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Departments of 1 Pediatrics and 2 Pharmacology, The University of Iowa, Iowa City, Iowa 52242
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Peroxynitrite-induced relaxation of isolated vessels may involve the formation of S-nitrosothiols. This study characterized the hemodynamic effects of systemically injected peroxynitrite in pentobarbital sodium-anesthetized rats and determined whether these effects were due to the formation of S-nitrosothiols. We utilized L-penicillamine, which attenuates the hemodynamic effects of systemically injected S-nitrosothiols. The hemodynamic effects of peroxynitrite and the S-nitrosothiols L-S-nitrosocysteine, L-S-nitrosoglutathione, and S-nitrosoalbumin were determined before and 25 min after the administration of L-penicillamine or saline. Peroxynitrite and the S-nitrosothiols produced dose-dependent reductions in mean arterial pressure and mesenteric and hindquarter vascular resistances. The hypotensive and vasodilator effects of the S-nitrosothiols were significantly reduced by L-penicillamine. In contrast, the hemodynamic actions of peroxynitrite were unaffected by L-penicillamine. Therefore, peroxynitrite produces hypotensive and vasodilator responses in anesthetized rats that are unlikely to be due to the formation of circulating S-nitrosothiols. The mechanisms by which peroxynitrite produces vasodilatation in vivo remain to be determined.
nitric oxide; S-nitrosocysteine; S-nitrosoglutathione; S-nitrosoalbumin; vasodilatation
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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THE REACTION OF NITRIC OXIDE with superoxide anion results in the formation of peroxynitrite (5, 14). In vitro cellular production of peroxynitrite has been demonstrated for rat alveolar macrophages (15), rat Kupffer cells (35), bovine endothelial cells (21), rat vascular smooth muscle (8), and human neutrophils (10). Moreover, peroxynitrite formation has been demonstrated in human inflammatory diseases (1, 2, 7, 20, 23). The biological effects of peroxynitrite include vascular relaxation (24, 34, 37) and inhibition of platelet aggregation (26). These effects of peroxynitrite may be due to its potent oxidant properties (4, 28), its ability to nitrate free and protein-associated tyrosines and other phenolic compounds (6, 16), or its capacity to form S-nitrosothiols via nitrosylation of reduced thiols (26, 37).
We have reported that the systemic injection of a 10 µmol/kg dose of peroxynitrite produces substantial falls in mean arterial blood pressure that were associated with reductions in vascular resistances in pentobarbital sodium-anesthetized rats (19, 22). At present, the mechanisms by which peroxynitrite produces its vasodilator effects on systemic injection have not been determined. On the basis of the in vitro experiments described above (24, 26, 34, 37), it is possible that the hemodynamic effects of peroxynitrite involve the formation of biologically active S-nitrosothiols, such as S-nitrosocysteine or S-nitrosoglutathione.
We have provided preliminary evidence that
L-
,-dimethylcysteine (L-penicillamine,
500 µmol/kg iv) markedly attenuates the vasodilator effects of the
S-nitrosothiol
L-S-nitrosocysteine in
anesthetized rats (3). The mechanism by which
L-penicillamine attenuates the vasodilator effects of
L-S-nitrosocysteine may involve the blockade of S-nitrosothiol
recognition sites in the vasculature (11, 32). The aims of the present
study were to determine 1) the
dose-dependent hemodynamic effects produced by the systemic injection
of peroxynitrite in pentobarbital sodium-anesthetized rats and
2) whether the vasodilator actions
of this compound involve the formation of biologically active
S-nitrosothiols in the circulation. In
these studies, we examined the dose-dependent effects of peroxynitrite, L-S-nitrosocysteine,
L-S-nitrosoglutathione,
and S-nitrosoalbumin before and after
the administration of either L-penicillamine or saline. To
evaluate the potential contribution of the decomposition products of
peroxynitrite, we also determined the hemodynamic effects produced by
the injection of equal volumes of decomposed peroxynitrite solutions.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Rats. The protocols described herein were approved by the University of Iowa Institutional Animal Care and Use Committee. These studies used male Sprague-Dawley rats (Madison, WI) weighing 300-400 g.
Surgical procedures. The rats were anesthetized with pentobarbital sodium (50 mg/kg ip), and catheters (PE-50) were placed in the left femoral artery and femoral vein for the measurement of mean arterial pressure and administration of chemicals, respectively. Supplementary pentobarbital sodium (3-5 mg iv) was given as required to maintain anesthesia. A midline laparotomy was performed, and miniature pulsed Doppler flow probes were placed on the superior mesenteric artery and the descending aorta for the measurement of mesenteric and hindquarter blood flows and for the determination of mesenteric and hindquarter vascular resistances (11). Details of the Doppler technique, including construction of the probes, the reliability of the method for estimation of flow velocity, and quantitative determination of percentage changes in vascular resistance, have been described by Haywood et al. (13). The arterial catheter was connected to a Beckman Dynograph-coupled pressure transducer (Cobe Laboratories) for measurement of pulsatile arterial pressure and mean arterial pressure. The wire leads from the flow probes were connected to a Doppler flowmeter (Department of Bioengineering, the University of Iowa, Iowa City, IA).
Experimental protocols. One group of rats (n = 6) received injections of L-S-nitrosocysteine (12.5-200 nmol/kg iv) followed by injections of peroxynitrite (0.5-10 µmol/kg iv). Each injection was given at least 1 min after the hemodynamic effects of the preceding dose had subsided. The animals were then injected with L-penicillamine (500 µmol/kg iv) and allowed 25-30 min to recover from the acute hemodynamic effects produced by the thiol. The rats were then injected with the above doses of L-S-nitrosocysteine and peroxynitrite. A dose of L-S-nitrosocysteine (200 nmol/kg iv) was given after the second set of peroxynitrite doses to ensure that L-penicillamine was still blocking the hemodynamic effects of the S-nitrosothiol.
In a second group of rats, the hemodynamic effects of chemically synthesized (n = 4) or commercially prepared (n = 6) L-S-nitrosoglutathione (50-200 nmol/kg) were determined before and after the administration of L-penicillamine (500 µmol/kg iv).
In a third group of rats (n = 9), the hemodynamic effects of S-nitrosoalbumin (350-1,400 nmol/kg) were determined before and after the administration of L-penicillamine (1,000 µmol/kg iv). To determine the effects of the higher dose of L-penicillamine on peroxynitrite-mediated hemodynamic changes, in a separate group of rats (n = 5), peroxynitrite dose responses (1-10 µmol/kg) were investigated before and after the administration of L-penicillamine (1,000 µmol/kg).
In a fourth group of rats, the hemodynamic effects of L-S-nitrosocysteine or peroxynitrite were determined before and after the injection of saline (0.9% wt/vol, NaCl).
In a fifth group of rats (n = 4), the hemodynamic effects produced by the injection of volumes of decomposed peroxynitrite that were equivalent to those of the injected peroxynitrite were examined.
Chemicals. Pentobarbital sodium for
anesthesia and sterile saline for the dilution of chemicals and
intravenous administration were obtained from Abbott Laboratories
(Chicago, IL). Sodium nitrite, L-cysteine,
L-glutathione, L-penicillamine,
L-S-nitrosoglutathione, and bovine serum albumin were from Sigma Chemical (St. Louis, MO).
Sterile saline or Millipore filtered water was used for the preparation
of all solutions.
L-S-nitrosocysteine and
L-S-nitrosoglutathione were synthesized just before use by reacting 1-ml solutions of 0.2 M
sodium nitrite (pH 
3) and 0.2 M L-cysteine or
L-glutathione, resulting in stable 0.1 M stock solutions of
the respective nitrosothiols (11). Nitrosoalbumin was synthesized as
described previously (25). Briefly, bovine serum albumin was dissolved
to a concentration of 150 mg/ml in buffer containing 100 mM NaCl, 10 µM bathocuproinedisulfonate, 10 µM deferoxamine mesylate, and 30 mM
sodium phosphate, pH 7.4. Dithiothreitol (10 mM) and EDTA (10 mM) were
added to reduce the albumin thiols and chelate free metals,
respectively. After 1 h at room temperature, the solution was passed
over a Sephadex G-25 column (Pharmacia, Piscataway, NJ) to remove the
dithiothreitol and EDTA.
S-nitrosylation of the albumin thiol
was executed via incubation with a fivefold molar excess of
n-butyl nitrite (Sigma) at 37°C
for 10-15 min. The solution was again passaged over a Sephadex
G-25 column, and the concentration of nitrosoalbumin was determined
spectrophotometrically [molar absorptivity (
) at 334 nm
(334) = 870 M
1 · cm1].
Peroxynitrite was synthesized in a quench flow reactor as described previously (5) and stored in 0.3 N NaOH at 
70°C. The
concentration of peroxynitrite was determined spectrophotometrically
(302 = 1,670 M1 · cm1).
During the course of each experimental protocol, the nitrosothiols and
peroxynitrite were kept on ice in the dark to minimize decomposition. For the experiments utilizing decomposed peroxynitrite, a sample of
peroxynitrite was left at room temperature for 2-3 wk, after which
no further absorbance was noted at 302 nm.
Statistics. Data are expressed as means ± SE. Vascular resistances were calculated by the following formula: resistance = mean arterial pressure/blood flow. The blood flow values were taken at the peak changes in mean arterial pressure. The maximal changes in mean arterial pressure and vascular resistances were calculated as the percentage change in these variables. The total changes in mean arterial pressure were also determined by calculating the area under the curve. The single SE term on each of the dose-response curves was determined by the formula (EMS/n)1/2, where EMS is the error mean square term from the analysis of variance (ANOVA) and n is the number of animals per group. The data were analyzed by repeated-measures ANOVA followed by Student's modified t-test with Bonferroni correction for multiple comparisons between means using the modified error mean square term from the ANOVA as previously described (11).
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Effects of L-penicillamine on baseline hemodynamic parameters. The resting hemodynamic values before and after the administration of L-penicillamine are summarized in Table 1. L-Penicillamine produced transient reductions in mean arterial pressure and mesenteric and hindquarter vascular resistances. After the administration of 500 µmol/kg of L-penicillamine, the baseline hemodynamic variables remained unchanged. After the administration of 1,000 µmol/kg of L-penicillamine, however, the mesenteric and hindquarter vascular resistances were significantly increased without change in the mean arterial pressure.
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Hemodynamic effects of L-S-nitrosocysteine, L-S-nitrosoglutathione, S-nitrosoalbumin, and peroxynitrite before and after administration of L-penicillamine. A typical example of the hemodynamic effects produced by the administration of L-S-nitrosocysteine (100 nmol/kg) in a pentobarbital sodium-anesthetized rat, before and after the administration of L-penicillamine (500 µmol/kg), is shown in Fig. 1. L-S-nitrosocysteine produced pronounced falls in mean arterial pressure and relatively minor changes in mesenteric and hindquarter blood flow velocities. Taken together, these changes resulted in substantial falls in mesenteric and hindquarter resistance. The hypotensive and vasodilator effects of L-S-nitrosocysteine were substantially diminished after the administration of L-penicillamine.
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A summary of the hemodynamic effects produced by L-S-nitrosocysteine before and after the administration of L-penicillamine is shown in Fig. 2. L-S-nitrosocysteine produced dose-dependent reductions in mean arterial pressure and mesenteric and hindquarter vascular resistance. These responses were substantially smaller after the administration of L-penicillamine. In addition, the total hypotension produced by L-S-nitrosocysteine, as measured by the area under the curve, was markedly reduced by L-penicillamine (Fig. 2).
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A summary of the hemodynamic effects produced by L-S-nitrosoglutathione before and after the administration of L-penicillamine is shown in Fig. 3. The responses to chemically synthesized versus commercially prepared L-S-nitrosglutathione were similar. Therefore, the data presented have been pooled from both sources of L-S-nitrosoglutathione. L-S-nitrosoglutathione produced dose-dependent reductions in mean arterial pressure and mesenteric and hindquarter vascular resistance. These responses were substantially smaller after the administration of L-penicillamine. In addition, the total hypotension produced by L-S-nitrosoglutathione, as measured by the area under the curve, was markedly reduced by L-penicillamine (Fig. 3).
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The hemodynamic responses to S-nitrosoalbumin were minimally inhibited by 500 µmol/kg L-penicillamine (data not shown). Therefore, the studies were repeated using 1,000 µmol/kg L-penicillamine. A summary of the hemodynamic effects produced by S-nitrosoalbumin before and after the administration of L-penicillamine (1,000 µmol/kg) is shown in Fig. 4. S-nitrosoalbumin produced dose-dependent reductions in mean arterial pressure and mesenteric and hindquarter vascular resistance. The hypotensive and hindquarter vasodilatory responses produced by S-nitrosoalbumin were significantly attenuated after the administration of L-penicillamine, whereas the mesenteric vasodilatory responses remained unaffected. Moreover, the total hypotension produced by S-nitrosoalbumin, as measured by the area under the curve, was markedly reduced by L-penicillamine (Fig. 4).
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A typical example of the hemodynamic effects produced by the administration of peroxynitrite (5 µmol/kg) in a pentobarbital sodium-anesthetized rat before and after the administration of L-penicillamine (500 µmol/kg) is shown in Fig. 1. Peroxynitrite produced substantial falls in mean arterial pressure and relatively minor changes in mesenteric and hindquarter blood flow velocities. Taken together, these changes resulted in substantial falls in mesenteric and hindquarter resistance. Unlike L-S-nitrosocysteine, the hypotensive and vasodilator effects of peroxynitrite were unaltered after the administration of L-penicillamine.
A summary of the hemodynamic effects of peroxynitrite before and after the administration of L-penicillamine (500 µmol/kg) is shown in Fig. 5. Peroxynitrite produced dose-dependent reductions in mean arterial pressure and mesenteric and hindquarter vascular resistances. The hemodynamic effects of these doses of peroxynitrite were comparable to those produced by L-S-nitrosocysteine, L-S-nitrosoglutathione, and S-nitrosoalbumin. In contrast to L-S-nitrosocysteine and L-S-nitrosoglutathione, the hemodynamic effects of peroxynitrite were not attenuated by 500 µmol/kg L-penicillamine (Fig. 5). Because the peroxynitrite dose-response curve was established after that for L-S-nitrosocysteine, it was possible that the effects of L-penicillamine had subsided. However, the hemodynamic effects of 200 nmol/kg L-S-nitrosocysteine, given after the doses of peroxynitrite, were still markedly attenuated (P < 0.05 for all comparisons). Moreover, in contrast to S-nitrosoalbumin, the hemodynamic effects produced by the systemic administration of peroxynitrite were also unaffected after the administration of 1,000 µmol/kg L-penicillamine (data not shown). Furthermore, human serum albumin, treated with peroxynitrite and systemically administered, produced only minimal changes in mean arterial pressure and mesenteric and hindquarter vascular resistances (data not shown).
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Hemodynamic effects of decomposed peroxynitrite. The systemic administration of volumes of decomposed peroxynitrite, equivalent to peroxynitrite doses of 1-10 µmol/kg, resulted in minor changes in hemodynamic parameters. For example, the administration of a volume equal to the highest dose of peroxynitrite (10 µmol/kg) produced decreases in mean arterial pressure, mesenteric resistance, and hindquarter resistance of 14 ± 3, 11 ± 6, and 22 ± 5%, respectively.
Hemodynamic effects of L-S-nitrosocysteine and peroxynitrite before and after administration of saline. The hemodynamic effects produced by L-S-nitrosocysteine (12.5-200 nmol/kg, n = 6) or peroxynitrite (0.5-10 µmol/kg, n = 6) were similar before and after the administration of saline (data not shown).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The systemic administration of peroxynitrite produced dose-dependent
reductions in mean arterial pressure that were accompanied by
dose-dependent and pronounced decreases in vascular resistances in the
mesenteric and hindquarter beds. These findings suggest that the
vasodilator effects of peroxynitrite are mediated principally by
relaxation of resistance vessels in the peripheral vasculature. In
contrast, decomposed peroxynitrite produced minor changes in these
hemodynamic parameters, suggesting that the stable decomposition products of peroxynitrite, such as nitrate and nitrite, make a minimal
contribution to the hemodynamic effects produced by the injection of
peroxynitrite. The relaxant effect of peroxynitrite on isolated vessels
is not endothelium dependent (24, 26). As such, the vasodilator effects
of peroxynitrite may be mediated by its direct action on the vascular
smooth muscle. Peroxynitrite has a calculated biological half-life of
~0.6 s (29). Based on a cardiac output of 40 ml · min1 · 100 g1 and a circulating volume
of 20 ml, the circulatory time for a 300-g rat would be 10 s, or 15 half-lives. Therefore, the concentration of peroxynitrite in the blood
reaching resistance arteries after injection of 10 µmol/kg
peroxynitrite would be ~5 nM. However, this concentration of
peroxynitrite produces minimal relaxation in isolated vessels (34).
This raises the possibility that peroxynitrite forms a factor with a
higher relaxant potency than peroxynitrite itself.
A number of potential endogenous vasodilators that could be formed by peroxynitrite have been identified. These include low-molecular-weight S-nitrosothiols (26), the high-molecular-weight S-nitrosothiol S-nitrosoalbumin (18), and a nitrosoglucose adduct (27). Peroxynitrite can form S-nitrosothiols with a yield of ~1% (26). Wu et al. (37) found that vasodilatation produced by peroxynitrite in isolated pulmonary arteries was partially inhibited (26%) by prior treatment with diethyl maleate, which decreases tissue glutathione levels. These findings suggest that the formation of low-molecular-weight S-nitrosothiols may be important in mediating the effects of systemically injected peroxynitrite. Although the addition of peroxynitrite to buffer containing glutathione forms S-nitrosoglutathione, peroxynitrite does not form detectable amounts of this nitrosothiol upon addition to plasma (24). Moreover, the addition of peroxynitrite to plasma, at a concentration similar to that reached in the blood in the present study (500 µM), does not cause a decrease in reduced thiol levels (33). The present study demonstrates that the hypotensive and vasodilator effects of the low-molecular-weight S-nitrosothiols L-S-nitrosocysteine and L-S-nitrosoglutathione were markedly attenuated by the prior administration of L-penicillamine. In contrast, the hemodynamic effects of peroxynitrite were unaffected by L-penicillamine. These findings suggest that the formation of low-molecular-weight S-nitrosothiols in the circulation is unlikely to be primarily responsible for the hemodynamic effects of peroxynitrite.
The concentrations of glutathione, 
-glutamylcysteine, and cysteine
in plasma are ~5, 4, and 33 µM, respectively (9, 12). Albumin has a
single cysteine residue capable of being nitrosylated and exists in
substantially higher concentration (0.5 mM) in the plasma (18).
S-nitrosoalbumin is a vasodilator with
a potency about seven times less than that of
S-nitrosocysteine (18). However,
S-nitrosoalbumin requires
low-molecular-weight thiols such as glutathione and cysteine to exert
its actions, presumably by transnitrosation of these
low-molecular-weight thiols (30). The present study demonstrates that
the hypotensive and vasodilator effects of nitrosoalbumin, but not the
hemodynamic effects of peroxynitrite, are attenuated by the prior
administration of L-penicillamine, suggesting that
biologically relevant amounts of
S-nitrosoalbumin are not formed after
the systemic administration of peroxynitrite.
When added to physiological buffer, peroxynitrite forms a nitrosoglucose adduct that has vasodilatory capabilities (27). With a yield of only 0.1%, however, the maximum serum concentration of the nitrosoglucose adduct formed from peroxynitrite administration in the present study would be ~150 nM. A comparable degree of vasodilatation was achieved at an approximate serum concentration of 3,000 nM for L-S-nitrosocysteine or L-S-nitrosoglutathione. Whereas the presumed mechanism of nitrosoglucose adduct-mediated vasodilatation is through the release of nitric oxide, the nitrosoglucose adduct would not be expected to be a more potent vasodilator than the nitrosothiols. Therefore, the low concentrations formed in the present study make the formation of a nitrosoglucose adduct unlikely to be of importance in peroxynitrite-mediated vasorelaxation. Hemoglobin-mediated inhibition of the vasorelaxation caused by peroxynitrite in vitro has been taken to indicate that the vasorelaxant effects of peroxynitrite are mediated by nitric oxide or a nitrosyl adduct that acts as a nitric oxide donor (24, 34). It should be noted that peroxynitrite undergoes a direct reaction with hemoglobin (31). As such, the ability of hemoglobin to reduce the vasorelaxant effects of peroxynitrite may be due to direct scavenging of peroxynitrite rather than nitric oxide derived from this compound. The soluble guanylate cyclase inhibitor LY-83583 markedly attenuates relaxation produced by peroxynitrite in isolated pulmonary arteries (37). This supports the possibility that the vasorelaxant effects of peroxynitrite involve the activation of soluble guanylate cyclase and the generation of guanosine 3',5'-cyclic monophosphate. However, LY-83583 also generates superoxide radicals that may diminish the vasorelaxant potency of peroxynitrite. This possibility is supported by evidence that the superoxide anion scavenger superoxide dismutase potentiates the vasorelaxant effects of peroxynitrite (24). Furthermore, low-dose peroxynitrite-mediated relaxation of cerebral arteries in anesthetized cats was not inhibitable by LY-83583 but was significantly inhibited by glyburide, an antagonist of ATP-sensitive potassium channels (36). Consistent with these results, the duration of the hypotensive effect of peroxynitrite was markedly inhibited after the administration of glibenclamide to pentobarbital sodium-anesthetized rats (unpublished observations), suggesting that peroxynitrite-mediated vasorelaxation occurs through the activation of ATP-sensitive potassium channels within the vascular smooth muscle.
In summary, the present study provides evidence that the systemic administration of peroxynitrite produces a dose-dependent hypotension and vasodilatation in anesthetized rats. The hemodynamic actions of peroxynitrite do not appear to involve the formation of biologically active S-nitrosothiols. At present, the precise mechanisms by which peroxynitrite relaxes vascular smooth muscle remain to be determined, but recent evidence suggests that peroxynitrite-mediated vasorelaxation may occur through hyperpolarization of the vascular smooth muscle due to the activation of ATP-sensitive potassium channels.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Heart, Lung, and Blood Institute Grant HL-14388 (to S. J. Lewis) and American Heart Association Iowa Affiliate Grant IA-97-GB-29 (to N. W. Kooy).
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FOOTNOTES |
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Address for reprint requests: N. W. Kooy, The Univ. of Iowa, Dept. of Pediatrics, RCP 5040-B, 200 Hawkins Dr., Iowa City, IA 52242.
Received 23 May 1997; accepted in final form 5 December 1997.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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) in mean arterial pressure,
hindquarter vascular resistance, mesenteric vascular resistance, and
the area under the mean arterial blood pressure curve produced by the
systemic administration of
L-S-nitrosocysteine before
and after the administration of L-penicillamine (500 µmol/kg) in pentobarbital sodium-anesthetized rats
(n = 6). Hemodynamic responses
produced by
L-S-nitrosocysteine are
expressed as means ± SE. * P < 0.05, post-L-penicillamine vs.
pre-L-penicillamine.
