodilation. Thus, NO ؊ is a redox-sensitive positive inotrope with selective venodilator action, whose cardiac effects are mediated by CGRP-receptor stimulation. This fact is evidence linking NO ؊ to redox-sensitive cardiac contractile modulation by nonadrenergic͞noncholinergic peptide signaling. Given its cardiac and vascular properties, NO ؊ may prove useful for the treatment of cardiovascular diseases characterized by cardiac depression and elevated venous filling pressures.
AJP: Heart and Circulatory Physiology, 2007
Vasostatins (VSs) are vasoactive peptides derived from chromogranin A (CgA), a protein contained in secretory granules of chromaffin and other cells. The negative inotropic effect and the reduction of isoproterenol-dependent inotropism induced by VSs in the heart, suggest that they have an anti-adrenergic function. However, the mechanisms of action of VSs need further investigation. Our study aims at defining the signaling pathways activated by VS-1 in mammalian ventricular myocardium and in cultured endothelial cells that lead to the modulation of cardiac contractility.