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Smooth Muscle Research Group, Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 4N1
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The renal microvascular actions of ACh were investigated using the in vitro perfused hydronephrotic rat kidney. ACh reversed ANG II-induced vasoconstriction in the afferent and efferent arteriole by 106 ± 2 and 75 ± 5%, respectively. Inhibition of nitric oxide synthase [NOS; 100 µmol/l NG-nitro-L-arginine methyl ester (L-NAME)] and cyclooxygenase (COX; 10 µmol/l ibuprofen) prevented the sustained response of the afferent arteriole but did not reduce the magnitude of the initial dilation (97 ± 7%). However, NOS/COX inhibition abolished the response of the efferent arteriole. The underlying mechanisms mediating this endothelium-derived hyperpolarizing factor (EDHF)-like response were characterized using K channel blockers. Ba (100 µmol/l), tetraethylammonium (1 mmol/l), and ouabain (3 mmol/l) had no effect, arguing against a role of an inward rectifier K channel, large-conductance Ca-activated K channel, or Na,K-ATPase. Charybdotoxin (10 nmol/l) and apamin (1.0 µmol/l) attenuated the response when administered alone (63 ± 7% and 37 ± 5%, respectively) and abolished the response when coadministered (0.1 ± 1.0%). These findings indicate that, as in other vascular beds, the renal EDHF-like response to ACh involves K channels that are sensitive to a combination of apamin and charybdotoxin. Our finding that EDHF modulates preglomerular, but not postglomerular, tone is consistent with the evolving concept that vasomotor mechanisms in cortical efferent arterioles do not involve voltage-gated Ca entry.
calcium-activated potassium channels; voltage-gated potassium channels; inward rectifier potassium channels; tetraethylammonium; apamin; charybdotoxin; 4-aminopyridine; barium
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ENDOTHELIUM-DEPENDENT VASODILATION is an important regulatory mechanism in the kidney, and a disruption of this process profoundly alters renal function (16, 44). Agents such as ACh elicit renal vasodilation through the actions of factors released from the endothelium, including nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor(s) (EDHF). The molecular identity of a putative EDHF is not resolved, but potential candidates range from endothelium-derived K ions to arachidonic acid metabolites (13, 33). Furthermore, it has been suggested that in resistance vessels endothelium-dependent hyperpolarization may not involve a released factor but rather may be mediated via myoendothelial gap junctional communication (4, 23, 35). Differing regions of the circulation exhibit considerable heterogeneity in regard to the nature of EDHF, its contribution to endothelium-dependent vasodilation, and the underlying ionic mechanisms (28, 39). Since its discovery, the role of NO in the regulation of renal hemodynamics has received considerable attention. However, the nature of EDHF in the kidney and its role in the regulation of the renal microcirculation have not received the same attention.
Information on the renal microvascular actions of EDHF is of particular interest. The afferent and efferent arterioles control the glomerular inflow and outflow resistances and thus have opposing effects on the pressure within the intervening glomerular capillaries (PGC), a major determinant of glomerular filtration rate (GFR). Hyperpolarization alters vascular tone predominantly by influencing the activity of voltage-gated Ca channels (30). The afferent and efferent arterioles differ in regard to their dependence on this type of Ca channel. We recently demonstrated (26) that ANG II stimulates a voltage-activated and nifedipine-sensitive Ca influx in the afferent arteriole but activates a voltage- and nifedipine-insensitive Ca influx in the efferent arteriole. These observations are consistent with the previous findings that ANG II elicits depolarization in the afferent arteriole but not in the efferent arteriole (24) and that pharmacological inhibition of voltage-gated Ca channels blocks the contractile responses of afferent, but not efferent, arterioles (2). Accordingly, one might anticipate that EDHF would exhibit segment-specific actions on the renal vasculature, selectively affecting the afferent arteriole. If correct, this postulate would have important implications in regard to the role of EDHF and its effects on PGC and GFR. Although previous studies suggested that an EDHF contributes to the renal actions of endothelium-dependent vasodilators, the pharmacological characteristics of a putative renal EDHF are not well defined, and the segmental actions of EDHF on the afferent and efferent arterioles have not been fully examined.
In the present study, we used an in vitro perfused hydronephrotic kidney preparation to investigate ACh responses of renal afferent and efferent arterioles. In previous investigations using this model, our laboratory characterized the determinants of the afferent arteriolar response to ACh (18) and examined the cGMP-dependent and -independent effects of NO on the afferent arteriole (40). The present study focuses on the segment-specific actions of the EDHF-like component of ACh-induced vasodilation and the characteristics of the underlying mechanisms.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Unilateral hydronephrosis was induced to facilitate direct observations of renal afferent and efferent arterioles (5, 40). The left ureters of young (6-7 wk) male Sprague-Dawley and Long-Evans rats were ligated under halothane-induced anesthesia to induce hydronephrosis. The hydronephrotic kidneys were harvested after 6-8 wk. The left renal artery was cannulated in situ, and the kidney was excised and transferred to a heated chamber on the stage of an inverted microscope without disruption of perfusion. The renal perfusate consisted of Dulbecco's modified Eagle's medium (GIBCO Life Technologies, Gaithersburg, MD) containing (in mmol/l) 30 bicarbonate, 5 glucose, and 5 HEPES. The perfusate was equilibrated with 95% air-5% CO2, and temperature and pH were maintained at 37°C and 7.40, respectively. For most studies, a single-pass perfusion was employed. The medium was pumped on demand through a heat exchanger to a pressurized reservoir connected to the renal arterial cannula. Perfusion pressure was monitored within the renal artery and maintained by adjusting the pressure within the perfusion reservoir. Kidneys were allowed to equilibrate for at least 1 h before study.
Kidneys were perfused at a constant renal arterial pressure of 80 mmHg. A fiber optic probe was used to stabilize and transilluminate a portion of the membranous renal cortex for vessel observations. The vessels studied originated from interlobular arteries <50 µm in diameter and were thus of cortical origin. Diameters were measured by on-line image processing. Afferent diameters were measured near the midpoint. Diameters of the corresponding efferent arterioles were measured within 20 µm of the glomerular origin. Vessel segments (10-20 µm in length) were scanned at a rate of ~3 Hz. Measurements were obtained at each pixel (30-40 measurements over the entire segment length) and averaged for each determination. Mean diameters were then averaged over the plateau of the response. Typically, each final value was derived from the mean of ~100 individual measurements of the mean diameter obtained over the length of the vessel segment.
All agents were added directly to the perfusate, which emptied through the renal vein into the tissue bath. Thus agents reached the arterioles from both the luminal and adluminal surfaces. Experiments using apamin, charybdotoxin, and carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) required the use of a recirculating perfusion system to conserve reagents. Antibiotics (penicillin and streptomycin) were added to the recirculating perfusate. In all other experiments, a single-pass perfusion was used and the media was not recirculated. 4-Aminopyridine (4-AP) was added directly to the perfusing medium (5 mmol/l), and the pH was adjusted to 7.40. All other agents were added from stock solutions. The data are expressed as means ± SE. Under control conditions, 10 µmol/l ACh reversed the ANG II-induced vasoconstriction by 106 ± 2%. The response to this concentration was defined as the Rmax. The pD2 values of the responses were calculated for each study and expressed as the mean negative log molar ACh concentration producing 50% of response produced by 10 µmol/l ACh. Differences between treatment groups were assessed by Bonferroni's t-test and one-way ANOVA. P values <0.05 were considered significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Comparison of ACh-induced vasodilation in afferent and efferent
arterioles.
The concentration-dependent actions of ACh on afferent and efferent
arterioles are depicted in Fig. 1. ANG II
(0.1 nmol/l) reduced afferent arteriolar diameters from 17.0 ± 0.9 to 5.2 ± 0.8 µm (n = 5) and efferent
arteriolar diameters from 11.7 ± 1.1 to 5.0 ± 0.8 µm
(n = 6). ACh, at concentrations up to 10 µmol/l, reversed the ANG II-induced vasoconstriction in the afferent arteriole in a concentration-dependent manner (Rmax = 106 ± 2%, pD2 = 6.28 ± 0.28). The dilation induced
by 10 µmol/l ACh in the efferent arteriole was 75 ± 5%
(pD2 = 6.36 ± 0.24), a value significantly less
than that seen in afferent arterioles (P < 0.01).
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Role of K channels in NOS/COX-independent actions of ACh on afferent arteriole. In addition to releasing NO and prostacyclin, ACh elicits vasodilation by endothelium-dependent hyperpolarization. This may reflect the actions of a released factor (EDHF) or myoendothelial coupling and may involve either K channel activation or a stimulation of the electrogenic Na,K-ATPase. Such a mechanism could explain the observed segmental specificity, because voltage-gated Ca influx is not seen in the efferent arteriole (2, 24, 26). Thus, in the efferent arteriole, hyperpolarization would not be anticipated to reduce Ca entry. To further address the mechanisms underlying the NOS/COX-independent effects of ACh on the afferent arteriole, we examined the effects of K channel blockade on this EDHF-like response of the afferent arteriole.
Figure 4 illustrates the effects of tetraethylammonium (TEA) chloride. At 1.0 mmol/l, TEA reduced afferent arteriolar diameter from 18.6 ± 0.8 to 11.3 ± 0.9 µm (P < 0.001) but did not alter the response to ACh (Rmax = 91 ± 6%, pD2 = 6.04 ± 0.28; n = 6, P > 0.05 vs. L-NAME and ibuprofen alone). At 10 mmol/l, TEA elicited a greater vasoconstriction (from 17.2 ± 1.0 to 7.9 ± 0.9 µm; P < 0.001) and significantly reduced the response to ACh, decreasing Rmax to 35 ± 5% (P < 0.001; pD2 = 4.70 ± 0.67). Although 10 mmol/l TEA attenuated the actions of ACh in the presence of L-NAME and ibuprofen, it had little effect on the ACh response when administered alone (n = 7; Fig. 4B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Our results indicate that ACh elicits an EDHF-like response in the renal afferent arteriole and that the underlying mechanism is blocked by apamin and charybdotoxin. As predicted, we found that the efferent arteriole response to ACh does not exhibit this EDHF-like component. A number of studies have demonstrated regional differences in regard to the role of EDHF (39). This study is the first to demonstrate that, within the renal microcirculation, EDHF contributes to the regulation of preglomerular tone but does not affect the postglomerular efferent arteriole.
There are at least two possible explanations for this segment-specific action. First, it is possible that the endothelial cells lining the afferent and efferent arterioles differ in regard to their ability to evoke hyperpolarization or elaborate an EDHF. We cannot rule out this possibility. However, a second and perhaps more likely explanation is that the activation mechanisms of the efferent arteriole are not attenuated by hyperpolarization. Hyperpolarization elicits vasodilation predominantly by reducing the activity of voltage-gated Ca channels (30). We demonstrated previously (26) that ANG II activates voltage-gated Ca influx in the afferent arteriole but that this mechanism is absent in the efferent arteriole. In the latter, ANG II stimulates a voltage-independent and nifedipine-insensitive Ca influx. Previous studies showed that ANG II constricts the efferent arteriole without eliciting membrane depolarization (24) and that L-type Ca channel blockers do not dilate this vessel (2). Moreover, KCl-induced depolarization, which activates L-type Ca channels, constricts the afferent arteriole but not the efferent arteriole (25). Thus we suggest that the lack of an EDHF-like response in the efferent arteriole may simply reflect an insensitivity of this vessel to membrane hyperpolarization. Our observations may relate primarily to cortical efferent arterioles. A study by Marchetti et al. (27) suggested that juxtamedullary efferent arterioles may respond to an EDHF released by bradykinin. Contractile responses were not examined in this study, but, rather, responsiveness was inferred from the changes in the fura 2 signal evoked by bradykinin in endothelium-intact arterioles. This imposes some restrictions on interpretations because both smooth muscle and endothelial cells were loaded with the Ca-sensing dye. Nevertheless, bradykinin reduced arteriolar Ca in the presence of ANG II but not KCl. Regional differences in the properties of the efferent arteriole might reconcile the findings of Marchetti et al. and those in our studies, because recent evidence suggests that cortical and juxtamedullary efferent arterioles may differ in regard to the presence of voltage-gated Ca channels. Thus Hansen et al. (17) reported that L-type Ca channels are not expressed in cortical efferent arterioles but are expressed in juxtamedullary efferent arterioles of the rabbit. Further investigations addressing this potential regional heterogeneity in regard to the efferent arteriolar actions of EDHF are warranted.
Our finding that EDHF acts selectively on the afferent arteriole in cortical vessels has important physiological implications. The afferent and efferent arterioles play distinct roles in regulating PGC and GFR in that they modulate pre- and postglomerular resistance, respectively. Because EDHF affects only the afferent arteriole whereas NO acts on both vessels, alterations in these two factors would impact on PGC and glomerular function. It is of interest in this context that EDHF is reported to be upregulated in the endothelial NOS knockout mouse (9) and in kidneys obtained from rats chronically treated with L-NAME (41). In contrast, EDHF-dependent vasodilation is reported to be diminished in vessels obtained from insulin-resistant rats (22). Our findings suggest that studies examining the impact of alterations in EDHF on renal function in pathophysiological models would be of considerable interest.
Renal vasodilator responses attributed to EDHF have been reported previously (15, 18, 19, 27, 29, 34, 42). In the isolated perfused rat kidney model, ACh responses that are resistant to blockade by NOS and COX inhibition are eliminated by elevated K and are attenuated by 10 mmol/l TEA (29). Similarly, our laboratory showed previously (18) that the transient afferent arteriolar dilation elicited by ACh in the presence of NOS and COX inhibition is abolished by elevating external [KCl], and in the present study this response was attenuated by 10 mmol/l TEA. However, 1.0 mmol/l TEA had no effect, ruling out a possible contribution of BKCa. Mieyal et al. (29) also found that the EDHF-like responses of the isolated perfused rat kidney were resistant to iberiotoxin. In both our study and in the study by Mieyal et al., 10 nmol/l charybdotoxin partially attenuated the EDHF-like response to ACh.
The combination of charybdotoxin plus apamin abolished the EDHF-like response in the afferent arteriole. In this regard, the afferent EDHF response is similar to those of a variety of other vessel types, including rat hepatic artery (13, 46), guinea pig coronary artery (43), rat mesenteric artery (12), guinea pig carotid artery (8), and guinea pig basilar artery (32). The requirement for both apamin and charybdotoxin could indicate that activation of two distinct K channel types is required for the full expression of actions of EDHF. In support of this postulate, apamin and charybdotoxin inhibited the EDHF-like responses by 35 ± 7 and 62 ± 5%, respectively, when added alone. Apamin preferentially blocks small-conductance Ca-activated K channels (SKCa) whereas charybdotoxin is reported to affect SKCa, BKCa , intermediate-conductance KCa, and KV (31, 36, 38). In our study, neither 1.0 mmol/l TEA nor 5 mmol/l 4-AP mimicked the actions of charybdotoxin, suggesting that BKCa and KV are not involved. Alternatively, the dual requirement for apamin and charybdotoxin may reflect an allosteric effect of these agents on the same K channel. Zygmunt et al. (46) showed that apamin enhances charybdotoxin binding, potentiating the actions of the K channel blocker. In any event, our findings suggest that the EDHF-like response of the afferent arteriole has pharmacological characteristics similar to EDHF responses described in other vessel types in that it is blocked by apamin and charybdotoxin but is insensitive to 1 mmol/l TEA and Ba.
Although the chemical identity of EDHF is unresolved, evidence implicates a cytochrome P-450 arachidonic acid metabolite (15, 19), perhaps an epoxyeicosatrienoic acid (EET) (33). In the isolated perfused kidney, 5,6-, 8,9-, and 11,12-EET all elicit vasodilation. However, the effects of 5,6-EET are COX dependent (3), militating against a role of this EET in the responses we observed. Imig et al. (20) found that 11,12-EET dilates the rat interlobular artery and juxtamedullary afferent arteriole by a COX-independent mechanism, whereas 8,9-EET had no effect on these vessels. More recently, Imig et al. (19) reported that bradykinin stimulates EET production in renal vessels and that epoxygenase inhibition, in combination with NOS and COX blockade, fully prevents bradykinin-induced dilation of juxtamedullary afferent arterioles. Using myocytes isolated from rat arcuate and interlobular arteries, Zou et al. (45) reported that 11,12-EET activated a K channel and elicited vasodilation in the intact vessels. These authors found that 1.0 mmol/l TEA blocked the affected K channels and abolished the vasodilator response. However, the EDHF-like responses we observed were not affected by 1.0 mmol/l TEA. Thus our findings are not consistent with the postulate that 11,12-EET mediates the EDHF component of the afferent arteriolar actions of ACh. In this regard, it is of interest that Fulton et al. (15) found that 5,8,11,14-eicosatetraynoic acid attenuated the response to bradykinin but did not alter responses to ACh in the isolated, perfused kidney. It is also important to note that our studies focused on cortical afferent arterioles. As discussed above, there may be regional differences in cortical vs. juxtamedullary vessels. Thus the determinants of the EDHF responses of juxtamedullary arterioles to ACh may differ from those of cortical vessels.
It has been suggested that the apamin/charybdotoxin-sensitive K channels involved in the actions of EDHF are not on the smooth muscle myocytes but rather are located on the endothelium (12, 13). Doughty et al. (12) found that apamin and charybdotoxin block vascular EDHF responses when they are selectively applied to the lumen of the isolated, perfused mesenteric artery but not when applied to the outer surface of the vessel. Our finding that apamin plus charybdotoxin inhibited the sustained component of the NOS-dependent response is consistent with this view, because endothelial K channel activation is required for Ca entry and sustained NO production (21). However, we cannot rule out the possibility that this action involved blockade of K channels on the myocytes. Edwards et al. (13) reported that in the rat hepatic artery ACh increases interstitial [K] through a mechanism that is blocked by apamin plus charybdotoxin. These authors found that Ba prevented the EDHF-mediated vasodilation of this vessel and suggested that activation of endothelial K channels leads to K efflux, which elicits hyperpolarization by increasing the outward current carried by KIR. In contrast, several laboratories have demonstrated that EDHF responses are distinct from those elicited by elevated [K] (1, 7, 10-11), even in the same hepatic artery preparation (1) used by Edwards and co-workers. Moreover, very small ion fluxes are generally required to produce hyperpolarization, and one might question whether this mechanism would elevate external [K] to the extent proposed. Furthermore, KIR is not expressed in all vessels exhibiting EDHF responses and some preparations used to examine the role of K as an EDHF employed vessels or conditions in which K-induced dilations were modest (7, 10). However, KIR does play a prominent role in regulation of basal tone in the afferent arteriole, and this vessel exhibits marked Ba-sensitive, K-induced dilation (5). Nevertheless, we found that the responses observed in the presence of 100 µmol/l Ba in this vessel were identical to those seen in controls (Fig. 8B), suggesting that KIR does not play a significant role in the EDHF response. Moreover, the combination of Ba plus ouabain did not prevent the vasodilation, further indicating that endothelium-derived K ions do not act as the EDHF mediating the response of the afferent arteriole to ACh.
Endothelial K channels could mediate hyperpolarization by a direct electrical coupling through myoendothelial gap junctions rather than by a released factor. Myoendothelial gap junctions are more prevalent in smaller vessels (35), in which EDHF is thought to play a more prominent role (37), and Emerson and Segal (14) demonstrated that outward currents injected into endothelial cells do evoke remote hyperpolarizing responses in arteriolar myocytes. Agents that block gap junctional communication are reported to attenuate EDHF responses in some vessels (4, 23). Future investigations will be required to determine whether the EDHF-like responses of the afferent arteriole involve a direct electrical communication or an endothelium-derived factor.
In conclusion, the present study demonstrates that the NO/COX-independent actions of ACh on the renal afferent arteriole are blocked by apamin and charybdotoxin but are insensitive to 1.0 mmol/l TEA and Ba and thus exhibit characteristics common to EDHF responses described in other vascular beds. In contrast to the afferent arteriole, the cortical efferent arteriole does not exhibit an EDHF-like response to ACh. We suggest that this segment-specific difference reflects the differing roles of membrane potential and voltage-gated Ca influx in afferent vs. efferent arterioles. Our finding that EDHF selectively modulates preglomerular arteriolar tone suggests that this factor may play a unique role in the regulation of renal function and PGC.
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ACKNOWLEDGEMENTS |
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The authors acknowledge the helpful comments and suggestions of Dr. C. R. Triggle.
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FOOTNOTES |
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This study was supported by a grant from the Heart and Stroke Foundation of Alberta, the Northwest Territories, and Nunavut. R. Loutzenhiser is a Senior Medical Scholar of the Alberta Heritage Foundation for Medical Research.
Address for reprint requests and other correspondence: R. D. Loutzenhiser, Dept. of Pharmacology and Therapeutics, Univ. of Calgary, Faculty of Medicine, 3330 Hospital Drive N.W., Calgary, AB, Canada T2N 4N1 (E-mail: rloutzen{at}ucalgary.ca).
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.
First published August 15, 2001; 10.1152/ajprenal.00157.2002
Received 17 May 2001; accepted in final form 15 August 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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;
n = 5) and efferent (EA, 
;
n = 6) arterioles. Vessels were preconstricted with 0.1 nmol/l ANG II. Responses are expressed as absolute diameter
(A) and %vasodilation (B). [ACh], ACh
concentration.
; B;
n = 7).
