Salt-Sensitive Blood Pressure and Exaggerated Vascular Reactivity in the Hypertension of Diabetes Mellitus MICHAELTUCK,M.D., DALILA~ORRY,M.D.,
ANGELINATRUJILLO,M.D., LosAnge/esandSepu/veda,Ca/ifornia
E
PURPOSE: This study evaluates the effects of dietary salt restriction and loading on blood pressure in normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM). Salt sensitivity of blood pressure responses is compared to vascular reactivity to infused angiotensin II on the two sodium diets. PATIENTS AND METHODS: We studied 19 patients with NIDDM (seven normotensive, 12 hypertensive) and seven nondiabetic control subjects under metabolic balance after 6 days on a constant low(20 mEq) sodium diet and again after 6 days on a high- (250 mEq) sodium diet. Salt sensitivity of blood pressure was determined by the increment in integrated 24-hour blood pressure values on changing from the low- to the high-sodium diet. Blood pressure and plasma aldosterone responses to a graded-dose infusion of angiotensin II were also examined on both sodium diets. RESULTS: Eight of 12 hypertensive patients with NIDDM displayed salt-sensitive blood pressure responses, whereas none of the normotensive patients with NIDDM or control subjects were salt-sensitive. Patients with NIDDM also had augmented blood pressure responses to infused angiotensin II on both sodium diets when compared to control subjects. Whereas controls had reduced vascular responses to angiotensin II on the low-sodium diet, these responses were not decreased in patients with NIDDM. Patients with NIDDM also retained more sodium on the high-sodium diet than did the control subjects. CONCLUSION: Hypertension in patients with NIDDM is frequently salt-sensitive, which may be due to sodium retention and enhanced vascular reactivity to angiotensin II. Since sodium restriction does not normally reduce vascular reactivity to angiotensin II in NIDDM, salt-restricted diets may be less effective in blood pressure control in hypertensive NIDDM.
nhanced vascular reactivity to pressor agents is a frequent finding in several forms of hypertension. Increased pressor sensitivity to pressor agents has been noted in patients with diabetes mellitus [l-4]. Enhanced vascular reactivity in diabetic patients is found in both normotensive and hypertensive subjects and in those with and without microvascular complications [l-4]. These observations indicate that diabetes per se rather than the prolonged hypertension or microvascular complications might be responsible for the increase in vascular sensitivity. Although not established, increased vascular reactivity could account for the high incidence of hypertension in the diabetic population, Patients with essential hypertension display a wide range of blood pressure responses to dietary sodium intake [5]. Thus, some individuals show increases in blood pressure in response to a high salt intake and are described as having salt-sensitive hypertension [5-91. Other patients with essential hypertension display little change in blood pressure after salt loading and are defined as salt-insensitive or -resistant. Attempts to reach standard definitions of salt sensitivity of blood pressure responses have been a problem. Some studies have used the increment in blood pressure between a low-sodium and high-sodium diet as the definition of salt sensitivity [6,7], although other protocols and definitions have been described [8,9]. As patients with diabetes mellitus have several recognized abnormalities in sodium handling [lo-131, it might be expected that their blood pressure regulation would be influenced by sodium intake. Several years ago it was shown that young diabetic subjects had significant elevations in systolic pressure during short-term dietary sodium loading [14,15]. Furthermore, the enhanced vascular responses to pressor agents can be corrected by diuretic therapy in diabetic patients [4], suggesting that sodium and volume expansion may be a factor in their enhanced vascular reactivity. Most studies describing increased angiotensin II pressor responses in diabetes mellitus have been performed without careful control of sodium intake [l-5]. This approach limits the interpretation of these results because the pressor sensitivity to angiotensin II is highly dependent on sodium balance [16,17], with a high-sodium diet increasing, and a low-sodium diet diminishing, vascular responses to angiotensin II. In the present study we have undertaken to simultaneously assess pressor sensitivity to angiotensin II and the alterations in basal blood pressure levels (salt sensitivity) in diabetic subjects during controlled low (20 mEq/day) and high sodium (250 mEq/day) intake. To avoid mixing diabetic study groups, we have selected only patients with non-insulin-dependent diabetes mellitus (NIDDM) with and without hypertension. Patients were also selected if they had no clinical evidence of microvascular complications.
From the UCLA School of Medlclne. Los Angeles, California, and the Veterans Administration Medical Center, Sepulveda. California. Requests for reprints should be addressed to Michael Tuck, M.D. (111-E). Veterans
210
March
1990
The American
Journal
of Medicine
Volume
88
SODIUM AND VASCULAR REACTIVITY IN DIABETES MELLITUS / TUCK ET AL
PATIENTS AND METHODS
TABLE I
We studied 19 subjects with diabetes mellitus, including 12 hypertensive and seven normotensive patients, under informed consent on the Metabolic Study Ward of the Veterans Administration (VA) Medical Center, Sepulveda, California. All patients had NIDDM treated with either oral hypoglycemic agents (n = 5), insulin (n = 13), or diet alone (n = 1). Control of blood glucose was held relatively constant during the study, with fasting blood glucose levels ranging from 150 to 240 mg/dL. Duration of diabetes was 9 to 25 years (mean, 13.5 years) for the hypertensive patients and 1 to 30 years (mean, 18.3 years) for the normotensive diabetics. The age range was 53 to 71 years in the hypertensive study group and 54 to 69 years in the normotensive group. Hypertension was defined as sitting diastolic levels of 90 mm Hg or above as determined on three separate occasions, and only patients with mild to moderate hypertension were enrolled in the study. Secondary forms of hypertension were excluded by appropriate testing. All antihypertensive medications were withdrawn 2 to 3 weeks prior to the study. Presence of retinopathy was evaluated by ophthalmoscopic examination in the VA Ophthalmology Clinic. Urine protein excretion was determined by dipstick testing and quantitative protein measurements. The presence or absence of neuropathy was excluded by a complete neurologic examination. Control subjects (n = 7) consisted of healthy, nondiabetic individuals ranging in age from 32 to 54 years. Patients were admitted to the Study Ward and on the second day of admission were placed on a 20-mEq sodium and lOO-mEq potassium constant diet for 6 days and then changed to a 250-mEq sodium and lOOmEq potassium diet for 6 additional days. Dietary sodium balance was checked by daily collection of 24hour urine samples for measurement of sodium, potassium, volume, and creatinine. Body weight was measured at 8 A.M. daily. With the exception of the special blood pressure studies for salt sensitivity, supine and upright blood pressures were recorded twice daily at 8 A.M. and 4 P.M. On Day 5 of each diet, patients had blood pressure measurements taken by auscultation every 4 hours over a 24-hour period to determine salt sensitivity. Patients remained supine from 11 P.M. the evening before the study, and at 7 A.M. the next morning had supine plasma renin activity and aldosterone samples drawn. During the remainder of the day, blood pressure determinations were made every 4 hours in the sitting position during the day and supine during sleeping hours. Blood pressure values are reported as mean arterial pressure (MAP) defined as diastolic pressure plus one third of pulse pressure. On Day 6 of each diet, an infusion of angiotensin II was performed using graduated doses ranging from subpressor to mildly pressor levels. At 7 A.M., a 19gauge needle was inserted into an antecubital vein for infusion of angiotensin II, and a second needle inserted in the opposite arm for withdrawal of blood samples. At 8 A.M., the infusion of angiotensin II (Hypertensin@, Ciba, Summit, New Jersey) in 5% dextrose and water (60 ng/mL) was begun using rates of 0.5,1.0, 2.0, and 3.0 rig/kg/hour via a Harvard infusion pump (Harvard Apparatus, Millis, Massachusetts). Each dose was infused for 30 minutes with samples for aldosterone obtained at 0, 30, 60, 90, and 120 minutes.
Clinical Characteristics, Sodium Balance, and Supine Plasma Renin Activity (PRA) in Nondiabetic Controls and Normotensive and Hypertensive Diabetic Patients (mean f SEM)
Data Age (years) Serum creatinine
(w/W
Creatinine clearance (ml/minute) Low (20 mEq) sodium diet Weight (kg) MAP (mm Hg) Urine sodium (mEq/24 hours) PRA (ng/mL/hour) High-(250 mEq) sodium diet Weight (kg) MAP (mm Hg) Urine sodium (mEq/24 houis) PRA (ng/mL/hours) p
ANGELINATRUJILLO,M.D., LosAnge/esandSepu/veda,Ca/ifornia
E
PURPOSE: This study evaluates the effects of dietary salt restriction and loading on blood pressure in normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM). Salt sensitivity of blood pressure responses is compared to vascular reactivity to infused angiotensin II on the two sodium diets. PATIENTS AND METHODS: We studied 19 patients with NIDDM (seven normotensive, 12 hypertensive) and seven nondiabetic control subjects under metabolic balance after 6 days on a constant low(20 mEq) sodium diet and again after 6 days on a high- (250 mEq) sodium diet. Salt sensitivity of blood pressure was determined by the increment in integrated 24-hour blood pressure values on changing from the low- to the high-sodium diet. Blood pressure and plasma aldosterone responses to a graded-dose infusion of angiotensin II were also examined on both sodium diets. RESULTS: Eight of 12 hypertensive patients with NIDDM displayed salt-sensitive blood pressure responses, whereas none of the normotensive patients with NIDDM or control subjects were salt-sensitive. Patients with NIDDM also had augmented blood pressure responses to infused angiotensin II on both sodium diets when compared to control subjects. Whereas controls had reduced vascular responses to angiotensin II on the low-sodium diet, these responses were not decreased in patients with NIDDM. Patients with NIDDM also retained more sodium on the high-sodium diet than did the control subjects. CONCLUSION: Hypertension in patients with NIDDM is frequently salt-sensitive, which may be due to sodium retention and enhanced vascular reactivity to angiotensin II. Since sodium restriction does not normally reduce vascular reactivity to angiotensin II in NIDDM, salt-restricted diets may be less effective in blood pressure control in hypertensive NIDDM.
nhanced vascular reactivity to pressor agents is a frequent finding in several forms of hypertension. Increased pressor sensitivity to pressor agents has been noted in patients with diabetes mellitus [l-4]. Enhanced vascular reactivity in diabetic patients is found in both normotensive and hypertensive subjects and in those with and without microvascular complications [l-4]. These observations indicate that diabetes per se rather than the prolonged hypertension or microvascular complications might be responsible for the increase in vascular sensitivity. Although not established, increased vascular reactivity could account for the high incidence of hypertension in the diabetic population, Patients with essential hypertension display a wide range of blood pressure responses to dietary sodium intake [5]. Thus, some individuals show increases in blood pressure in response to a high salt intake and are described as having salt-sensitive hypertension [5-91. Other patients with essential hypertension display little change in blood pressure after salt loading and are defined as salt-insensitive or -resistant. Attempts to reach standard definitions of salt sensitivity of blood pressure responses have been a problem. Some studies have used the increment in blood pressure between a low-sodium and high-sodium diet as the definition of salt sensitivity [6,7], although other protocols and definitions have been described [8,9]. As patients with diabetes mellitus have several recognized abnormalities in sodium handling [lo-131, it might be expected that their blood pressure regulation would be influenced by sodium intake. Several years ago it was shown that young diabetic subjects had significant elevations in systolic pressure during short-term dietary sodium loading [14,15]. Furthermore, the enhanced vascular responses to pressor agents can be corrected by diuretic therapy in diabetic patients [4], suggesting that sodium and volume expansion may be a factor in their enhanced vascular reactivity. Most studies describing increased angiotensin II pressor responses in diabetes mellitus have been performed without careful control of sodium intake [l-5]. This approach limits the interpretation of these results because the pressor sensitivity to angiotensin II is highly dependent on sodium balance [16,17], with a high-sodium diet increasing, and a low-sodium diet diminishing, vascular responses to angiotensin II. In the present study we have undertaken to simultaneously assess pressor sensitivity to angiotensin II and the alterations in basal blood pressure levels (salt sensitivity) in diabetic subjects during controlled low (20 mEq/day) and high sodium (250 mEq/day) intake. To avoid mixing diabetic study groups, we have selected only patients with non-insulin-dependent diabetes mellitus (NIDDM) with and without hypertension. Patients were also selected if they had no clinical evidence of microvascular complications.
From the UCLA School of Medlclne. Los Angeles, California, and the Veterans Administration Medical Center, Sepulveda. California. Requests for reprints should be addressed to Michael Tuck, M.D. (111-E). Veterans
210
March
1990
The American
Journal
of Medicine
Volume
88
SODIUM AND VASCULAR REACTIVITY IN DIABETES MELLITUS / TUCK ET AL
PATIENTS AND METHODS
TABLE I
We studied 19 subjects with diabetes mellitus, including 12 hypertensive and seven normotensive patients, under informed consent on the Metabolic Study Ward of the Veterans Administration (VA) Medical Center, Sepulveda, California. All patients had NIDDM treated with either oral hypoglycemic agents (n = 5), insulin (n = 13), or diet alone (n = 1). Control of blood glucose was held relatively constant during the study, with fasting blood glucose levels ranging from 150 to 240 mg/dL. Duration of diabetes was 9 to 25 years (mean, 13.5 years) for the hypertensive patients and 1 to 30 years (mean, 18.3 years) for the normotensive diabetics. The age range was 53 to 71 years in the hypertensive study group and 54 to 69 years in the normotensive group. Hypertension was defined as sitting diastolic levels of 90 mm Hg or above as determined on three separate occasions, and only patients with mild to moderate hypertension were enrolled in the study. Secondary forms of hypertension were excluded by appropriate testing. All antihypertensive medications were withdrawn 2 to 3 weeks prior to the study. Presence of retinopathy was evaluated by ophthalmoscopic examination in the VA Ophthalmology Clinic. Urine protein excretion was determined by dipstick testing and quantitative protein measurements. The presence or absence of neuropathy was excluded by a complete neurologic examination. Control subjects (n = 7) consisted of healthy, nondiabetic individuals ranging in age from 32 to 54 years. Patients were admitted to the Study Ward and on the second day of admission were placed on a 20-mEq sodium and lOO-mEq potassium constant diet for 6 days and then changed to a 250-mEq sodium and lOOmEq potassium diet for 6 additional days. Dietary sodium balance was checked by daily collection of 24hour urine samples for measurement of sodium, potassium, volume, and creatinine. Body weight was measured at 8 A.M. daily. With the exception of the special blood pressure studies for salt sensitivity, supine and upright blood pressures were recorded twice daily at 8 A.M. and 4 P.M. On Day 5 of each diet, patients had blood pressure measurements taken by auscultation every 4 hours over a 24-hour period to determine salt sensitivity. Patients remained supine from 11 P.M. the evening before the study, and at 7 A.M. the next morning had supine plasma renin activity and aldosterone samples drawn. During the remainder of the day, blood pressure determinations were made every 4 hours in the sitting position during the day and supine during sleeping hours. Blood pressure values are reported as mean arterial pressure (MAP) defined as diastolic pressure plus one third of pulse pressure. On Day 6 of each diet, an infusion of angiotensin II was performed using graduated doses ranging from subpressor to mildly pressor levels. At 7 A.M., a 19gauge needle was inserted into an antecubital vein for infusion of angiotensin II, and a second needle inserted in the opposite arm for withdrawal of blood samples. At 8 A.M., the infusion of angiotensin II (Hypertensin@, Ciba, Summit, New Jersey) in 5% dextrose and water (60 ng/mL) was begun using rates of 0.5,1.0, 2.0, and 3.0 rig/kg/hour via a Harvard infusion pump (Harvard Apparatus, Millis, Massachusetts). Each dose was infused for 30 minutes with samples for aldosterone obtained at 0, 30, 60, 90, and 120 minutes.
Clinical Characteristics, Sodium Balance, and Supine Plasma Renin Activity (PRA) in Nondiabetic Controls and Normotensive and Hypertensive Diabetic Patients (mean f SEM)
Data Age (years) Serum creatinine
(w/W
Creatinine clearance (ml/minute) Low (20 mEq) sodium diet Weight (kg) MAP (mm Hg) Urine sodium (mEq/24 hours) PRA (ng/mL/hour) High-(250 mEq) sodium diet Weight (kg) MAP (mm Hg) Urine sodium (mEq/24 houis) PRA (ng/mL/hours) p
