Reduction of the NO-mediated response in the rat aorta by metalloporphyrins

2000 ◽  
Vol 78 (6) ◽  
pp. 457-461 ◽  
Author(s):  
Hendrik J Vreman ◽  
Guido R MM Haenen ◽  
David K Stevenson ◽  
Aalt Bast
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Carbon Monoxide ◽  
Aortic Ring ◽  
Rat Aorta ◽  
Ring System ◽  
Zinc Protoporphyrin ◽  
Maximal Effect

Metalloporphyrins (MPs) have been found to affect the production of carbon monoxide (CO) and nitric oxide (NO). Unlike that for CO, little is known about the mechanism of action of MPs on the NO system. We determined the in vitro ability of ferrous protoporphyrin (heme, FePP), zinc protoporphyrin (ZnPP), and bilirubin (BR) to scavenge NO. Heme and ZnPP were studied in the rat aortic ring system for their ability to affect phenylephrine-induced contraction and methacholine-stimulated relaxation. Heme was found to be a good NO scavenger with a ks= 0.53 ± 0.19 x 104M-1·s-1(n = 6). ZnPP and BR did not scavenge NO. Neither heme nor ZnPP treatment affected the phenylephrine response as measured by -logEC50and the maximal effect. However, heme and ZnPP treatments decreased the -logEC50and the maximal effects of methacholine, therefore decreasing vasorelaxation. We conclude that when ZnPP is administered in vivo blood pressure should be carefully monitored.Key words: carbon monoxide, heme, NO scavenger, vasorelaxation, zinc protoporphyrin.

scholarly journals Heme proteins mediate the conversion of nitrite to nitric oxide in the vascular wall

2008 ◽  
Vol 295 (2) ◽  
pp. H499-H508 ◽  
Author(s):  
Wael F. Alzawahra ◽  
M. A. Hassan Talukder ◽  
Xiaoping Liu ◽  
Alexandre Samouilov ◽  
Jay L. Zweier
Keyword(s):  
Nitric Oxide ◽  
Heme Proteins ◽  
Soluble Guanylyl Cyclase ◽  
Vascular Wall ◽  
Rat Aorta ◽  
No Production ◽  
Paramagnetic Resonance ◽  
Physiological Importance

Nitric oxide (NO) has been shown to be the endothelium-derived relaxing factor (EDRF), and its impairment contributes to a variety of cardiovascular disorders. Recently, it has been recognized that nitrite can be an important source of NO; however, questions remain regarding the activity and mechanisms of nitrite bioactivation in vessels and its physiological importance. Therefore, we investigated the effects of nitrite on in vivo hemodynamics in rats and in vitro vasorelaxation in isolated rat aorta under aerobic conditions. Studies were performed to determine the mechanisms by which nitrite is converted to NO. In anesthetized rats, nitrite dose dependently decreased both systolic and diastolic blood pressure with a threshold dose of 10 μM. Similarly, nitrite (10 μM-2 mM) caused vasorelaxation of aortic rings, and NO was shown to be the intermediate factor responsible for this activity. With the use of electrochemical as well as electron paramagnetic resonance (EPR) spectroscopy techniques NO generation was measured from isolated aortic vessels following nitrite treatment. Reduction of nitrite to NO was blocked by heating the vessel, suggesting that an enzymatic process is involved. Organ chamber experiments demonstrated that aortic relaxation induced by nitrite could be blocked by both hemoglobin and soluble guanylyl cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). In addition, both electrochemical and EPR spin-trapping measurements showed that ODQ inhibits nitrite-mediated NO production. These findings thus suggest that nitrite can be a precursor of EDRF and that sGC or other heme proteins inhibited by ODQ catalyze the reduction of nitrite to NO.

scholarly journals The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects

2021 ◽  
Vol 14 (8) ◽  
pp. 799
Author(s):  
Magdalena Kotańska ◽  
Monika Kubacka ◽  
Marek Bednarski ◽  
Noemi Nicosia ◽  
Małgorzata Szafarz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Vessels ◽  
Heart Function ◽  
Oxidative Potential ◽  
Antioxidant Power ◽  
Vascular Dilatation ◽  
Ferric Reducing Antioxidant Power

GPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of selective GPR18 receptor ligands, namely PSB-KD-107 (agonist) and PSB-CB-92 (antagonist), on blood pressure, electrocardiogram (ECG), and vascular dilatation in vitro and in vivo, as well as their anti-oxidative potential in in vitro ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical (DPPH) assays. Our results clearly show that PSB-KD-107 dilates blood vessels. This effect is related to its activation of GPR18 as it can be blocked by the GPR18 antagonist PSB-CB-92. Moreover, our finding confirms the presence of GPR18 in blood vessels. The mechanism of the vasorelaxant activity of PSB-KD-107 is mainly related to endothelial nitric oxide generation; however, we cannot exclude additional nitric oxide-independent mechanisms or a direct influence on K+ channels. PSB-KD-107 may affect blood pressure and heart function after a single administration; however, this effect was no longer observed after repeated administrations once daily for eight days. PSB-KD-107 does not affect platelet aggregation—an important feature considering the safety of its administration. PSB-KD-107 also shows a significant anti-oxidant effect and further studies of its antioxidant activity in vivo are justified.

Roles of Carbon Monoxide in Leukocyte and Platelet Dynamics in Rat Mesentery during Sevoflurane Anesthesia

2001 ◽  
Vol 95 (1) ◽  
pp. 192-199 ◽  
Author(s):  
Hiroshi Morisaki ◽  
Tomihiro Katayama ◽  
Yoshifumi Kotake ◽  
Masaharu Ito ◽  
Takuya Tamatani ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Carbon Monoxide ◽  
Protoporphyrin Ix ◽  
Heme Oxygenase 1 ◽  
Zinc Protoporphyrin ◽  
Sevoflurane Anesthesia ◽  
Mechanically Ventilated ◽  
Rat Mesentery ◽  
Platelet Dynamics

Background Heme oxygenase 1 (HO-1), induced by a variety of stressors, provides endogenous carbon monoxide (CO) and bilirubin, both of which play consequential roles in organs. The current study aimed to examine whether induction of HO-1 and its by-products modulated endothelial interaction with circulating leukocytes and platelets evoked by sevoflurane anesthesia in vivo. Methods Rats, pretreated with or without hemin, were anesthetized with sevoflurane in 100% O2, and lungs were mechanically ventilated. Platelets labeled with carboxyfluorescein diacetate succinimidyl ester and leukocyte behavior in mesenteric venules were visualized during sevoflurane anesthesia at 1,000 frames/s using intravital ultrahigh-speed intensified fluorescence videomicroscopy. To examine the mechanisms for the effects of HO-1 on leukocyte and platelet behavior, these studies were repeated with superfusion of either CO, bilirubin, or Nomega-nitro-L-arginine methyl ester (L-NAME). Results As reported previously, the elevation of sevoflurane concentration evoked adhesive responses of leukocytes, concurrent with platelet margination and rolling. Pretreatment with hemin, a HO-1 inducer, prevented such sevoflurane-elicited changes in the microvessels. These changes were restored by zinc protoporphyrin IX, a HO inhibitor, and repressed by CO but not by bilirubin. During sevoflurane anesthesia, however, nitric oxide suppression by L-NAME deteriorated microvascular flows irrespective of the presence or absence of the HO-1 induction. Conclusions These results indicate that endogenous CO via HO-1 induction attenuates sevoflurane-induced microvascular endothelial interactions with leukocytes and platelets, although local nitric oxide levels appear to dominate microvascular flow in situ.

Adventitia-derived nitric oxide in rat aortas exposed to endotoxin: cell origin and functional consequences

2000 ◽  
Vol 279 (6) ◽  
pp. H2743-H2751 ◽  
Author(s):  
Andrei L. Kleschyov ◽  
Bernard Muller ◽  
Thérèse Keravis ◽  
Marie-Elisabeth Stoeckel ◽  
Jean-Claude Stoclet
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Diseases ◽  
Early Stage ◽  
Rat Aorta ◽  
Paramagnetic Resonance ◽  
Dinitrosyl Iron ◽  
Functional Consequences ◽  
Resonance Spin

The role of adventitial cells in bacterial lipopolysaccharide (LPS)-induced vascular nitric oxide (NO) overproduction has been largely ignored. In rat aortas exposed to LPS in vitro or in vivo, it was found that adventitia contained the major part of NO synthase (NOS)-2 protein (Western blot and immunohistochemistry) and generated the largest amount of NO (electron paramagnetic resonance spin trapping). NOS-2 immunoreactive cells were mainly resident macrophages at an early stage (5 h, in vitro or in vivo) and fibroblasts at a later stage (20 h, in vitro). Adventitial NOS-2 activity largely accounted for 1) the relaxing effect of l-arginine in rings exposed to LPS in vivo, 2) generation of an “NO store” revealed by N-acetylcysteine-induced relaxation, and 3) formation of protein-bound dinitrosyl iron complexes in the medial layer of aortic rings exposed to LPS in vitro. In conclusion, the adventitia is a powerful source of NO triggered by LPS in the rat aorta. This novel source of NO has an important impact on smooth muscle function and might be implicated in various inflammatory diseases.

scholarly journals Zinc Protoporphyrin: A Metabolite with a Mission

1999 ◽  
Vol 45 (12) ◽  
pp. 2060-2072 ◽  
Author(s):  
Robert F Labbé ◽  
Hendrik J Vreman ◽  
David K Stevenson
Keyword(s):  
Bone Marrow ◽  
Carbon Monoxide ◽  
Competitive Inhibition ◽  
Iron Status ◽  
Preventive Measure ◽  
Degradation Pathway ◽  
Iron Nutrition ◽  
Zinc Protoporphyrin

Abstract Zinc protoporphyrin (ZnPP) is a normal metabolite that is formed in trace amounts during heme biosynthesis. The final reaction in the biosynthetic pathway of heme is the chelation of iron with protoporphyrin. During periods of iron insufficiency or impaired iron utilization, zinc becomes an alternative metal substrate for ferrochelatase, leading to increased ZnPP formation. Evidence suggests that this metal substitution is one of the first biochemical responses to iron depletion, causing increased ZnPP to appear in circulating erythrocytes. Because this zinc-for-iron substitution occurs predominantly within the bone marrow, the ZnPP/heme ratio in erythrocytes reflects iron status in the bone marrow. In addition, ZnPP may regulate heme catabolism through competitive inhibition of heme oxygenase, the rate-limiting enzyme in the heme degradation pathway that produces bilirubin and carbon monoxide. Physiological roles, especially relating to carbon monoxide and possibly nitric oxide production, have been suggested for ZnPP. Clinically, ZnPP quantification is valuable as a sensitive and specific tool for evaluating iron nutrition and metabolism. Diagnostic determinations are applicable in a variety of clinical settings, including pediatrics, obstetrics, and blood banking. ZnPP analytical methodologies for clinical studies are discussed. In addition to diagnostic tests and metabolic studies, ZnPP has a potential therapeutic application in controlling bilirubin formation in neonates as a preventive measure for hyperbilirubinemia. Biochemical research techniques, both in vivo and in vitro, are described for further studies into the role of ZnPP in metabolism and physiology.

N-acetyl-L-cysteine potentiates depressor response to captopril and enalaprilat in SHRs

1994 ◽  
Vol 267 (3) ◽  
pp. R767-R772 ◽  
Author(s):  
F. J. Ruiz ◽  
M. G. Salom ◽  
A. C. Ingles ◽  
T. Quesada ◽  
E. Vicente ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Sulfhydryl Groups ◽  
Vascular Effects ◽  
Converting Enzyme Inhibitors ◽  
Depressor Response ◽  
Antihypertensive Response

Recently, in vivo and in vitro studies have implicated nitric oxide as a mediator of the vascular effects of angiotensin-converting enzyme inhibitors (ACEIs). In the present study we hypothesized that N-acetyl-L-cysteine (NAC), by increasing the availability of reduced sulfhydryl groups, would enhance the antihypertensive response to the ACEIs captopril and enalaprilat by a mechanism dependent on nitric oxide. The experiments were performed on instrumented, indomethacin-pretreated, awake spontaneously hypertensive rats (SHRs). Thirty minutes after a bolus of captopril (10 mg/kg iv) was administered, blood pressure decreased from 167 +/- 5 to 147 +/- 6 mmHg (n = 8). The pretreatment with the donor of thiol groups NAC (300 mg/kg iv) potentiated the depressor response to captopril because blood pressure decreased from 172 +/- 3 to 139 +/- 4 mmHg (n = 6). At the dose of 60 micrograms/kg iv, the ACEI enalaprilat did not acutely modify the blood pressure of SHRs (from 172 +/- 5 to 167 +/- 4 mmHg; n = 6). However, when the SHRs were pretreated with NAC, the same dose of enalaprilat significantly reduced blood pressure from 176 +/- 5 to 151 +/- 5 mmHg (n = 6). This potentiation of the depressor response to ACEIs, due to NAC, was not observed when SHRs were pretreated with the nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 50 micrograms.kg-1.min-1 iv). The results of this study suggest that NAC, a donor of sulfhydryl groups, potentiates the antihypertensive response to captopril and enalaprilat in SHR by a nitric oxide-dependent mechanism.

Intramuscular gene transfer of CGRP inhibits neointimal hyperplasia after balloon injury in the rat abdominal aorta

2004 ◽  
Vol 287 (4) ◽  
pp. H1582-H1589 ◽  
Author(s):  
Wang Wang ◽  
Wei Sun ◽  
Xian Wang
Keyword(s):  
Nitric Oxide ◽  
Gene Transfer ◽  
Neointimal Hyperplasia ◽  
Rat Aorta ◽  
Nitric Oxide Donor ◽  
Protective Effects ◽  
Balloon Injury ◽  
Neointimal Formation

CGRP is a well-known neuropeptide that has various protective effects on cardiovascular system. Our previous studies have shown that CGRP inhibits vascular smooth muscle cell (VSMC) proliferation in vitro. The present study aimed to explore the role of the CGRP in neointimal formation after balloon injury in the rat aortic wall and the underlying mechanism. Gene transfer of CGRP was performed with the use of intramuscular electroporation in a balloon-injured rat aorta model. Apoptosis in VSMCs was determined by electrophoresis assessment of DNA fragmentation and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay. Overexpression of the CGRP gene significantly inhibited the neointimal formation after balloon injury compared with the mock transfer, as assessed by the intima-to-media ratio 14 days after balloon injury (29.2 ± 3.7% vs. 52.7 ± 5.4%; n = 9–12, P < 0.05). In addition, CGRP gene expression increased the number of apoptotic cells in the neointima in vivo 14 days after balloon injury. Similarly, the addition of bioactive CGRP and the nitric oxide donor induced similar apoptosis in cultured VSMCs. The antagonist of the CGRP1 receptor and inhibitors of cAMP-PKA and nitric oxide blocked CGRP-mediated apoptosis. Furthermore, CGRP gene transfer increased inducible nitric oxide synthase and p53 but decreased PCNA and Bcl-2 protein levels in balloon-injured rat aorta. Our data demonstrated that CGRP potently inhibited neointimal thickening in the rat aorta, at least in part through its distinct effects on apoptosis and proliferation of VSMCs both in vivo and in vitro. Therefore, delivery of the CGRP gene may have therapeutic implications in limiting vascular restenosis.

Endothelium-dependent vasorelaxation evoked by desmopressin and involvement of nitric oxide in rat aorta

1993 ◽  
Vol 264 (2) ◽  
pp. E203-E207 ◽  
Author(s):  
K. Yamada ◽  
M. Nakayama ◽  
H. Nakano ◽  
N. Mimura ◽  
S. Yoshida
Keyword(s):  
Nitric Oxide ◽  
Specific Inhibitor ◽  
Rat Aorta ◽  
Receptor Antagonists ◽  
Response Curves ◽  
V2 Vasopressin Receptor ◽  
In Vitro Effects ◽  
The Right

It is known that in vivo administration of desmopressin (DDAVP; a selective V2-vasopressin receptor agonist) results in prostacyclin-independent vasodilation. The in vitro effects of DDAVP and its mechanisms were examined using rat aortic strips. DDAVP from a concentration of 1 x 10(-9) M caused a concentration-dependent relaxation of the aorta precontracted with norepinephrine (10(-7) M) with intact endothelium. However, no relaxation was induced in aorta with the endothelium removed. The DDAVP-induced relaxation was not influenced by the presence of indomethacin but was inhibited by L-NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide (NO) synthesis. The inhibition by L-NMMA was reversed by the addition of L-arginine but not D-arginine. Further, the endothelium-dependent relaxation due to DDAVP was potentiated by superoxide dismutase, a scavenger of superoxide anions, and was inhibited by hemoglobin. DDAVP induced an increase in guanosine 3',5'-cyclic monophosphate levels in the aorta with endothelium but not in aorta without endothelium, and this was suppressed by L-NMMA and hemoglobin. The suppression by L-NMMA was also partially reversed by L-arginine but not by D-arginine. Two selective V2-receptor antagonists had no effect on the DDAVP-induced vasorelaxation. Selective V1-receptor antagonists (a peptidic and a nonpeptidic) caused a concentration-dependent but nonparallel shift to the right of the concentration-response curves to DDAVP. However, DDAVP did not affect the tension of the strip with or without endothelium in nonprecontracted aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension

2006 ◽  
Vol 291 (2) ◽  
pp. R481-R488 ◽  
Author(s):  
Jeffrey L. Segar ◽  
Robert D. Roghair ◽  
Emily M. Segar ◽  
Melissa C. Bailey ◽  
Thomas D. Scholz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Vascular Reactivity ◽  
Systemic Hypertension ◽  
Arterial Baroreflex ◽  
Vascular Responses ◽  
Early Gestation ◽  
Arterial Blood

Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces alterations in postnatal cardiovascular physiology, including hypertension. To determine whether autonomic function and systemic vascular reactivity are altered by in utero programming before the development of systemic hypertension, we examined arterial baroreflex function and in vivo hemodynamic and in vitro vascular responses to vasoactive agents in 10- to 14-day-old newborn lambs exposed to early gestation glucocorticoids. Dexamethasone (Dex, 0.28 mg·kg−1·day−1) or saline was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term 145 days), and lambs were allowed to deliver ( n = 6 in each group). Resting mean arterial blood pressure (MABP; 77 ± 1 vs. 74 ± 3 mmHg) and heart rate (HR; 249 ± 9 vs. 226 ± 21 beats/min) were similar in Dex-exposed and control animals, respectively. The arterial baroreflex curve, relating changes in HR to MABP, was significantly shifted toward higher pressure in the Dex-exposed lambs although no change in the sensitivity (gain) of the response was seen. In vivo changes in blood pressure in response to bolus doses of ANG II (20, 50, and 100 ng/kg) and phenylephrine (2, 5, and 10 μg/kg) were similar in the two groups. However, Dex lambs displayed greater decreases in MABP in response to ganglionic blockade with tetraethylammonium bromide (10 mg/kg; −30 ± 3 vs. −20 ± 3 mmHg, P < 0.05) and greater increases in MABP after nitric oxide synthase blockade with NG-nitro-l-arginine (25 mg/kg; 23 ± 3 vs. 13 ± 2 mmHg, P < 0.05) compared with control lambs. By in vitro wire myography, mesenteric and femoral artery microvessel contractile responses to KCl were similar, whereas responses to endothelin (in mesenteric) and norepinephrine (in femoral) were significantly attenuated in Dex lambs compared with controls. Femoral vasodilatory responses to forskolin and sodium nitroprusside were similar in the two groups ( n = 4). These findings suggest that resetting of the baroreflex, accompanied by increased sympathetic activity and altered nitric oxide-mediated compensatory vasodilatory function, may be important contributors to programming of hypertension.

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