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Effect of alpha1-blockade on diminished forearm blood flow in diabetics
Diabetes Research and Clinical Practice, 12 (1991) 157-162
0 1991 Elsevier Science Publishers
B.V. 0168-8227/91/$03.50
157
DIABET 00498
Effect of alpha,-blockade
on diminished forearm blood flow in diabetics
Mami Ide, Shigehiro Katayama, Shigeki Akabane, Munemichi Inaba, Yoshiko Maruno, Kiyohiko Negishi, Masao Suzuki, Keiichi Takahashi, Akira Itabashi and Jun Ishii The Fourth Department
of Medicine, Saitama Medical School, Saitama, Japan
(Received 29 January 1990) (Revision accepted 16 January 1991)
Summary An increased risk of atherosclerotic disease has been reported in patients with diabetes mellitus. The present study was therefore designed to determine forearm blood flow (FBF) in patients with essential hypertension or those with diabetes mellitus with or without hypertension. FBF determined by venous occlusion plethysmography decreased with age in controls as well as in patients with essential hypertension, whereas FBF in diabetics was significantly lower irrespective of age or blood pressure. As a result, vascular resistance was significantly higher in diabetics than in controls or patients with essential hypertension. Glycemic control in normotensive diabetics during 3 weeks significantly augmented a diminished FBF. q-Blockade by oral administration of 1 mg of prazosin also augmented the diminished FBF in diabetics, in association with a significant decrease in mean blood pressure and vascular resistance. These results suggest that FBF may be a simple and useful index for determining arterial and/or venous distensibility, and that q-blocker therapy, in addition to glycemic control, may be a first-line antihypertensive treatment for diabetics with associated hypertension. Key words: Forearm
blood flow; Diabetes mellitus; Essential hypertension
Introduction It is well known that diabetics have a higher prevalence of hypertension than in non-diabetic individuals [ 1,2]. Hypertension may carry a greater risk for development of vascular complications such as diabetic retinopathy [ 31 and nephropathy
Correspondence to: S. Katayama, gun, Saitama 350-04. Japan.
Moroyama-cho,
Iruma-
[ 41 in addition to cerebrovascular accidents [ 51, particularly with advancing age and duration of diabetes mellitus. Progressive arteriosclerosis may be the basis for this higher incidence of vascular disease. In fact, increased pulse wave velocity [6,7] and diminished arterial wall compliance [8] have been reported in diabetics. The present study was therefore designed to determine forearm blood flow (FBF) non-invasively using venous occlusion plethysmography in diabetic patients with or without associated hypertension,
158
and also in individuals with essential hypertension. Since x,-blocker therapy has been reported as a first-line treatment for hypertension associated with diabetes mellitus [ 61, the effect of prazosin on FBF was also investigated.
Subjects and Methods Patients admitted to Saitama Medical School Hospital were selected on the basis of a diagnosis of essential hypertension (n = 9) or non-insulindependent diabetes mellitus with or without hypertension (n = 8 each) after routine laboratory tests. Hypertension was diagnosed on the basis of a diastolic blood pressure of more than 90 mmHg. All medication was stopped at least two weeks before the study and all diabetics tested were on diet therapy alone. Age-matched healthy subjects served as controls. The backgrounds of controls as well as the patients are shown in Table 1. FBF was determined by venous occlusion plethysmography [ 91 using a strain-gauge (Vaculab, U.S.A.) with the patient in a recumbent position after an overnight fast. Circulation in the hand was excluded using an inflated pneumatic cuff at the wrist to create suprasystolic pressure during all measurements. The initial slope of the volume
record, obtained by rapidly inflating the congestion cuff to 60 mmHg, was used as an index of FBF and expressed as ml/100 ml/min. Blood also determined. Triplicate pressure was measurements were obtained and the average of these values was used for analysis. Forearm vascular resistance was calculated by dividing the mean blood pressure by FBF. To see the effects of glycemic control on blood pressure as well as FBF and vascular resistance, these parameters were determined before and about three weeks after intensive glycemic control achieved by diet therapy and/or administration of sulfonylurea in the separate group of normotensive diabetics (n = 5) aged 58.2 + 4.2 years (SEM). Body mass index (BMI) averaged 23.2 & 2.3 in this group. In patients with essential hypertension and those with diabetes mellitus-associated hypertension, 1 mg of prazosin was administered immediately after the first FBF and blood pressure determination. The second measurement of these parameters was performed two hours later with the patient in a supine position. All data are expressed as the mean + SEM. Statistical analysis was performed using paired or unpaired Student’s t-test and differences at P < 0.05 were considered to be significant.
TABLE I Backgrounds
of the patients,
and basal blood pressure,
forearm blood flow and vascular resistance __ _.___ ___~
CONTROLS II Age Body mass index HbA, (“0) Duration of diabetes (years) Mean blood pressure (mmHg) Forearm blood flow (ml/LOO ml/mm) Vascular resistance (mmHg/ml/lOO ml/min)
15 52.5 k 6.0 23.2 k 2.3 89.2 + 4.0 1.38 + 0.24 89.2 k 4.0
EHT 9 58.3 22.5 103.4 1.65 92.0
DMHT
f 4.2 * 0.1
f 4.9” k 0.28 + 29.7
Each value indicates mean f SEM. EHT: essential hypertension, DMHT: diabetics without hypertension. “P < 0.05 vs controls or EHT; ‘P < 0.01 vs controls or EHT; LP < 0.05 vs DMHT.
8 64.6 + 4.2 21.2 + 1.2 12.5 f 2.0 13.5 +_ 1.3 113.9 f 7.7b 0.45 + 0.09b 326.3 f 63.8
DMNT 8 54.6 23.1 13.0 10.6 92.1 0.70 92.2
.. with hypertension, DMNT:
f k * f + * f
5.9 1.2 1.0 1.0 4.5’ 0.13” 41.5”
diabetics
159
Results Table 1 shows the basal mean blood pressure, FBF and vascular resistance in the four groups. In diabetics, irrespective of whether they were hypertensive or not, FBF was significantly lower and vascular resistance was significantly higher in comparison with those in healthy controls or patients with essential hypertension. As illustrated in Fig. 1, FBF in controls and patients with essential hypertension decreased with age, whereas diabetics demonstrated a diminished FBF even in younger patients, i.e. those in their 30s or 40s. Duration of diabetes mellitus was not correlated with FBF in diabetics. Effects of glycemic control on mean blood pressure, FBF and vascular resistance in five noninsulin-dependent diabetics are shown in Table 2. When glycemic control was improved as evidenced by a decrease in fasting plasma glucose and HbA, levels after 20.6 + 2.2 days, FBF was augmented and vascular resistance was attenuated significantly without a significant change in blood pressure. The effects of prazosin administration on mean blood pressure, FBF and vascular resistance in the patients with essential hypertension and those with diabetes mellitus-associated hypertension are illustrated in Fig. 2. Two h after prazosin administration, mean blood pressure was decreased significantly in both groups. In response to prazosin administration, FBF in both groups was augmented, but not significantly. However, the
CONTROLS 0 q
EHT
A
DMNT
0
DMHT
0
. 00
20
40
60
80
AGE (years)
Fig. 1. Relationship between forearm blood flow (FBF) and age in controls, patients with essential hypertension (EHT) or those with diabetes mellitus with (DMHT) or without (DMNT) hypertension. In controls and patients with essential hypertension, a significant negative correlation was obtained (P < 0.05).
increment of FBF in diabetic hypertensives reached 1.5 times the basal value, although the absolute increase was rather small in comparison with that in the patients with essential hypertension. As a result, prazosin significantly diminished the vascular resistance in diabetics, whereas vascular resistance in the patients with essential hypertension did not show any change.
TABLE 2 Changes in mean blood pressure,
forearm blood flow and vascular resistance
Fasting plasma glucose (mg/dl) HbA,
Mean blood pressure (mmHg) Forearm blood flow (ml/100 ml/min) Vascular resistance (mmHg/ml/100 ml/min) Each value indicates
Before
P value
After
235.8 f 21.1
P < 0.01 P < 0.01
148.4 f 18.2 11.0 * 1.3
14.1 f 1.0
(X)
mean k SEM.
after glycemic control during 20.6 + 2.2 days
83.8 k 3.1 0.95 * 0.19 102.4 f 22.6
ns
79.9 + 1.7
P < 0.05 P < 0.01
66.0 f 22.5
1.57 f 0.36
160
EHT
DMHT
1201
0 I
3
P.001
3
I 0 &l
0IL+ P,
0 01
300
0 Lk
BEFORE AFTER
BEFORE AFTER mean1
SE
r P. 0 05.
+*p
0 01
Fig. 2. Changes in mean blood pressure (MBP: upper panel), forearm blood flow (FBF: middle panel) and vascular resistance (VR: lower panel) in 9 patients with essential hypertension (EHT: left column) or diabetes mellitus with hypertension (DMHT: right column) 2 h after oral administration of 1 mg of prazosin.
Discussion
Venous occlusion plethysmography is widely accepted to provide reliable noninvasive measurements of blood flow in extremities. By this technique, we have clearly demonstrated that FBF and hence vascular resistance in controls and patients with essential hypertension may be a function of age, indicating that FBF may be a possible indicator of generalized arterial and/or venous distensibility. This result is consistent with
previous studies demonstrating a significant correlation of pulse wave velocity or arterial wall compliance with age [ 10,111. On the other hand, diabetics did show adiminished FBF (i.e. a higher vascular resistance) from their 30s onwards. In addition, a decreased FBF was observed in diabetics, irrespective of whether they were hypertensive or normotensive, although FBF in hypertensive diabetics tended to be lower than that in normotensive diabetics. Using other methods for determining arterial compliance, diabetics have been found to show an increased pulse wave velocity [ 81 as well as a diminished arterial compliance [6,7] in comparison with non-diabetic controls. The lower FBF in hypertensive diabetics in comparison with the patients with essential hypertension and the lack of correlation between diabetes mellitus duration and FBF suggest that hyperglycemia per se and/or other metabolic abnormalities in diabetes mellitus may accelerate the vascular changes resulting in arterial stiffening from a rather earlier stage, perhaps 4 to 10 years after the onset of diabetes mellitus. This hypothesis was supported by the present observation that glycemic control even for three weeks augmented a diminished FBF. There are several studies in the literature reporting slightly elevated FBF in young diabetic patients [ 12,131. The present results suggest therefore that FBF is different in younger and elderly diabetic patients. Of interest is the observation that prazosin was more effective for diabetic hypertension, based on the significant reduction seen in vascular resistance. Although small, the increase in FBF produced in response to prazosin administration was 1.5-fold. Such an increase could be very important for improving the peripheral circulation in diabetics. On the other hand, it seems very curious that vascular resistance did not decrease after prazosin administration in the patients with essential hypertension. In fact, some previous studies have shown no changes in vascular resistance after prazosin administration in patients with essential hypertension [ 141. Studies that have previously demonstrated reduced blood pressure due to decreased systemic vascular resis-
161
tance were performed only in patients responding well to cc,-blockade [ 15-171. One of the reasons why we were unable to show any reduction in vascular resistance in patients with essential hypertension may have been due to the fact that we did not select responders to prazosin. In any event, diabetics with a higher vascular resistance appear to respond well to an xi-blocker. It has been reported that the degree of orthostatic depressor response to an initial dose of prazosin is inversely correlated with the basal level of plasma renin activity [ 181. It is well known that diabetics sometimes show low renin activity. Furthermore, plasma catecholamine levels are reported to be lower in diabetics [ 191. Vascular reactivity to angiotensin II or norepinephrine has been shown to be enhanced in diabetics with retinopathy [20]. In addition, sympathetic nerve activity may be slightly more increased in the forearm in diabetic patients as a compensatory phenomenon to the distal autonomic neuropathy [ 2 11. This unique sensitivity of diabetic hypertension to prazosin may reflect an underlying increase of cr,-tone, a low-renin state and/or low plasma catecholamine levels. In the recent report by the Working Group on Hypertension in Diabetes [22], a,-blocker was listed as one of the first-line hypotensive agents for diabetic hypertensive patients. Administration of an a,-blocker does not alter insulin secretion and has little or no effect on the control of diabetes, in addition to exerting a favorable effect on lipid metabolism. The unique sensitivity to a, -blockade in diabetic hypertensives demonstrated in our present study may add further credence for the use of cr,-blocker as a first-line therapy in these patients. References Pell, S. and D’Alonzo, C.A. (1967) Some aspects of hypertension in diabetes mellitus. J. Am. Med. Assoc. 202, 104-I 10. Garcia, M.J., McNamara, P.M., Gordon, T. and Kannel, W.B. (1974) Morbidity and mortality in diabetics in the Framingham population. Sixteen-year follow-up study. Diabetes 23, 105-l 11.
3 Knowler, WC., Bennett, P.H. and Ballintine, E.J. (1980) Increased incidence of retinopathy in diabetics with elevated blood pressure. N. Engl. J. Med. 302, 645-650. 4 Mogensen, C.E. (1980) Long-term antihypertensive treatment inhibiting the progression of diabetic nephropathy. Acta Endocrinol. (Copenhagen) 42 (Suppl.), 31-32. 5 Asplund, K., Hagg, E., Helmers, C., Lithner, F., Strand, T. and Westor, P.O. (1980) The natural history of stroke in diabetic patients. Acta Med. Stand. 207. 417-424. 6 Woolam, G.L., Schunur, P.L., Vallbona, C. and Hoff, H.E. (1962) The pulse wave velocity as an early indicator of atherosclerosis in diabetic subjects. Circulation 25, 533-539. 7 Gunn, G.C., Dobson, H.L., Gray, J., Geddes, L.A. and Vallbona, C. (1965) Studies on pulse wave velocity in potential diabetic subjects. Diabetes 14, 489-492. 8 Walqvist, M.L., Lo, C.S., Myers, K.A., Simpson, R.W. and Simpson, J.M. (1988) Putative determination of arterial wall compliance in NIDDM. Diabetes Care 11, 787-790. of volume 9 Whitney, R.J. (1953) The measurement changes in human limbs. J. Physiol. 121, l-27. 10 Avolio, A.P., Chen, S., Wang, R., Zhang, C., Li, M. and O’Rourke, M.F. (1983) Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation 68, 50-58. 11 Relf, I.R.N., Myers, K.A. and Wahlqvist, M.L. (1986) Risk factors for changes in aorto-iliac arterial compliance in healthy men. Arteriosclerosis 6, 105-108. N.J. (1969) Spontaneous variations in 12 Christensen, resting blood flow, post ischemic peak time and vibratory perception in the feet of diabeteics. Diabetologia 5, 171-17s. 13 Jorgensen, R.G., Russo, L.. Mattioli, L. and Moore, W. (1988) Early detection of vascular dysfunction in type I diabetes. Diabetes 37, 292-296. 14 Eklund, B.. Hjemdahl, P.. Seideman. P. and Atterhog, J.H. (1983) Effects of prazosin on hemodynamics and sympatho-adrenal activity in hypertensive patients. J. Cardiovasc. Pharmacol. 5, 384-391. 15 Koshy, M.C., Mickley, D., Bourgoignie, J. and Blaufox, M.D. (1977) Physiologic evaluation of a new antihypertensive agent: prazosin HCl. Circulation 55. 533-537. 16 Safar. M.E.. Weiss, Y.A., London, G.L. and Milliez, P.L. (1974) Short-term hemodynamic studies with prazosin. In: D.W. Cotton (Ed.), Prazosin-Evaluation of a New Antihypertensive Agent, Excerpta Medica Foundation, Amsterdam, pp. 63-70. Masoni, A.. Tommasi, A.M., Baggioni. F. and Bagni, B. (1974) Hemodynamic study in men of medium-term treatment with a new amino-quinazoline antihypertensive agent. In: D.W. Cotton (Ed.), Prazosin-Evaluation of a New Antihypertensive Agent, Excerpta Medica Foundation, Amsterdam, pp. 54-62. Nicholson, J.P., Resnick. L.M.. Pickering. T.G., Marison,
162 R.. Sullivan, P. and Laragh, J.H. (1985) Relationship of blood pressure response and the renin-angiotensin system to first-dose prazosin. Am. J. Med. 78. 241-242. 19 Christensen, N.J. (1972) Plasma catecholamine in longterm diabetes with and without neuropathy and in hypophysectomized subjects. J. Clin. Invest. 51, 779-787. 20 Christlieb, A.R., Janka, H.. Kraus, B., Gleason, R.E.. Icasas-Carbal. E.A.. Aiello, L.M., Carbal, B.V. and Solano, A. (1976) Vascular reactivity to angiotensin II
and to norepinephrine in diabetic subjects. Diabetes 26, 268-274. 21 Christensen, N.J., Dejgaard, A. and Hilsted, J. (1988) Plasma dihydroxyphenylglycol as an index of diabetic autonomic neuropathy. Clin. Physiol. 8, 577-580. 22 The Working Group on Hypertension in Diabetes: statement on hypertension in diabetes mellitus (1987) Final Report. Arch. Intern. Med. 147, 830-842.
0 1991 Elsevier Science Publishers
B.V. 0168-8227/91/$03.50
157
DIABET 00498
Effect of alpha,-blockade
on diminished forearm blood flow in diabetics
Mami Ide, Shigehiro Katayama, Shigeki Akabane, Munemichi Inaba, Yoshiko Maruno, Kiyohiko Negishi, Masao Suzuki, Keiichi Takahashi, Akira Itabashi and Jun Ishii The Fourth Department
of Medicine, Saitama Medical School, Saitama, Japan
(Received 29 January 1990) (Revision accepted 16 January 1991)
Summary An increased risk of atherosclerotic disease has been reported in patients with diabetes mellitus. The present study was therefore designed to determine forearm blood flow (FBF) in patients with essential hypertension or those with diabetes mellitus with or without hypertension. FBF determined by venous occlusion plethysmography decreased with age in controls as well as in patients with essential hypertension, whereas FBF in diabetics was significantly lower irrespective of age or blood pressure. As a result, vascular resistance was significantly higher in diabetics than in controls or patients with essential hypertension. Glycemic control in normotensive diabetics during 3 weeks significantly augmented a diminished FBF. q-Blockade by oral administration of 1 mg of prazosin also augmented the diminished FBF in diabetics, in association with a significant decrease in mean blood pressure and vascular resistance. These results suggest that FBF may be a simple and useful index for determining arterial and/or venous distensibility, and that q-blocker therapy, in addition to glycemic control, may be a first-line antihypertensive treatment for diabetics with associated hypertension. Key words: Forearm
blood flow; Diabetes mellitus; Essential hypertension
Introduction It is well known that diabetics have a higher prevalence of hypertension than in non-diabetic individuals [ 1,2]. Hypertension may carry a greater risk for development of vascular complications such as diabetic retinopathy [ 31 and nephropathy
Correspondence to: S. Katayama, gun, Saitama 350-04. Japan.
Moroyama-cho,
Iruma-
[ 41 in addition to cerebrovascular accidents [ 51, particularly with advancing age and duration of diabetes mellitus. Progressive arteriosclerosis may be the basis for this higher incidence of vascular disease. In fact, increased pulse wave velocity [6,7] and diminished arterial wall compliance [8] have been reported in diabetics. The present study was therefore designed to determine forearm blood flow (FBF) non-invasively using venous occlusion plethysmography in diabetic patients with or without associated hypertension,
158
and also in individuals with essential hypertension. Since x,-blocker therapy has been reported as a first-line treatment for hypertension associated with diabetes mellitus [ 61, the effect of prazosin on FBF was also investigated.
Subjects and Methods Patients admitted to Saitama Medical School Hospital were selected on the basis of a diagnosis of essential hypertension (n = 9) or non-insulindependent diabetes mellitus with or without hypertension (n = 8 each) after routine laboratory tests. Hypertension was diagnosed on the basis of a diastolic blood pressure of more than 90 mmHg. All medication was stopped at least two weeks before the study and all diabetics tested were on diet therapy alone. Age-matched healthy subjects served as controls. The backgrounds of controls as well as the patients are shown in Table 1. FBF was determined by venous occlusion plethysmography [ 91 using a strain-gauge (Vaculab, U.S.A.) with the patient in a recumbent position after an overnight fast. Circulation in the hand was excluded using an inflated pneumatic cuff at the wrist to create suprasystolic pressure during all measurements. The initial slope of the volume
record, obtained by rapidly inflating the congestion cuff to 60 mmHg, was used as an index of FBF and expressed as ml/100 ml/min. Blood also determined. Triplicate pressure was measurements were obtained and the average of these values was used for analysis. Forearm vascular resistance was calculated by dividing the mean blood pressure by FBF. To see the effects of glycemic control on blood pressure as well as FBF and vascular resistance, these parameters were determined before and about three weeks after intensive glycemic control achieved by diet therapy and/or administration of sulfonylurea in the separate group of normotensive diabetics (n = 5) aged 58.2 + 4.2 years (SEM). Body mass index (BMI) averaged 23.2 & 2.3 in this group. In patients with essential hypertension and those with diabetes mellitus-associated hypertension, 1 mg of prazosin was administered immediately after the first FBF and blood pressure determination. The second measurement of these parameters was performed two hours later with the patient in a supine position. All data are expressed as the mean + SEM. Statistical analysis was performed using paired or unpaired Student’s t-test and differences at P < 0.05 were considered to be significant.
TABLE I Backgrounds
of the patients,
and basal blood pressure,
forearm blood flow and vascular resistance __ _.___ ___~
CONTROLS II Age Body mass index HbA, (“0) Duration of diabetes (years) Mean blood pressure (mmHg) Forearm blood flow (ml/LOO ml/mm) Vascular resistance (mmHg/ml/lOO ml/min)
15 52.5 k 6.0 23.2 k 2.3 89.2 + 4.0 1.38 + 0.24 89.2 k 4.0
EHT 9 58.3 22.5 103.4 1.65 92.0
DMHT
f 4.2 * 0.1
f 4.9” k 0.28 + 29.7
Each value indicates mean f SEM. EHT: essential hypertension, DMHT: diabetics without hypertension. “P < 0.05 vs controls or EHT; ‘P < 0.01 vs controls or EHT; LP < 0.05 vs DMHT.
8 64.6 + 4.2 21.2 + 1.2 12.5 f 2.0 13.5 +_ 1.3 113.9 f 7.7b 0.45 + 0.09b 326.3 f 63.8
DMNT 8 54.6 23.1 13.0 10.6 92.1 0.70 92.2
.. with hypertension, DMNT:
f k * f + * f
5.9 1.2 1.0 1.0 4.5’ 0.13” 41.5”
diabetics
159
Results Table 1 shows the basal mean blood pressure, FBF and vascular resistance in the four groups. In diabetics, irrespective of whether they were hypertensive or not, FBF was significantly lower and vascular resistance was significantly higher in comparison with those in healthy controls or patients with essential hypertension. As illustrated in Fig. 1, FBF in controls and patients with essential hypertension decreased with age, whereas diabetics demonstrated a diminished FBF even in younger patients, i.e. those in their 30s or 40s. Duration of diabetes mellitus was not correlated with FBF in diabetics. Effects of glycemic control on mean blood pressure, FBF and vascular resistance in five noninsulin-dependent diabetics are shown in Table 2. When glycemic control was improved as evidenced by a decrease in fasting plasma glucose and HbA, levels after 20.6 + 2.2 days, FBF was augmented and vascular resistance was attenuated significantly without a significant change in blood pressure. The effects of prazosin administration on mean blood pressure, FBF and vascular resistance in the patients with essential hypertension and those with diabetes mellitus-associated hypertension are illustrated in Fig. 2. Two h after prazosin administration, mean blood pressure was decreased significantly in both groups. In response to prazosin administration, FBF in both groups was augmented, but not significantly. However, the
CONTROLS 0 q
EHT
A
DMNT
0
DMHT
0
. 00
20
40
60
80
AGE (years)
Fig. 1. Relationship between forearm blood flow (FBF) and age in controls, patients with essential hypertension (EHT) or those with diabetes mellitus with (DMHT) or without (DMNT) hypertension. In controls and patients with essential hypertension, a significant negative correlation was obtained (P < 0.05).
increment of FBF in diabetic hypertensives reached 1.5 times the basal value, although the absolute increase was rather small in comparison with that in the patients with essential hypertension. As a result, prazosin significantly diminished the vascular resistance in diabetics, whereas vascular resistance in the patients with essential hypertension did not show any change.
TABLE 2 Changes in mean blood pressure,
forearm blood flow and vascular resistance
Fasting plasma glucose (mg/dl) HbA,
Mean blood pressure (mmHg) Forearm blood flow (ml/100 ml/min) Vascular resistance (mmHg/ml/100 ml/min) Each value indicates
Before
P value
After
235.8 f 21.1
P < 0.01 P < 0.01
148.4 f 18.2 11.0 * 1.3
14.1 f 1.0
(X)
mean k SEM.
after glycemic control during 20.6 + 2.2 days
83.8 k 3.1 0.95 * 0.19 102.4 f 22.6
ns
79.9 + 1.7
P < 0.05 P < 0.01
66.0 f 22.5
1.57 f 0.36
160
EHT
DMHT
1201
0 I
3
P.001
3
I 0 &l
0IL+ P,
0 01
300
0 Lk
BEFORE AFTER
BEFORE AFTER mean1
SE
r P. 0 05.
+*p
0 01
Fig. 2. Changes in mean blood pressure (MBP: upper panel), forearm blood flow (FBF: middle panel) and vascular resistance (VR: lower panel) in 9 patients with essential hypertension (EHT: left column) or diabetes mellitus with hypertension (DMHT: right column) 2 h after oral administration of 1 mg of prazosin.
Discussion
Venous occlusion plethysmography is widely accepted to provide reliable noninvasive measurements of blood flow in extremities. By this technique, we have clearly demonstrated that FBF and hence vascular resistance in controls and patients with essential hypertension may be a function of age, indicating that FBF may be a possible indicator of generalized arterial and/or venous distensibility. This result is consistent with
previous studies demonstrating a significant correlation of pulse wave velocity or arterial wall compliance with age [ 10,111. On the other hand, diabetics did show adiminished FBF (i.e. a higher vascular resistance) from their 30s onwards. In addition, a decreased FBF was observed in diabetics, irrespective of whether they were hypertensive or normotensive, although FBF in hypertensive diabetics tended to be lower than that in normotensive diabetics. Using other methods for determining arterial compliance, diabetics have been found to show an increased pulse wave velocity [ 81 as well as a diminished arterial compliance [6,7] in comparison with non-diabetic controls. The lower FBF in hypertensive diabetics in comparison with the patients with essential hypertension and the lack of correlation between diabetes mellitus duration and FBF suggest that hyperglycemia per se and/or other metabolic abnormalities in diabetes mellitus may accelerate the vascular changes resulting in arterial stiffening from a rather earlier stage, perhaps 4 to 10 years after the onset of diabetes mellitus. This hypothesis was supported by the present observation that glycemic control even for three weeks augmented a diminished FBF. There are several studies in the literature reporting slightly elevated FBF in young diabetic patients [ 12,131. The present results suggest therefore that FBF is different in younger and elderly diabetic patients. Of interest is the observation that prazosin was more effective for diabetic hypertension, based on the significant reduction seen in vascular resistance. Although small, the increase in FBF produced in response to prazosin administration was 1.5-fold. Such an increase could be very important for improving the peripheral circulation in diabetics. On the other hand, it seems very curious that vascular resistance did not decrease after prazosin administration in the patients with essential hypertension. In fact, some previous studies have shown no changes in vascular resistance after prazosin administration in patients with essential hypertension [ 141. Studies that have previously demonstrated reduced blood pressure due to decreased systemic vascular resis-
161
tance were performed only in patients responding well to cc,-blockade [ 15-171. One of the reasons why we were unable to show any reduction in vascular resistance in patients with essential hypertension may have been due to the fact that we did not select responders to prazosin. In any event, diabetics with a higher vascular resistance appear to respond well to an xi-blocker. It has been reported that the degree of orthostatic depressor response to an initial dose of prazosin is inversely correlated with the basal level of plasma renin activity [ 181. It is well known that diabetics sometimes show low renin activity. Furthermore, plasma catecholamine levels are reported to be lower in diabetics [ 191. Vascular reactivity to angiotensin II or norepinephrine has been shown to be enhanced in diabetics with retinopathy [20]. In addition, sympathetic nerve activity may be slightly more increased in the forearm in diabetic patients as a compensatory phenomenon to the distal autonomic neuropathy [ 2 11. This unique sensitivity of diabetic hypertension to prazosin may reflect an underlying increase of cr,-tone, a low-renin state and/or low plasma catecholamine levels. In the recent report by the Working Group on Hypertension in Diabetes [22], a,-blocker was listed as one of the first-line hypotensive agents for diabetic hypertensive patients. Administration of an a,-blocker does not alter insulin secretion and has little or no effect on the control of diabetes, in addition to exerting a favorable effect on lipid metabolism. The unique sensitivity to a, -blockade in diabetic hypertensives demonstrated in our present study may add further credence for the use of cr,-blocker as a first-line therapy in these patients. References Pell, S. and D’Alonzo, C.A. (1967) Some aspects of hypertension in diabetes mellitus. J. Am. Med. Assoc. 202, 104-I 10. Garcia, M.J., McNamara, P.M., Gordon, T. and Kannel, W.B. (1974) Morbidity and mortality in diabetics in the Framingham population. Sixteen-year follow-up study. Diabetes 23, 105-l 11.
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162 R.. Sullivan, P. and Laragh, J.H. (1985) Relationship of blood pressure response and the renin-angiotensin system to first-dose prazosin. Am. J. Med. 78. 241-242. 19 Christensen, N.J. (1972) Plasma catecholamine in longterm diabetes with and without neuropathy and in hypophysectomized subjects. J. Clin. Invest. 51, 779-787. 20 Christlieb, A.R., Janka, H.. Kraus, B., Gleason, R.E.. Icasas-Carbal. E.A.. Aiello, L.M., Carbal, B.V. and Solano, A. (1976) Vascular reactivity to angiotensin II
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