scholarly journals Nitric oxide as a second messenger in parathyroid hormone-related protein signaling

2001 ◽  
Vol 170 (2) ◽  
pp. 433-440 ◽  
Author(s):  
L Kalinowski ◽  
LW Dobrucki ◽  
T Malinski
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Parathyroid Hormone ◽  
Smooth Muscles ◽  
Calcium Ionophore ◽  
No Production ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
No Release ◽  
Pthrp Receptor

Parathyroid hormone (PTH)-related protein (PTHrP) is produced in smooth muscles and endothelial cells and is believed to participate in the local regulation of vascular tone. No direct evidence for the activation of endothelium-derived nitric oxide (NO) signaling pathway by PTHrP has been found despite attempts to identify it. Based on direct in situ measurements, it is reported here for the first time that the human PTH/PTHrP receptor analogs, hPTH(1--34) and hPTHrP(1--34), stimulate NO release from a single endothelial cell. A highly sensitive porphyrinic microsensor with a response time of 0.1 ms and a detection limit of 1 nmol/l was used for the measurement of NO. Both hPTH(1--34) and hPTHrP(1--34) stimulated NO release at nanomolar concentrations. The peak concentration of 0.1 micromol/l hPTH(1--34)- and 0.1 micromol/l hPTHrP(1--34)-stimulated NO release was 175+/-9 and 248+/-13 nmol/l respectively. This represents about 30%--40% of maximum NO concentration recorded in the presence of (0.1 micromol/l) calcium ionophore. Two competitive PTH/PTHrP receptor antagonists, 10 micromol/l [Leu(11),d -Trp(12)]-hPTHrP(7--34)amide and 10 micromol/l [Nle(8,18),Tyr(34)]-bPTH(3--34)amide, were equipotent in antagonizing hPTH(1--34)-stimulated NO release; [Leu(11),d -Trp(12)]-hPTHrP(7--34)amide was more potent than [Nle(8,18),Tyr(34)]-bPTH(3--34)amide in inhibiting hPTHrP(1--34)-stimulated NO release. The PKC inhibitor, H-7 (50 micromol/l), did not change hPTH(1--34)- and hPTHrP(1--34)-stimulated NO release, whereas the combined effect of 10 micromol/l of the cAMP antagonist, Rp-cAMPS, and 50 micromol/l of the calmodulin inhibitor, W-7, was additive. The present studies show that both hPTH(1--34) and hPTHrP(1--34) activate NO production in endothelial cells. The activation of NO release is through PTH/PTHrP receptors and is mediated via the calcium/calmodulin pathway.

Abstract 318: Eicosapentaenoic Acid Improved Nitric Oxide Bioavailability and Reduced Nitroxidative Stress in Human Endothelial Cells in Contrast to Arachidonic Acid In Vitro

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Preston Mason ◽  
Hazem Dawoud ◽  
Samuel Sherratt ◽  
Peter Libby ◽  
Deepak L Bhatt ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Arachidonic Acid ◽  
Fatty Acid ◽  
Eicosapentaenoic Acid ◽  
Calcium Ionophore ◽  
High Dose ◽  
No Production ◽  
Time Points ◽  
No Release

Treatment with prescription, high dose, stable icosapent ethyl (IPE), which is eicosapentaenoic acid (EPA), an omega-3 fatty acid (O3FA), significantly reduced clinical events in high-risk patients with diabetes and other risk factors or cardiovascular disease (REDUCE-IT). Previous studies suggest that the benefits of EPA correlate positively with its levels and ratio to arachidonic acid (AA) in circulation. Unlike EPA, AA is an omega-6 fatty acid (O6FA) that, along with its metabolites, contributes to inflammation and diabetes. One mechanism of benefit of an increased EPA to AA ratio may be improved endothelial cell (EC) function, as evidenced by increased nitric oxide (NO) release and decreased nitroxidative (ONOO – ) stress. In this study, human umbilical vein endothelial cells (HUVECs) were pretreated with EPA or AA at equimolar levels (10 μM) at various time points (4-24 hr) in 5% FBS. Following treatment, the cells were stimulated with calcium ionophore and assayed for the ratio of NO and ONOO – release, an indicator of eNOS coupling, using tandem porphyrinic nanosensors. ECs treated with EPA had significantly greater NO release following stimulation compared with vehicle at all time points, including 17% and 21% at 4 and 24 hr, respectively (p<0.05 and p<0.01) without changes in eNOS expression. By contrast, AA did not significantly improve NO production. ECs treated with EPA also showed a non-significant reduction in ONOO - release by 10% at 4 hr and 14% at 24 hr. EPA, but not AA, increased NO/ONOO - release ratio by 42% (4.03 ± 0.06 vs 2.83 ± 0.05; p <0.01) by 24 hr. Thus, EPA increased NO bioavailability in human ECs, unlike AA, due to improved eNOS coupling and reduced oxidative stress. These findings support a preferential benefit of EPA on endothelial function as compared to AA and supports further investigation.

Parathyroid Hormone–Related Protein Upregulates Interleukin-1β–Induced Nitric Oxide Synthesis

Hypertension ◽  
1997 ◽  
Vol 30 (4) ◽  
pp. 922-927 ◽  
Author(s):  
Bingbing Jiang ◽  
Shigeto Morimoto ◽  
Jin Yang ◽  
Keisuke Fukuo ◽  
Atsushi Hirotani ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Parathyroid Hormone ◽  
Interleukin 1Β ◽  
Nitric Oxide Synthesis ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein

Effects of homocysteine on endothelial nitric oxide production

2000 ◽  
Vol 279 (4) ◽  
pp. F671-F678 ◽  
Author(s):  
Xiaohui Zhang ◽  
Hong Li ◽  
Haoli Jin ◽  
Zachary Ebin ◽  
Sergey Brodsky ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Redox State ◽  
Calcium Ionophore ◽  
No Production ◽  
Cellular Redox ◽  
A Cell ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Peroxynitrite Scavengers

Hyperhomocysteinemia (HHCy) is an independent and graded cardiovascular risk factor. HHCy is prevalent in patients with chronic renal failure, contributing to the increased mortality rate. Controversy exists as to the effects of HHCy on nitric oxide (NO) production: it has been shown that HHCy both increases and suppresses it. We addressed this problem by using amperometric electrochemical NO detection with a porphyrinic microelectrode to study responses of endothelial cells incubated with homocysteine (Hcy) to the stimulation with bradykinin, calcium ionophore, or l-arginine. Twenty-four-hour preincubation with Hcy (10, 20, and 50 μM) resulted in a gradual decline in responsiveness of endothelial cells to the above stimuli. Hcy did not affect the expression of endothelial nitric oxide synthase (eNOS), but it stimulated formation of superoxide anions, as judged by fluorescence of dichlorofluorescein, and peroxynitrite, as detected by using immunoprecipitation and immunoblotting of proteins modified by tyrosine nitration. Hcy did not directly affect the ability of recombinant eNOS to generate NO, but oxidation of sulfhydryl groups in eNOS reduced its NO-generating activity. Addition of 5-methyltetrahydrofolate restored NO responses to all agonists tested but affected neither the expression of the enzyme nor formation of nitrotyrosine-modified proteins. In addition, a scavenger of peroxynitrite or a cell-permeant superoxide dismutase mimetic reversed the Hcy-induced suppression of NO production by endothelial cells. In conclusion, electrochemical detection of NO release from cultured endothelial cells demonstrated that concentrations of Hcy >20 μM produce a significant indirect suppression of eNOS activity without any discernible effects on its expression. Folates, superoxide ions, and peroxynitrite scavengers restore the NO-generating activity to eNOS, collectively suggesting that cellular redox state plays an important role in HCy-suppressed NO-generating function of this enzyme.

scholarly journals Vasorelaxant Properties of Parathyroid Hormone-Related Protein in the Mouse: Evidence for Endothelium Involvement Independent of Nitric Oxide Formation1

Endocrinology ◽  
1999 ◽  
Vol 140 (5) ◽  
pp. 2077-2083 ◽  
Author(s):  
Roy L. Sutliff ◽  
Craig S. Weber ◽  
Jin Qian ◽  
Marion L. Miller ◽  
Thomas L. Clemens ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Parathyroid Hormone ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein

Parathyroid hormone-related protein-(1-34) inhibits intrinsic pump activity of isolated murine lymph vessels

2001 ◽  
Vol 281 (1) ◽  
pp. H60-H66 ◽  
Author(s):  
Risuke Mizuno ◽  
Nobuyuki Ono ◽  
Toshio Ohhashi
Keyword(s):  
Parathyroid Hormone ◽  
Smooth Muscles ◽  
Related Protein ◽  
Vascular Smooth Muscles ◽  
Lymph Vessels ◽  
Parathyroid Hormone Related Protein ◽  
Low Concentrations ◽  
Pump Activity ◽  
Endogenous Nitric Oxide ◽  
High Concentrations

Parathyroid hormone-related protein (PTHrP) was originally found as a tumor-derived vasoactive factor and has also been known to produce significant relaxation of vascular smooth muscles. Thus effects of PTHrP-(1-34), a PTH receptor-binding domain, on spontaneous lymphatic pump activity was investigated in isolated pressurized lymph vessels of mice. Low concentrations (1 × 10−10 and 3 × 10−10 M) of PTHrP-(1-34) dilated lymph vessels and reduced the frequency of pump activity, whereas high concentrations (1 × 10−9 to 1 × 10−8 M) of PTHrP-(1-34) caused dilation with cessation of the lymphatic pump activity. N ω-nitro-l-arginine methyl ester (l-NAME; 3 × 10−5 M) but not indomethacin (1 × 10−5 M) significantly reduced the PTHrP-(1-34)-induced inhibitory responses of the lymphatic pump activity. In the presence of l-NAME (3 × 10−5 M) and l-arginine (1 × 10−3 M), the l-NAME-induced inhibition in the PTHrP-(1-34)-mediated responses was significantly reduced. Glibenclamide (1 × 10−6 M) significantly suppressed the inhibitory responses of the lymphatic pump activity induced by PTHrP-(1-34) and S-nitroso- N-acetyl-penicillamine. The PTHrP-(1-34)-mediated inhibitory responses were significantly reduced by treatment with PTHrP-(7-34) (1 × 10−7 M). These results suggest that PTHrP-(1-34) inhibits spontaneous pump activity of the isolated lymph vessels via PTH receptors and that production and release of endogenous nitric oxide and activation of ATP-sensitive K+ channels in the lymph vessels contribute to the PTHrP-(1-34)-mediated inhibitory responses of the lymphatic pump activity.

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