Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216
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ABSTRACT |
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Nitric oxide (NO) plays an important role in the
regulation of vascular tone, and evidence suggests that
endothelial-dependent relaxation, possibly mediated via NO, is impaired
in diabetes. However, the role of the endothelium in arterial pressure
control early in diabetes, before dysfunction develops, is not known. This was evaluated in the present study by comparing the responses to
induction of diabetes in vehicle-treated rats (D, n = 7) vs. rats chronically treated with
NG-nitro-L-arginine methyl ester
(L-NAME; D+L, n = 8). A nondiabetic group
also was treated with L-NAME (L, n = 7) to
control for L-NAME effects over time, independent of
diabetes. After baseline measurements, rats were given either vehicle
or L-NAME (10 µg · kg1 · min
1 iv)
infusion throughout the experiment. Six days later, streptozotocin (60 mg/kg iv) was administered, followed by a 3-wk diabetic study period.
Induction of diabetes in the D+L rats caused a marked and progressive
increase in mean arterial pressure throughout the diabetic period,
averaging ~70 mmHg greater than in the D rats and ~20 mmHg greater
than in the L rats. Glomerular filtration rate and renal plasma flow
tended to increase during diabetes, but this trend was reversed in the
D+L rats. In addition, plasma renin activity increased in the D and D+L
rats during week 1 of diabetes but then returned to control
in the D rats, while continuing to increase in the D+L rats. These
results suggest that, in the early stages of diabetes, NO synthesis is
important to prevent hypertension from developing, possibly through
actions to maintain glomerular filtration and suppress renin secretion.
NG-nitro-L-arginine methyl ester; arterial pressure; glucose; angiotensin II; vasodilation
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INTRODUCTION |
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THERE IS CONSIDERABLE EVIDENCE suggesting that endothelial function is impaired in diabetes (13, 27-29, 33). The impairment has been linked to numerous circulatory derangements in diabetes, including increased capillary permeability (37), enhanced platelet aggregation (10), and accelerated progression of diabetic nephropathy (13). In addition, loss of endothelial-dependent vasodilator capacity, mediated to a great extent by nitric oxide (NO), may cause excessive vasoconstriction in some vascular beds (7, 18, 27, 34). However, emphasis on the role of an impaired endothelium in mediating cardiovascular dysfunction during the established stages of diabetes has diverted attention, somewhat, away from the importance of a normal endothelium at the onset of diabetes.
Even under baseline conditions in normal animals and humans, NO production by the endothelium is important in maintaining normal blood flow and arterial pressure, as evidenced by the significant vasoconstrictor and hypertensive responses to NO synthesis inhibition (44). Although some data suggest that glucose may impair NO production (20), there also is evidence that NO production actually is increased in the early stages of diabetes and also is important in maintaining the increased renal blood flow (13, 22). Blockade of NO synthesis under those conditions, therefore, might be expected to cause an even greater hypertensive response, especially when the tendency for poor glycemic control to increase arterial pressure is considered (9, 23, 24). Therefore, we tested the hypothesis that, at the onset of diabetes, before there has been time for endothelial dysfunction to develop, there is increased dependence of arterial pressure and renal vascular resistance on NO synthesis.
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METHODS |
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The experiments were conducted in 22 male Sprague-Dawley rats (345 ± 3 g, Harlan Sprague Dawley, Madison, WI). Surgery and care of the rats were conducted in accordance with National Institutes of Health guidelines with protocols that had previous approval from the Animal Care and Use Committee of the University of Mississippi Medical Center. Anesthesia was induced with pentobarbital sodium (50 mg/kg ip), and atropine (40 µg/rat ip) was administered to ensure an unobstructed airway. Body temperature was maintained at ~37°C by use of a servo-controlled heating pad. Under aseptic conditions, a laparotomy was performed, and a nonocclusive, polyvinyl catheter was implanted in the abdominal aorta through a puncture wound in the aortic wall made with the tip of an L-shaped 18-gauge needle. The insertion point was sealed with cyanoacrylate adhesive, and the catheter was exteriorized through the lateral abdominal wall. A femoral vein catheter was implanted through a separate incision, and the tip was maneuvered into the inferior vena cava caudal to the kidneys. All incisions were infiltrated with penicillin G procaine (300,000 U/ml) and Sensorcaine at closure, and the catheters were routed subcutaneously to the scapular region and exteriorized through a Dacron-covered stainless steel button sutured subcutaneously over the scapulae.
The rats were allowed to recover from surgery in a warmed cage. Thereafter, rats were placed in individual metabolic cages in a quiet, air-conditioned room with a 12:12-h light-dark cycle. Throughout the study, the rats received food and water ad libitum. The catheters were connected to a dual-channel infusion swivel (Instech, Plymouth Meeting, PA) mounted above the cage and were protected by a stainless steel spring that also served as a tethering device.
The arterial catheter was filled with heparin solution (1,000 USP U/ml) and connected, via the hydraulic swivel, to a pressure transducer (Cobe, Lakewood, CO) mounted on the cage exterior at the level of the rat. The amplified pulsatile arterial pressure signals were sent to an analog-to-digital converter and analyzed by computer with customized software. The analog signals were sampled for 4 s each minute, 24 h/day. The venous catheter was connected, also via the hydraulic swivel, to a syringe pump (Harvard Apparatus, Millis, MA) that ran continuously throughout the study. Total sodium intake throughout the experiment was maintained constant at ~3.1 mmol/day by continuous intravenous infusion of 25 ml of sterile 0.9% saline per day, combined with sodium-deficient rat chow (0.006 mmol sodium/g; Teklad, Madison, WI). A sodium-deficient diet ensured that the daily sodium intake could be controlled precisely at normal levels by the infusion, independent of food intake. The infusion was started immediately after placement of rats in their cages, and ~1 wk was allowed for recovery and acclimation before baseline measurements were made.
Experimental protocol. To test the role of NO in controlling arterial pressure at the onset of diabetes, two groups of rats were made diabetic, with one group subjected to chronic nonselective NO synthase (NOS) inhibition with NG-nitro-L-arginine methyl ester (L-NAME) throughout the study. To control for effects of L-NAME over time, independent of diabetes, a separate group of normal rats was treated with the same chronic dose of L-NAME.
The rats were divided randomly into three groups: diabetic (D, n = 7), diabetic pretreated with L-NAME (D+L, n = 8), and normal rats pretreated with L-NAME (L, n = 7). After 5 days of baseline measurements, the NOS inhibitor L-NAME (10 µg · kgAnalytical methods.
Glomerular filtration rate (GFR) and renal plasma flow (RPF) were
measured by use of a 4-h fasted plasma sample after a 24-h intravenous
infusion of [125I]iothalamate (Glofil) and
[131I]iodohippuran (both at 0.015 C · kg1 · min
1).
Because steady state was achieved during the 24-h infusion and the
infusate sample was counted, the isotope infusion rate was substituted
for urinary isotope excretion rate to calculate clearance. Urinary
sodium and potassium concentrations were determined using ion-sensitive
electrodes (NOVA, Waltham, MA).
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RESULTS |
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Mean arterial pressure (MAP) averaged 95 ± 2, 93 ± 2, and 93 ± 2 mmHg in the D, D+L, and L groups, respectively, during
the baseline precontrol period (Fig. 1).
Starting treatment with the NO synthase inhibitor L-NAME
produced a rapid and significant increase in MAP in the D+L and L rats
that plateaued at ~23 mmHg above baseline levels by day 6 of the control period (groupwise P < 0.001). After the
induction of diabetes, there was a significant effect of treatment on
the arterial pressure responses among the three groups of rats
(groupwise P < 0.001, Fig.
1). Induction of diabetes in the D+L rats
caused a marked and progressive increase in MAP throughout the diabetic
period. In the last week of diabetes, MAP in the D+L rats averaged
~70 mmHg greater than in the D rats and ~20 mmHg greater than in
the L rats. The effects may be seen more clearly as the change in
pressure from control (Fig. 2). Control was an average of the last 3 days before the day on which diabetes was induced in the D and D+L
rats. Also included for reference are data from a previous study
(8) (NORMAL) showing the stability of MAP measured over
the same time course in similarly instrumented and maintained normal
rats, but with only saline vehicle infused throughout. These data show,
therefore, that chronic inhibition of NO synthesis caused diabetes to
induce a significant increase in MAP that was greater than the effect
of L-NAME alone.
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Heart rates were not different between groups during the precontrol period, and L-NAME treatment in the D+L and L rats decreased heart rate by ~25 beats/min (Fig. 1). Heart rate in the L rats remained relatively constant at that lower rate for the remainder of the experiment. There was a significant effect of treatment on the heart rate responses to the induction of diabetes in the three groups of rats (groupwise P < 0.001). The induction of diabetes caused pronounced bradycardia in the D rats, to a rate that averaged 101 ± 6 beats/min below control levels by day 20 of the diabetic period. Heart rate in the D+L rats showed a similar response initially, but after decreasing by 43 ± 3 beats/min by day 5 of diabetes, heart rate began to increase and reached levels not different from those of L rats by day 20. Thus L-NAME treatment in diabetic rats attenuated the decline in, and eventually eliminated, the bradycardic effect of diabetes.
Sodium intake was fixed at 3.1 mmol/day throughout the course of the study. During the control period, urinary sodium excretion was not significantly different among the three groups, averaging 2.4 ± 0.2, 3.1 ± 0.1, and 3.1 ± 0.3 mmol/day for the D, D+L, and L rats, respectively. However, the induction of diabetes in the D and D+L rats produced a marked increase in sodium excretion, resulting in a progressively greater sodium loss during the 3-wk diabetic period (groupwise P < 0.001). In the D+L rats, however, there was a notable tendency for blunting of the sodium loss, although this did not reach statistical significance. At the end of the diabetic period, the cumulative sodium loss was 22.7 ± 1.5 mmol in the D rats compared with a negative sodium balance of 16.6 ± 2.2 mmol in the D+L rats (Fig. 1).
During the control period, GFR averaged 3.6 ± 0.1 ml/min in the D
rats and was significantly lower in the L-NAME-treated
groups, averaging 3.2 ± 0.2 and 2.9 ± 0.1 ml/min in the D+L
and L rats, respectively (Fig. 3,
P < 0.05). Similarly, RPF tended to decrease after
L-NAME treatment, averaging 7.2 ± 0.4 and 6.7 ± 0.1 ml/min in the D+L and L rats, respectively, compared with 8.2 ± 0.5 ml/min in the D rats during the control period. With induction
of diabetes, GFR and RPF tended to increase in the D rats, although the
increase was not statistically significant. L-NAME
treatment, however, not only prevented those increases during diabetes
in the D+L rats but actually resulted in significant decreases in GFR
and RPF during week 3 of diabetes (groupwise
P < 0.05). In the L rats, these variables remained
stable for the 3-wk experimental period. Thus the decrease in GFR and
RPF in the D+L rats during week 3, which did not occur in
the L rats, suggests there was increasing dependence on NO for
maintenance of GFR during diabetes. It also is noteworthy in that
regard that the decline in GFR in the D+L rats during week 3 of diabetes coincided with a significant difference in the rate of
increase in MAP in the D+L vs. the L rats (Fig. 1).
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L-NAME treatment tended to decrease PRA, averaging
2.49 ± 0.18 and 3.46 ± 0.32 ng angiotensin I (ANG
I) · ml1 · h
1 in the D+L
and L rats, respectively, compared with 4.13 ± 0.53 ng ANG
I · ml
1 · h
1 in the D rats,
but the changes were not significant. After the induction of diabetes,
PRA increased significantly in both diabetic groups by day
5, increasing by 3.00 ± 0.78 and 5.44 ± 0.88 ng ANG
I · ml
1 · h
1 in the D and
D+L rats, respectively (Fig. 4, groupwise
P = 0.05). In addition, PRA continued to rise in the
L-NAME-treated rats, with the level in the D+L rats
significantly greater than that in the L rats by day 20 (P < 0.05). In the D rats, on the other hand, PRA
returned to control levels during the remainder of the diabetic period.
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Blood glucose was not different among the three groups of rats during the control period, averaging 7.1 ± 0.2, 7.1 ± 0.2, and 6.9 ± 0.1 mmol/l in the D, D+L, and L rats, respectively, and it did not change in the L rats over the next 3 wk. After the induction of diabetes, blood glucose increased markedly and remained at hyperglycemic levels throughout the study, averaging 23.7 ± 0.7 and 21.3 ± 1.9 mmol/l in the D and D+L rats, respectively, for the 3-wk period. Interestingly, glucose in the D+L rats began to decrease toward control during the last week of diabetes, averaging 17.8 ± 2.4 mmol/l for the last 7 days. This was significantly lower than in the D rats (groupwise P < 0.05), and the insulin dose was decreased progressively to correct the fall. Beginning on day 3 after induction of diabetes, insulin was administered to both diabetic groups, through continuous intravenous infusion, to try and maintain fasting blood glucose in the range of 20-25 mmol/l. In the D rats, the insulin infusion dose averaged 0.6 ± 0.3 U/day for the first 7 days of treatment and then stabilized at an average of 0.3 ± 0.2 U/day for the remainder of the diabetic period. In the D+L rats, the insulin infusion dose was significantly higher initially, averaging 1.2 ± 0.2 U/day for the first week (groupwise P = 0.05), but was not different from the D rats during week 3, averaging 0.6 ± 0.2 U/day. Food intake was not different among the three groups during the control period, averaging 22 ± 1, 19 ± 1, and 20 ± 1 g/day for the D, D+L, and L rats, respectively, and did not change in the L rats over the next 3 wk. After the induction of diabetes, both the D and D+L rats increased their eating, and by day 14, food intake was 35 ± 3 and 27 ± 2 g/day in the D and D+L rats, respectively (groupwise P < 0.001). During the last week of diabetes, however, food intake in the D+L rats decreased toward control levels.
Plasma protein concentration tended to increase during the experimental period in all groups, but the increase (11%) was significant only in the D rats (P < 0.001). During the diabetic period, hematocrit increased in the D rats (increasing from 0.41 ± 0.00 to 0.43 ± 0.01) while decreasing in the D+L rats (decreasing from 0.43 ± 0.00 to 0.40 ± 0.01).
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DISCUSSION |
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These results show that blockade of NO synthesis causes a significant increase in MAP at the onset of diabetes. Although we have shown previously that there is a consistent trend for MAP to increase with poor glycemic control in diabetic rats (7, 9), the increase in arterial pressure was three- to fourfold greater with NO synthesis inhibition. Associated closely with the increase in MAP, the L-NAME-treated diabetic rats also showed a significant impairment in their ability to maintain GFR, and a much greater increase in PRA. Thus at the onset of diabetes, NO synthesis is essential to prevent hypertension from developing, perhaps in part because of actions that maintain glomerular filtration and suppress renin secretion.
Activity of the NO system in diabetes is somewhat controversial, with studies providing evidence for either an increase (12, 14, 22, 28) or a decrease (3, 28, 35) in the synthesis of NO in the diabetic state. Likewise, endothelial-mediated vasodilation has been reported to be impaired in diabetic humans (17, 21) and animals (1, 27), but not all studies report impairment (7, 15, 31). In addition, NO synthesis may not accurately reflect NO activity in various stages of diabetes, because the level of free radical production can greatly affect activity, even causing a decrease in NO activity despite increased synthesis (12, 14). Thus, although the endothelium may function normally, particularly at the early stages of diabetes, a dysfunctional response to endothelium-dependent vasodilatory stimuli may occur. The reason for the discrepancies between observations in different studies is not known but could be the influence of ambient glucose concentrations at the time of the study, tissue specific responses, or differences in the duration of diabetes at the time of testing. This study was not designed to address this complex issue, but we have shown that the vasodilatory response to acute acetylcholine infusion is not impaired during the 1st wk of diabetes in this model (7), and the present results suggest, furthermore, that the ability to synthesize NO is important to prevent significant increases in arterial pressure during the early stages of diabetes.
The observation that blockade of NO synthesis caused MAP to increase significantly at the onset of diabetes does not exclude the possibility that mechanisms other than removal of the vasodilator influence of NO contributed to the hypertension. A role of the sympathetic nervous system, for example, is suggested by the heart rate response to NO synthesis inhibition in the diabetic state. The bradycardia in the diabetic rats (D) is consistent with suppression of the sympathetic nervous system, and the increase in heart rate in the diabetic rats treated with L-NAME (D+L) suggests that activation of the sympathetic nervous system occurred in the absence of NO. Indeed, it has been demonstrated that NO can suppress sympathetic nervous system activity (43). Thus inhibition of sympathetic nervous system activity may have contributed to NO's action to prevent increases in arterial pressure at the onset of diabetes, and likewise, increased sympathetic activity may have mediated a significant component of the marked hypertension in the L-NAME-treated diabetic rats (D+L).
Another, although not necessarily unrelated, mechanism whereby NO could affect arterial pressure at the onset of diabetes is through the control of renal vascular resistance. Our previous studies have shown that the onset of diabetes in rats is associated with a modest increase in arterial pressure (9) and a marked decrease in 24 h/day-measured hindquarter blood flow (7), consistent with peripheral vasoconstriction. One possibility, therefore, is that renal hyperfiltration and natriuresis serve as mechanisms to counteract an increase in arterial pressure. These renal responses could also be acting to balance a shift in the pressure-natriuresis relationship, but because glucose-mediated osmotic diuresis contributes to the renal sodium loss in diabetes, it is not clear how the induction of diabetes actually shifts pressure natriuresis. Regardless, however, it is tempting to speculate that NO plays at least a permissive role in the development and persistence of the hyperfiltration and natriuresis, and that these actions help counteract a pressor stimulus associated with diabetes in rats (9). If so, then blockade of NO synthesis during diabetes should attenuate the renal responses and increase arterial pressure. The natriuresis showed signs of being attenuated in the D+L rats compared with the D rats, but the differences were not statistically significant. GFR, on the other hand, tended to increase in the diabetic rats but did not increase with induction of diabetes in the L-NAME-treated rats, and arterial pressure increased more in the latter group. Moreover, GFR actually decreased significantly during the latter stages of this study in the D+L rats, and this was associated with a further increase in the rate of the arterial pressure rise. Thus, although other factors likely are important in determining the renal responses, sodium excretion in particular, the ability to increase or maintain GFR at the onset of diabetes appears to be dependent on NO synthesis and may be a mechanism through which NO prevents arterial pressure from increasing.
The control of GFR in diabetes is not well understood, even though it is recognized that at the early stages of both clinical and experimentally induced diabetes there is a significant increase in GFR (25, 41). The maintenance of increased GFR in the face of natriuresis suggests that there has been a resetting or impairment in the feedback control of GFR via the macula densa mechanism (6), and NO could affect these relationships through several mechanisms. There is good evidence that NO blunts tubuloglomerular feedback (TGF) (5, 40), and an effect of diabetes to increase NO production is consistent with the blunting of TGF associated with diabetes (6, 38). Because this change in TGF has been proposed to explain, at least in part, the hyperfiltration in diabetes (6, 25, 41), the failure of GFR to increase in the diabetic rats with NO synthesis blocked is consistent with this mechanism. However, increased NO production at the onset of diabetes also could raise GFR through direct vascular actions (22). Likewise, other factors could mediate the increase in GFR, and basal NO production may be required only to offset the influence of vasoconstrictor stimuli; however, this study cannot differentiate between these possible mechanisms.
The actions of NO on the renal vasculature and macula densa also mediate much of its effect on renin secretion (19), and our results suggest that changes in renin secretion may have affected the arterial pressure responses to the onset of diabetes as well. This is consistent with the findings of Miller et al. (24), who demonstrated that short periods of hyperglycemia in early type 1 diabetic patients increased renin secretion and also increased the dependence of arterial pressure on angiotensin II (23). Similarly, in our study, PRA increased in both diabetic groups during the 1st wk of diabetes. As diabetes progressed, however, PRA returned to control in the D rats but continued to increase in the D+L rats. This suggests that increased NO production was responsible for the decrease in renin secretion back to control levels during the last 2 wk of diabetes in the D rats. The mechanism for the initial increase in PRA is not clear but appears to be independent of NO, because it increased in both the D and D+L rats. In addition, that stimulus seemed to be maintained, because PRA in the D+L rats was significantly greater than in the L rats on day 20 of the experimental period. Although the mechanism for the effect of NO on renin secretion is not known, the renin-suppressing effect of NO during the last 2 wk of this study was associated closely with the ability to prevent arterial pressure from increasing during diabetes.
Other important variables that must be considered in mediating the effects of NO synthesis inhibition in this study relate to food intake and glucose utilization. All diabetic rats received the same dose of STZ, and porcine insulin was added to the infusate as needed to keep all diabetic rats between 20 and 25 mmol/l. By about the 5th day of diabetes, a stable insulin dose per rat was achieved, and blood glucose in both diabetic groups was very similar. However, during the 3rd wk of diabetes, blood glucose began to decrease toward 17 mmol/l in the D+L diabetic rats, and they required a decrease in the insulin dose to try and keep glucose in the desired range. This suggests that insulin sensitivity improved and that this change was accompanied by a decrease in food intake toward normal levels. The explanation for these changes is not known, and additional studies will be required to explore the mechanism as well as potential effects on the hemodynamic responses we measured. For example, decreases in food intake generally are associated with decreases in blood pressure (39), PRA (26), and sympathetic nervous system activity (36), which are contrary to what we observed and proposed in the D+L rats; however, the decrease in food intake may have been secondary to increased insulin sensitivity, which could alter those relationships. The return of food intake toward normal also may have contributed to the change in GFR at week 3 in the D+L rats (42). Thus many relationships along these lines remain to be studied, and because there is evidence that NO may increase insulin sensitivity (3) and affect stimulus-secretion coupling for insulin secretion (32), there is ample rationale to consider these possibilities.
Thus several mechanisms may have contributed to the effect of L-NAME to cause MAP to increase significantly at the onset of diabetes. It could be linked to increased sympathetic nervous system activity due to withdrawal of a suppressing effect of NO on the sympathetic nervous system, on increased renin secretion, or even on a decrease in the vascular actions of NO. In addition, changes in insulin sensitivity and food intake caused by L-NAME treatment in the diabetic rats either directly or indirectly may have contributed to our results. To our knowledge, this is the first study that has tested the effect of long-term L-NAME treatment on blood pressure control beginning at the onset of diabetes, and clearly there are many new questions that remain to be answered. Regardless, however, these results indicate that an intact ability to synthesize NO is important at the onset of diabetes to prevent hypertension and perhaps to enable hyperfiltration. We speculate, in addition, that the renal vasodilator action of NO may be a mechanism during the early stages of diabetes for preventing an increase in arterial pressure. That effect, however, although beneficial for short-term arterial pressure control, could contribute to accelerated progression of renal injury in diabetes. Further study will be needed to test these hypotheses and to determine the role of the specific NOS isoforms in mediating these effects.
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ACKNOWLEDGEMENTS |
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We thank Allison Hailman and Rico McGowan for technical assistance.
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FOOTNOTES |
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This research was supported by National Heart, Lung, and Blood Institute Grants HL-56259 and HL-51971 and was conducted during the tenure of an Established Investigator Grant from the American Heart Association (AHA) and Genentech. Dr. Fitzgerald is the recipient of a Postdoctoral Fellowship award from the Mississippi Affiliate of the AHA Southern Research Consortium.
Address for reprint requests and other correspondence: S. M. Fitzgerald, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505 (E-mail: sfitzgerald{at}physiology.umsmed.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.
Received 14 January 2000; accepted in final form 22 May 2000.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Angulo, J,
Sanchez-Ferrer CF,
Peiro C,
Marin J,
and
Rodriguez-Manas L.
Impairment of endothelium-dependent relaxation by increasing percentages of glycosylated human hemoglobin.
Hypertension
28:
583-592,
1996
2.
Arnal, JF,
Warin L,
and
Michel JB.
Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase.
J Clin Invest
90:
647-652,
1992[ISI][Medline].
3.
Balon, TW,
and
Nadler JL.
Evidence that nitric oxide increases glucose transport in skeletal muscle.
J Appl Physiol
82:
359-363,
1997
4.
Bank, N,
and
Aynedjian HS.
Role of EDRF (nitric oxide) in diabetic renal hyperfiltration.
Kidney Int
43:
1306-1312,
1993[ISI][Medline].
5.
Braam, B,
and
Koomans HA.
Nitric oxide antagonizes the actions of angiotensin II to enhance tubuloglomerular feedback responsiveness.
Kidney Int
48:
1406-1411,
1995[ISI][Medline].
6.
Braam, B,
Mitchell KD,
Koomans HA,
and
Navar LG.
Relevance of the tubuloglomerular feedback mechanism in pathophysiology.
J Am Soc Nephrol
4:
1257-1274,
1993[Abstract].
7.
Brands, MW,
and
Fitzgerald SM.
Acute endothelium-mediated vasodilation is not impaired at the onset of diabetes.
Hypertension
32:
541-547,
1998
8.
Brands, MW,
Garrity CA,
Holman MG,
Keen HL,
Alonso-Galicia M,
and
Hall JE.
High fructose diet does not raise 24-hour mean arterial pressure in rats.
Am J Hypertens
7:
104-109,
1994[ISI][Medline].
9.
Brands, MW,
and
Hopkins TE.
Poor glycemic control induces hypertension in diabetes mellitus.
Hypertension
27:
735-739,
1996
10.
Ceriello, A.
Hemostatic abnormalities in diabetes mellitus: consequence of hyperglycemia.
Nutr Met Cardiovasc Dis
5:
237-240,
1995[ISI].
11.
Claxton, CR,
Brands MW,
Fitzgerald SM,
and
Cameron JA.
Inhibition of nitric oxide synthesis potentiates hypertension during chronic glucose infusion in rats.
Hypertension
35:
451-456,
2000
12.
Cosentino, F,
Hishikawa K,
Katusic ZS,
and
Luscher TF.
High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells.
Circulation
96:
25-28,
1997
13.
Craven, PA,
DeRubertis FR,
and
Melhem M.
Nitric oxide in diabetic nephropathy.
Kidney Int
52, Suppl60:
S-46-S-53,
1997.
14.
Graier, WF,
Simecek S,
Kukovetz WR,
and
Kostner GM.
High D-glucose-induced changes in endothelial Ca2+/EDRF signaling are due to generation of superoxide anions.
Diabetes
45:
1386-1395,
1996[Abstract].
15.
Houben, AJHM,
Schaper NC,
de Haan CHA,
Huvers FC,
Slaaf DW,
de Leeuw PW,
and
Kruseman ACN
Local 24-h hyperglycemia does not affect endothelium-dependent or -independent vasoreactivity in humans.
Am J Physiol Heart Circ Physiol
270:
H2014-H2020,
1996
16.
Hu, L,
Manning RD, Jr,
and
Brands MW.
Long-term cardiovascular role of nitric oxide in conscious rats.
Hypertension
23:
185-194,
1994[Abstract].
17.
Johnstone, MT,
Creager SJ,
Scales KM,
Cusco JA,
Lee BK,
and
Creager MA.
Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.
Circulation
88:
2510-2516,
1993[Abstract].
18.
Kiff, RJ,
Gardiner SM,
Compton AM,
and
Bennett T.
Selective impairment of hindquarter vasodilator responses to bradykinin in conscious Wistar rats with streptozotocin-induced diabetes mellitus.
Br J Pharmacol
103:
1357-1362,
1991[Abstract].
19.
Kurtz, A,
and
Wagner C.
Role of nitric oxide in the control of renin secretion.
Am J Physiol Renal Physiol
275:
F849-F862,
1998
20.
Lash, JM,
Nase GP,
and
Bohlen HG.
Acute hyperglycemia depresses arteriolar NO formation in skeletal muscle.
Am J Physiol Heart Circ Physiol
277:
H1513-H1520,
1999
21.
Makimattila, S,
Virkamaki A,
Groop PH,
Cockcroft J,
Utriainen T,
Fagerudd J,
and
Yki-Jarvinen H.
Chronic hyperglycemia impairs endothelial function and insulin sensitivity via different mechanisms in insulin-dependent diabetes mellitus.
Circulation
94:
1276-1282,
1996
22.
Mattar, AL,
Fujihara CK,
Ribeiro MO,
De Nucci G,
and
Zatz R.
Renal effects of acute and chronic nitric oxide inhibition in experimental diabetes.
Nephron
74:
136-143,
1996[ISI][Medline].
23.
Miller, JA.
Impact of hyperglycemia on the renin angiotensin system in early human type 1 diabetes mellitus.
J Am Soc Nephrol
10:
1778-1785,
1999
24.
Miller, JA,
Floras JS,
Zinman B,
Skorecki KL,
and
Logan AG.
Effect of hyperglycemia on arterial pressure, plasma renin activity, and renal function in early diabetes.
Clin Sci (Colch)
90:
189-195,
1996[ISI][Medline].
25.
O'Bryan, GT,
and
Hostetter TH.
The renal hemodynamic basis of diabetic nephropathy.
Semin Nephrol
17:
93-100,
1997[ISI][Medline].
26.
Paller, MS,
and
Hostetter TH.
Dietary protein increases plasma renin and reduces pressor reactivity to angiotensin II.
Am J Physiol Renal Fluid Electrolyte Physiol
251:
F34-F39,
1986[ISI][Medline].
27.
Pflueger, AC,
Osswald H,
and
Knox FG.
Adeonsine-induced renal vasoconstriction in diabetes mellitus rats: role of nitric oxide.
Am J Physiol Renal Physiol
276:
F340-F346,
1999
28.
Pieper, GM.
Review of alterations in endothelial nitric oxide production in diabetes.
Hypertension
31:
1047-1060,
1998
29.
Poston, L,
and
Taylor PD.
Endothelium-mediated vascular function in insulin-dependent diabetes mellitus.
Clin Sci (Colch)
88:
245-255,
1995[ISI][Medline].
30.
Qiu, C,
Muchant D,
Beierwaltes WH,
Racusen L,
and
Baylis C.
Evolution of chronic nitric oxide inhibition hypertension. Relationship to renal function.
Hypertension
31:
21-26,
1998
31.
Smits, P,
Kapma JA,
Jacobs MC,
Lutterman J,
and
Thien T.
Endothelium-dependent vascular relaxation in patients with type I diabetes.
Diabetes
42:
148-153,
1993[Abstract].
32.
Strandgaard, C,
and
Curry DL.
Does nitric oxide play a role in stimulus-secretion and/or synthesis-secretion coupling of insulin?
Pancreas
19:
175-182,
1999[ISI][Medline].
33.
Tesfamariam, B.
Free radicals in diabetic endothelial cell dysfunction.
Free Radic Biol Med
16:
383-391,
1994[ISI][Medline].
34.
Tesfamariam, B,
Jakubowski JA,
and
Cohen RA.
Contraction of diabetic rabbit aorta caused by endothelium-derived PGH2-TxA2.
Am J Physiol Heart Circ Physiol
257:
H1327-H1333,
1989
35.
Trachtman, H,
Futterweit S,
and
Crimmins DL.
High glucose inhibits nitric oxide production in cultured rat mesangial cells.
J Am Soc Nephrol
8:
1276-1282,
1997[Abstract].
36.
Troisi, RJ,
Weiss ST,
Parker DR,
Sparrow D,
Young JB,
and
Landsberg L.
Relation of obesity and diet to sympathetic nervous system activity.
Hypertension
17:
669-677,
1991[Abstract].
37.
Tucker, BJ.
Early onset of increased transcapillary albumin escape in awake diabetic rats.
Diabetes
39:
919-923,
1990[Abstract].
38.
Vallon, V,
Blantz RC,
and
Thomson S.
Homeostatic efficiency of tubuloglomerular feedback is reduced in established diabetes mellitus in rats.
Am J Physiol Renal Fluid Electrolyte Physiol
269:
F876-F883,
1995
39.
VanNess, JM,
Casto RM,
and
Overton JM.
Antihypertensive effects of food-intake restriction in aortic coarctation hypertension.
J Hypertens
15:
1253-1262,
1997[ISI][Medline].
40.
Wilcox, CS,
and
Welch WJ.
Macula densa nitric oxide synthase: expression, regulation, and function.
Kidney Int
54, Suppl67:
S-53-S-57,
1998.
41.
Wiseman, MJ,
Saunders AJ,
Keen H,
and
Viberti GC.
Effect of blood glucose control on increased glomerular filtration rate and kidney size in insulin-dependent diabetes.
N Engl J Med
312:
617-621,
1985[Abstract].
42.
Woods, LL,
Mizelle HL,
Montani J-P,
and
Hall JE.
Mechanisms controlling renal hemodynamics and electrolyte excretion during amino acids.
Am J Physiol Renal Fluid Electrolyte Physiol
251:
F303-F312,
1986[ISI][Medline].
43.
Zanzinger, J,
Czachurski J,
and
Seller H.
Inhibition of sympathetic vasoconstriction is a major principle of vasodilation by nitric oxide in vivo.
Circ Res
75:
1073-1077,
1994[Abstract].
44.
Zatz, R,
and
Baylis C.
Chronic nitric oxide inhibition model six years on.
Hypertension
32:
958-964,
1998