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Smooth Muscle Research Group, Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada T2N 4N1
Submitted 28 March 2003 ; accepted in final form 30 April 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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-nitro-L-arginine
methyl ester (100 µmol/l) and the cyclooxygenase inhibitor ibuprofen (10
µmol/l) did not prevent this dilation when tone was established by ANG II
but fully blocked the response when tone was established by elevated
extracellular KCl, which suggests roles for both NO and endothelium-derived
hyperpolarizing factor (EDHF). We had previously shown that the EDHF-like
response of the afferent arteriole evoked by ACh was fully abolished by a
combination of charybdotoxin (ChTX;10 nmol/l) and apamin (AP; 1 µmol/l).
However, in the current study, treatment with ChTX plus AP only reduced the
EDHF-like component of the BK response from 98 ± 5 to 53 ± 6%
dilation. Tetraethylammonium (TEA; 1 mmol/l), which had no effect on the
EDHF-induced vasodilation associated with ACh, reduced the EDHF-like response
to BK to 88 ± 3% dilation. However, the combination of TEA plus ChTX
plus AP abolished the response (0.3 ± 1% dilation). Similarly,
17-octadecynoic acid (17-ODYA) did not prevent the dilation when it was
administered alone (77 ± 9% dilation) but fully abolished the EDHF-like
response when added in combination with ChTX plus AP (-0.5 ± 4%
dilation). These findings suggest that BK acts via multiple EDHFs: one that is
similar to that evoked by ACh in that it is blocked by ChTX plus AP, and a
second that is blocked by either TEA or 17-ODYA. Our finding that a component
of the BK response is sensitive to TEA and 17-ODYA is consistent with previous
suggestions that the EDHF released by BK is an epoxyeicosatrienoic acid. arteriole; endothelium-derived hyperpolarizing factor; acetylcholine; 17-octadecynoic; epoxyeicosatrienoic acids; tetraethylammonium; charybdotoxin; apamin; potassium channels
We recently demonstrated (36) that the EDHF associated with the renal microvascular response to ACh is similar to that seen in several other vascular beds in that it is abolished by a combination of charybdotoxin (ChTX) and apamin (AP). This EDHF-like component accounted for 95% of the initial phasic vasodilatory response to ACh but did not contribute to the sustained phase of the vasodilation nor did it contribute to the efferent arteriolar actions of ACh. Although the pharmacological properties of the renal EDHF associated with ACh were similar to those described for other vascular beds, these properties differed from the properties of the EDHF associated with BK-induced renal vasodilation. Specifically, we found 1 mmol/l tetraethylammonium (TEA) to have no effect on the EDHF associated with ACh, whereas several other laboratories found TEA to attenuate the EDHF component of the BK response (10, 26, 29). Moreover, Imig et al. (16) observed BK to release epoxyeicosatrienoic acids (EETs) from the renal vasculature, and the hyperpolarization elicited by EETs in isolated myocytes and the preglomerular vasodilatory actions of EETs are blocked by TEA (38). When interpreted in concert with our observations, these findings suggest that BK may release an EDHF that is distinct from that associated with ACh. In support of this premise, Fulton et al. (11) observed that the cytochrome P-450 inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA) attenuated the response of the isolated perfused kidney to BK but did not alter the response to ACh.
Thus in the present study, we used the in vitro perfused hydronephrotic rat kidney model to investigate the determinants of the renal afferent arteriolar response to BK, and we compared these results to previous studies that employed this model to characterize the EDHF associated with ACh. Our findings suggest the presence of at least two differing pathways that mediate the COX- and NOS-independent EDHF-like responses in the renal microcirculation. One component is abolished by ChTX plus AP. The second pathway is resistant to this treatment but is blocked by either TEA (1 mmol/l) or the cytochrome P-450 inhibitor 17-octadecynoic acid (17-ODYA).
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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3 Hz. Mean diameter values were then averaged over the
plateau or peak of the response. Typically, each determination was derived
from the mean of 50-100 individual measurements of the average diameter over
the vessel segment. All agents were added directly to the perfusate. The venous effluent emptied into the perfusion chamber, thus agents reached both the luminal and adluminal surfaces of the arterioles. Experiments that employed AP and ChTX required the use of a recirculating perfusion system as previously described (36). In all other experiments, single-pass perfusion was employed. The data are expressed as means ± SE. Differences between treatment groups were assessed by Bonferroni's t-test and one-way ANOVA. P values <0.05 were considered significant. The two rat strains, Sprague-Dawley and Long-Evans, were used based on availability. No significant differences were observed between these two strains, and the data were combined.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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In a separate series of kidneys (n = 7), we assessed the effects
of pretreatment with 10 µmol/l ibuprofen and 100 µmol/l
N-nitro-L-arginine methyl ester
(L-NAME) on the response to BK. As shown in
Fig. 3B and subsequent
figures (i.e., see Figs. 5,
6,
7), inhibition of COX and NOS
had little effect on basal afferent arteriolar diameter. Similar findings were
reported in past publications using this model
(35,
36). Moreover, we also
observed this treatment to have no effect on basal perfusate flow of the
isolated perfused normal rat kidney in the absence of an added vasoconstrictor
(13). As further depicted in
Fig. 3, inhibition of COX and
NOS had very modest effects on the profile of the response to BK (100 nmol/l),
which suggests a prominent role of additional factors such as EDHF. In the
control kidneys, BK (100 nmol/l) elicited a peak dilation of 97 ± 2%
(from 6.2 ± 1.1 to 16.4 ± 0.4 µm; basal, 16.7 ± 0.6
µm; n = 7). In the kidneys pretreated with L-NAME and
ibuprofen, BK elicited a peak dilation of 83 ± 4% (n = 7;
P = 0.009; from 5.4 ± 0.3 to 15.5 ± 0.7 µm; basal,
16.9 ± 1.7 µm). The vasodilatory responses decayed with a similar
time course in these two settings. For example at 4 and 6 min, diameter
measurements of controls (10.8 ± 2.7 and 7.1 ± 1.2 µm) were
not statistically different from those of kidneys pretreated with
L-NAME (5.3 ± 0.6 and 4.8 ± 0.5 µm; P =
0.06 and P = 0.11, respectively).
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To further assess the contribution of a hyperpolarizing factor, we determined the effects of these inhibitors on the actions of BK on arterioles that had been preconstricted with elevated extracellular K+. As illustrated in Fig. 4, BK partially reversed the vasoconstrictor actions of 25 mmol/l KCl. Treatment with KCl reduced diameter measurements from 18.7 ± 0.6 to 9.9 ± 0.7 µm, and BK caused a peak dilation to 14.7 ± 1.4 µm (n = 5; P = 0.007) thus eliciting a 55 ± 11% dilation (Fig. 4B, solid bar). Pretreatment with ibuprofen alone (10 µmol/l) did not significantly alter this response (50 ± 13% vasodilation, Fig. 4B, open bar), whereas treatment with L-NAME (100 µmol/l) abolished this action (-0.1 ± 1.5% vasodilation). We interpret these findings as indicating that the phasic vasodilatory response to BK seen in the presence of KCl-induced vasoconstriction is mediated by NO production, and that the NOS- and COX-independent actions of BK, which are seen when the afferent arteriole is preconstricted by ANG II, were blocked by an elevation of extracellular K+. The latter observation is consistent with a proposed EDHF-like component of the afferent arteriolar actions of BK.
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Effects of K+-channel blocking agents on NOS- and COX-independent actions of BK. We have shown that like BK, ACh elicits a phasic vasodilator response that is independent of COX and NOS but is blocked by elevated K+ (14, 36). In the case of ACh, this EDHF-like response was abolished by a combination of 10 nmol/l ChTX plus 1 µmol/l AP. We therefore examined the effects of this treatment on the BK response that is elicited in the presence of ibuprofen and L-NAME. These findings are summarized in Fig. 5. In these experiments (n = 6), diameter measurements in the presence of ibuprofen (10 µmol/l) and following treatment with L-NAME (100 µmol/l) and then the combination of ChTX (10 nmol/l) and AP (1 µmol/l) were 17.8 ± 0.8, 17.7 ± 0.8, and 17.3 ± 0.8 µm, respectively. The subsequent administration of ANG II (0.1 nmol/l) reduced diameter values to 4.8 ± 0.8 µm. In this setting, 100 nmol/l BK caused a transient vasodilation to a peak value of 12.6 ± 1.2 µm (P = 0.003), which corresponds to a 46 ± 6% vasodilation (P = 0.003 vs. 83 ± 4% vasodilation in the presence of L-NAME and ibuprofen alone). Thus in contrast to our previous findings with ACh (presented as solid bars in Fig. 5C for illustrative purposes; data taken from 36), ChTX plus AP attenuated but did not abolish the EDHF-like response to BK.
We next examined the effects of TEA both alone and in combination with ChTX plus AP. TEA is a nonselective K+-channel blocker at high concentrations, but at a concentration of 1 mmol/l, TEA blocks large-conductance Ca2+-activated K+ channels (BKCa) while having minimal effects on other K+-channel species (19). After treatment with ibuprofen and then L-NAME (diameter, 15.2 ± 0.5 and 14.8 ± 0.5 µm, respectively; n = 5), the addition of 1 mmol/l TEA reduced the diameter to 13.6 ± 0.7 µm (P > 0.05). In this setting, ANG II reduced the diameter to 4.9 ± 0.6 µm, and 100 nmol/l BK caused a transient dilation to 14.1 ± 0.6 µm (107 ± 9% vasodilation vs. diameter in TEA alone; P = 0.0004). In a separate series of seven kidneys, basal (ibuprofen) diameter values and measurements after treatment with L-NAME and ChTX plus AP were 15.5 ± 0.8, 15.1 ± 0.7, and 14.7 ± 0.8 µm, respectively (Fig. 6B). The addition of TEA (1 mmol/l) reduced diameter to 13.5 ± 0.7 µm. In this setting, ANG II reduced diameter to 6.6 ± 0.6 µm, and the administration of BK (100 nmol/l) had no effect (6.6 ± 0.6 µm, 0 ± 1% vasodilation). Thus whereas TEA or ChTX plus AP only partially attenuated the EDHF-like response to BK when added alone, these agents abolished this response when added concurrently (Fig. 6C).
These findings suggest that two components may contribute to the EDHF-like response to BK: one that (as previously shown for ACh) is blocked by ChTX plus AP and a second that is sensitive to TEA. BK has been shown to stimulate the release of EETs from the renal vasculature (16), and 11,12-EET has been reported to elicit afferent arteriolar vasodilation by a mechanism that is blocked by 1 mmol/l TEA (17, 38). We therefore determined whether the cytochrome P-450 inhibitor 17-ODYA would also block the component of the BK response that was insensitive to ChTX plus AP. The results of these experiments are summarized in Fig. 7. Alone or in combination with TEA, 17-ODYA (50 µmol/l) did not prevent the EDHF-like response to BK. After treatment with ibuprofen, L-NAME, and 50 µmol/l 17-ODYA, diameter measurements were 17.0 ± 0.9, 16.8 ± 0.9, and 16.0 ± 1.2 µm, respectively. ANG II reduced diameter to 6.0 ± 0.5 µm, and 100 nmol/l BK elicited a peak dilation to 13.4 ± 1.0 µm, which corresponds to a 77 ± 9% vasodilation (n = 4; Fig. 7A). Similarly, after treatment with ibuprofen and L-NAME (diameters, 15.18 ± 1.1 and 14.8 ± 1.0 µm, respectively), the addition of 1 mmol/l TEA reduced diameter to 13.8 ± 1.4 µm (P = 0.10) and addition of 17-ODYA reduced diameter to 11.5 ± 1.5 µm (P = 0.02). In this setting, ANG II reduced diameter to 4.0 ± 0.5 µm, and 100 nmol/l BK caused a transient dilation to 11.6 ± 1.1 µm (n = 5; P = 0.002; 106 ± 13% vasodilation of ANG II response vs. 17-ODYA alone, data not shown). Thus the inhibitory effects of TEA and 17-ODYA on BK responses were not additive. In a separate series of six kidneys, basal (ibuprofen) diameter measurements and values after treatment with L-NAME and ChTX plus AP were 15.6 ± 0.5, 15.1 ± 0.5, and 14.2 ± 0.6 µm (Fig. 7B). The addition of 17-ODYA (50 µmol/l) reduced diameter to 12.5 ± 0.8 µm (P = 0.01). In this setting, ANG II reduced diameter to 5.2 ± 0.2 µm, and the administration of BK (100 nmol/l) had no effect (5.2 ± 0.3 µm, 0 ± 6% vasodilation). Accordingly, as seen with TEA, 17-ODYA abolished that component of the EDHF-like response to BK that was resistant to ChTX plus AP. These results are summarized in Fig. 7C.
Contribution of NO to vasodilation elicited by BK. As shown in Fig. 4, during KCl-induced vasoconstriction, BK elicited a dilation that was NO dependent (e.g., blocked by L-NAME). Nevertheless, L-NAME had little effect on the magnitude or profile of the BK-induced vasodilation when ANG II was used to establish basal tone (see Fig. 3). To further assess the contribution of NO in this setting, we examined the response elicited following pretreatment with ibuprofen, TEA, and ChTX plus AP, which would block the COX- and EDHF-dependent components, and compared these results to those in which L-NAME was also present (see Fig. 6A). These findings are summarized in Fig. 8, A and B. Diameter measurements were 16.9 ± 0.5 µm in the presence of ibuprofen and 16.8 ± 0.5 and 15.7 ± 0.1 µm following ChTX plus AP and TEA, respectively. The addition of ANG II reduced diameter to 7.4 ± 1.2 µm, and the subsequent administration of BK resulted in a maximal dilation to 12.3 ± 1.0 µm, which corresponds to a 62 ± 7% vasodilation (n = 5). These findings suggest that, as seen during KCl-induced vasoconstriction, NO production contributes to the transient BK-induced afferent arteriolar vasodilation that is observed during ANG II-induced vasoconstriction.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We suggest that the EDHF-like response to BK consists of two components, one of which was blocked by a combination of ChTX plus AP. We had previously shown that this combination fully abolished the EDHF-like response of the afferent arteriole to ACh (36). Indeed, treatment with ChTX plus AP has been shown to block the vasodilator responses attributed to EDHF in a variety of blood vessels under diverse conditions (for review, see Refs. 23, 34). At the concentrations employed, these toxins are known to block small- and intermediate-conductance KCa channels (32, 33). It has been suggested by a number of investigators that these K+-channel blockers may attenuate EDHF-like responses by blocking K+ channels that are present on the endothelium rather than on the vascular myocyte (e.g., 4, 5, 7). An elegant demonstration of this was provided by Doughty et al. (5), who reported that ChTX and AP inhibit EDHF responses when selectively applied to the endothelial cells within the vessel lumen but not when selectively applied to the outer surface of a perfused mesenteric artery. These authors interpret these observations to suggest that these agents act on the endothelium rather than the smooth muscle myocytes. Accordingly, in small vessels, in which such EDHF-like responses are more prevalent, endothelial agonists may activate K+ channels in the endothelium, and the resultant hyperpolarization may be transmitted to the underlying smooth muscle layer via electrical communication through myoendothelial gap junctions (30). An obligate role of myoendothelial gap junctions in responses attributed to EDHF is suggested by several studies (e.g., 3, 18, 30).
The present study did not specifically address this issue. However, we previously demonstrated that the combination of ChTX plus AP not only blocks the transient EDHF-like component of the afferent arteriolar dilation evoked by ACh but also inhibits the sustained phase of the ACh response that is dependent on NO formation (36). This latter observation is consistent with the premise that endothelial K+-channel activation and the resultant hyperpolarization contribute to Ca2+ entry (see Ref. 24 for review). Thus by interfering with this mechanism, the blockade of endothelial K+ channels by ChTX and AP would be anticipated to inhibit the sustained component of NO formation as we have observed. Accordingly, our previous finding that ChTX plus AP blocks the sustained NO-dependent component of the ACh response would be consistent with the postulate put forward by others (4, 5, 7) that the K+ channels affected by these toxins are in the endothelium. ACh and BK are both known to release intracellular Ca2+ stores in the endothelium by stimulating phospholipase C, increasing levels of inositol 1,4,5-trisphosphate (IP3), and activating IP3 receptors present in the endoplasmic reticulum. Thus these two agents could activate the same population of KCa channels in the endothelium (24). Such a scheme (see Fig. 9) could explain our finding that although the characteristics of the EDHF-like response to BK and ACh were quite different (e.g., see Fig. 3), a common component of the response to each of these agents was blocked by ChTX and AP. Although the present study does not provide a direct test of this postulate, our findings would be consistent with this scheme.
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We previously found that treatment with ChTX plus AP fully blocked the EDHF-like response to ACh (36); however, in the present study, we found that this treatment alone was not sufficient to prevent the EDHF-like response to BK (see Fig. 5). The component of the EDHF-like response to BK that remained after treatment with ChTX plus AP was completely eliminated by treatment with either 1 mmol/l TEA or 50 µmol/l 17-ODYA. In the absence of ChTX and AP, TEA or 17-ODYA administered either alone or in combination did not block the EDHF-like response to BK. We interpret these observations to indicate that a second, ChTX- and AP-insensitive but TEA- and 17-ODYA-sensitive component contributes to the EDHF-like afferent arteriolar response to BK. The properties of this second component are consistent with the suggestion put forward by other investigators that the EDHF-like response to BK involves the elaboration of an EET (9, 12, 16, 17, 28, 38) that in turn activates the TEA-sensitive BKCa channels (1, 17, 38) present in the vascular myocytes (e.g., see Fig. 9).
Growing evidence implicates cytochrome P-450 products,
particularly the EETs, as candidate EDHFs (reviewed in Refs.
23,
28,
34). This is particularly true
of EDHF responses evoked by BK. Fulton et al.
(11) demonstrated that the
cytochrome P-450 inhibitor ETYA attenuated the response of the
isolated perfused kidney to BK. Imig and co-workers
(16) demonstrated not only
that cytochrome P-450 inhibitors prevented the EDHF-like response of
the afferent arteriole to BK, but also that BK treatment augmented EET
production by isolated renal vascular tissues. Moreover, Imig et al.
(17) found 11,12-EET to dilate
the rat ILA and juxtamedullary afferent arteriole via a COX-independent
mechanism, whereas 8,9-EET had no effect on these vessels. Zou et al.
(38) reported that 11,12-EET
activated a K+ channel in isolated renal vascular myocytes and
elicited vasodilation in the intact vessels, and both of these actions were
abolished by 1.0 mmol/l TEA, a finding consistent with our observation that
17-ODYA and 1.0 mmol/l TEA abolished the same component of the EDHF-like
response to BK. Gebremedhin et al.
(12) elegantly demonstrated,
using a bioassay system, that BK released a substance from a perfused bovine
coronary artery that stimulated BKCa channels in a downstream
myocytes and that the release of this factor was blocked by endothelium
removal or treatment with 17-ODYA. More recently, Archer et al.
(1) identified 11,12-EET as a
likely EDHF candidate in human internal mammary arteries and demonstrated that
this agent activates BKCa channels in this preparation. Fisslthaler
et al. (9) demonstrated that
chronic treatment of native coronary artery endothelial cells with
-naphthoflavone enhanced cytochrome P-450 (2C) expression
levels, augmented 11,12-EET production, and enhanced both the vasodilator
response and the hyperpolarization induced by BK in coronary artery segments.
These findings and many others (see Refs.
23,
27,
28,
34) support the postulate that
BK stimulates endothelial production of an epoxygenase product that in turn
can evoke vasodilation by activating TEA-sensitive BKCa channels
present in the underlying vascular myocytes.
It is important to emphasize that although our findings are consistent with this postulate in regard to the actions of BK, we did not see a similar profile of the EDHF-like response of the afferent arteriole to ACh. Thus ChTX and AP treatment alone were sufficient to prevent the EDHF-like response to this agent (see Ref. 36). These observations suggest that there are multiple components to the EDHF-like response and that the relative contributions of these two components or pathways may differ with different endothelial-dependent vasodilator agents. Very few studies have compared the determinants of the EDHF component of the vasodilator response to differing agents. However, Fulton et al. (11) previously reported that ETYA prevented the response of the isolated perfused kidney to BK but did not prevent the response of this preparation to ACh and suggested differing pathways (27). Frieden et al. (10) also observed marked differences in the pharmacological profile of the EDHF associated with BK vs. substance P, in that the response to the latter did not involve the cytochrome P-450 pathway. Moreover, the determinants of the EDHF-like response to an agent may vary with blood vessel type. In regard to the latter, it is important to note that a number of studies report EDHF-like responses to BK that are not prevented by cytochrome P-450 inhibition alone (e.g., Refs. 2, 6, 22, 25). However, a further complication is that a concomitant activation of the two EDHF-like pathways (see Effects of K+-channel blocking agents on NOS- and COX-independent actions of BK) may obscure interpretations of experiments in which only a single pathway is inhibited. The present study is an example of this phenomenon, in that we could only demonstrate a major effect of blocking the cytochrome P-450 pathway or 1.0 mmol/l TEA when the vessels were concomitantly treated with ChTX plus AP.
When both of the EDHF-like or NO-independent mechanisms were blocked (by the combined treatment with AP, ChTX, and 1 mmol/l TEA), BK elicited a phasic vasodilation that could be blocked by further treatment with L-NAME (see Fig. 8). Similarly, when the afferent arteriole was preconstricted by elevation of extracellular K+ (which would eliminate the effects of EDHF or K+-channel activation), BK elicited a transient and NO-dependent increase in diameter (see Fig. 4). These findings illustrate that both NO and EDHF contribute to the phasic vasodilatory response of the afferent arteriole to BK. Moreover, although K+-channel blockade (e.g., 1 mmol/l TEA, ChTX, AP) or elevation of extracellular K+ eliminated the vasodilator actions of EDHF, a significant component of the NO-dependent vasodilation persisted in these settings. Thus while evidence suggests a prominent role of BKCa channels in the vasodilatory actions of NO (e.g., Ref. 31), these data suggest that additional mechanisms contribute to the response of the afferent arteriole to NO and/or cGMP. It is widely acknowledged that multiple pathways contribute to cGMP-dependent vasodilation and that the resultant smooth muscle relaxation may involve both K+-channel-dependent and -independent mechanisms (20).
Finally, we must comment on our observation that the cortical afferent arterioles of our preparation exhibited a phasic or transient vasodilator response to BK. The literature suggests a high degree of variability in regard to the profile of the renal vascular responses to BK. Thus Edwards (8) reported that the afferent arteriole of the rabbit does not respond to BK, whereas Yu et al. (37) found the same preparation to exhibit vasodilation at very low BK concentrations and vasoconstriction at concentrations above 0.1 nmol/l. Ihara et al. (15) reported triphasic responses of the porcine ILA to BK, characterized by an initial dilation that was followed by a constriction and then a more slowly developing sustained dilation. In each of these cases, the constriction was dependent on COX and thromboxane, whereas in our studies, the transient nature of the response persisted during COX inhibition. Imig et al. (16) reported sustained vasodilator responses of the blood-perfused juxtamedullary afferent arteriole. It is possible that observed differences in the time course of BK responses might reflect differences in the experimental preparations used, the impact of acute trauma associated with the surgical preparations, the imposition of hydronephrosis, species-related differences, or perfusate-type differences. The possibility of regional differences in the profile of the response within the renal microcirculation is also quite likely, as we observed sustained responses in larger segments of the ILA in the present study (see Fig. 2). Studies to address regional differences in the temporal profile of the responses and any regional differences in the determinants of the vasodilation produced by BK would be of considerable interest.
In summary, the present study demonstrates that a component of the EDHF-like response of cortical afferent arterioles in the in vitro perfused hydronephrotic rat kidney preparation to BK is sensitive to inhibition by either cytochrome P-450 inhibition by 17-ODYA or by blockade of BKCa channels by 1.0 mmol/l TEA. These findings are consistent with the proposed involvement of an EET in the EDHF-like response of this vessel to BK (16, 17, 38). However, we also found an additional component of the EDHF-like response to BK, and this component was not prevented by 17-ODYA or TEA but was sensitive to inhibition by a combination of ChTX plus AP. This ChTX- and/or AP-sensitive component of the EDHF-like response was similar to that previously reported for ACh-induced vasodilation of the afferent arteriole (36). These findings cannot be explained by a single EDHF. Thus based on these observations, we suggest that multiple factors or hyperpolarizing pathways contribute to the EDHF-like response of the renal afferent arteriole.
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ACKNOWLEDGMENTS |
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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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