Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7545
Submitted 21 October 2003 ; accepted in final form 10 December 2003
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ABSTRACT |
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vascular smooth muscle cells; endothelial cells; renal vascular resistance; nitric oxide
There is general agreement that administration of ET-1 produces renal vasoconstriction (38). However, reports on the relative influence of receptor subtypes are highly variable. This ranges from exclusive mediation by ETA receptors (8, 23, 36) to only that of ETB receptors (12, 25, 30), including other studies suggesting a more balanced contribution (4, 11, 18, 28, 31, 41). Furthermore, there is also controversy about the actions of endothelial ETB receptors, ranging from no dilation (10, 12, 18, 27, 40) to strong dilator effects of ETB receptors (1, 2, 5, 28, 31).
The factors governing the relative effects of ETA and ETB receptors and the reasons for the discrepancy of previous findings are difficult to discern. Specific vascular beds, vessel size, species (22, 33), hydration status (34), or strength of stimulation (34) may play a role. Anesthesia does not seem to be a major factor for either the finding of predominant ETA- mediated constriction (7, 8, 23, 36) or predominant ETB- mediated renal vasoconstriction (25, 36). However, an important contributing factor seems to be the experimental strategy employed. The contribution of ETA receptors is based mainly on effects of ETA-specific antagonists. The contribution of ETB-mediated constriction is assessed from either the remnant response after ETA receptor inhibition, the effect of ETB receptor inhibition, or direct stimulation with ETB-specific agonists. It appears that the contribution of dilator and constrictor functions of ETB receptors depends on whether ETB receptors are stimulated alone or in conjunction with ETA receptors. Inhibition of ETB receptors usually augments ET-1-induced constriction in rats (1, 28, 31), rabbits (13), dogs (11), and humans (5), suggesting a net dilator influence of ETB receptors, although exceptions are noted in rats (4, 10, 18). A primary constrictor action of ETB receptors is suggested by the finding that an ETB agonist reduces renal blood flow (RBF) in rats (12, 18, 23, 25, 28, 30, 31, 41), mice (4), and pigs (10). It is important to appreciate that only few studies have used multiple pharmacological combinations of approaches, including ETA antagonist, ETB antagonist, and ETB agonist in a systematic, comprehensive fashion (10, 13, 18, 28, 31). However, even those studies do not give a uniform picture. While the apparently opposing influences of ETB receptors were observed in the same preparation in two of those reports (28, 31), others concluded that the effects of ETB stimulation are limited to either only the dilator (13) or only the constrictor effects (10, 18). A limitation of those studies is that drugs were administered intravenously, with the possibility of confounding systemic effects secondarily to changes in arterial pressure, or investigations were performed in the hydronephrotic kidney model (18) with administration of drugs to the tissue bath, which may differ from the normal situation.
The purpose of our study was to investigate comprehensively the participation of ET receptor subtypes in the renal hemodynamic response to ET-1 by employing a battery of tools (ETA and ETB antagonists, and ETB agonist). Because the tonic influence of endogenous ET-1 is known to be small (24), we concentrated on the response to exogenous ET-1. To allow a more quantitative analysis of direct renal effects than has been done in previous rat studies, we employed injections of vasoactive agents directly into the renal artery to avoid confounding systemic effects. In addition, we conducted paired studies in that ET-1 responses were evaluated during control, experimental, and recovery periods in the same animal.
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METHODS |
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Surgical Preparation
After induction of anesthesia by pentobarbital sodium (Nembutal, 5060 mg/kg body wt ip, Abbott, Chicago, IL), a rat was placed on a temperature-controlled table kept at 37°C. The depth of anesthesia was monitored by the response to ear or toe pinching. The left femoral artery was catheterized (PE-50) for measurement of arterial pressure, and two femoral vein catheters (PE-10) were used for infusion of volume replacement and pentobarbital sodium. The trachea was cannulated (PE-240) to facilitate respiration. Via a midline abdominal incision, the aorta and left renal artery were exposed. A catheter (PE-10 with bent tip) was inserted into the left common iliac artery and advanced until its tip faced the origin to the left renal artery for infusion of pharmacological agents into the renal artery. An ultrasound transit-time flow probe (1RB, Transonic, Ithaca, NY) was placed around the left renal artery and filled with ultrasonic coupling gel (HR Lubricating Jelly, Carter-Wallace, New York, NY, or Surgilube, Fugera, Melville, NY). Urine was drained from the bladder by gravity via a 23-gauge needle. Isoncotic bovine serum albumin (4.75 g/dl) was infused initially at 50 µl/min to replace surgical losses (1.25 ml/100 g body wt), followed by a maintenance rate of 10 µl/min. The renal artery catheter was perfused with normal saline at 5 µl/min. Additional doses of pentobarbital sodium were given (iv) as required. All syringes and catheters in contact with peptides were pretreated with albumin solution (0.5 g/dl) to reduce surface adhesion. At least 60 min were allowed after surgery before the experiments were started.
Measurements
Femoral arterial pressure (AP) was measured via a pressure transducer (Statham P23 DB). Renal blood flow (RBF) was measured by a flowmeter (T 206, low-pass filter, 30 Hz, Transonic). Zero offset was determined at the end of an experiment after cardiac arrest. AP and RBF were recorded on a computer (Pentium III+DataTranslation A/D converter+Labtech Notebook-Pro 10.1) at 100 Hz and stored at 1 Hz as consecutive mean values over 1-s periods. AP was also stored at 100 Hz for later determination of heart rate (HR).
Protocols
The RBF response to a bolus injection of ET-1, sarafotoxin-6C (S6C), or IRL-1620 (IRL) into the renal artery was measured during control conditions as well as during an experimental period, and a recovery period. In the first series of studies, different inhibitors of endothelin receptor subtypes were infused in the experimental period. Five minutes before the bolus injection, the renal arterial infusion rate was increased from 5 to 140 µl/min. A 10-µl bolus of ET-1, S6C, or IRL was then injected into the infusion line by a microinjector valve (Cheminert, Valco Instruments, Houston, TX), and a new recording was started. Because it took 2224 s for the bolus to travel from the injector to the kidney, the initial 20 s of the recording served as the baseline values of AP and RBF. Ten minutes after the ET-1 bolus, the infusion rate was returned to 5 µl/min. The recording was continued until 30 (ET-1) or 15 min (S6C and IRL) after the injection. To achieve ET receptor inhibition, saline was replaced by an infusion of an antagonist (7 nmol/min). AP and RBF were recorded from 1 min before infusion of an antagonist and continuing for an additional 5 min. Subsequently, a new recording was started simultaneously with intrarenal injection of ET or S6C. Thirty to thirty-five minutes were allowed for recovery after each injection of ET-1 and 1520 min after S6C or IRL.
Renal hemodynamic effects of ET-1 during inhibition of ETA receptors. To delineate the contribution of ETA receptors, responses to injection of ET-1 (10 µl x 0.5 µM) into the renal artery were recorded during infusion of saline (control), during infusion of ETA receptor inhibition by BQ-123 (7 nmol/min), and again during infusion of saline (recovery) in intervals of 3035 min, each.
RBF effects of ET-1 during inhibition of ETB receptors. The influence of ETB receptors was tested using the same protocol, except that the ETB-receptor antagonist BQ-788 (7 nmol/min) was used in the experimental period.
RBF effects of ET-1 during combined inhibition of ETA and ETB receptors. To determine the completeness of receptor subtype inhibition, the ET-1 response was assessed during combined infusion of both antagonists (7 nmol/min, each).
Renal hemodynamic response to activation of ETB receptors. ETB receptors were stimulated by injection of the selective ETB-receptor agonist S6C (10 µl x 0.5 µM) or IRL-1620 (10 µl x 0.5 µM).
Time control experiments. To establish similar RBF responses to repeated injections of ET-1, ET-1 was injected three times in intervals of 3035 min.
Completeness of inhibition by ETA- or ETB-receptor antagonists. Vasoconstrictor responses to injection of ET-1 into the renal artery were blocked by BQ-123 at the standard dose (7 nmol/min) and also at 3x and at 10x lower doses (2.3 and 0.7 nmol/min) in random order. Reversibility was confirmed in a recovery period. In other animals, BQ-788 was infused at 7 nmol/min and also at lower doses (2.3 and 0.7 nmol/min) in random order, followed by a recovery period.
Renal vascular effects of S6C before and during inhibition of ETA and ETB receptors. To test the specificity of BQ-123 and BQ-788, reactivity to S6C was evaluated after a control period by infusing either BQ-123 or BQ-788 (7 nmol/min, each), followed by a recovery period.
Dose-response curves for ET-1 and S6C. To test whether dilator effects of ET-1 or S6C might prevail at low concentrations and to compare the responses to selective ETB receptor stimulation to those to stimulation of both ET receptors, each agent was injected into the renal artery in increasing doses (0.02, 0.1, 0.5, 2, and 10 µM x 10 µl) in intervals of 3035 min. Because of the long-lasting effect of ET-1, the doses were given in ascending order. Doses of S6C were given in ascending order at intervals of 1520 min.
Drugs and Chemicals
ET-1, S6C, BQ-123, and BQ-788 were obtained from American Peptide (Vista, CA). BQ-788 was also obtained from Peninsula Labs (San Carlos, CA). IRL-1620 was from California Peptide Research (Napa, CA), and albumin was from Sigma (St. Louis, MO).
Data Analysis
The maximum RBF decrease after each injection was determined off-line by custom-built software (AJ) from the 1-Hz data after smoothing by sliding the average over five values. The change was expressed as percentage of the baseline value. Baseline RBF and AP were determined from the average of the first 20 s of each recording immediately before injection. To obtain mean time courses, the original 1-Hz recordings (without smoothing) from all animals in a group were averaged for each experimental period. HR was determined from the 100-Hz recording of AP off-line. Data are expressed as means ± SE. Statistical significance among groups was tested by ANOVA in conjunction with Holm-Sidak's or Tukey's test for multiple comparisons (SigmaStat 3.00, SPSS, Chicago, IL). In the case of nonnormal distribution, data were transformed by square root before analysis. A paired t-test was used to detect changes within a group. P < 0.05 was considered statistically significant.
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RESULTS |
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Renal Hemodynamic Effects of Endogenous ET-1 Mediated by ETA and ETB Receptors
Renal vascular responses to administration of receptor antagonists are shown in Fig. 1. Inhibition of ETA receptors by infusion of BQ-123 into the renal artery increased RBF by 9 ± 3%. Intrarenal infusion of the ETB antagonist BQ-788 reduced RBF by 9 ± 2%. Infusion of both antagonists together had no net effect on RBF (3 ± 3%, P > 0.2). AP and heart rate were stable during these intrarenal infusions, as was the case in subsequent studies. Collectively, these findings indicate that endogenous ET exerts a tonic renal vasoconstriction via ETA receptors and an offsetting tonic dilator tone via ETB receptors, effects that cancel each other out under basal conditions.
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Renal Hemodynamic Effects of Exogenous ET-1
Injection of ET-1 into the renal artery caused a 25 ± 2% reduction in RBF (in both Fig. 2, A and B). No dilatory phase was evident. The ET-1 maximum response was reached between 1 and 2 min after injection. Recovery was slow; RBF was 18 ± 1 and 15 ± 2% below baseline at 15 and 30 min, respectively (pooled controls before ETA or ETB inhibition). As a result, the next injection of ET-1 was made before complete recovery. RBF recovery at 3035 min was regarded as a reasonable compromise between sufficient recovery and length of an experiment. To demonstrate consistent ET-1 responses during repeated stimulation, time control experiments were conducted. To test reversibility of receptor antagonists, ET-1 was given after antagonist during a recovery period.
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Time Control Series
Repeated injection of ET-1 produced similar degrees of renal vasoconstriction over time: 24 ± 4, 26 ± 1, and 27 ± 3% for injections made at 0 min, 3035 min, and 6070 min, respectively, even though there was a progressive reduction of baseline RBF (from 4.2 ± 0.3 to 3.3 ± 0.2 ml·min-1·g-1, n = 4).
RBF Responses to ET-1 Mediated by ETA Receptors
The ETA-receptor antagonist BQ-123 reduced the constrictor response to ET-1 from 25 ± 2 to 15 ± 1% (P < 0.001, Fig. 2A). The inhibition was reversible as the constrictor response to ET-1 during the recovery period was even larger than during the control period (35 ± 3%, P < 0.001 vs. BQ-123, P < 0.01 vs. control). During ETA inhibition, ET-1 produced transient renal vasodilation lasting <20 s (Fig. 2A, ). Nevertheless, the major sustained 15% vasoconstriction due to ETB receptors was larger than that during inhibition of both ET receptors (7 ± 1%, P < 0.001, Fig. 2A). Note that recovery was accelerated such that RBF returned to baseline by 10 min (Fig. 2A).
RBF Vascular Effects of ET-1 Mediated by ETB Receptors
During BQ-788 inhibition of ETB receptors, the constrictor response to ET-1 was enhanced more than twofold (-60 ± 5 vs. -25 ± 2%, Fig. 2B, P < 0.001). The more pronounced renal vasoconstriction was reversible; the ET-1 response during the recovery period returned to values close to control (-33 ± 4% RBF, P < 0.001 vs. BQ-788). This indicates a net vasodilator role of ETB receptors under these conditions. Despite the overall larger response, the recovery rate was not affected by ETB inhibition; RBF recovered by 29 ± 3 and 43 ± 5% after 15 and 30 min during ETB inhibition compared with control values of 22 ± 8 and 36 ± 11%, respectively (data not shown).
Renal Hemodynamic Response to Activation of ETB Receptors
Administration of the ETB-receptor agonist S6C produced obvious renal vasoconstriction (Fig. 2C). The maximum effect (25 ± 3% decrease in RBF) was similar to that seen in response to ET-1 injection (25 ± 2%). The recovery in the S6C group was faster, reaching 70 ± 11% after 15 min compared with 26 ± 6% for ET-1 (P = 0.001).
Early Hemodynamic Effects of ET-1
During ETA inhibition, ET-1 produced a transient renal vasodilation reaching 3 ± 1% at 3032 s after injection (P < 0.05 vs. baseline, Fig. 3). ET-1 alone elicited no obvious dilator response. However, during ETB inhibition, the ET-1-induced constriction started 510 s earlier than during control (Fig. 3). ET-1-induced RBF reduction reached 10 ± 2% at 3032 s during ETB inhibition (P < 0.001), whereas after ET-1 alone RBF was unchanged at the same time point (0 ± 1%, P > 0.6, Fig. 3). These data suggest a small initial dilator effect of ET-1 that is mediated by ETB receptors.
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Completeness of Inhibition by ETA- or ETB-Receptor Antagonists
To test the efficiency of receptor inhibition using the standard dose (7 nmol/min), receptor antagonists were also infused at lower doses. BQ-123 exerted the same inhibitory effect at the 3x lower dose but was less effective at 10x lower dose (Fig. 4A). BQ-788 displayed a similar degree of inhibition for all doses tested. Thus maximum inhibition was likely achieved at the employed standard doses of both antagonists. The ETB agonist IRL-1620 mimicked the constrictor effects of S6C (41 ± 7 vs. 35 ± 10% after S6C), establishing that the constrictor effect was not agent specific.
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Renal Vascular Effects of S6C Before and During Inhibition of ETA and ETB Receptors
Inhibition of ETA receptors by BQ-123 did not affect ETB receptor stimulation with S6C (24 ± 5 vs. 23 ± 5%, Fig. 5). In contrast, inhibition of ETB receptors by BQ-788 attenuated the response to S6C to 8 ± 2 (Fig. 5). Taken together, these results demonstrate that the inhibitors exerted the expected subtype specificity.
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Dose-Response Curves for ET-1 and S6C
Dose-response curves for ET-1 and S6C revealed renal vasoconstriction at doses above 1 pmol. The maximum constrictor effect of both compounds was similar over all doses (Fig. 6A). There was no difference in sensitivity or reactivity to ET-1 or S6C. However, the recovery rate was faster after S6C (Fig. 6B), a difference that was more pronounced at higher doses.
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DISCUSSION |
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The effects of endogenous ET, based on receptor antagonism during basal conditions, generally agree with the pattern of receptor blockade observed during administration of exogenous ET-1. The ETA-mediated vasoconstriction and the net dilator actions of ETB receptors averaged 510% of basal RBF, consistent with most reports that utilized systemic administration of antagonists (for a review, see Ref. 24). Because of these small changes, quantitative analysis was done from the responses to exogenous ET-1. Most previous publications investigating the effects of exogenous ET-1 have assessed the function of a single receptor subtype, only. Few have systematically investigated receptor actions and interactions in a comprehensive manner in the same study (10, 13, 18, 28, 31). In three of these studies, neither the constrictor (13) nor the dilator component of ETB receptor activation (10, 18) was found, in contrast to our findings. The reason for the differences is not clear, but may be related, at least in part, to species differences between rats and pigs (10) or rabbits (13). The third study was conducted in a chronic hydronephrotic preparation of the rat renal vasculature, and agents were added to the abluminal bath (18). The site of application may be important as the proposed clearance function of ETB receptors may depend on a concentration gradient for ET-1 from the lumen to the outer vascular wall (20). In the two in vivo rat studies (28, 31), results qualitatively similar to our observations were found. A major difference in experimental design was that ET agonists and antagonists were administered systemically in these earlier studies, and the impact of changes in renal perfusion pressure and other extrarenal factors could not be excluded. By design, our more quantitative analysis of local effects utilized intrarenal administration of vasoactive agents. The present in vivo results highlight the local opposing actions of ETB receptor activation in the renal microcirculation, independent of systemic influences. To date, these provocative findings have received relatively little attention and await a unifying explanation. We document that antagonists to ETA and ETB receptors exert near-complete inhibition at the doses employed. Sufficient subtype specificity was demonstrated by the effects of antagonists on the response to S6C (Fig. 5) and the similarity of actions of S6C and IRL stimulation of ETB receptors.
To better understand the apparent discrepancy in results, especially with regard to the opposing actions of ETB receptors, and to gain insight into receptor actions and interactions, three models are presented in Fig. 7. Predicted single-receptor responses are compared with the observed net reductions in RBF. Model A has strictly additive receptor actions such that 1) stimulation of all receptors by ET-1 produces 25% renal vasoconstriction and 2) the constrictor response to ET-1 is reduced from 25 to 13% during ETA receptor inhibition (Fig. 7A). Clearly, the two additional sets of observations do not fit with model A: 1) the 60% constriction produced by selective stimulation of ETA receptors by ET-1 during ETB inhibition is considerably more than the predicted 13% decrease in RBF and 2) the 25% decline in RBF elicited by the ETB-receptor agonist S6C is greater than the predicted 13%. Thus some but not all of our major findings can be accounted for by this simple model. No fixed combination of simply additive contributions can explain all of our observations.
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Model B (Fig. 7B) is based on the two original assumptions and the additional qualification that ETA receptor-induced constriction is about five times greater during ETB receptor blockade than it is when both ET receptor classes are stimulated simultaneously. Unexplained is the observation that the constriction produced by ETB receptor stimulation with S6C (-25%) is about twice the constriction produced by ETB receptor activation by ET-1+ETA antagonist (-13%). Model C considers the possibility that the renal vasoconstriction by ETA and smooth muscle ETB receptors is modulated to a variable extent by endothelial ETB receptors such that their dilator influence is roughly proportional to the amount of the contemporaneous net constrictor response (Fig. 7C).
Reasonable biological explanations, which are not mutually exclusive, exist to explain variations in the constrictor effect of ETA receptors or the variable dilator effect of endothelial ETB receptors. For example, enhanced ETA receptor-mediated constriction would be expected during ETB receptor blockade (model B) if ETB receptors function to clear local ET-1. ET-1 is rapidly removed from plasma with a half-life of <1 min (21, 39), an action that may be largely, if not exclusively, due to ETB receptors (16, 21), although the precise anatomic location of the receptors responsible for clearance is not known. Because receptor binding is extremely strong and nearly irreversible, ET-1 may preferentially bind to endothelial receptors exposed to the highest concentration and closest to the production site (20). Thus disruption of the postulated ETB receptor clearance function may allow more ET-1 to be available to activate ETA receptors. However, the vast majority of plasma clearance occurs in the lung, whereas the kidneys contribute only 10% (42), and, of this, 50% seems to be independent of ET receptors (21). Furthermore, the potential impact of renal ET clearance by ETB receptors on renal vascular control is limited by the fact that most ET receptors, particularly the ETB subtype, are located in the renal medulla (8, 25), separate from cortical resistance vessels. Therefore, it is uncertain whether immediate renal clearance is of sufficient magnitude to account for the observed strong enhancement of the ETA response localized to the renal microcirculation.
A second possibility is that the dilator effect of endothelial ETB receptors is substantially larger during concurrent ETA receptor stimulation than during stimulation of ETB receptors alone (model C). Such a buffering action may primarily oppose vasoconstriction without the need to produce vasodilation on its own. In this regard, the magnitude of the dilator-like effect may be covert, absent when there is little constriction to offset, and varying as a function of the strength of concurrent constriction. Accordingly, in the absence of ETA-mediated constriction, a smaller fraction of the ETB dilator-like action would be evident. The magnitude of the buffering depends on the relative contribution of ETA and ETB receptors to the constrictor effect. Previous studies have shown that renal NO can exert strong buffering of constrictor agents without exhibiting net dilation on its own (9). It is reasonable to propose that such a mechanism is operative in the present study, with endothelial ETB receptors effectively counteracting ET-1-induced renal vasoconstriction. In addition, differences have been reported between the intracellular signaling pathways of ETA and ETB receptors on smooth muscle cells. It is therefore conceivable that the buffering effect of NO may preferentially affect ETA receptor-mediated constriction (3), which may also explain variable ETB-mediated dilator effects as a function of concomitant ETA receptor stimulation.
A finding not accommodated in any of the models is that the response to S6C or IRL-1620, selective ETB agonists, was almost the same as that to activation of both ET-1 receptor subtypes (25% reduction in RBF). We observed that the renal vasculature exhibited the same sensitivity and reactivity to selective ETB receptor stimulation and to dual-receptor activation by ET-1. There are mixed results on this point in the literature. Previous rat RBF studies report that the relative strength of the vasoconstrictor response to ETB receptor stimulation varies, being two to three times smaller (31), equal to (12, 41), or twofold greater than, that of ET-1 (25). Others report variability depending on dose (30). It is not clear why S6C and ET-1 produce a similar degree of renal vasoconstriction and why the amount is greater than the response to ET-1 during ETA inhibition. There is an equal distribution of ETA and ETB receptors reported for preglomerular renal microvessels (15, 17; unpublished observations). We found that the RBF response to S6C is not affected by ETA antagonism, so tonic stimulation of ETA receptors seems an unlikely explanation as is nonspecific activation of ETA receptors by S6C. Also possible is preferential activation of ETB receptors on smooth muscle vs. endothelial cells by S6C and IRL-1620. Given that ETB receptors are formed from the same gene (32), differential activation would be surprising. Although indications for slight differences in the susceptibility of the two ETB receptor locations to different ETB antagonists have been reported (26, 28), the similarity of the responses to ETB agonists S6C and IRL-1620 in the present study speaks against a major difference in sensitivity of endothelial and smooth muscle ETB receptors, at least at the employed doses of ETB agonists. Finally, it has been suggested that the relative influence of the dilator effect of endothelial ETB receptors is smaller or absent at lower doses of ET-1 (35, 36), possibly due to a higher affinity of endothelial than smooth muscle ETB receptors for ET-1. However, binding curves for ET-1 are typically monophasic, including renal microvascular tissue (15, 17), thus giving no indication for different affinities of endothelial and smooth muscle receptors. In addition, the dose-response relationships in the present data showed similar strength of ET-1 and S6C responses at all doses and failed to detect a significant dilator effect at any dose (Fig. 6). Accordingly, at least a major shift in the influence of the dilator effect of endothelial ETB receptors with the dose of ET-1 seems unlikely from the present data.
Another noteworthy finding is the faster recovery after stimulation of ETB receptors (ET-1+ETA inhibition or S6C or IRL-1620) compared with stimulation of both ET receptors (ET-1 alone) or stimulation of ETA receptors (ET-1+ETB inhibition). This time course has been reported previously (1, 5, 19, 31). The reason for the difference in the recovery rate is not clear. In view of the exceptionally tight ligand-receptor binding (20), the sluggish reversibility may be related to receptor trafficking (29). Internalized ETA and ETB receptors may experience different fates such as preferential lysosomal destruction of ETB receptors and recycling of ETA receptors to the cell surface (6).
In conclusion, our comprehensive study provides new insight into the mechanisms by which ETA and ETB receptors contribute to renal vasomotor responses in the normal kidney of euvolemic rats. Our studies highlight a complex interaction between ETA and ETB receptors that impact on their respective function. Selective activation of ETB receptors mediates net renal vasoconstriction. In marked contrast, ETB receptors provide a strong dilator-like influence to buffer constriction produced by ETA receptor stimulation. Opposition of ETA-mediated constriction may be due to the ability of ETB receptors to clear ET from the plasma and lower the effective concentration available for ETA receptors. Another possibility that is not mutually exclusive is that endothelial ETB receptors, presumably via release of endothelial nitric oxide, effectively attenuate the constrictor responses to ETA receptor stimulation rather than eliciting frank dilation on their own. The extent to which ETB receptors on endothelial cells and smooth muscle cells contribute to the proposed interaction by either or both of these mechanisms awaits further investigation.
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ACKNOWLEDGMENTS |
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This work was supported by National Heart, Blood, and Lung Institute Grant HL-02334.
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FOOTNOTES |
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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.
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REFERENCES |
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