Different studies demonstrate that endothelins are potent renal vasoconstrictors that enhance renovascular resistance and reduce glomerular filtration rate (1-6). These effects have been described in several animal species, including rabbits (6), dogs (7-9), and rats (1-4). The decrease of glomerular filtration rate by endothelins suggests an important contractile effect in the preglomerular vasculature. Different authors proposed that renovascular effects of endothelins are mainly preglomerular (2,6,9), although a predominant action on the efferent arteriolar resistance has been suggested (4,5,10). The direct visualization of endothelin vasoactive effects in the hydronephrotic rat kidney preparation indicates higher contractile responses in afferent than in efferent arterioles (11,12). However, in isolated rabbit afferent and efferent arterioles, contractility to endothelins is similar but slightly higher in the efferent ones (13). Taken together, all these data suggest that endothelins contract either the pre- and postglomerular vasculature, therefore increasing renovascular resistances by acting on the entire vascular tree of the kidney (14-16). In rabbit and human kidney, endothelin vasoconstrictor effects are mediated by endothelin ETA receptors (17-19), whereas in rat, an important role for ETB receptors was described (20-24).
The contractile effects of endothelins on the renal vasculature may be modulated by endogenous vasoactive substances, like prostanoids. Thus the inhibitors of cyclooxygenase increase the vascular contractility to endothelin-1 in kidneys from dogs (10,25,26), rabbits (17), and rats (27) but reduce the endothelin-3-induced renal vasoconstriction in dogs (26). Other suggest that the tonic component of the endothelin-1-evoked contractions in rat afferent arterioles may involve the release of vasoconstrictor cyclooxygenase products (10).
Despite the proposed role for endothelins in cardiovascular and renal diseases (15,16), the renal effects of these peptides in hypertension are not clear. In spontaneously hypertensive rats (SHR), a higher sensibility of the renal vasculature to endothelins has been suggested in comparison with normotensive Wistar-Kyoto rats (WKY) (1,28). Other authors do not report differences between WKY and SHR in the renovascular actions of endothelin-1 (2), or even a lower vasoconstrictor response in SHR kidneys has been reported (29). In addition, the renal SHR production of endothelin-1 is reduced (30,31). However, endothelin-receptor blockade within the SHR kidney improves either renal hemodynamics or excretory function (32). The possible intrarenal vascular mechanisms modulating endothelin effects in SHR are not known, but in those pathologic situations affecting renovascular resistances in rats, like diabetes (33,34), hypercholesterolemia (35), or hypertension (36-42), evidence has been presented for an enhanced role of vasoconstrictor prostanoids, such as thromboxane A2 or prostaglandin H2.
Therefore our work was designed to investigate the contractile effects of endothelin-1 on the afferent arterioles of WKY and SHR, as well as the modulation of these responses by cyclooxygenase blockade or by the prostacyclin analog iloprost. For this purpose, the juxtamedullary nephron preparation was employed, which allows visualizing the entire renal preglomerular vasculature preserving nephron function and the relation between vascular and tubular structures (43,44).
The study was performed in male WKY and SHR (350-450 g; Iffa-Creddo, Domaine des Oncins, L'Abresle, France). The experiments were performed in control or hypertensive animals of matched ages (16-20 weeks). The animals were maintained for 4 weeks (at the facilities of the Facultad de Medicina Autónoma de Madrid) with regular chow. The animals were anesthetized with 70 mg/kg of sodium pentobarbital, administered i.p. Mean arterial pressure was registered by cannulating the carotid artery and connecting the cannula to a pressure transducer (Letica, Barcelona, Spain) with a recorder (Letica Polygraph 2006).
Rat juxtamedullary nephron preparation
A described procedure (44) was followed, modified from that described by Casellas and Navar (43). A midline abdominal incision was made, and a double-lumen catheter was introduced in the abdominal aorta and placed in the left renal artery for perfusion of the kidney. One channel was connected to a peristaltic pump (Gilson HP-4; Villiers le Bel, France) for perfusion, whereas the other was used for continuously measuring perfusion pressure. The kidney was perfused with Krebs-Henseleit solution (KHS) containing 5% bovine serum albumin (Sigma, St. Louis, MO, U.S.A.). Before the addition of albumin, the KHS was oxygenated with a mixture of 95% O2 and 5% CO2 to maintain a pH of 7.4. After cannulation of the left renal artery, the renal vein was tied off near the vena cava and incised to drain renal effluent. The left kidney was then removed from the animal, placed in an organ chamber at 37°C, and superfused with oxygenated KHS (not containing albumin). The kidney was continuously perfused with KHS and 5% albumin throughout the ensuing dissection procedure and the experiment. The osmotic pressure of the perfusate was between 289 and 300 mOsm/L. During the experiment, the perfusion pressure was maintained constant at 100 mm Hg with a peristaltic pump with pressure servocontrol (Living System Instrumentation, Burlington, VT, U.S.A.) connected to a computerized recorder (MacLab 4 for Apple Macintosh; Analog Digital Instruments Ltd., Castle Hill, Australia).
The kidney was hemisected, being careful to retain the renal papilla intact within the perfused tissue, in the anterior portion of the kidney. Most of the renal cortex was resected by incisions on each side of the papilla along the lateral fornices. The renal papilla was carefully reflected under a binocular microscope (Wild M8; Wild Heerbrugg, Heerbrugg, Switzerland), exposing the pelvic surface, and adipose and connective tissue that normally covers the inner cortical surface. After removing this overlying tissue, tubules, glomeruli, and related vasculature of the juxtamedullary nephrons were exposed. The arterial supply feeding the exposed microvasculature (10-20 glomeruli) was isolated by tying off all other branches of the renal vasculature with polyethylene ligatures (Ethicon Microsurgical, 35 μm in diamter; Edinburgh, U.K.). Trypan blue (0.1%; Sigma) was added to the perfusate to provide contrast to the perfused vascular segment. We documented flow through the system by observing a color change in the glomeruli from opaque to blue after addition of trypan blue. After completion of the dissection procedure, a perfusion pressure of 100 mm Hg was applied to the preparation for 90 min before the administration of any drug.
Measurements of the vascular diameter were made with a high-resolution binocular microscope, coupled to a video system composed of a camera (Sony CCD-Iris; Sony Corporation, Tokyo, Japan), TV monitor (Sony KX-14CP1), VCR (JVC HR-D950EH; Victor Company of Japan, Tokyo, Japan), and a TV micrometer system (Brian Reece RMC-D4; The Industrial State, Berkshire, U.K.). The measuring system was calibrated by using a stage micrometer (smallest division, 10 μm). Final magnification on the video screen was ×350. Repeated measurements of the vessel images at unmodified pressure conditions yielded diameter values that were reproducible to within 0.2 μm. Both in WKY and SHR, the renal artery divides into two to four main arcuate arteries. Most of the afferent arterioles originated directly from arcuate arteries, but a fraction arose from first-order branches of arcuate, named interlobular arteries. The vascular segments analyzed were the afferent arterioles within 200 μm of the glomerulus.
Experimental protocols and statistics
After the 90-min equilibration period, the basal diameter of the selected afferent arterioles was determined. In some preliminary experiments, 10 μM norepinephrine (Sigma) was added to the perfusate, and the same vessels were measured after 10 min of drug effect. Concentration-dependent curves to endothelin-1 human, porcine (100 pM-1 μM; Sigma), or to iloprost (1 nM-1 μM; a generous gift from Schering AG, Berlin, Germany) were performed by adding these agents to the perfusate. After every drug concentration, 10 min was allowed before measuring afferent diameters. In separate experiments, the effects on endothelin-1-induced contractions of 1 μM nifedipine (Bayer AG, Wuppertal, Germany), 20 μM indomethacin (Sigma), and 10 nM, 100 nM, or 1 μM iloprost were analyzed by superfusing these drugs 15 min in advance and during endothelin perfusion. In these experiments, the afferent diameter was also measured after 10 min of superfusion with the respective drug and before endothelin administration.
The vascular-diameter changes are expressed as a percentage of the respective basal diameter of each vessel in the absence of any drug. Mean values ± SEM are presented. Statistical significances between concentration-dependent curves were determined by using a two-way analysis of variance. Differences between single diameter changes were analyzed by using a paired Student's t test. A value of p < 0.05 was considered significant.
Solution and drug preparation
The compostion of the KHS (in millimoles) was NaCl, 115; CaCl2, 2.5; KCl, 4.6; KH2PO4, 1.2; MgSO4.7H2O, 1.2; NaHCO3, 25; glucose, 11.1; and Na2EDTA, 0.03. Stock solution (10 mM) of endothelin-1 was made in distilled water containing 0.1% bovine serum albumin. Stock solutions (10 mM) of iloprost were made in distilled water, whereas nifedipine (10 mM) was dissolved in 99.5% ethanol, and indomethacin (10 mM) in distilled water with Na2CO3 (1.5 mM). Norepinephrine stock solution was made with 0.9% NaCl-ascorbic acid (0.01% wt/vol). These solutions were kept at -20°C, and appropriate dilutions were made on the day of the experiment. Nifedipine was protected from the light, and the ability of the vehicle ethanol to modify contractile responses was discarded.
Mean arterial pressure
Mean arterial pressure was 115.7 ± 4.9 and 208.2 ± 4.1 mm Hg for WKY (n = 34) and SHR (n = 39), respectively (p < 0.05).
Afferent contractility to endothelin-1: Interference by nifedipine
At a basal perfusion pressure of 100 mm Hg and in the absence of any drug, vascular diameter of afferent arterioles in WKY juxtamedullary nephron preparations was 38.4 ± 0.8 μm (186 measurements from 30 animals), whereas in SHR was 35.1 ± 0.9 μm (218 measurements from 37 animals; p < 0.05). When endothelin-1 (100 pM to 1 μM) was perfused into the pressurized renal vasculature, contractile responses of the afferent arterioles were observed, without statistical differences between WKY and SHR prepararions (Fig. 1). Although nonsignificant, there was a tendency toward a higher response in SHR; thus maximal contraction reached by endothelin-1 reduced afferent diameter by 3.43 ± 0.88 μm in WKY and by 5.60 ± 0.75 μm in SHR preparations, respectively (p = 0.069). These responses were in the range of those obtained by the infusion of 10 μM norepinephrine, which contracted by 3.21 ± 0.57 μm in WKY (22 measurements in three experiments) and by 3.59 ± 0.44 μm (17 measurements from four experiments) in SHR, respectively.
The pretreatment with 1 μM nifedipine did not change basal diameter in WKY afferent arterioles but increased the caliber of this vasculature in the SHR juxtamedullary nephron preparation (Table 1). Nifedipine abolished endothelin-1-induced contractions in the afferent arterioles of either WKY or SHR kidneys (Fig. 2).
Effects of indomethacin on the endothelin-induced afferent contractions
The preincubations of the juxtamedullary nephron preparations from WKY and SHR with 20 μM indomethacin reduced slightly the basal diameter in both strains (Table 1). In addition, when indomethacin was present, the afferent contractility to endothelin-1 was significantly increased in the WKY preparations but antagonized in SHR kidneys (Fig. 3).
Effects of iloprost on endothelin-induced afferent contractions
The perfusion of iloprost (1 nM-1 μM) into the pressurized renal vasculature did not modify the basal diameters of the afferent arterioles in the WKY preparations, whereas a small vasodilatation was observed in the SHR afferent vasculature (Fig. 4).
In a different set of experiments, the vessels were superfused for 15 min with iloprost at concentrations of 10 nM, 100 nM, or 1 μM. In these conditions, basal diameters of afferent arterioles were not modified, either in WKY or SHR preparations (Table 1). When the curves of endothelin-1 were measured in the presence of iloprost, the contractile effects of the peptide were abolished by even the lowest concentration of 10 nM iloprost (Fig. 5).
The ability of endothelins to increase rat renovascular resistance has been widely reported (1-4,11,12). In these experiments, by using the rat juxtamedullary nephron preparation, endohelin-1 induced concentration-dependent reduction of afferent diameters either in WKY and SHR kidneys. The magnitude of these contractile responses was rather similar in both types of preparations and in the same range of those obtained by norepinephrine, the latter being consistent with those observed in previous studies with the same technique in WKY or SHR kidneys (44,45). Therefore these results do not support a very potent effect of this peptide on the preglomerular vasculature, as proposed by other researchers. The reasons for such discrepancies are not entirely clear, but they may be based on differences in the experimental approach. In contrast with other techniques, which use cortical vessels, we studied afferent arterioles from juxtamedullary nephrons. In addition, the surrounding renal tissue is preserved with this technique and has an important role in determining afferent reactivity (44,46). Indeed, the results obtained with hydronephrotic kidneys or isolated afferent arterioles, concerning either basal diameters or vasoconstrictor responses (47,48), are slightly different from those of the studies using the rat juxtamedullary nephron preparation (44-46).
By using the rat juxtamedullary nephron preparation, the efferent arterioles cannot be visualized, so we could not check the effect of endothelin-1 on this vascular segment. Nevertheless, our results do not support a predominant preglomerular action of endothelin, but rather they allow speculation about important post-glomerular effects of endothelin-1, in agreement with that proposed by several authors for the rat kidney with micropuncture studies (4,5,10). Furthermore, experiments with isolated rat (10) and rabbit (13) afferent and efferent arterioles also indicate a slightly greater sensitivity of the efferent vessels to the contractile effects of endothelin. However, other experimental approaches suggest a higher contractility to endothelin in afferent rather than in efferent arterioles (11,12). Therefore, it seems reasonable to suggest that endothelins increase renovascular resistances by acting on either the pre- or postglomerular vasculature, the differences reported being dependent on the techniques used.
In our experiments, the afferent contractile responses induced by endothelin-1 were inhibited by nifedipine, either in WKY and SHR preparations, indicating its dependence on extracellular calcium. These results were in agreement with previous reports showing that renovascular effects of endothelins in rats are blocked by calcium antagonists, in both in vivo (49,50) and in vitro experiments (11). Calcium blockers also antagonize endothelin-1-induced contractions in isolated rabbit afferent arterioles (13), as well as the renovascular effects of the peptide in humans (51). All these effects are consistent with the reported predominant antagonism of preglomerular vasoconstrictions by calcium blockers (52-54). Nifedipine effects were higher in the SHR juxtamedullary preparations, which showed a marked afferent vasodilatation in the presence of the calcium blocker. It is important to remark, however, that this enhanced action of the dihydropyridine was essentially caused by a relaxation that occured in basal conditions before the administration of endothelin. Indeed, previous basal diameters were augmented by nifedipine in SHR but not in WKY preparations. Furthermore, in the entire afferent population studied, either in WKY and SHR kidneys, we observed that the diameters in basal conditions were significantly less in the hypertensive strain at the same perfusion pressure of 100 mm Hg. These data agree with the enhancement of renovascular resistances in SHR proposed by several researchers (46,55) and may be on the basis of the higher sensitivity to calcium blockers of the SHR renal vasculature (45,56).
There is different speculations about the possible role for endothelins in hypertensive or renal diseases or both (16). However, the effects of endothelins in the SHR renal vasculature are not clear. In isolated segments from main renal arteries (1) and isolated perfused kidneys (28), a higher sensitivity of the SHR renal vasculature to endothelin-1 in comparison with WKY has been described, although maximal responses are similar. Other researchers found that the endothelin-1-induced decrease of renal blood flow is similar between anesthetized WKY and SHR (2), or it is reduced in SHR (29). In addition, a decreased endogenous endothelin production in the SHR kidney compared with age-matched WKY has been reported (30,31). However, an important support for a role of endothelins in modulating SHR intrarenal vascular resistances is the enhancement of glomerular filtration rate and renal blood flow after infusion of endothelin-receptor antagonists in the SHR kidney (32).
In our experiments, a tendency to higher contractions in response to endothelin-1 was observed in afferent arterioles from SHR juxtamedullary preparations, although there were no statistical differences. It is important, however, that both types of preparations were identically perfused throughout the experiments at a constant pressure of 100 mm Hg, which is far from the SHR renal prefusion pressure in vivo. Despite the similar contractile responses to endothelin in control conditions, after incubation of the WKY and SHR juxtamedullary nephron preparations with indomethacin, the endothelin-1-induced contractions were markedly different. In both strains, a small but significant reduction in basal diameters was observed, suggesting there is some vasodilatory tone dependent on cyclooxygenase derivates. Furthermore, the administration of endothelin-1 in these conditions produced a higher contractility in the WKY afferent arterioles, whereas the vasoconstrictions observed in SHR vessels were abolished. These results could be explained if indomethacin were blocking the production of different cyclooxygenase derivatives in WKY and SHR kidneys. Thus it could be speculated that, in normotensive WKY juxtamedullary preparations, endothelin-1 releases vasodilator prostanoids, like prostacyclin or prostaglandin E2, whereas in SHR preparations, vasoconstrictor prostanoids may predominate, such as prostaglandin E2α or thromboxane A2.
The ability of endothelin-1 to stimulate the renal production of vasodilator prostanoids, mainly prostacyclin, has been demonstrated in dogs (7,25,26) and rabbits (17,57); in these studies, renovascular effects of endothelin-1 were potentiated after cyclooxygenase blockade, suggesting that prostacyclins negatively modulate the contractility to endothelin-1. These kinds of effects, however, may be different depending on the studied species or the type of endothelin used. In the dog kidney, endothelin-3 releases thromboxane A2, the contractions evoked by the peptide being abolished by cyclooxygenase blockade (26). In kidneys from Sprague-Dawley rats, an enhancement of renovascular constriction to endothelin-1 has been reported, similar to that observed in dogs and rabbits (27). Nevertheless, other researchers demonstrated that the kidneys from normotensive Sprague-Dawley and Wistar rats may release, in response to endothelin-1 and endothelin-3, either vasodilator (prostacyclin and prostaglandin E2) or vasoconstrictor prostanoids (prostaglandin F2α), respectively (20,58). The release of these cyclooxygenase derivatives by endothelins appears to be mediated through activation of a mixed population of both ETA and ETB receptors (20). Additionally, it has been reported in normotensive Wistar kidneys that the maintenance of long-lasting contractions to endothelin-1 is dependent on cyclooxygenase activity, likely by the production of prostaglandin F2α but not of thromboxane A2(10).
An enhanced role for vasoconstrictor prostanoids has been proposed in the rat renal vasculature when pathologic conditions occur, like diabetes (33,34), hypercholesterolemia (35), or hypertension (36-42). In SHR, by using different vasoactive agents, evidence has been presented either for an impairment in the renal vasodilatations or for an increase in the renal vasoconstrictions due to cyclooxygenase derivates; indeed, there is a reduced production or vasodilatation or both mediated by prostacyclin or prostaglandin E2, as well as an enhancement of the contractility because of prostaglandin H2 or thromboxane A2(36-42). In addition, determination of prostanoid derivatives in the perfusate of isolated kidneys from WKY and SHR indicates a higher basal release of prostacyclin and prostaglandin E2 in WKY, whereas an enhancement of thromboxane A2 and prostaglandin F2α is obtained in SHR kidneys (59). Therefore it seems reasonable to suggest that the abolition of the endothelin-1 contractility in the juxtamedullary nephron preparations from hypertensive animals by cyclooxygenase inhibition likely reflects the predominance of those types of vasoconstrictor prostanoids in the renal vasculature of SHR.
Further to investigate the modulation by prostanoids of the endothelin-1 renal contractility, experiments were designed in the presence of the prostacyclin analog iloprost, which possesses important hemodynamic effects in rats and dogs, including antihypertensive actions and renal vasodilatation (60,61). The administration of iloprost in adult WKY and SHR induces similar enhancements of renal blood flow; after cyclooxygenase blockade with indomethacin, however, this effect further increases in SHR but not in WKY (40). Constrasting with these previous reports, concentration-dependent administration of iloprost did not modify basal diameters of the afferent arterioles in the WKY juxtamedullary nephron preparation, whereas a weak vasodilatatory effect was observed in the SHR afferent vasculature. In both WKY and SHR preparations, single administrations of iloprost (10 nM-1 μM) previous to the concentration-dependent curves to endothelin, did not affect basal afferent caliber, further indicating that iloprost, at least in our experimental conditions, has no very potent vasorelaxant properties by itself, in the absence of other vasoactive substances.
Nevertheless, the endothelin-1-induced contractility of the afferent arterioles was abolished by iloprost, even at the lowest used concentration (10 nM), either in WKY and SHR kidneys. With the highest concentration of iloporst, endothelin even caused relaxant responses in the afferent arterioles, which were significantly greater in SHR preparations. Therefore despite its limited role as a direct renal vasodilator, iloprost seems to be very effective in modulating the vasoconstrictions induced by endothelin-1 in the rat kidney vasculature, especially in hypertension. Indeed, it may be speculated that in situations with a defective production of prostacyclin or prostaglandin E2, an enhancement of the renal vasoconstrictor ability of endothelins will occur, which may be relevant in those diseases in which a pathophysiologic role for these peptides has been proposed (15,16).
Our results do not fully agree with previous data from other researchers, who reported more prominent renal effects for iloprost in normotensive rats. Thus in normotensive Wistar rats, iloprost decreases the renal vasoconstrictor effects of angiotensin II, norepinephrine, or thromboxane A2(62). In addition, the treatment with iloprost reduces the renal vasoconstrictor responses to angiotensin II in WKY but not in SHR, although the number of prostacyclin receptors is similar in the kidneys from both strains (41). Similarly, iloprost reduces the contractions evoked by thromboxane A2 in the WKY but not in SHR renal vasculature, although the recovery from vasoconstrictions was facilitated in both strains (42). In none of these articles, however, is endothelin used as a renal vasoconstrictor; indeed, to our knowledge, the interactions in vivo between endothelins and iloprost or other prostacyclin analogs have not been yet studied.
In conclusion, although the contractions evoked by endothelin-1 were similar in the afferent arterioles from both WKY and SHR juxtamedullary nephron preparations, the responses observed in the hypertensive strain were more sensitive to either the calcium channel blockade with nifedipine or the vasorelaxant effects of the prostacyclin analog iloprost. In addition, the contractility to endothelin-1 appears to be modulated by vasodilator prostanoids in the renal WKY vasculature, whereas vasoconstrictor cyclooxygenase derivatives seem to be involved in the responses elicited by the afferent arterioles of SHR kidney. This may be relevant for elucidating the possible role of endothelins in the regulation of the renal blood flow in hypertension.
Acknowledgment: This study was supported by grants from F.I.S.S. (93/0916E and 95/1954), Comunidad de Madrid (CAM I + D0017/94), SHESA (PFIF 44/87-10020), and Bayer España.
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