Nephrology Research Unit and Departments of Medicine and Anesthesiology, Mayo Clinic/Foundation, Rochester; and University of Minnesota, Minneapolis, Minnesota 55905
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ABSTRACT |
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In the glycerol model of renal injury we describe an acute rise
in systemic arterial pressure which is attended by a reduced vasodilatory response to acetylcholine in vivo; vasodilatory responses to verapamil, however, were not impaired. Neither arginine nor sodium
nitroprusside diminished this rise in blood pressure;
N-nitro-L-arginine methyl ester
(L-NAME) elevated
basal mean arterial pressure and markedly blunted the rise in mean
arterial pressure following the administration of glycerol. Aortic
rings from the glycerol-treated rat demonstrate an impaired
vasodilatory response to acetylcholine, an effect not repaired by
arginine; the vasodilatory responses to nitric oxide donors, sodium
nitroprusside and SIN-1, were also impaired; 8-bromo-cGMP,
at higher doses, evinced a vasodilatory response comparable to that
observed in the control rings. This pattern of responses was not a
nonspecific effect of aortic injury, since aortic rings treated with
mercuric chloride, a potent oxidant, displayed an impaired vasodilatory
response to acetylcholine but not to sodium nitroprusside. We conclude
that in the glycerol model of heme protein-induced tissue injury, there
is an acute elevation in mean arterial pressure attended by impaired
endothelium-dependent vasodilatation in vitro and in vivo. We suggest
that the acute scavenging of nitric oxide by heme proteins depletes the
blood vessel wall of its endogenous vasodilator and permeation of heme proteins into the blood vessel wall may contribute to such sustained effects as observed in vitro.
nitric oxide; vasoconstriction; rhabdomyolysis
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INTRODUCTION |
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THE INTRAMUSCULAR INJECTION of hypertonic glycerol into rats induces myolysis, hemolysis, and attendant heme protein-induced renal injury and has long been used as a model of acute renal failure (3, 28). The mechanisms accounting for such renal injury rely on three main pathogenetic pathways, namely, renal vasoconstriction, direct tubular toxicity, and intratubular cast formation (28). Renal vasoconstriction occurs promptly and prominently in this setting and is assigned a critical role in the ensuing injury (2, 11, 13, 28). Vasoconstriction induces ischemia and a spectrum of metabolic perturbations including ATP and GSH depletion (1, 28, 29); such metabolic perturbations may be directly damaging and/or conspire with heme protein-dependent mechanisms of renal injury. For example, iron-mediated oxidant stress, which is one of the dominant pathways of nephrotoxicity in this model (3), is critically exacerbated by GSH depletion (1); heme protein-dependent cast formation in the kidney may be exacerbated by prior ischemic conditioning (28, 30). Thus vasoconstriction induced by heme proteins renders the kidney more vulnerable to the injurious effects of heme proteins, and for such reasons, understanding the mechanisms accounting for vasoconstriction and abnormal vascular behavior, in general, in this and other models, represents an important aspect of the study of acute renal failure (7, 28).
In the course of studies involving the glycerol model of acute renal failure, we noted that within seconds of the administration of glycerol there is a marked rise in mean arterial pressure that persists for up to 2 h. Thus vasoconstriction in this model is not localized to the kidney but appears as part of a more generalized response. Our attention was drawn to this phenomenon for several reasons. Although utilized as a model of rhabdomyolysis, a condition that is often associated with hypotension and shock incurred, in part, by the sequestration of interstitial fluid (28), glycerol-induced acute renal failure is ushered in, ironically, by acute elevation in systemic arterial pressure. Additionally, a remarkable feature of the glycerol model is the acute elevation in the plasma concentrations of heme proteins that promptly occurs (28). Since heme proteins possess the capacity to potently bind nitric oxide (16, 17), such presence of heme proteins in the plasma compartment could efficiently remove nitric oxide from the vasculature, thereby depriving the vasculature of its endogenous vasodilator (5, 15). Such elevation in arterial pressure thus provides a novel in vivo model for the exploration of elevation in arterial pressure observed with heme proteins, a critical issue in current attempts to develop safe, hemoglobin-based red blood cell substitutes (6, 9, 12, 16, 24).
The present study represents the first available characterization of such elevation in systolic arterial pressure; it encompasses in vivo studies and in vitro studies of aortic rings in this disease model, and it focuses on the scavenging of nitric oxide as an underlying mechanism for such elevation in systolic arterial pressure.
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METHODS |
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Studies in vivo. Studies involving the glycerol model of acute renal injury were approved by the respective Institutional Animal Care and Use Committees of the University of Minnesota and the Mayo Clinic. Studies were performed in male Sprague-Dawley rats in which the glycerol model of renal failure was induced by the injection of 50% glycerol (dissolved in distilled water) into the anterior thigh muscle at a dose of 3.75 or 10 ml/kg body wt, with one-half of the dose injected into each anterior thigh muscle under ether anesthetic (20, 21). The lower dose of glycerol was used in those studies in which rats were studied for an extended period of time under anesthesia, since at the higher dose there is significant mortality under such conditions. In studies in which the mean arterial pressure was continuously monitored, rats were anesthetized with an intraperitoneal injection of 5-sec-butyl-5-ethyl-2-thiobarbituric acid (Inactin, 100 mg/kg body wt) and placed on a temperature-regulated table. Body temperature was maintained between 37 and 38°C (21). A PE-50 polyethylene catheter was inserted into the left femoral artery for blood sampling and blood pressure measurements via a pressure transducer (model PP-23DB; Statham Instruments, Oxnard, CA) connected to a duograph recorder (model 1CT-2H; Gilson Medical Electronics, Middletown, WI). The trachea was catheterized with a PE-240 polyethylene tubing. Pharmacological agents were administered via a catheter fashioned from PE-50 tubing inserted into the jugular vein. To test the integrity of endothelium-dependent vasorelaxation in vivo, rats were treated with intramuscular glycerol (10 ml/kg body wt, 50% solution in distilled water) and 1 h after administration of glycerol when the rise in mean arterial pressure was fully developed, acetylcholine, 10 µg/kg body wt, was injected intravenously, and mean arterial pressure was recorded at intervals of 1 min for 3 min (27).
In studies in which inhibitors or inducers of the nitric oxide system
were studied, rats were pretreated with the following infusions for 45 min prior to, and for 120 min after, the administration of hypertonic
glycerol: N-nitro-L-arginine
methyl ester (L-NAME, 50 µg · kg
1 · min
1
in normal saline), L-arginine
hydrochloride (180 mg · kg
1 · h
1
in normal saline) (18), sodium nitroprusside (10 µg · kg
1 · min
1)
(4), or saline vehicle. Forty-five minutes after the commencement of
one of these infusions intramuscular glycerol was injected at dose of
3.75 ml/kg body wt of a 50% solution, with one-half of the dose
injected into each anterior thigh muscle, and the mean
arterial pressure was followed for 2 h thereafter.
To test the effect of nitric oxide-independent vasodilators on vascular
responses in rats subjected to hypertonic glycerol, we examined the
efficacy of verapamil in reducing mean arterial pressure in rats
subjected to hypertonic glycerol (3.75 ml/kg body wt of a 50%
solution, with one-half of the dose injected into each anterior thigh
muscle) administered 3 h previously and in control rats. Rats were
anesthetized with Inactin and surgically prepared as described above.
Mean arterial pressure was monitored prior to and after the
administration of verapamil. Verapamil was administered at a
maintenance infusion rate of 40 µg · kg1 · min
1
after an initial bolus of 0.1 mg/kg, a regimen modified from that
employed by Baylis et al. (4).
Studies in vitro. The glycerol model was induced in rats as described above by intramuscular injection of 50% glycerol (10 ml/kg body wt), and animals were killed 90 min later by decapitation. The thoracic aorta was rapidly removed and placed in physiological saline solution. Aortas were dissected free of fat and loose connective tissue, and 5-mm rings were cut for in vitro studies. The chemical composition of the solution used for dissection and in subsequent experiments was as follows (in mM): 137.0 Na, 5.0 K, 1.8 Ca, 1.0 Mg, 140.6 Cl, 1.0 HPO4, 8.0 dextrose, and 10.0 HEPES, pH 7.4. Solutions with K+ concentration other than 5 mM were made by isosmotic adjustment of the KCl and NaCl content. All solutions were at 37°C and gassed with air.
The isometric force developed by vascular rings was measured using standard techniques (6, 12). Tissues were allowed to equilibrate for 45 min after mounting in organ chambers (20 ml volume), and the passive tension was then slowly adjusted to 1.0 g. The contractile response to 25 mM KCl depolarization was determined repeatedly at steadily increasing passive tension. The resting tension at which the maximal KCl contraction occurred was determined, and the remainder of the study was performed with that level of resting tension. Optimal resting tension was 2.25-2.75 g for the rings used in these studies.
Aortic rings were contracted with phenylephrine
(107 M) for subsequent
studies assessing vascular relaxation. Dose-response relationships for
vasodilators were then determined by cumulative addition to the bathing
solution. Data are expressed as percent relaxation of the phenylephrine
contraction induced in the individual tissues.
Additional experiments contrasted the effects of mercuric chloride (HgCl2) on relaxation of aortic rings in vitro. For these experiments, all tissues were dissected from control aortae and prepared for experimentation as above. Functional endothelium was confirmed in all tissues by relaxation to acetylcholine. Experimental tissues were then treated with HgCl2 at the indicated concentration by addition to the bathing solution for 20 min; tissues were then washed free of HgCl2 by exchanging the bathing solution three times over 30 min. Control tissues were treated in identical fashion except for omission of HgCl2.
Statistics. Results are expressed as means ± SE and are considered statistically significant for P < 0.05. For comparison between unpaired groups, the Student's t-test or the Mann-Whitney test was employed. For comparison among three or more groups, ANOVA and the Tukey-Kramer test were employed.
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RESULTS |
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Studies in vivo. Following the
intramuscular administration of hypertonic glycerol, a prompt elevation
in mean arterial pressure occurs. In all of the five animals so
treated, a marked elevation of blood pressure occurred, which peaked
some 60 min after the administration of glycerol representing a mean
elevation in arterial pressure of 28 ± 4 mmHg (Fig.
1A).
For up to 150 min after the administration of hypertonic glycerol, the
increment in mean arterial pressure was significantly greater than in
the control rats (Fig. 1B).
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To determine whether endothelium-dependent vasodilatation was impaired
in this setting, we examined the vasodilatory response to acetylcholine
at a time when vasoconstriction and elevation in mean arterial pressure
was clearly manifest after the administration of glycerol, namely, 60 min after its administration. As shown in Fig.
2, the reduction in mean arterial pressure
in response to acetylcholine was less in the glycerol-treated animal
compared with the control animal when sequentially determined at 1, 2, and 3 min after the administration of acetylcholine. Thus the elevation
in mean arterial pressure that occurs following the administration of
hypertonic glycerol is attended by an impaired endothelium-dependent
vasorelaxation.
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To probe further the possible involvement of the nitric oxide system in
elevation of mean arterial pressure following the administration of
glycerol, we studied four groups of rats all subjected to intramuscular
glycerol and treated with either saline (control), arginine, sodium
nitroprusside, or L-NAME, begun
45 min prior to the administration of glycerol. Figure
3 shows the temporal profiles for mean
arterial pressure in these conditions. The results of these studies
demonstrate that arginine failed to affect the basal blood pressure or
the rise in blood pressure following the injection of glycerol; indeed,
the blood pressure profiles for the rats treated with arginine- and the
saline-treated controls were virtually superimposable, prior to and
after the administration of glycerol (Fig. 3); the maximum rise in mean arterial pressure was not significantly different in saline-treated and
arginine-treated rats (24 ± 1 and 26 ± 2 mmHg,
respectively). The administration of sodium nitroprusside
did not alter the peak arterial pressure achieved after the
administration of glycerol (Fig. 3); however, since sodium
nitroprusside significantly lowered mean arterial pressure prior to the
administration of glycerol, the increment in mean arterial pressure in
response to the administration of glycerol in nitroprusside-treated
rats, namely, 41 ± 2 mmHg, was significantly
increased. On the other hand, the administration of
L-NAME, while expectedly and
significantly elevating basal blood pressure prior to the
administration of glycerol, markedly blunted the rise in mean arterial
pressure that occurred in response to intramuscular glycerol, namely,
6 ± 3 mmHg (Fig. 3).
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To determine whether the vasculature in glycerol-treated rats is nonspecifically injured such that responses to nitric oxide-independent vasodilators are impaired, we performed additional studies in which we determined the efficacy of the same dose of a nitric oxide-independent vasodilator, verapamil, in reducing mean arterial pressure. There were no significant differences in mean arterial pressure in control and glycerol-treated rats (injected 3 h previously) just prior to the administration of verapamil (133 ± 2 vs. 142 ± 5 mmHg; n = 4 in each group, P = NS) and following the administration of verapamil (104 ± 3 vs. 101 ± 6 mmHg; n = 4 in each group, P = NS); the reductions in mean arterial pressures were not significantly different between control and glycerol-treated rats (29 ± 2 vs. 41 ± 5 mmHg; n = 4 in each group, P = NS). Thus the vasculature is not impaired in its response to nitric oxide-independent vasodilators in glycerol-treated rats.
Studies in vitro. We also studied the
behavior of aortic rings in vitro in animals subjected to
glycerol-induced acute renal failure. As demonstrated in Fig.
4, there was a markedly attenuated relaxation response to an endothelium-dependent vasodilator,
acetylcholine, in rats subjected to glycerol-induced acute renal
failure compared with aortic rings harvested from control animals. This
blunted vasodilatory response in glycerol-treated animals was not
repaired by the presence of arginine at a concentration of 250 µM in
the extracellular medium. Thus the impaired vasodilatory response observed in the glycerol model is not ameliorated by the provision of
excess arginine, a finding consistent with the effects of arginine administered in vivo, and one that suggests that neither deficiency nor
unavailability of arginine account for the impaired vasodilatation in
glycerol-induced acute renal failure.
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To determine whether the provision of nitric oxide would affect this
impaired vasodilatory response in rat aortic rings in vitro, we studied
the relaxation response of aortic rings to nitric oxide delivered in
the form of sodium nitroprusside (Fig. 5)
or in the form of SIN-1 (Fig. 6); these
compounds release nitric oxide in vitro and are used as pharmacological
systems that deliver nitric oxide. The vasodilatory response in aortic
rings from the glycerol model to either form of delivery system of
nitric oxide was clearly blunted compared with the vasodilatation
achieved in the control rings; only in the presence of very high
concentrations of nitroprusside
(106 M) was the
vasorelaxation response comparable to control aortic rings.
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We also examined the relaxatory response of aortic rings to
8-bromo-cGMP (Fig. 7). At lower
concentrations the relaxation response in aortic rings from
glycerol-treated rats was less than that observed in controls; however,
at higher concentrations, namely,
104 M, of 8-bromo-cGMP, the
relaxation response in aortic rings from glycerol-treated rats was
comparable to that observed in controls (Fig. 7). Thus, at higher but
not at lower concentrations of 8-bromo-cGMP, the distal effector for
vasodilatation in the nitric oxide-dependent system, namely, cGMP,
elicits a comparable amplitude of vasodilatation in aortic rings from
glycerol-treated and control rats. In contrast, the provision of
arginine completely fails, and pharmacological nitric oxide-generating
systems are attenuated, in the capacity to achieve such effects.
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In an attempt to determine specificity of the changes we observed in
the glycerol model, we examined the behavior of vascular responses in
another model of acute renal insufficiency, one induced by
HgCl2 and one that is heme
protein-independent.
HgCl2, in micromolar concentrations, is a potent generator of hydrogen peroxide and induces
hydrogen peroxide-renal injury that can be significantly vitiated by
scavengers of hydrogen peroxide such as catalase and pyruvate (22). As
demonstrated in Fig. 8, with increasing
doses of HgCl2, there is a
stepwise impairment in the vasodilatory response to acetylcholine
indicating impairment, in part, of endothelium-dependent relaxation.
However, unlike the aortic rings in the glycerol model, the
HgCl2-treated rings respond to
sodium nitroprusside in a manner quite similar to aortic rings from
control animals (Fig. 9). To underscore the
role of oxidants in HgCl2-induced
injury, the presence of pyruvate, a scavenger of hydrogen peroxide,
protected against the defect in acetylcholine-induced vasodilatation
induced by HgCl2 (data not shown).
Thus, in a model of heme protein-independent, oxidant-mediated vascular
injury induced by HgCl2, the
provision of the nitric oxide-generating agent sodium nitroprusside
induces vasodilatation comparable to controls (Fig. 9),
quite unlike the circumstance with vascular rings from glycerol-treated
rats (Fig. 5).
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DISCUSSION |
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Prior studies of the glycerol model that include systemic hemodynamic measurements provide no clear consensus on the systemic arterial pressure profile shortly after the administration of glycerol: some studies observe no significant elevation in arterial pressure (13), others have measured blood pressure but have not commented on whether significant increments in mean arterial pressure occur (2), and finally, there is one available report which, although containing data demonstrating statistical increments in mean arterial pressure, neither draws attention to, nor discusses, the biological significance of these changes in mean arterial pressure (11). Our study is the first to demonstrate an invariant elevation in mean arterial pressure in the early phase following the administration of glycerol and to highlight what we regard as the pathobiological significance of these changes in light of current interest in the nitric oxide system in blood pressure regulation (5, 15). The inconsistent findings with regard to the elevation in mean arterial pressure in previously published studies are difficult to explain, but this may reflect the modulatory vasoactive effects of different anesthetics employed in these studies. The utilization of in vivo and in vitro preparations, as incorporated in our study, provides complementary approaches: studies utilizing aortic rings attest to abnormal vascular behavior in this disease model, and they allow more detailed examination of the physiological basis for these changes.
The glycerol model leads to the release of myoglobin from injured muscle as well as pronounced hemolysis (28). The plasma in rats subjected to the glycerol model rapidly turns pink in color, a change that reflects the release of hemoglobin from red cells. The heme prosthetic group in heme proteins possesses a remarkable capacity to bind nitric oxide (16, 17). In view of the capacity of heme proteins to avidly bind nitric oxide, we pursued the possibility that such binding of nitric oxide by extracellular heme proteins, hemoglobin and myoglobin, would deprive the vasculature of its endogenous vasodilator, nitric oxide, thereby contributing to the rapid rise in mean arterial pressure. In support of this possibility are our findings that demonstrate an impaired vasodilatory response to the endothelium-dependent vasodilator acetylcholine both in vivo and in vitro. Evidence in support of a deficiency of nitric oxide was provided by studies in which L-NAME was administered prior to the administration of glycerol. L-NAME-treated rats, predictably, mounted a prominent hypertensive response compared with rats treated with saline prior to the administration of glycerol; such elevation in arterial pressure following the administration of L-NAME reflects the deficiency of nitric oxide in vasculature (5). If net deficiency or unavailability of nitric oxide underlies the hypertensive response following the administration of glycerol, then this hypertensive response induced by hypertonic glycerol should be markedly blunted if nitric oxide is already depleted in tissues by prior administration of L-NAME. Indeed, this is what we observed in this circumstance: the elevation of mean arterial pressure induced by hypertonic glycerol pretreated with L-NAME was approximately one-fourth of that observed following the administration of glycerol in rats pretreated with saline. These findings are consistent with the thesis that the rise in mean arterial pressure reflects, at least in part, deficiency of nitric oxide in the vasculature.
The administration of arginine either in vivo or in vitro failed to repair the impaired vasodilatory response observed; thus the simple provision of substrate for nitric oxide synthase fails to mitigate the impaired vasodilatory response; additionally, these findings indicate that the deficiency of arginine per se was not a critical factor underlying these changes. Nitric oxide donors, such as nitroprusside and SIN-1, also failed to evince a vasodilatory response in glycerol tissues comparable to that observed in control tissues for most of the range of concentrations with which these nitric oxide donors were employed in vitro. Interestingly, in prior studies, the vasodilatory effects of nitric oxide donors such as sodium nitroprusside are attenuated in the presence of heme proteins, which are in all likelihood effects that reflect the scavenging by heme proteins of nitric oxide generated by nitroprusside (23). In our studies, only with very large concentrations of one of these nitric oxide donors (nitroprusside, see Fig. 5) was a comparable vasodilatory response elicited in aortic tissue from the glycerol-treated rats. These latter observations suggest that, at least for the lower and middle range of concentrations employed for these agents, either the vascular smooth muscle was incapable of responding to nitric oxide-instigated vasodilatation or that any nitric oxide that was administered by these donors was consumed or inactivated. We sought to differentiate between these possibilities by examining the effect of the analog of cGMP, 8-bromo-cGMP, in aortic rings. cGMP is the effector mechanism for nitric oxide-instigated vasodilatation, and is generated by guanylate cyclase after the latter is activated by nitric oxide. The vasodilatory response in aortic rings to the analog of cGMP, 8-bromo-cGMP, from glycerol-treated rats was comparable to the response observed in control rings at the highest concentrations but was significantly less at lower concentrations; the comparability of responses to cGMP at the highest concentration tested indicates preservation of responsivity to cGMP at such concentration. However, at lower concentrations, impaired responsivity to cGMP by vascular smooth muscle cells may also contribute to the abnormal hemodynamic response observed in the glycerol model.
On the basis of these findings, we suggest the following mechanism may contribute, at least in part, to the vascular behavior we observed in vivo and in vitro. The presence of heme proteins in plasma siphons off nitric oxide from the vasculature with attendant rise in arterial pressure. Such a mechanism would account for the impaired vasodilatory response to acetylcholine in vivo and the attenuation in the elevation of arterial pressure in response to hypertonic glycerol in rats pretreated with L-NAME. The failure of arginine and nitroprusside to mitigate the elevation of arterial pressure in vivo indicates that the availability of such additional sources of nitric oxide do not swamp the capacity of heme proteins to bind nitric oxide, at least under the conditions employed and permissible in vivo. Our in vitro studies indicate that the impaired vasodilatory response is preserved in vitro. The presence of this impaired vasodilation in vitro may arise from the permeation of heme proteins in the blood vessel wall (9, 14, 16, 19). When hemoglobin is released from red cells in the circulation, it dissociates from its tetrameric form into dimers of molecular mass of ~32 kDa (28). Such species enter the subendothelial and intercellular spaces of the vasculature and thus can provide ongoing scavenging of nitric oxide in blood vessel walls (14, 19). It is possible that other mechanisms may also contribute to the elevation in arterial pressure we observed in this model including the inactivation of nitric oxide synthase by heme proteins, the generation of reactive oxygen species, or the production of vasoactive substances such as endothelin.
Our findings in the glycerol model are consistent with a large literature centered on the vasoconstrictive effects of hemoglobin in vivo and in vitro. Such studies indicate that the scavenging of nitric oxide by hemoglobin is a critical determinant of the vasoconstriction that ensues (16, 17, 25). Such effects of hemoglobin pose a problem in the development of safe, hemoglobin-based, red blood cell substitutes. Many of the available preparations are associated with systemic hypertension and vasoconstriction, which may adversely affect tissue perfusion (6, 9, 16, 17, 25). Polymerized hemoglobin, in contrast to hemoglobin in the dimeric or tetrameric form, is less vasoconstrictive (9, 10, 16), in part because of absence of permeation of polymerized hemoglobin into blood vessel walls; dimeric and tetrameric hemoglobin may permeate the endothelial surface of blood vessels, enter the vasculature, and thus divert nitric oxide away from smooth muscle cells more effectively compared with such hemoglobin species restricted to the luminal compartment of the vasculature (14, 19). Similarly, hemoglobin prepared in liposomes exerts less vasoconstriction, a beneficial attribute that may also be due to inability of such hemoglobin preparations to permeate blood vessel walls (9, 16).
The nitric oxide system has been studied in renal impairment associated with heme proteins. For example, infusion of myoglobin leads to a decrease in renal blood flow and in creatinine clearance in conjunction with decreased urinary excretion of nitrate and nitrite and cGMP (26). In contrast to the vascular effects reported in the present study, these renal effects are attenuated by the administration of arginine (26). Similarly, in the glycerol model of acute renal failure, the administration of arginine seems to protect against renal dysfunction, whereas the administration of an inhibitor of nitric oxide synthase worsens renal function (18). These latter studies indicate that impairment in the nitric oxide system induced by heme proteins in these settings contributes to the renal dysfunction that is observed.
In summary, in a disease model studied for more than 40 years (8), the present study provides the first available characterization of an overlooked, acute, reversible, systemic hypertension that swiftly follows the administration of glycerol; utilizing in vivo studies and in vitro studies of aortic rings, physiological evidence is provided that scavenging of nitric oxide provides, at least in part, an underlying mechanism for such elevation in arterial pressure.
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ACKNOWLEDGEMENTS |
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We gratefully acknowledge the expert secretarial assistance provided by Sharon Heppelmann.
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FOOTNOTES |
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These studies were supported by a National Institutes of Health FIRST Award Grant HL-48238 (to D. H. Warden) and by National Institutes of Health Grants DK-47060 and HL-55552 (to K. A. Nath).
Portions of the data in this report have been published in abstract form (J. Am. Soc. Nephrol. 3: 548, 1992; and J. Invest. Med. 44: 304, 1996).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: K. A. Nath, Mayo Clinic 200 First St., SW, 542 Guggenheim Bldg., Rochester, MN 55905.
Received 9 October 1998; accepted in final form 18 March 1999.
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