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Oral Arginine Reduces Systemic Blood Pressure in Type 2 Diabetes: Its Potential Role in Nitric Oxide Generation

Department of Internal Medicine, Harbor-UCLA Medical Center, UCLA School of Medicine, Torrance, California

Address reprint requests to: John A. Tayek, M.D., 1000 W. Carson Street, Box 428, Torrance, CA 90509. E-mail: tayek{at}humc.edu

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
Objectives: Arginine is converted in the endothelial cells to nitric oxide (NO) and citrulline. NO is a potent vasodilator in humans, but diabetics may have a reduced generation of NO which results in endothelial dysfunction. The aim of this study was to evaluate the effects of oral arginine on nitric oxide production, counter-regulatory hormones and blood pressure in mildly hypertensive type 2 diabetic patients.

Methods: A prospective, crossover clinical trial was performed over a three-day stay in the General Clinical Research Center. Six patients with type 2 diabetes mellitus and mild hypertension consented and were given orally three grams of arginine per hour for 10 hours on either day 2 or day 3. On both days 2 and 3, blood pressure was monitored between 5 AM and 4 PM and mean pressure determined.

Results: Oral arginine increased plasma citrulline from 31.3 ± 6.0 to 41.5 ± 6.0 µmol/L (mean ± SEM; p < 0.05) which may reflect an increased conversion of arginine into NO and citrulline. Arginine reduced systolic BP from 135 ± 7 to 123 ± 8 mmHg; p < 0.05. Diastolic BP fell from 86.9 ± 1.7 to 80.7 ± 2.4 mmHg; p < 0.05). The reduction in BP was noted to occur two hours after starting oral arginine, and BP returned to normal within one hour of stopping the arginine. The oral arginine had no effect on C-peptide, insulin or other hormone concentrations.

Conclusions: These data suggest that oral arginine may increase endothelial nitric oxide synthase (NOS) to increase vascular NO and temporally reduce blood pressure in mildly hypertensive type 2 diabetic patients.

Key words: blood pressure, nitric oxide, arginine

	INTRODUCTION

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No one knows why diabetic patients have a sixfold increase in cardiovascular disease when compared to non-diabetic individuals. Endothelial dysfunction may be one possible explanation for the higher risk for coronary artery disease. Endothelial dysfunction is common in type 2 diabetes [1]. Insufficient arginine concentration in the endothelial cells may hamper the ability to generate nitric oxide (NO).

Nitric oxide (NO) is generated by the conversion of arginine into citrulline and NO. Nitric oxide synthase (NOS) enzymes are known to exist in three forms (endothelial or eNOS, inducible or iNOS and neuronal or nNOS). Of the three types, eNOS is believed to be a major contributor to the endothelial dysfunction that occurs in type 2 diabetes and in non-diabetic patients who have insulin resistance [2].

Arginine administration can improve endothelium dependent vasodilation in normal volunteers [3] and in patients with coronary artery disease [4]. Administration of an analog of L-arginine (L-NAME) in normal volunteers increases mean blood pressure by 8 mmHg [5]. The removal of arginine availability for its conversion into NO may explain the rise in blood pressure observed. As in the human model, mean arterial pressure increases more in diabetic rats after the administration L-NAME than in non-diabetic rats [6]. We know that tissue arginine concentration are reduced in the rat [1]. While there are no reports of tissue arginine concentration in humans, the administration of arginine to humans has a blunted effect on blood pressure in type 2 diabetic patients [7]. This suggests that there may be a state of arginine resistance in that the effects of arginine are blunted in the type 2 diabetic patient compared to in a normal volunteer [7].

Overnight fasting plasma arginine concentrations have been reported to be increased in patients with type 2 diabetes [8,9]. While a high salt diet can double plasma arginine (165 ± 10 to 83 ± 7 µmol/L) in rats [10], there are no published data in humans. Plasma arginine remains significantly increased in diabetic patients even after ingestion of a 55-gram protein meal [9]. The exact mechanism and reason for an increased plasma arginine concentration in diabetic patients are not known.

Additional arginine given as three grams, three times a day for one month decreases systolic blood pressure in non-hypertensive lean type 2 diabetic volunteers [11]. While plasma arginine concentrations were not determined in this study, the additional arginine reduced systolic blood pressure. Arginine had no effect on serum insulin, which can also lower blood pressure [11]. Recently, oral arginine supplementation given to six healthy normal volunteers also reduced systolic and diastolic blood pressure [12].

The purpose of this study was to test if three grams an hour of oral arginine would increase NO generation and reduce systolic and diastolic blood pressure in mildly hypertensive type 2 diabetic volunteers. NO bioavailability was estimated by the increase in plasma citrulline when arginine was converted into NO and citrulline by NOS. We also measured C-peptide, insulin, epinephrine, norepinephrine and other hormones to determine if this dose of arginine had an effect on hormone secretion which may also influence blood pressure.

	METHODS

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Study Population
Six patients with mild hypertension, stable weight and a history of type 2 diabetes consented after approval by the institutional review committee. The diabetic patients had type 2 diabetes for five years; the other characteristics are listed in Table 1. Blood pressure and diabetic medications were withdrawn on the evening prior to admission. All volunteers were admitted for three days on a low sodium diet into the General Clinical Research Center. Patients were randomized to arginine on day 2 or day 3 of the study. A placebo was not used on the non-arginine treatment day. Resting energy expenditure was measured on days 2 and 3 by indirect calorimeter (Delta track, Sensor Medics, Yorba Linda, CA).

Statistical Analysis
All data are mean ± SEM at each time interval. Comparisons were done by ANOVA. Significance was defined as p < 0.05. There was no order effect, so that the arginine treatment day was compared to the non-treatment day. The hormonal data are represented at hourly measurements and amino acids every two hours. A paired t test was done on groups only if ANOVA was significant.

	RESULTS

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The administration of arginine had no effect on the hourly mean C-peptide secretion (0.88 ± 0.11 vs. 0.86 ± 0.13 pg/mL, arginine vs. no-arginine treatment, respectively). Oral arginine also had no effect on hourly mean cortisol (10.4 ± 2.0 vs. 10.4 ± 2.2 µg/dL), epinephrine (42 ± 5.4 vs. 37 ± 4) or norepinephrine (421 ± 60 vs. 328 ± 100) concentration. In addition, arginine had no effect on insulin, glucagon, GH, IGF-1 (data not shown). Resting energy expenditure was similar with arginine administration (2520 ± 350 vs. 2510 ± 280 kcals/day, mean ± SEM). There was no difference in the hourly mean blood glucose while taking oral arginine (212 ± 33 vs. 212 ± 34 mg/dL). There were no GI or other side effects to taking arginine.

After two hours of ingesting three grams of arginine per hour, plasma arginine concentrations doubled and remained doubled over the eight-hour study period (Fig. 1). Plasma ornithine concentrations doubled after two hours of starting oral arginine and its concentration continued to increase during the eight-hour study period to become 3.6-fold higher at 2:00 PM (Fig. 2). While taking three grams of oral arginine per hour, it took approximately 2.5 hours for plasma ornithine to reach half-maximal concentration. On the other hand, it appears that plasma citrulline was at a maximum concentration as early as two hours after starting oral arginine. Mean plasma citrulline concentrations increased by only 30% above baseline (31.3 ± 6.0 to 41.5 ± 6.0 µmol/L; p < 0.05, Fig. 3). At individual time points, citrulline was increased at hours 10 and 12. In comparison, six normal volunteers under a similar protocol increased citrulline to 50.9 ± 6.0 µmol/L (unpublished data). In comparison to the doubling of plasma ornithine concentration while taking oral arginine, plasma citrulline increased by only 30% in the diabetic patients. In addition, there was no further increase in plasma citrulline over the entire 10-hour ingestion period (Fig. 3). The failure to increase citrulline may reflect an inability to increase conversion of arginine into NO and citrulline in the patients with type 2 diabetes mellitus.

View larger version (28K): [in this window] [in a new window]   Fig. 1. This figure demonstrates the mean plasma arginine concentration with or without oral arginine supplements.

View larger version (27K): [in this window] [in a new window]   Fig. 2. This figure demonstrates the mean ornithine with or without oral arginine supplements. There was a significant difference by ANOVA (p < 0.01) and a significant increase over time (p < 0.05).

View larger version (28K): [in this window] [in a new window]   Fig. 3. This figure demonstrates the mean citrulline concentration while taking oral arginine supplements. The mean difference between the arginine and the non-arginine ingestion day was significant (p < 0.05). Individual determinations at each time point resulted in significant differences at time 10:00 and 12:00 after correction for multiple comparisons (p < 0.05).

View larger version (30K): [in this window] [in a new window]   Fig. 4. This figure demonstrates the hourly mean systolic blood pressure (mean ± SEM) in volunteers with or without oral arginine supplements. ANOVA testing demonstrated a significant difference during the treatment period (Hour 5:00 to Hour 14:00, i.e., 5:00 AM to 2:00 PM). The effect of arginine on systolic blood pressure was not significant until 7:00 AM. There was no difference between groups after arginine was discontinued (Hours 15:00 and 16:00). Please note that the arginine was stopped at hour 14:00 or 2:00 PM. The hypotensive influence was not present one hour after stopping the arginine for systolic measurements. A significant difference between the two groups at each time point by paired testing is indicated by a star (p < 0.05).

View larger version (35K): [in this window] [in a new window]   Fig. 5. This figure demonstrates the hourly mean diastolic blood pressure in volunteers with or without oral arginine supplements. ANOVA testing demonstrated a significant difference during the treatment period (Hour 5:00 to Hour 14:00, i.e., 5:00 AM to 2:00 PM). There was no difference between groups after arginine was discontinued (Hour 15:00, 16:00 and 24:00 or 0:00). Please note that the arginine was stopped at hour 14:00 or 2:00 PM. The hypotensive influence was not present one hour after stopping the arginine. Significant difference between the two groups at each time point by paired testing is indicated by a star (p < 0.05).

	DISCUSSION

It is well known that acute arginine increases insulin secretion which can reduce blood pressure. However, type 1 diabetic patients have insulin deficiency, yet arginine reduces blood pressure in type 1 diabetic patients [14]. The influence on blood pressure is short lived. Within 10 minutes of stopping intravenous arginine, blood pressure returned to normal in hypertensive patients with type 2 diabetes mellitus [14]. An elevation in blood pressure occurred just after stopping the arginine even though serum insulin concentrations were still elevated. Therefore, the influence of serum insulin was not substantial enough to maintain an effect, if any, on blood pressure after stopping arginine. Since insulin and c-peptide concentrations were not altered while taking arginine in the current study, the effects on blood pressure were likely related to the arginine-nitric oxide system.

In NO production, citrulline is produced when arginine is converted by NOS into NO. Citrulline concentration increased by 30% which suggests that arginine was able to induce NO generation (Fig. 3). Other cationic amino acids such as lysine do not decrease blood pressure [15]. The vasodilatory properties of amino acids appear to be unique to that of L-arginine.

Hyperglycemia and Nitric Oxide (NO) Availability
Acute hyperglycemia is associated with a reduced NO generation as demonstrated by a reduction in leg blood flow and an increase in both systolic and diastolic blood pressures in normal volunteers [16]. Hyperglycemia has also been shown to reduce NO production in cultured cells; this may explain why diabetic patients have a reduced bioavailability of NO [17]. Infusion of an arginine analog (L-NAME) under hyperglycemic conditions increases blood pressure more than hyperglycemia alone [16]. This suggests that, while hyperglycemia may increase blood pressure, the competitive removal of arginine with L-NAME can increase blood pressure even further. Under hyperglycemic conditions, arginine administration returns blood pressure to normal [16]. This suggests that arginine prompts vasodilation via NO generation even in hyperglycemia.

Similarly to what is seen with acute hyperglycemia, patients with type 2 diabetes have impaired coronary artery dilation [18]. While arginine can decrease systemic blood pressure, intravenous arginine does not improve coronary vasodilation in patients with type 2 diabetes mellitus [18]. These authors suggest that the coronary arteries of diabetic patients have an increased inactivation of nitric oxide. This is consistent with the current study which demonstrates loss of the hypotensive influence within one hour of stopping the oral arginine (Figs. 4 and 5). However, other mechanisms [19] may be responsible, such as a rebound in the sympathetic system or changes in the renin-aldosterone system [20]. Unfortunately neither of these were measured in our patients after stopping the oral arginine.

Tissue Arginine and Tetrahydrobiopterin (BH4) Concentrations in Diabetes
Arginine has been reported to be reduced in the plasma [7,8] and lacrimal fluid of diabetic patients [21] and in the plasma [1] and aorta of diabetic animals [19]. Plasma arginine concentration in the current study (131 ± 5 µmol/L) was similar to that concentration seen in earlier work in obese non-hypertensive diabetic patients (120 ± 5 µmol/L) [8]. Obese non-diabetic subjects have a lower concentration of plasma arginine (76 ± 4 µmol/L; p < 0.05) when compared to obese diabetic volunteers [8]. Normal-weight healthy volunteers also have a reduced arginine concentration when compared to normal-weight diabetic patients (110 ± 7 vs. 85 ± 3 µmol/L; p < 0.05; [8]). An increased plasma arginine in diabetic patients has also been seen by others [9]. The reason for the greater arginine concentration in type 2 diabetes is unclear. It is possible that the higher plasma levels of arginine reflect a deficient intracellular state of arginine. This may be true because recent data suggests that arginine fails to improve coronary dilation in patients with type 2 diabetes mellitus [18].

In addition to tissue arginine concentrations, endothelial tetrahydrobiopterin (BH4) is also reduced in a rat model of diabetes [22]. BH4 is an important cofactor for NOS which aids in the binding of arginine for the generation of NO. In the diabetic rats, tissue concentration of BH4 was only 12% of that concentration seen in normal rats. The activity of NOS is dependent on the availability of the cofactor BH4. Administration of BH4 has recently been shown to improve endothelium-dependent vasodilation by increasing nitric oxide activity in patients with type 2 diabetes mellitus [23]. It has also been shown to increase coronary blood flow in normal volunteers [24]. Therefore, the administration of arginine may have facilitated NO generation, but the transient nature of the effect may be due to a limitation of other co-factors such as BH4 [22]. This might explain the shorter half life of NO known to occur in patients with type 2 diabetes [1,2].

Recently it has also been suggested that deficiency of BH4 may cause NOS to be uncoupled where superoxide production is increased and NO activity is reduced [18]. In the placenta of patients with type 1 diabetes mellitus, there is an increased endothelial generation of superoxide products such as peroxynitrite [24]. Oxidation products such as peroxynitrite can oxidize BH4 and reduce its tissue bioavailability for the generation of NO [24]. Also, as mentioned above, the BH4 tissue concentration is reduced in animals with diabetes [22]. Plasma levels are not reliable due to its rapid oxidation. It has recently been demonstrated that NOS expression in cardiac muscle is similar in diabetics and non-diabetics [25]. Therefore, NOS concentration is less likely to be reduced in diabetes.

Lastly, there has been recent evidence that nitric oxide may play a role in salt sensitive hypertension. In a rat model of hypertension, the administration of intravenous L-arginine increases nitric oxide production and prevents salt sensitive hypertension [26]. Intravenous arginine’s influence was also transient; this suggests other factors play a role in the maintenance of blood pressure.

In summary, oral arginine increases NO generation as estimated by a small increase in the plasma citrulline concentration in patients with type 2 diabetes. Oral arginine administration has a hypotensive influence, but its influence is very short lived. The limited influence of oral arginine on increasing plasma citrulline concentrations and decreasing blood pressure in all patients would suggest that factors such as BH4 may be required to normalize NO production in patients with type 2 diabetes mellitus.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 
We would like to thank Stephanie Griffiths, Mario Paredes and Maria Lajoie from the GCRC lab, Jennifer Naritomi, Leah Abellon, Rose Umali, Edmund Aception and Connie Soriano from the GCRC, for all their help with obtaining the blood samples and performing all the biochemical measurements.

	FOOTNOTES

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This study was supported by the NIH Clinical Investigator Award KO8DK02083 and MO1-RR-00425.

Received January 18, 2002. Accepted May 20, 2002.

	REFERENCES

TOP FOOTNOTES ABSTRACT INTRODUCTION METHODS RESULTS ACKNOWLEDGMENTS REFERENCES

 

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This Article Abstract Figures Only Full Text (PDF) Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huynh, N. T. Articles by Tayek, J. A. Search for Related Content PubMed PubMed Citation Articles by Huynh, N. T. Articles by Tayek, J. A.