Department of Pharmacology, New York Medical College, Valhalla, New York 10595
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ABSTRACT |
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We studied the effects of the heme oxygenase (HO) inhibitor stannous mesoporphyrin (SnMP; 40 µmol/kg iv) on renal hemodynamics in anesthetized rats with and without 48-h pretreatment with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis. SnMP decreased renal blood flow (RBF) and increased renal vascular resistance (RVR) in both groups. The SnMP-induced reduction of RBF in L-NAME-pretreated rats was more prominent than in rats without pretreatment (43 ± 7 vs. 13 ± 3%) as was the SnMP-induced elevation of RVR (87 ± 31 vs. 14 ± 5%). The renal vasoconstrictor effect of SnMP is linked, in part, to amplification of prevailing neurohormonal constrictor mechanisms, since in L-NAME-pretreated rats it was prevented by concurrent administration of prazosin or losartan. However, SnMP (15 µmol/l) also elicits vasoconstriction in isolated, pressurized renal interlobular arteries and the response is more intense in vessels obtained from L-NAME-pretreated rats than from rats without pretreatment. These data indicate that the status of NO synthesis conditions the vascular response to HO inhibition in the rat kidney.
carbon monoxide; renal hemodynamics; angiotensin II; norepinephrine; renal vascular reactivity
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INTRODUCTION |
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HEME OXYGENASE (HO)-1 and -2 metabolize heme to biliverdin, ferrous iron, and carbon monoxide (CO) (1, 18). The heme-HO system is ubiquitous and relevant to many biological processes that are influenced by heme or by the products of heme metabolism by HO (1, 10, 11, 18, 26). In the kidney, HO-1 and HO-2 are expressed in both vascular and tubular structures, and HO-1 is upregulated in experimental models of renal injury (2, 5, 11, 16, 28). The renal heme-HO system was reported to promote cytoprotective mechanisms (11) and to participate in the regulation of renal function (2, 19, 28) and eicosanoid production (4).
Metalloporphyrins which inhibit HO decrease renal medullary blood flow in normal rats (28) and total renal blood flow in chronically hypoxic rats (19), suggesting the contribution of one or more HO products to renal vasodilatory mechanisms. HO-derived CO is a logical candidate for subserving a renal vasodilatory function, because exogenous CO dilates isolated, perfused rat afferent arterioles (23) and decreases the reactivity of renal interlobar arteries to constrictor agonists (16). CO-induced vasorelaxation and inhibition of agonist-induced vasoconstriction have been linked to activation of soluble guanylyl cyclase (24) and/or stimulation of calcium-activated potassium (KCa) channels (16, 24) in vascular smooth muscle.
Recent studies have identified areas of interaction between the heme-HO and the L-arginine-nitric oxide (NO) synthase systems that may have great functional relevance. On one hand, NO interferes with the ability of CO to stimulate KCa channels in vascular smooth muscle (25), induces HO-1 expression (8, 9), and decreases HO activity (6, 15) as well as ferrochelatase activity (22), the terminal enzyme of the heme synthetic pathway. On the other hand, CO attenuates NO-induced activation of soluble guanylyl cyclase (12) and inhibits NO synthase (23). That CO and NO affect the formation and action(s) of each other raises the possibility that the vasoregulatory functions of the heme-HO and the L-arginine-NO synthase systems are interdependent.
To the extent that NO influences the formation and actions of HO-derived CO, the status of NO synthesis may determine the nature and/or intensity of the regulatory influence of the heme-HO system on the renal vasculature. To test this hypothesis, we contrasted untreated rats and rats undergoing treatment with an inhibitor of NO synthase in terms of the renal hemodynamic response to the administration of stannous mesoporphyrin (SnMP), a nonselective inhibitor of HO isoforms (7). In addition, we compared the effect of SnMP and HO products, CO and biliverdin, on the internal diameter of isolated, pressurized renal interlobular arteries taken from normal untreated rats and rats treated with an inhibitor of NO synthesis.
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MATERIALS AND METHODS |
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Chemicals and Solutions
SnMP, an inhibitor of HO, was purchased from Frontier Scientific (Logan, UT). SnMP was dissolved in 50 mmol/l Na2CO3, sonicated, and filtered immediately before use. Because of the photosensitivity of porphyrins, SnMP solutions were prepared and experiments were performed under reduced light conditions. CO was purchased from Tech Air (White Plains, NY), and a CO-saturated solution (1 mmol/l) was prepared shortly before use (17). Other chemicals were obtained from Sigma (St. Louis, MO) and diluted in NaCl (0.15 mol/l). The composition of Krebs buffer used in the studies was (in mmol/l) 118.5 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 KH2PO4, 1.2 MgSO4, 25.0 NaHCO3, and 11.1 dextrose.Animals
All protocols employed in this study were reviewed and approved by the Institutional Animal Care and Use Committee of New York Medical College. We used male Sprague-Dawley rats (300-325 g body wt; Charles River, Wilmington, DE) with access to a standard chow and tap water ad libitum. Studies were conducted in animals treated and not treated with NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase (21). L-NAME was provided in the drinking water at a daily dose of 70 mg/kg body wt commencing 48 h before experimentation.Experimental Design
Protocol to contrast the effect of SnMP on renal hemodynamics in
rats treated and not treated with L-NAME.
Animals were anesthetized with thiobutabarbital (100 mg/kg ip) and
placed on a thermostatically controlled board to maintain body
temperature at 36-37°C. Polyethylene cannulas were placed in the
trachea (PE-205) to aid ventilation, the bladder (PE-60) for urine
collection, the left femoral vein (PE-50) for administration of fluid
and drugs, and the left femoral artery (PE-50) for blood sampling and
the measurement of mean arterial pressure by means of a pressure
transducer (model p23 ID, Oxnard, CA) coupled to a polygraph (model 7D,
Grass Instruments, Quincy, MA). Next, the left kidney was exposed
through a midline abdominal incision and a flow probe (model EP102,
2.0-mm circumference, Carolina Medical Instruments, King, NC) was
placed around the left renal artery for measurement of renal blood flow
using a square-wave electromagnetic flowmeter (model FM 501, Carolina
Medical Instruments). After completion of the cannulation and
instrumentation procedures, an infusion of 0.15 mol/l NaCl (2.5 ml/h
iv) was initiated and maintained throughout the study. In some
experiments, [3H]inulin (American Radiolabeled Chemicals,
St. Louis, MO) was included into the infusion (1 µCi/ml) for
measurement of glomerular filtration rate. To this end, timed urine
collections were made before and during experimental interventions, and
arterial blood samples (200 µl) were collected at the midpoint of
urine collections. The concentration of [3H]inulin in
urine and plasma was determined by liquid scintillation counting and
the clearance of inulin, calculated using the standard formula, was
taken to reflect the glomerular filtration rate. Renal vascular
resistance was calculated by dividing the value of mean arterial
pressure by the value of renal blood flow. The filtration fraction was
calculated by the formula: glomerular filtration rate/renal blood flow
(1 hematocrit). Data collection was initiated after a 60-min
equilibration period.
Protocols to investigate the effects of CO and the HO inhibitor SnMP in isolated renal interlobular arteries taken from rats treated and not treated with L-NAME. Animals were anesthetized (60 mg/kg ip pentobarbital sodium), the kidneys were removed and placed on a dish containing ice-cold Krebs buffer, and interlobular arteries were dissected free of surrounding tissue. Vascular segments 1- to 2-mm in length, with an internal diameter of ~40 µm in the absence of flow and transmural pressure, were mounted between two micropipettes in the chamber (1 ml) of a pressure-myograph (Living System Instrumentation, Burlington, VT) filled with Krebs buffer gassed with 95% O2-5% CO2, which was exchanged at a rate of 1 ml/min (27). To measure vascular diameter, the vessel chamber was placed on the stage of a microscope fitted with a video camera (Javelin, Newburgh, NY) linked to a video caliper (Texas A & M, College Station, TX) and a recorder (27). Intraluminal pressure was increased slowly to 100 mmHg using a pressure servo-controller, and this level of pressure was maintained throughout the study unless indicated otherwise. Experiments were conducted after a 60-min equilibration period in vessels that developed a spontaneous tone while pressurized to 100 mmHg. The internal diameter of vessels was measured continuously before and after inclusion of SnMP (15 µmol/l), CO (0.1 and 1.0 µmol/l), or biliverdin (1 µmol/l) into the Krebs buffer flowing into the myograph chamber.
To gain information on whether NO synthesis remains inhibited during ex vivo superfusion of vessels taken from L-NAME-treated rats, a limited number of experiments were conducted to contrast the effect of L-arginine (10 µmol/l) on the diameter of pressurized renal interlobular arteries taken from rats with and without L-NAME pretreatment. The vessels were superfused with Krebs buffer for 90-120 min before the experimental intervention. The inclusion of L-arginine in the superfusion buffer increased (P < 0.05) the internal diameter of arteries taken from rats without L-NAME pretreatment from 69.7 ± 3.1 to 77.5 ± 5.0 µm (n = 4). In contrast, L-arginine did not change the diameter of arteries taken from rats pretreated with L-NAME (68.0 ± 3.9 vs. 68.0 ± 3.9 µm; n = 4). That the dilatory effect of L-arginine is blunted in vessels from rats pretreated with L-NAME implies that NO synthesis in such vessels remains inhibited even after ex vivo superfusion for up to 90-120 min. Additional experiments were conducted to contrast the effect of SnMP (15 µmol/l) on the intraluminal pressure-internal diameter relationship in renal interlobular arteries taken from rats treated and not treated with L-NAME. After equilibration at 100 mmHg for 60 min, intraluminal pressure was decreased to ~0 mmHg and, after 10 min, it was increased in 20-mmHg steps until it reached 100 mmHg. The pressure was maintained for ~5-10 min at each pressure step so that the vessels could reach a steady-state diameter. Finally, the vascular preparation was superfused with calcium-free Krebs buffer containing 1 mmol/l EGTA and the pressure-diameter relationship was examined again to obtain the passive diameter of the vessels at each level of intraluminal pressure. The internal diameter during superfusion of the vessel with calcium-containing buffer (absolute diameter) and with calcium-free buffer (passive diameter) is expressed in micrometers. The normalized diameter refers to the absolute diameter expressed as a percentage of the passive diameter.Data Analysis
Results are expressed as means ± SE. Data on renal hemodynamics in vivo are the average of two consecutive 15-min observation periods. Data were analyzed by unpaired Student's t-test and by one- or two-way ANOVA followed by the Newman-Keuls post hoc test or the Fisher test. The null hypothesis was rejected at P < 0.05. ![]() |
RESULTS |
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Effects of SnMP on Renal Hemodynamics
Table 1 shows data on renal hemodynamics before and after the administration of SnMP or drug vehicle only to rats pretreated and not pretreated with the NO synthesis inhibitor L-NAME. Relative to data in rats without L-NAME pretreatment, rats pretreated with L-NAME displayed elevated mean arterial pressure, decreased renal blood flow, and increased renal vascular resistance, filtration fraction, and hematocrit, without significant changes in glomerular filtration rate. Estimates of renal HO activity did not differ significantly in rats with (96 ± 16 pmol · mg
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The possibility that SnMP elicits renal vasoconstriction by amplifying
the renal vascular actions of endogenous vasoconstrictors was examined
by contrasting the effects of SnMP on renal hemodynamics in rats
pretreated with L-NAME alone, L-NAME plus
prazosin to block adrenergically mediated vasoconstriction, and
L-NAME plus losartan to block ANG II-induced
vasoconstriction. Relative to corresponding data in rats pretreated
with L-NAME alone, before the administration of SnMP, rats
pretreated with L-NAME and prazosin displayed decreased
mean arterial pressure (112 ± 8 vs. 130 ± 3 mmHg,
P < 0.05) and renal vascular resistance (19.4 ± 3.1 vs. 26.2 ± 1.4 mmHg · ml1 · min · g
1,
P < 0.05), whereas renal blood flow showed a slight
tendency to increase (6.2 ± 0.6 vs. 5.1 ± 0.4 ml · min
1 · g
1,
P = 0.14). Rats pretreated with L-NAME and
losartan exhibited unchanged mean arterial pressure (129 ± 6 mmHg), diminished renal vascular resistance (15.8 ± 2.1 mmHg · ml
1 · min · g
1,
P < 0.05), and increased renal blood flow (8.7 ± 0.7 ml · min
1 · g
1,
P < 0.05). In rats pretreated with L-NAME
alone, SnMP decreased mean arterial pressure, reduced renal blood flow,
and increased renal vascular resistance but had no effect on any of
these parameters in rats pretreated with L-NAME and
prazosin (Fig. 1). In rats pretreated
with L-NAME and losartan, SnMP slightly reduced mean arterial pressure and renal blood flow but was without effect on renal
vascular resistance (Fig. 1). Thus the renal vasoconstriction induced
by the HO inhibitor, in rats pretreated with L-NAME, is blunted in animals undergoing pharmacological blockade of
1-adrenergic or angiotensin AT1 receptors.
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Figure 2 illustrates the result of
experiments comparing the effect of renal arterial infusion of
norepinephrine (2 nmol · kg1 · min
1), or ANG
II (5 pmol · kg
1 · min
1),
on renal hemodynamics in rats before and after treatment with SnMP.
Both constrictor agonists decreased renal blood flow and increased
renal vascular resistance without altering mean arterial pressure. The
renal vasoconstrictor effect of norepinephrine and ANG II was
significantly magnified after the administration of SnMP. Thus
inhibition of HO amplifies the renal vasoconstrictor action of
norepinephrine and ANG II.
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Effect of SnMP on the Internal Diameter of Isolated, Pressurized Renal Interlobular Arteries
Inclusion of SnMP into the Krebs buffer superfusing pressurized renal interlobular arteries elicited a sustained reduction of internal diameter in vessels taken from rats treated and not treated with L-NAME (Fig. 3). In vessels obtained from rats not treated with L-NAME, SnMP decreased (P < 0.05) the internal diameter by 6.0 ± 0.8, 8.5 ± 1.1, 9.5 ± 1.1, and 9.8 ± 1.1 µm after 5, 10, 20, and 30 min of exposure to the HO inhibitor, respectively. In vessels obtained from rats treated with L-NAME, SnMP decreased (P < 0.05) the internal diameter by 13.1 ± 1.6, 18.1 ± 1.3, 22.4 ± 1.3, and 23.3 ± 1.4 µm after 5, 10, 20, and 30 min of exposure to the HO inhibitor, respectively. Importantly, at all time points, the SnMP-induced reduction of internal diameter was greater (P < 0.05) in vessels obtained from L-NAME-treated rats than in vessels obtained from untreated rats. Thus exposure to SnMP brings about constriction of renal interlobular arteries and this effect is intensified in vessels taken from rats treated with an inhibitor of NO synthesis.
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The vasoconstrictor effect of HO inhibitors in isolated, pressurized
resistance vessels has been linked to magnification of the prevailing
myogenic tone (17). To investigate whether SnMP promotes
myogenic behavior and, if so, to determine whether this effect is
conditioned by the status of NO synthesis, we contrasted the effect of
SnMP on the pressure-diameter relationship in isolated renal
interlobular arteries obtained from rats treated and not treated with
L-NAME. As shown in Fig. 4,
stepwise elevation of intraluminal pressure elicited a
pressure-dependent reduction (P < 0.05) of internal
diameter in vessels taken from rats treated and not treated with
L-NAME. Before exposure to SnMP, vessels from rats treated
and not treated with L-NAME did not differ from each other
in terms of internal diameter over the pressure range 20 to 100 mmHg.
The inclusion of SnMP into the superfusion buffer enhanced
(P < 0.05) the pressure-induced reduction of internal diameter in both groups of vessels. In preparations exposed to SnMP,
the internal diameter reduction of vessels obtained from L-NAME-treated rats surpassed (P < 0.05)
that of vessels taken from rats not treated with L-NAME
over the pressure range of 40 to 100 mmHg. Thus SnMP enhances
pressure-induced constriction of renal interlobular arteries and
this effect is further intensified in vessels obtained from rats
treated with a NO synthesis inhibitor.
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To the extent that the vascular response to an inhibitor of HO results
from decreased vascular formation of an HO product capable of
influencing vasomotor function, the increased constrictor effect of
SnMP in renal interlobular arteries of L-NAME-treated rats
may be linked to alterations in the responsiveness of such vessels to
the products of HO activity. This possibility was investigated by
comparing the effects of CO and biliverdin on the internal diameter of
isolated, pressurized renal interlobular arteries taken from rats with
and without L-NAME treatment. As shown in Fig.
5, the inclusion of 1 µmol/l CO into
the superfusion buffer elicited a sustained reduction
(P < 0.05) of internal diameter in vessels taken from
rats not treated with L-NAME. In contrast, 1 µmol/l CO
brought about augmentation of internal diameter in vessels taken from
rats treated with L-NAME. At 0.1 µmol/l, CO was without
effect on the diameter of vessels taken from either rats with and
without L-NAME treatment. Biliverdin at 1 µmol/l did
not affect the internal diameter of renal interlobular arteries obtained from either untreated rats (n = 4; 68 ± 2 and 69 ± 2 µm before and 30 min after, respectively) or
L-NAME-treated rats (n = 4; 67 ± 4 and 68 ± 4 µm before and 30 min after, respectively).
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DISCUSSION |
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The present studies provide information on whether the status of NO synthesis influences the renal vascular response to treatment with an inhibitor of HO. In anesthetized rats, we found that the administration of SnMP increases renal vascular resistance and lowers renal blood flow and that both responses are more intense in rats pretreated with L-NAME than in control rats without pretreatment. Intensification after L-NAME pretreatment of the renal vasoconstrictor and blood flow-lowering effects of SnMP was accompanied by a major elevation in filtration fraction, an observation consistent with SnMP-induced vasoconstriction at postglomerular sites and/or increase of the ultrafiltration coefficient. We also found that the exposure of isolated, pressurized renal interlobular arteries to SnMP elicits sustained reduction of internal diameter and that this response is more intense in vessels taken from L-NAME-treated rats than in vessels from untreated controls. Hence, the results of both the in vivo and ex vivo studies indicate that the expression of renal vasoconstriction after treatment with SnMP is magnified in settings in which NO synthesis is inhibited with L-NAME. Inhibition of NO synthesis also facilitates development of vasoconstriction after treatment with an inhibitor of HO in rat hindlimbs in vivo and in isolated gracilis muscle arterioles (13).
According to the present study, in vitro estimates of renal HO activity in L-NAME-treated rats do not differ significantly from estimates in untreated control rats. Yet, there are reports that exogenous NO decreases HO activity (6, 15), which prompt expectation of enhanced HO product generation during NO synthesis inhibition. In line with this notion, a preliminary assessment of CO in the headspace of urine samples, using gas chromatography-mass spectroscopy (16), indicates that the urinary excretion of CO in anesthetized rats undergoing pretreatment with L-NAME for 48 h (15.3 ± 4.5 pmol/min; n = 4) surpasses (P < 0.05) the CO excretion rate in untreated controls (2.2 ± 0.5 pmol/min; n = 4) (Rodriguez F, Kemp R, and Nasjletti A; unpublished observations). In rats pretreated with L-NAME, augmentation of HO product generation in vivo may condition intensification of SnMP-induced renal vasoconstriction.
Treatment with SnMP magnifies the reduction of renal blood flow produced by renal arterial infusion of norepinephrine or ANG II. This finding fits well with reports that interventions that attenuate the expression or activity of HO enhance the sensitivity of renal arterial vessels to constrictor agonists (16). It is conceivable, then, that the renal vasoconstrictor effect of SnMP is linked, at least in part, to amplification of prevailing neurohormonal constrictor mechanisms. This seems to be the case in anesthetized rats treated with L-NAME, because concurrent treatment with prazosin or losartan prevents SnMP from increasing renal vascular resistance.
Previous studies indicate that the increase in renal vascular resistance elicited by the systemic administration of an inhibitor of NO synthesis relies, in part, on a constrictor mechanism involving the sympathetic nervous and renin-angiotensin systems (3). In line with this notion, we found that the values of renal vascular resistance in rats treated with L-NAME alone exceed the corresponding values in rats concurrently treated with L-NAME and prazosin or L-NAME and losartan. In view of these findings, consideration should be given to the possibility that intensification of the renal vasoconstrictor effect of SnMP in L-NAME-treated rats is conditioned by the recruitment, after inhibition of NO synthesis, of a constrictor mechanism dependent on the sympathetic nervous and renin-angiotensin systems.
According to the present study, the conditioning influence of L-NAME pretreatment on SnMP-induced vasoconstriction is also demonstrable in renal interlobular arteries, isolated and pressurized, under experimental conditions that preclude participation of the sympathetic nervous and renin-angiotensin systems in vasomotor regulation. The constrictor effect of SnMP in these vessels is attributable to amplification of the prevailing myogenic tone, as documented previously in gracilis muscle arterioles (17, 27), because inclusion of SnMP into the superfusion buffer magnifies the reduction of vessel diameter produced by stepwise elevation of intraluminal pressure. This effect of SnMP enhancing myogenic constrictor responsiveness is prominently expressed in renal arteries taken from rats pretreated with L-NAME, which could explain the greater constrictor effect of the HO inhibitor in such vessels.
A priori, the renal vasoconstrictor effect of SnMP may be expected to result from diminished synthesis of one or more HO products capable of effecting vasodilation. Biliverdin does not dilate pressurized renal interlobular arteries and, therefore, it is unlikely that a decreased production of biliverdin contributes to the vasoconstrictor effect of the HO inhibitor. Because renal arteries taken from rats without L-NAME pretreatment respond to exogenous CO with constriction, like gracilis muscle arterioles not treated with an inhibitor of NO synthesis (14), the constrictor effect of SnMP cannot be explained on the basis of diminished CO production in such vessels, unless it is postulated that exogenous CO and CO manufactured by vascular structures have divergent vasomotor activity. On the other hand, exogenous CO was found to cause prompt dilation of renal arteries taken from rats pretreated with L-NAME, which is in agreement with the notion that the constrictor effect of SnMP in such vessels is a consequence of reduced CO production. On the basis of these observations, intensification of the renal vasoconstrictor effect of SnMP in L-NAME-treated rats may be conditioned by the preeminence of renal vasodilatory mechanisms mediated by endogenous CO in settings in which NO synthesis is impaired.
The vasodilatory effect of exogenous CO is ascribed to activation of soluble guanylate cyclase (24) and/or stimulation of KCa channels (16, 24) in vascular smooth muscle, whereas the vasoconstrictor effect is attributed to inhibition of NO production by the endothelium (14). That renal arteries from rats without L-NAME pretreatment respond to exogenous CO with constriction rather than dilation implies that CO-induced inhibition of NO synthesis subserves a vasoconstrictor action that prevails over the direct vasodilatory actions of the gas mediator. On the other hand, when the ability of CO to inhibit NO synthesis is rendered inconsequential, as in renal arteries taken from rats pretreated with L-NAME, the vasodilatory actions of CO are unmitigated. The preferential expression of CO-induced dilation of vessels from rats pretreated with L-NAME may also be due to facilitation of CO-induced stimulation of KCa channels in vascular smooth muscle, an action that is inhibited by NO (25).
From the preceding discussion, it would appear that the net effect of CO, both exogenous CO and CO manufactured by vascular tissues, is determined by the balance between actions on the smooth muscle, to effect vasodilation, and actions on the endothelium, to inhibit NO synthesis and bring about vasoconstriction. If so, the nature and intensity of the vasomotor response elicited by exogenous CO and CO of vascular origin may be determined not only by the status of NO synthesis but also by the relative access of the gas mediator to sites of actions in the endothelium and smooth muscle. For example, in vessels from rats without L-NAME pretreatment, CO manufactured by the smooth muscle may be expected to preferentially promote vasodilation, reflecting unfettered access to sites of action in smooth muscle coupled to suboptimal access to sites of action in the endothelium, whereas exogenous CO and CO produced by the endothelium are expected to preferentially promote vasoconstriction.
In summary, this study demonstrates that the HO inhibitor SnMP produces renal vasoconstriction and that this effect is greatly magnified in rats pretreated with L-NAME. The study also shows that SnMP amplifies the renal vasoconstriction induced by norepinephrine or ANG II, that pretreatment with either prazosin or losartan prevents the HO inhibitor from increasing renal vascular resistance in L-NAME-treated rats, and that CO elicits dilation and constriction, respectively, of renal interlobular arteries taken from rats with and without L-NAME pretreatment. Thus the status of NO synthesis impacts importantly on the regulatory influence of the heme-HO system on the renal vasculature.
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ACKNOWLEDGEMENTS |
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We thank J. Brown for secretarial assistance.
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FOOTNOTES |
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This study was supported by National Institutes of Health Grants HL-18579 and HL-34300 and American Heart Association, New York Affiliate, Grant 0020152T. F. Rodriguez was supported by Fundacion Seneca, Spain.
Address for reprint requests and other correspondence: F. Rodriguez, Dept. of Pharmacology, New York Medical College, Valhalla, NY 10595 (E-mail: francisca_rodrigues{at}nymc.edu).
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. Section 1734 solely to indicate this fact.
10.1152/ajprenal.00435.2002
Received 19 December 2002; accepted in final form 28 February 2003.
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