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Am J Physiol Renal Physiol 294: F795-F800, 2008. First published January 16, 2008; doi:10.1152/ajprenal.00392.2007
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Effects on kidney filtration rate by agmatine requires activation of ryanodine channels for nitric oxide generation

Joseph Satriano,1,2 Robyn Cunard,1 Orjan W. Peterson,1 Thomas Dousa,4 Francis B. Gabbai,1 and Roland C. Blantz1,3

1Nephrology-Hypertension Division, 2Stein Institute for Research on Aging, and 3Bioengineering Institute, University of California, School of Medicine, and San Diego Veterans Affairs Healthcare System, San Diego, California; and 4Department of Physiology, Mayo Graduate School, Rochester, Minnesota

Submitted 23 August 2007 ; accepted in final form 7 January 2008


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Agmatine, decarboxylated arginine, is produced in the kidney and can increase nephron and kidney filtration rate via renal vasodilatation and increases in plasma flow. This increase in filtration rate after agmatine is prevented by administration of nitric oxide synthase (NOS) inhibitors. In endothelial cells, agmatine-stimulated nitrite production is accompanied by induction of cytosolic calcium. NOS activity requires calcium for activation; however, the source of this calcium remains unknown. Ryanodine receptor (RyR) calcium-activated calcium release channels are present in the kidney cortex, and we evaluated if RyR contributes to the agmatine response. Agmatine microperfused into Bowman's space reversibly increases nephron filtration rate (SNGFR) by ~30%. cADP-ribose (cADPR) regulates RyR channel activity. Concurrent infusion of agmatine with the cADPR blocker 8-bromo-cADPR (2 µM) prevents the increase in filtration rate. Furthermore, direct activation of the RyR channel with ryanodine at agonist concentrations (5 µM) increases SNGFR, and, like agmatine, this increase is prevented by administration of NG-monomethyl-L-arginine, a nonselective NOS blocker. We demonstrate that agmatine does not elicit ADPR cyclase activity in vascular smooth muscle membranes and does not directly affect RyR calcium channel responses using sea urchin egg homogenates. These results imply interplay between endothelial cell cADPR/RyR/Ca2+/NO and the cADPR/RyR/Ca2+ pathways in vascular smooth muscle cells in arterioles in the regulation of kidney filtration rate. In conclusion, we show that agmatine-induced effects require activation of cADPR and RyR calcium release channels for NO generation, vasodilation, and increased filtration rate.

ryanodine; agmatine; glomerular filtration rate; nitric oxide

THE AMINO ACID ARGININE and specific arginine metabolites exhibit vasodilatory capacities in the kidney as well as other vascular beds (15, 17, 33). Arginine, when infused systemically, leads to renal vasodilatation and an increase in the glomerular filtration rate (GFR). Nitric oxide (NO) is a well-known arginine metabolite that acts as a vasodilator (22, 31). A second arginine metabolite, agmatine, decarboxylated arginine, also produces renal vasodilatation and increases in nephron filtration rate (26, 35). We have demonstrated arginine decarboxylase, the synthetic enzyme for agmatine, and diamine oxidase, the degrading or metabolizing enzyme, activities in kidney tissue (26). Agmatine exists in micromolar concentrations in the plasma and can attain much higher levels in cells and organs, including the kidney (27). We also have shown that administration of nitric oxide synthase (NOS) blockers inhibits agmatine-induced renal vasodilatation (35). Furthermore, agmatine applied to endothelial cells in culture stimulates NO production via a calcium signaling mechanism (30). The source of this calcium signal, however, had not been determined.

The best known of calcium release mechanisms involves the inositol 1,4,5-trisphosphate (IP3) pathway via channels in the endoplasmic and sarcoplasmic reticula (2, 28). The IP3 calcium release mechanism is generally associated with the action of various vasoconstrictors but can also be activated by hormones that induce vasodilatation. A second important intracellular calcium release mechanism involves calcium-induced calcium release from intracellular stores. Ryanodine receptor (RyR) channels release calcium by this mechanism. These channels are composed of at least three subtypes distributed throughout skeletal muscle, cardiac muscle, and a variety of adapted muscles in other tissues. Type 1 RyR channels are expressed predominantly in skeletal muscle, type 2 in cardiac muscle, and type 3 in other muscular tissues and brain (29). IP3 and RyR channels are both unique in that they are very large channels. The RyR channel is composed of four 560-kDa proteins that interact with FK-binding protein, a prolyl isomerase that is known to interact with certain immunosuppressive agents, FK-506, and rapamycin (28, 29). Blockade of the IP3 receptor does not prevent calcium transients universally, suggesting that the RyR channel participates in the process.

cADP-ribose (cADPR), a cyclic nucleotide derived from NAD, functions as an endogenous regulator of the RyR channel (13, 23). The action of cADPR appears to be, at least in part, through increasing the sensitivity of the RyR channel to calcium. Glomerular extracts, mesangial cells, and vascular smooth muscle cells have all exhibited high ADPR cyclase activity (4, 7, 49). Significant ADPR cyclase activity in the kidney demonstrated by these and other publications imply the presence of RyR receptors (4, 10, 43, 49). Several mammalian cell systems are responsive to ryanodine and agonists such as caffeine that operate through the RyR channel. Presently, RyR channels have been described in preglomerular vascular smooth muscle cells, i.e., kidney afferent arterioles, glomerular mesangial cells, human embryonic kidney cells, the kidney epithelial cell line LLC-RK1, and endothelial cells (5, 8–10, 12, 24, 32, 39, 45, 49). We have also examined RyR channels in isolated afferent arterioles from kidneys and found mRNA for types 1 and 2 RyR channels by PCR (unpublished observations).

The current study was designed to determine whether vasodilatory effects of agmatine within the kidney are mediated by activity of the RyR channel. We assessed whether blockade of cADPR activity could modify the vasodilatation induced by agmatine. Because NO has been demonstrated as a permissive cofactor for vasodilatation (35), the question was raised as to whether NO may have some role in maintaining the activity of the RyR channel as a necessary requirement for agmatine-induced vasodilatation. The current studies examine these issues within the kidney microvasculature.


   METHODS
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 METHODS
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Animal experiments described herein were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Studies were conducted under approvals of the Institutional Animal Care and Use Committee. Studies were conducted on male Wistar rats initially weighing between 220 and 250 g when purchased from Harlan (Indianapolis, IN). Studies were performed in Frömter-Wistar rats derived from a colony maintained at the Veterans Affairs San Diego Healthcare System Animal Research Facility. These rats possess multiple glomeruli and urinary spaces on the surface of the kidney, expressing at least 20–30 glomeruli on the exposed micropuncture surface. They were used for in vivo studies to test the effects of agmatine, blockers of cADPR, ryanodine, and NOS inhibitors, as well as the PCR studies of RyR isoforms. Animals were prepared for surgery as previously described (26, 41, 42). After a left subcostal incision and dissection, kidneys were placed in a Lucite cup, and the left ureter was cannulated with a PE-50 catheter. Kidneys were surrounded with dilute agar, leaving the micropuncture surface exposed. A systemic infusion (1 ml/h isotonic NaCl-NaHCO3) containing [3H]inulin delivers 60–80 µCi/h for clearance and nephron filtration rate (SNGFR) measurement. A simultaneous infusion of 1% body wt and 0.15% body wt/h of plasma was infused to maintain volume status.

Nephron microperfusion studies. These experiments utilize the urinary space of surface glomeruli for microperfusion. The studies involve a control period of 10 min, a perfusion period of 10 min, and a recovery period of 10 min in which the impact of perfused substances on nephron filtration rate was evaluated (26). The late proximal tubule associated with surface glomeruli was localized by injection of a dilute dye in isotonic NaCl-NaHCO3 in the urinary space. At the end of each of three periods (control, perfusion, and recovery periods), a 2.5- to 3-min collection of tubular fluid from the late proximal tubular segment was obtained proximal to a tubular oil block. The tubule proximal to the oil block was vented to the surface fluid after each collection. Therefore, by design, tubular fluid did not enter the Loop of Henle and distal tubule. This means that changes in fluid and NaCl delivery to the macula densa could not have influenced tubuloglomerular feedback activity and SNGFR. Six-micrometer tip pipettes connected to one or two Hampel nanoliter microperfusion pumps were inserted in the urinary space of test nephrons. In inhibitor studies, 8-bromo-cADPR (Sigma-Aldrich, St. Louis, MO), a blocker of cADPR activity, contained in the pump pipette was infused at 2 µM concentrations throughout all three periods (7). Agmatine (Sigma-Aldrich) administration (1 µM) was tested during the perfusion period followed by a recovery period in either the presence or absence of 8-bromo-cADPR. Reagent concentrations in the urinary space were computed from a Hampel pump rate of 5 nl/min and the known ambient SNGFR. Three period time controls were also performed with no agents infused. The effects of 8-bromo-cADPR were also evaluated after a control period in separate studies. In other studies, the effects of 5 µM ryanodine (Sigma-Aldrich) in the second perfusion period were tested by perfusion either in the presence or in the absence of continuous inhibition of NOS by the systemic administration of NG-monomethyl-L-arginine (L-NMMA). We also evaluated the effects of 8-bromo-cGMP (Sigma-Aldrich) perfusion alone on nephron filtration rate. The micropuncture data were analyzed by two-way ANOVA.

Effects of agmatine on ADPR cyclase. To evaluate ADPR cyclase enzyme activity, we analyzed the membrane fraction from primary cultures of rat vascular smooth muscle cells. These cells were derived from rat abdominal aorta explant outgrowths, as described by de Toledo et al. (7). ADPR cyclase activity was determined by using the NAD analog nicotinamide guanine dinucleotide and measuring its conversion to fluorescent cGDP-ribose in a spectrofluorometer (3). We examined the direct effects of agmatine on ADPR cyclase activity in this system.

Effects of agmatine on the function of the RyR calcium channel. Homogenates were prepared from sea urchin eggs of lytechinus pictus suspended in a medium containing 2 U/ml of creatine kinase, 4 mM phosphocreatine, 1 mM ATP, 3 µg/ml oligomycin, and 3 µg/ml of antimycin (4, 13). Incubation with 3 µM fluo 03 (Molecular Probes, Eugene, OR) was performed at 17°C for 3 h. Fluo 3 fluorescence was monitored at 490 nm excitation and 535 nm emission in a 250-µl cuvette. A spectrofluorometer was used to assess the effects of agmatine on calcium fluorescence. Calcium-induced fluorescence was measured after 100 nM cADPR was added to the homogenates and after the addition of 1 mM agmatine followed by cADPR.


   RESULTS
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Microperfusion studies with agmatine, ryanodine, or a cGMP analog in single nephrons with surface glomeruli. Figure 1, A and B, demonstrate results from microperfusion studies from the surface urinary space of single nephrons. Agmatine produced a consistent ~30% increase in single nephron filtration rate during the experimental microperfusion period with a prompt return in the postperfusion recovery period (Fig. 1A). (Control SNGFR was 37 ± 4 nl/min and 44 ± nl/min during agmatine, P < 0.01). Concurrent infusion of 8-bromo-cADPR (2 µM), a blocker of cADPR activity, completely prevented the effects of agmatine on SNGFR. In separate studies, we demonstrated that 8-bromo-cADPR exerted no effects on SNGFR during normal control conditions [35 ± 4 to 36 ± 4 nl/min, not significant (NS)]. Time controls without any agent also showed no change in SNGFR (37 ± 2, 38 ± 2, and 34 ± nl/min, NS). In addition, we tested the agonist effects of ryanodine (5–6 µM) during the microperfusion experimental period. This dose of ryanodine significantly increased nephron filtration rate by ~15% with a prompt recovery during the postinfusion period (31 ± 2 to 36 ± 3 nl/min to 30 ± 2, P < 0.002). Systemic infusion of L-NMMA, a nonselective NOS blocker, completely prevented the ryanodine effects on SNGFR (Fig. 1B). The results with L-NMMA are consistent with those obtained previously with agmatine (35), demonstrating a NOS dependence of the effects of both agmatine and ryanodine. Of note, systemic infusion of L-NMMA alone does not change GFR or SNGFR in our hands. Moreover, L-NMMA infused during the control, experimental, and recovery periods produced no changes in SNGFR when compared with the untreated controls, which is consistent with our earlier results (6, 35).


Figure 1
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  		Fig. 1. Effects of agmatine on nephron filtration rate and concurrent effects of 8-bromo-cADP-ribose. A: there is approximately a 30% increase in single nephron filtration rate with agmatine treatment, an effect that is reversible (6 rats). This effect was completely blocked by concurrent infusion of 8-bromo-cADPr (2 µM), a blocker of cADPr activity (5 rats). B: the effects of ryanodine (5–6 µM) are demonstrated (7 rats). Ryanodine produced a modest increase in nephron filtration rate, an effect that was completely inhibited by systemic administration of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase blocker (5 rats). Bars represent SEs. *P < 0.05.

 
We previously demonstrated that the agmatine-induced increase in SNGFR requires NO. Because cGMP is a signal transduction product of NO, we used 8-bromo-cGMP, an analog of cGMP, to determine whether cGMP can mimic the effects of agmatine and ryanodine in regulation of SNGFR. Perfusion with 8-bromo-cGMP produced no change in nephron filtration rate (39 ± 3 to 40 ± 3 to 38 ± 3 nl/min) (Fig. 2).


Figure 2
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  		Fig. 2. Comparison of effects of agmatine and a cGMP analog on SNGFR. 8-Bromo-cGMP, an analog of cGMP, was infused in the urinary space and did not change SNGFR (4 rats) when compared with infusion of agmatine. A: %change in SNGFR. B: absolute values of SNGFR. Bars represent SEs. *P < 0.05.

 
Agmatine effects on ADPR cyclase in vascular smooth muscle cells. We examined the effects of agmatine in a vascular smooth muscle membrane preparation known to possess ADPR cyclase activity. Generation of the fluorescent product cGDPR was continuously monitored using a Hitachi spectrofluorometer F2000 at 300 nm excitation and 410 nm emission. Increasing doses of agmatine had no observable effect on ADPR cyclase activity (Fig. 3). Assays were performed on two separate occasions with identical results.


Figure 3
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  		Fig. 3. Effects of agmatine on ADP-ribose cyclase activity in vascular smooth muscle cells. Agmatine had no effect on cADPR cyclase activity as measured by the conversion of +nicotinamide guanine dinucleotide (NGD) to fluorescent cGDP-ribose in rat vascular smooth muscle cells. Assays were performed on two separate occasions with identical results.

 
Direct effects of agmatine on RyR calcium channels. To determine if agmatine can directly potentiate RyR activation, we tested the effects of agmatine on calcium release from calcium-preloaded sea urchin homogenates known to contain RyR channels. Agmatine neither increased nor decreased calcium release, whereas cADPR triggered calcium release readily and caused desensitization to the second dose of cADPR (Fig. 4A). In addition, agmatine did not influence the course of calcium release triggered by cADPR (Fig. 4B).


Figure 4
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  		Fig. 4. Agmatine does not directly alter calcium release from ryanodine receptor (RyR) channels. We examined the effects of large doses of agmatine on calcium release from a sea urchin egg homogenate containing RyR channels. A: agmatine at 1 mM had no impact on calcium fluorescence measured by fluo 03, whereas 100 nM of cADPr produced a significant response and also desensitized the channels to a second dose of cADPr. B: agmatine was administered after calcium release had been induced by 100 nM cADPr. Agmatine at 1 mM does not modulate calcium release from RyR channels previously stimulated with cADPr. Each trace is representative of 3 experiments.

 

   DISCUSSION
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 ABSTRACT
 METHODS
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Intrarenal or intranephronal infusion of agmatine increases nephron filtration rate. This increase results from vasodilatation, suggesting that agmatine decreases renal vascular resistance (26). In earlier studies, we observed that administration of the nonselective NOS inhibitor L-NMMA prevents the increase in nephron filtration rate during agmatine infusion (35). Calcium is a limiting factor for enzyme activation of endothelial NOS. The results of the current studies show that agmatine-induced vasodilatation requires the participation of the RyR, the calcium-induced calcium release channel. Thus it would appear that intracellular calcium stores are used to activate NOS and generate NO in this system. However, what was unexpected was that activation of the RyR channels by ryanodine was also inhibited by L-NMMA. Thus the mechanism is more complex than originally considered and likely involves interactions between NO and the RyR channel and between activity at the level of endothelial cells and the vasculature.

In the present studies, blockers of cADPR prevented the agmatine-induced increase in SNGFR. We have also demonstrated that ryanodine, in low, agonist-level doses, increases SNGFR. Interestingly, these effects, like with agmatine, were also eliminated by prior treatment with nonselective NOS inhibitors. Receptor-dependent generation of NO by agmatine has been demonstrated in endothelial cells via a calcium-dependent mechanism (20, 30). In human umbilical vein endothelial cells, 10 µM agmatine significantly increases NO synthesis. This activation is effectively blocked by rauwolscine, an {alpha}2-adenoreceptor blocker (20). In cultured bovine pulmonary artery endothelial cells, agmatine-stimulated NO generation is inhibited by idazoxan, implying imidazoline receptor involvement (30). In this report, 8-bromo-cADPR, a cADPR inhibitor, suppresses in vivo NO generation by agmatine. Bradykinin also elicits an increase in cADPR activity accompanied by activation of the RyR channel, intracellular calcium mobilization, and NO generation in coronary artery endothelial cells (51). Conversely, activation of cADPR and RyR in afferent arteriolar preparations by ANG II, oxidative stress, or calcium entry via calcium-gated calcium channels results in vasoconstriction (8, 9, 11). This increase in the cADPR/RyR/Ca2+ axis with resultant vasoconstriction is also observed in coronary artery smooth muscle cells in response to superoxide, in mesangial cells administered ANG II (12, 50), and with in vivo administration of ANG II via the renal artery (40). Thus, activation of cADPR/RyR/Ca2+ gives rise to vasoconstriction in vascular smooth muscle cells and mesangial cells, and yet activation of this pathway in endothelial cells generates NO and vasodilation. Here we demonstrate that agmatine does not affect ADPR cyclase activity in vascular smooth muscle preparations.

Polyamines can directly affect RyR channel activity, as shown in sea urchin egg preparations (3), and may be endogenous regulators of the channel (3, 23). Because agmatine is a polyamine analog, we investigated its effects in sea urchin egg homogenates, a preparation rich in RyR channels. We show that, unlike polyamines, agmatine does not directly activate calcium release from RyR stores nor augment the effects of cADPR calcium release in this system. Overall, it is likely that agmatine does not act upon vascular smooth muscle cells to either influence cyclase activity or directly influence the RyR channel in these cells. These results are compatible with a receptor-mediated endothelial cell response to agmatine (20, 30) and not to effects on the vascular smooth muscle cell component or a direct effect on the RyR channel itself.

The kidney maintains a high intracellular concentration of agmatine, whereas the plasma contains only ~2 µM (25). A question then arises as to the initial target cell for the agmatine effects observed, given this method of administration. Clearly, the design of the nephron protocols excluded a significant effect on proximal tubular reabsorption or directly on macula densa cells, thereby affecting tubuloglomerular feedback activity to contribute to changes in SNGFR since all studies were conducted during zero flow and NaCl delivery in the Loop of Henle and distal tubule. We concluded that this experimental approach of urinary space infusion with late proximal collections was preferable to other in vivo assessments, since this method focuses the candidate cells to those near the glomerular vasculature. Intrarenal artery infusions of agents cannot completely exclude tubular reabsorptive or tubuloglomerular feedback effects on nephron filtration rate, blood flow, and renal vascular resistance (40). How then do the agents infused in the urinary space, agmatine, ryanodine, etc., access their target cells? The results of this in vivo study have not completely answered this question directly. Rosivall and colleagues (34) have recently shown that the most distal portion of the afferent arteriole, one-third to one-half the length, is characterized by a highly fenestrated endothelium, and the urinary space is often in close proximity to this vessel and the adjacent extraglomerular mesangial cells. As stated, agmatine can activate receptors on endothelial cells that may generate NO via ryanodine and cyclic ADPR-dependent mechanisms (20, 30), yet, as shown here, agmatine does not activate Ca2+ release from vascular smooth muscle cells. Furthermore, we find that administration of the RyR agonist ryanodine by an identical route does not result in vasoconstriction, as would be expected by vascular smooth muscle cell involvement, but rather NO-dependent vasodilation. The anatomic relationship described could permit an agmatine effect via actions on endothelial cells.

A highly pertinent issue relates to the question of interaction of NO, and its signal transduction pathways, with the cADPR/RyR channel system. Some internal contradictions arise on the role of NO in this system. Although NO mobilizes calcium from intracellular stores in tissues and sea urchin eggs and elevates cADPR levels (36, 44, 47), it has also been shown to inhibit cyclase activity in coronary vascular smooth muscle cells (48). Competitive inhibitors of ADPR cyclase and cADPR prevent the calcium-mobilizing actions of NO (46, 47). It would appear that NO induces a positive feedback loop that could result in continuous RyR calcium channel activation and further stimulation of NOS. However, NO may act at several steps in the ADPR cyclase/RyR channel complex. In porcine tracheal smooth muscle cells, Kannan and coworkers (21) demonstrated that the RyR channel responses to caffeine were blunted by prior exposure to nitro donors. NO donors also inhibit induction of cADPR and intracellular calcium in vascular smooth muscle cells, resulting in vasodilation. 8-Bromo-cADPR or antagonistic concentrations of ryanodine attenuate this effect (48). These effects of NO may be explained, at least in part, by the complex array of cysteines present in the RyR channel that are subject to nitrosylation and oxidation (1, 37, 38). Our unexpected results with L-NMMA suppression of ryanodine activation of the RyR channel suggest ryanodine activation of the endothelial cell RyR/Ca2+ axis gives rise to NO generation, resulting in inhibition of vascular smooth muscle cell cADPR/RyR/Ca2+, vasodilation, and increased filtration rate. In aggregate, these studies indicate that NO exerts permissive activity in the cell that may be necessary for the normal function and activation of the RyR channel. Results from the current studies support such a concept.

Because vasodilation by agmatine requires NO generation, we performed studies to determine if cGMP plays a role in this effect. In addition, there is some support in the literature to suggest that cGMP might interact with the ADPR cyclase or with cADPR generation (14, 18). An overall summary of a complex literature is that cGMP and NO may exert either positive or negative effects on RyR channels, and this is probably cell-type dependent (19). Alternatively, reduction of intracellular calcium, as produced by NO on the cADPR/RyR/Ca2+ pathway in vascular smooth muscle cells (48), can give rise to vasodilation independent of cGMP (16, 21). In the current study, large concentrations of 8-bromo-cGMP, a stable cGMP analog, produced no increase in nephron filtration rate when infused in the urinary space of surface glomeruli. Although this result does not exclude a role for cGMP in agmatine-induced vasodilatation, it does suggest that large doses of cGMP do not duplicate the effects of agmatine or ryanodine administered by an identical route. In total, both agmatine and ryanodine induce calcium release and generate NO to increase SNGFR. NO can affect neighboring cells by diffusion and may induce a positive feedback loop in those cells that could result in further RyR calcium channel activation and stimulation of NOS, as described above. Calcium could also travel to networks of interconnecting cells, thus also expanding beyond the immediate area of the initial agmatine/ryanodine responsive cell. 8-Bromo-cGMP, on the other hand, would be restricted in its actions to cells within Bowman's capsule. Our results are suggestive of autocrine and paracrine cellular networking in the regulation of glomerular filtration.

This is the first in vivo study to demonstrate vasodilatation in response to biological agents in the kidney that require the participation of the ADPR cyclase/RyR channel system. These results, in conjunction with prior publications, suggest that NOS blockade is capable of inhibiting the biological agents, either agmatine or agonist concentrations of ryanodine, from increasing SNGFR. Our in vitro results show that this vasodilatory axis is unlikely confined to vascular smooth muscle cells. It must involve a second or primary cell that is responding to agmatine and generating NO by mechanisms that involve cyclic ADPr and ryanodine channel mechanisms. That NO generation is required for the response, and a cGMP analog does not invoke a similar response, supports the impression that two cells may be involved in this process. This adds complexity to a system in which NO is known to somehow maintain the function of the ryanodine calcium channel and now introduces the concept that activation of ryanodine calcium release can generate NO, likely from endothelial cells. These studies do not definitely prove participation of endothelial cells, since in vivo studies make such judgments difficult, a fact shared by other in vivo attempts to define actions of vasoactive compounds. We propose that agmatine and ryanodine effects require normal intracellular NOS activity to maintain RyR channels responsive to calcium-induced activation (37), thereby allowing the interplay between the endothelial cADPR/RyR/Ca2+/NO response and the resultant suppression of afferent arteriole cADPR/RyR/Ca2+ and vasodilation. We conclude that the renal effects of agmatine, an arginine metabolite, require activation of the RyR channel and NO generation to produce increased filtration rate.


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These studies were conducted with funds supplied by the National Institutes of Health (DK-28602, T32-HL-7671, DK-070123, and DK-070667) and from Veterans Affairs Research Service.


   ACKNOWLEDGMENTS
 
We thank John Reeves for assistance in the preparation of this manuscript.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. C. Blantz, Division of Nephrology-Hypertension, Univ. of California, San Diego and Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, M.C. 9111-H, San Diego, CA 92161 (e-mail: rblantz{at}ucsd.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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