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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
Received June 14, 2005; accepted August 19, 2005.
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Abstract |
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-nitro-L-arginine methyl ester (L-NAME) adenosine was unable to alter superficial blood flow and resistance significantly indicating that adenosine-induced dilatation is NO-dependent. Absence of a dilatory effect in endothelial nitric-oxide synthase (NOS) –/– mice suggests endothelial NOS as the source of NO. When infused into the subcapsular interstitium, adenosine reduced superficial blood flow through A1AR activation. Adenosine (10–7 M) constricted isolated perfused afferent arterioles when added to the bath but not when added to the luminal perfusate. Luminal adenosine caused vasoconstriction in the presence of L-NAME or the A2AR antagonist 3,7-dimethyl-1-(2-propynyl)xanthine. Our data show that global elevation of renal adenosine causes steady-state vasorelaxation resulting from adenosine 2 receptor (A2AR)-mediated generation of NO. In contrast, selective augmentation of adenosine around afferent arterioles causes persistent vasoconstriction, indicating A1AR dominance. Thus, adenosine is a renal constrictor only when it can interact with afferent arteriolar A1AR without affecting the bulk of renal A2AR at the same time.
). On the other hand, several early studies have established that the blood vessels in the kidney are exceptional in that the administration of adenosine can cause vasoconstriction (Drury and Szent-Gyorgy, 1929; Thurau, 1964). Furthermore, isolated afferent arterioles have been found to vasoconstrict in response to bath addition of adenosine (Weihprecht et al., 1992). This property of adenosine has been suggested to mediate the vascular constrictor response to increases in luminal NaCl concentration at the macula densa (Schnermann and Briggs, 2000). Vasoconstriction by adenosine in the kidney has been considered appropriate in an organ in which a positive coupling between work load and blood flow would seem nonhomeostatic (Thurau, 1964; Spielman and Thompson, 1982).
Nevertheless, several observations suggest that the view of a dominant vasoconstrictor action of adenosine in the renal vasculature needs to be qualified. It has been observed that adenosine elicits a pronounced constrictor response in an intact animal only under conditions where angiotensin II formation occurs at normal rates (Thurau, 1964; Osswald et al., 1975; Hall et al., 1985; Traynor et al., 1998). More importantly, the vasoconstrictor effect of adenosine is seen only when the nucleoside is administered as a single intravascular injection (Thurau, 1964; Osswald et al., 1975). When adenosine is given by constant infusion, on the other hand, there is only a transient reduction of renal blood flow that is followed by a rapid return to normal or supranormal values (Tagawa and Vander, 1970; Osswald, 1975, 1978; Hall et al., 1985). Thus, the stable response of the entire renal vascular bed to an increase in plasma adenosine levels consists more often in a vasodilatation than in a vasoconstriction. A vasodilator response to exogenous adenosine is not implausible since the kidney, in addition to expressing the vasoconstricting adenosine 1 receptor (A1AR), possesses abundant adenosine 2 receptors (A2AR) that in many vascular beds mediate vasorelaxation. Clearly, steady-state vasodilatation in vivo does not seem to be in accord with several in vitro studies in which adenosine has been shown to cause persistent rather than transient vasoconstriction of the afferent arteriole, a major renal resistance vessel (Joyner et al., 1988; Nishiyama et al., 2001; Hansen et al., 2003).
The present experiments were performed to further define the factors that determine whether adenosine causes vasodilator or vasoconstrictor responses in the kidney. Specifically, we asked whether the steady-state response to intravenous infusion in mice is vasodilatation or vasoconstriction, whether the dilator response to adenosine includes an endothelium-dependent component, and whether the response to adenosine depends upon the route of administration. The goal of these studies was to further examine whether the vasodilator potential of adenosine is compatible with its assumed role as a regulator of the constrictor tone of afferent arterioles. We conclude that approaches in which adenosine levels are elevated throughout the kidney cause renal vasorelaxation in most cases indicative of a preponderance of A2AR in the renal vasculature as a whole. Selective application to the afferent arteriole equivalent to selective local generation of adenosine is required to generate a constrictor response through activation of A1AR.
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Materials and Methods |
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). Brother-sister mating of heterozygous mice generated wild-type and –/– genotypes in a mixed 129J/C57BL6 genetic background. Genotyping was done on tail DNA using PCR as described previously (Sun et al., 2001). eNOS–/– mice and wild-type controls were derived from heterozygous breeder pairs obtained from The Jackson Laboratory (Bar Harbor, ME). Genotyping of offspring from brother-sister matings was done as described previously (Schnermann et al., 2001). Mice were kept on standard rodent chow and tap water. Measurements of Total and Superficial Renal Blood Flow. Mice were anesthetized with 100 mg/kg inactin intraperitoneally and 100 mg/kg ketamine intramuscularly. Cannulas were placed in the trachea, in the femoral artery for measurement of arterial blood pressure, and in the femoral vein for an i.v. maintenance infusion of 2.25 g/dl bovine serum albumin in saline at a rate of 0.35 ml/h. The left renal artery was approached from a flank incision and carefully dissected free to permit placement of a 0.5-mm V-type ultrasonic flow probe (Transonic Systems Inc., Ithaca, NY). The probe was held in place with a micromanipulator. The size of the probe available for these studies demanded the use of older mice. In addition, the preparation of the renal artery may interfere with renal nerve integrity. Therefore, we complemented determinations of total renal blood flow (RBF) with measurements of superficial blood flow (SBF), often in the same mice, but also in independent groups of animals. With the kidney stabilized in a Lucite cup, the laser Doppler flow probe mounted on a micromanipulator was placed on the renal surface. SBF was measured using a real-time dual laser Doppler flowmeter (PeriFlux System 5000; Perimed Inc., Stockholm, Sweden). RBF and SBF signals were digitized and analyzed using PowerLab software (ADInstruments, Colorado Springs, CO). After achieving stability in the RBF and/or SBF recordings, an intravenous continuous infusion of adenosine at 5, 10, or 20 µg/min or of CHA at 5 and 10 µg/min was started. At each dose, recordings were made for approximately 20 min with 15-min recovery periods between administrations of each drug, allowing RBF and arterial blood pressure to return to baseline.
To assess a role of NO in adenosine-induced vasodilatation, the effect of i.v. adenosine at 5, 10, or 20 µg/min was tested after the administration of 10 mg/kg L-NAME. The effect of infusion of increasing adenosine concentrations was also examined in eNOS–/– mice. A possible involvement of A2aAR was investigated with an intravenous administration of the specific A2aAR antagonist ZM-241385. ZM-241385 at a dose of 20 mg/kg was administered before the application of increasing concentrations of adenosine. The A2aAR agonist CGS 21860 was infused at 0.25, 0.5, and 1 µg/kg/min to further support a role of this adenosine receptor subtype. Steady-state mean arterial blood pressures were divided by steady-state RBF or SBF to obtain renal vascular resistance (RVR) or superficial vascular resistance (SVR).
Measurement of SBF during Local Application. After placement of the laser Doppler probe on the renal surface, a pipette with a tip diameter of about 10 µm was inserted into the subcapsular space close to the edge of the laser probe. The infusion pipette contained 10–6 M adenosine, 10–6 M CHA, or isotonic saline as control. The infusion fluid was stained with lissamine green to visualize the area of distribution. Test fluids were injected manually at a rate that caused visible staining in the area under and extending slightly beyond the laser probe. SBF was compared between preinfusion levels and steady-state levels achieved after 1 to 2 min of infusion. In general, the responses of two or three infusion periods were averaged.
Isolation and Microperfusion of Renal Afferent Arterioles. Mouse afferent arterioles with attached glomerulus were perfused as described in detail previously (Hansen et al., 2003). In brief, arterioles from A1AR+/+ mice of either sex (19–28 g) were dissected from slices of mouse kidneys at 4°C, transferred to a thermoregulated chamber, cannulated, and perfused with a pipette (tip diameter 5–6 µm) mounted on a moveable track system. The perfusate consisting of a physiological salt solution + 1% bovine serum albumin was driven from a reservoir pressurized to 60 to 90 mm Hg. The temperature was increased to 37°C, and the vessel was allowed to recover for 30 min and then was challenged with potassium (10–1 M) to ensure viability. Sequences of interest were recorded with a digital camera (CoolSNAP-Pro; Media Cybernetics Inc., Silver Spring, MD) for later determination of luminal vessel diameters using imaging software (Image Pro-Plus; Media Cybernetics Inc.).
The effect of adenosine on inner arteriolar diameter was tested during application of adenosine either from the interstitial/bath or from the luminal side of the vessel. The vessel was exposed to 10–7 M adenosine in the bath for 3 min. After 30-min washout, adenosine (10–7 M) was applied from the luminal side by adding adenosine to the perfusion pipette. The perfusate contained Keystone Green to visually verify perfusate exchange in the vessel. As positive control, the same protocol was repeated using angiotensin II (10–9 M) instead of adenosine. As a time control, adenosine was applied twice from the bath to ensure the ability of adenosine to constrict the vessels consecutively.
In another set of experiments the involvement of NO in the vascular response to adenosine was investigated. After bath application of adenosine (10–7 M; 3 min) and washout, arterioles were treated with L-NAME (5 x 10–5 M) for 20 min. In the presence of L-NAME, adenosine (10–7 M) and Keystone Green were then added to the perfusate.
Because A2AR are known to have a vasodilatory effect in the afferent arteriole, we investigated their involvement in the response to luminally applied adenosine. After establishing the effect of bath application of 10–7 M adenosine on afferent arteriolar diameter, the bath solution was changed to Dulbecco's modified Eagle's medium containing the A2 antagonist DMPX (10–5 M). After 15 min of DMPX pretreatment, adenosine (10–7 M) and DMPX were added to the perfusate. The ability of 0.1 M K+ to elicit constriction was tested after all experiments.
Statistics. Results are given as means ± S.E.M. Statistical comparisons used the Student's t test for paired data sets with a p < 0.05 considered significant. For multiple comparisons, we used an ANOVA with repeated measures in combination with the Bonferroni post hoc test.
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Infusion of adenosine in A1AR-deficient mice caused increases in RBF and SBF and reductions of RVR and SVR that were qualitatively similar than in wild-type mice (Table 1). However, as shown in Fig. 1, the percent changes of RBF, SBF, and RVR were significantly larger in A1AR–/– than wild-type mice. The reduction of arterial blood pressure caused by adenosine, on the other hand, was comparable between genotypes (Table 1). These data suggest that there is some activation of A1AR in wild-type mice that attenuates the full renal dilator effect of adenosine. Adenosine over the dose range tested did not affect heart rate of A1AR–/– mice, in contrast to wild animals in which we observed a dose-dependent decrease in heart rate that achieved significance at the highest dose.
To independently verify the contribution of A1AR activation to the overall effect of adenosine, we determined the effect of the A1AR agonist CHA under similar experimental conditions (n = 5). In wild-type mice, intravenous administration of CHA at 5 and 10 µg/min caused a reduction of mean arterial blood pressure and SBF, whereas SVR increased (Table 2). As expected, CHA did not alter mean arterial blood pressure, SBF, or SVR in A1AR–/– mice. Thus, A1AR activation reduces the dilatory effect of intravenous adenosine to some extent.
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To verify that the vasodilator effect of adenosine is mediated by A2AR and to determine the receptor isoform, the effect of the A2aAR-specific antagonist ZM-241385 on the renovascular effects of systemic adenosine was assessed in wild-type mice (n = 8). The results are summarized in Table 3. Administration of ZM-241385 caused a significant increase of mean arterial blood pressure by aprpoximately 25% and significant increases of calculated RVR and SVR, suggesting that ambient adenosine levels mediate tonic vasodilatation through activation of A2aAR receptors. Increases of RBF and SBF and decrements of RVR and SVR compared with basal in response to adenosine were prevented by the A2aAR blocker. The results of studies in five wild-type mice examining the effects of the A2aAR agonist CGS 21680 are summarized in Table 4. CGS 21680 caused a significant increase in RBF at the dose of 1 µg/kg min (by 16 ± 8%) and significant reductions of RVR at both 0.5 and 1 µg/kg min (by 21 ± 3 and 22 ± 5%, respectively). We conclude from this part of the study that the systemic administration of adenosine causes a steady-state reduction of total renal vascular and cortical resistance to flow and that this effect is mainly the result of A2aAR activation that dominates over the constrictor action of simultaneous stimulation of A1AR.
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Effect of Adenosine on SBF during NOS Inhibition. To assess the contribution of NO on the dilatory effect of adenosine, we determined the response of superficial blood flow to adenosine, both after administration of L-NAME (10 mg/kg) and in eNOS–/– mice. Data are summarized in Table 5. As can be seen, L-NAME increased arterial pressure and calculated resistance and decreased SBF. Increases of SBF and decreases of SVR caused by i.v. adenosine in both wild-type (n = 6) and A1AR–/– animals (n = 5) were markedly attenuated by L-NAME. The effect of adenosine on blood pressure was also found to be reduced. Furthermore, adenosine did not alter SVR in eNOS–/– mice over the entire dose range tested, suggesting that eNOS is required for adenosine to elicit vasodilatation.
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Effect of Subcapsular Application of Adenosine on SBF. To determine the in vivo effect of an interstitial application of adenosine, we determined SBF before and during infusion of the nucleoside into the subcapsular interstitial space under the laser probe. In wild-type mice, SBF fell significantly during the injection of 10–6 M adenosine from 144 ± 14 to 127.6 ± 15 perfusion units (n = 6; p < 0.0001). Similarly, injection of CHA reduced SBF from 98 ± 13 to 87 ± 12 perfusion units (p < 0.01). In A1AR–/– mice, there was a small increase in SBF from 117 ± 3 to 126 ± 2 units (n = 6; p < 0.05). The subcapsular infusion of saline had no measurable effect on SBF in either wild-type or A1AR–/– mice. There was no change in arterial blood pressure during any of these infusion periods. Percent changes of SBF induced by the subcapsular infusion of adenosine, CHA, or saline in wild-type and A1AR–/– mice are shown in Fig. 2. Thus, in contrast to intravenous application, the local interstitial administration of adenosine caused a vasoconstriction characterized by immediate onset and stability for the duration of the infusion period of 1 to 2 min. The findings in A1AR–/– suggest that the magnitude of the constriction is reduced by activation of A2AR.
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). As noted previously, the addition of adenosine to the bath significantly decreased the luminal diameter of the perfused afferent arterioles from 8.0 ± 0.8 to 4.0 ± 0.3 µm, and diameters returned to baseline after adenosine washout. In contrast, the luminal diameter of the same vessels did not significantly change during luminal application of adenosine at 10–7 M (7.9 ± 0.8 to 6.8 ± 0.8 µm) (Fig. 3A). To exclude the possibility that vessels are unable to respond to two successive exposures of adenosine because of desensitization, we recorded diameter responses to two consecutive bath applications with intermittent recovery. In these studies, adenosine elicited significant diameter reductions to both the first and second exposure (Fig. 3B). At the end of all of the experiments, we confirmed that the addition of K+ induced full constriction of the vessels. In contrast to adenosine, angiotensin II caused vasoconstriction of the isolated perfused afferent arteriole with both bath and perfusate applications; at a concentration of 10–9 M, it reduced vessel diameters from 8.0 ± 0.8 to 1.1 ± 0.8 µm during bath application and from 7.9 ± 1.4 to 2.1 ± 1.5 µm during luminal application (Fig. 3C). Thus, a vasoconstrictor effect of adenosine is seen during bath application, whereas luminal administration is ineffective.
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; Hall et al., 1985), which have shown that adenosine causes a short-lasting vasoconstriction and persistent vasorelaxation. Because we find it difficult to access the renal artery of the mouse, adenosine and other agents were infused intravenously. Thus, in contrast to earlier studies in which adenosine was infused into the renal artery, the administration of adenosine in the present experiments caused a dose-dependent blood pressure reduction. This raises the possibility that an autoregulatory reduction of resistance contributes to the relaxation caused by adenosine. However, a purely autoregulatory response is not expected to cause a resistance reduction large enough to increase RBF as seen at the lowest rate of adenosine infusion (Table 1). Thus, any pressure-induced dilatation seems to be augmented by a direct dilator effect of adenosine. Furthermore, the blood pressure reduction is expected to elicit a reflex activation of renal sympathetic nerves. Increased adrenergic input would be predicted to cause vasoconstriction, the opposite of the finding that the infusion of adenosine led to a significantly reduced renal vascular resistance. Nevertheless, an increasing renal sympathetic nerve activity may have been responsible for the result that the reduction in RVR did not show dose dependence in wild-type mice (Fig. 1).
Thus, in mice, the steady-state effect of an infusion-induced increase in plasma adenosine above the normal 10–7 to 10–6 M range is associated with a steady-state vasorelaxation (Kost and Jackson, 1991; Zhang et al., 1994; Chen et al., 2002). If the vessel wall does not act as a barrier to the free distribution of the systemically supplied adenosine, one may assume that most available free adenosine receptors will be activated. Equilibration of adenosine across the vessel is suggested by the finding that the effect of an interstitial infusion of adenosine through implanted capsules resembles that of intravascular administration in that it also causes a short-lasting constriction to bolus injections and no constriction during prolonged infusion (Pawlowska et al., 1987; Agmon et al., 1993). Vasorelaxation in response to the infused adenosine may either reflect a greater number of unoccupied A2AR than A1AR and/or a greater total number of A2AR. Although it is difficult to compare the total expression levels of A2AR and A1AR, it is clear that A2AR are widely expressed throughout the renal vasculature, whereas the expression of A1AR is more concentrated to the vascular pole (Morton et al., 1998; Zou et al., 1999; Jackson et al., 2002). This distribution agrees with the finding that the adenosine-induced dilatation is greater in larger renal vessels (renal, arcuate, and interlobular arteries) than in afferent arterioles, whereas the constrictor effect is greater in the smaller arterioles (Gabriels et al., 2000). The contribution of efferent arterioles to the overall vasodilator response is unclear. Nevertheless, the reduction in the filtration fraction by adenosine is consistent with vasorelaxation of postglomerular arterioles (Tagawa and Vander, 1970; Murray and Churchill, 1984). Vasodilatation during infusion of adenosine is likely the result of a relaxation of several resistance vessels that is greater than the constriction of glomerular afferent arterioles. We have not investigated the causes for the fall in glomerular filtration rate that has been reported to result from adenosine infusions in the absence of any reduction of renal blood flow. Afferent arteriolar vasoconstriction may be the dominant cause in superficial nephrons (Osswald et al., 1978), but for the kidney as a whole a combination of efferent dilatation and reductions of the filtration coefficient is more compatible with the vasodilatation seen in our study and other studies.
The vasodilator effects of adenosine seem to be mediated at least in part by NO since L-NAME prevented the SBF increase in response to adenosine in both wild-type and A1AR–/– mice. Furthermore, adenosine did not affect SBF in eNOS-deficient mice, suggesting that the endothelial isoform of NOS is responsible for the adenosine-induced NO formation. Nevertheless, adenosine did not cause vasoconstriction in wild-type mice after blocking dilatation with L-NAME and in eNOS–/– mice, indicating that the A2AR-mediated relaxation is to some extent NO-independent. The abolished vasodilatation in the superficial vascular bed by ZM-241385 indicates that NO formation is primarily the result of A2aAR activation. These conclusions agree with previous studies in excised renal and nonrenal vessel preparations showing consistent increases in NOS activity and NO release in response to adenosine, usually through an A2AR-mediated process (Zanzinger and Bassenge, 1993; Martin and Potts, 1994; Abebe et al., 1995; Grbovic et al., 2000). Adenosine has also been shown to dilate rabbit renal arteries through an undefined endothelial relaxing factor that does not seem to be NO (Rump et al., 1999). In addition, adenosine stimulates the production of NO in cultured endothelial cells, usually through mediation of an A2AR-dependent mechanism (Li et al., 1998; Olanrewaju and Mustafa, 2000; Wyatt et al., 2002). The dependence of most of the renal dilatation on NO formation may explain why the onset of the dilator response lags behind the constrictor action, which is presumably a direct receptor-mediated event.
Stable vasoconstriction was observed when adenosine was infused into the subscapsular space or when it was applied to the bath of perfused afferent arterioles. This constrictor effect is A1AR-mediated since subcapsular CHA infusion mimicked the effect of adenosine and since vasoconstriction was not observed during subcapsular infusion of CHA in A1AR–/– mice (Holz and Steinhausen, 1987; Dietrich et al., 1991; Weihprecht et al., 1992; Hansen et al., 2003). Previous studies have already shown that adenosine does not constrict isolated perfused afferent arterioles from A1AR–/– mice (Hansen et al., 2003). We assume that subcapsular infusion through a micropipette restricts the distribution of adenosine to a limited area in which the main resistance vessels are the glomerular arterioles. The resultant vasoconstriction suggests that, in this part of the renal vasculature, A1AR is the dominant receptor subtype. Alternatively, adenosine concentrations that are high enough to activate A2AR may not be reached with subcapsular application. Detection of a vasoconstrictor effect in the isolated arteriole is probably facilitated by the fact that basal adenosine levels are close to zero, and A1AR are therefore largely unoccupied. However, this is not the case in the supcapsular infusion approach, suggesting that the A1AR occupancy by ambient adenosine concentrations is incomplete. Although the vasoconstriction during intravascular infusion is transient, the contraction induced by interstitial adenosine is long-lasting (Hansen et al., 2003), concordant with the finding that expressed native or recombinant A1AR desensitize slowly over a time frame of hours to days rather than minutes (Palmer et al., 1996; Palmer and Stiles, 1997). Thus, the waning nature of the vasoconstrictor response of the entire renal vasculature does not reflect an inherent receptor property of A1AR but results from a slightly delayed activation of an opposing dilator action.
Prevalence of vasodilatation during intravenous application and of vasoconstriction during subcapsular and bath administration suggests that adenosine causes opposite effects when applied to the bloodstream or to the outside of the vessel. Thus, the balance between activation of A1AR and A2AR may depend on the route of adenosine administration, with luminal adenosine being unable to interact with A1AR on smooth muscle cells. However, the ability of luminally applied adenosine to constrict the afferent arteriole after L-NAME treatment or during A2AR blockade clearly indicates accessibility of A1AR to luminal adenosine. Thus, absence of vasoconstriction of isolated afferent arterioles during luminal application is probably due to balanced activation of A1AR and A2AR rather than inaccessibility of A1AR. Enhanced constriction during A2AR blockade has previously been observed in afferent arterioles of juxtamedullary nephrons with both agonists and antagonists supplied by vessel superfusion (Nishiyama et al., 2001). The vasodilatation caused by subcapsular adenosine in A1AR–/– mice also indicates that adenosine can cross the vessel wall. Predominant constriction with abluminal application may result from a dilution effect of arteriolar flow-limiting attainment of sufficiently high luminal adenosine concentrations. In addition, the expression of A2AR in afferent arterioles particularly in its distal portions may be lower than in larger renal arterial vessels. Because adenosine is released into or generated in the interstitial spaces, interstitial increments of the nucleoside may represent the primary means by which changes in adenosine receptor activation are achieved physiologically. In the minority of vessels that express A1AR and that include the afferent arteriole, these interstitial elevations of adenosine are expected to cause vasoconstriction.
In summary, the present study indicates that an elevation of renal adenosine by intravenous infusion causes a steady-state vasorelaxation that reflects preponderance of A2AR in the renal vasculature as a whole and that largely results from A2AR-mediated generation of NO. In contrast, selective augmentation of adenosine around afferent arterioles causes persistent vasoconstriction, indicating A1AR dominance. Specific targeting of adenosine to afferent arteriolar A1AR requires changes of local interstitial nucleoside concentrations that are largely independent of systemic levels and therefore do not affect the bulk of renal adenosine receptors that are vasodilator in nature.
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P.B.H. and S.H. contributed equally to this work.
ABBREVIATIONS: A1AR, adenosine 1 receptor; PCR, polymerase chain reaction; eNOS, endothelial nitric-oxide synthase; RBF, renal blood flow; SBF, superficial blood flow; CHA, N6-cyclohexyladenosine; L-NAME, N-nitro-L-arginine methyl ester; ZM-241385, 4-(2-[7-amino-2-(2-furyl) [1,2,4]triazolo [2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol; CGS 21860, 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamido-adenosine hydrochloride; RVR, renal vascular resistance; SVR, superficial vascular resistance; A2AR, adenosine 2 receptor; DMPX, 3,7-dimethyl-1-(2-propynyl)xanthine; ANOVA, analysis of variance; NOS, nitric-oxide synthase.
Address correspondence to: Dr. Jurgen Schnermann, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg. 10, Room 4 D51, 10 Center Dr., MSC 1370, Bethesda, MD 20892. E-mail: jurgens{at}intra.niddk.nih.gov
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