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Effects of nipradilol, a new nitroester-containing beta-blocker, on forearm blood flow
CURRENT THERAPEUTIC RESEARCH VOL. 52, NO. 4, OCTOBER1992
EFFECTS OF NIPRADILOL, A NEW NITROESTER-CONTAINING BETA-BLOCKER, ON FOREARM BLOOD FLOW SHIGEKI AKABANE, SHIGEHIRO KATAYAMA, AKIRA ITABASHI, MUNEMICHI INABA, YOSHIKO MARUNO, HIDEYUKI KASHIWABARA, SHINGO SANESHIGE, TAKAYOSHI SENDA, AND JUN ISHII The Fourth Department of Medicine, Saitama Medical School, Saitama, Japan
ABSTRACT B e t a - b l o c k e r s w i t h o u t i n t r i n s i c s y m p a t h o m i m e t i c a c t i o n have been r e p o r t e d to p r o d u c e an increase in p e r i p h e r a l v a s c u l a r resistance. The p r e s e n t s t u d y was designed to d e t e r m i n e t h e effects o f a new b e t a - b l o c k e r , n i p r a d i l o l (3,4-dihydro-8-(-hydroxy-3-isopropylamino) p r o p o x y - 3 - n i t r o x y - 2 H - l - b e n z o p y r a n ) , on f o r e a r m blood flow ( F B F ) in seven p a t i e n t s ( m e a n age, 51.6 -+ 6.7 y e a r s ) w i t h e s s e n t i a l hypertension. A f t e r o v e r n i g h t fasting, F B F was d e t e r m i n e d u s i n g venous occlusion s t r a i n - g a u g e p l e t h y s m o g r a p h y before a n d two h o u r s a f t e r oral a d m i n i s t r a t i o n o f 6 m g n i p r a d i l o l or 20 m g p r o p r a n o l o l . B o t h betab l o c k e r s p r o d u c e d a significant decrease in blood pressure, and h e a r t r a t e also t e n d e d to decrease. As a result, t h e p r o d u c t o b t a i n e d by m u l t i p l y i n g systolic blood p r e s s u r e by h e a r t r a t e was r e d u c e d a f t e r b o t h n i p r a d i l o l a n d p r o p r a n o l o l . N i p r a d i l o l i n c r e a s e d F B F f r o m 0.78 -+ 0.10 ml/100 m l / m i n to 1.72 - 0.28 ml/100 m l / m i n ( P < 0.02), while p r o p r a n o l o l d e c r e a s e d F B F (from 0.99 -+ 0.29 ml/100 m l / m i n to 0.73 0.24 ml/100 ml/min, P < 0.02). V a s c u l a r resistance, c a l c u l a t e d by dividing m e a n blood pressure by F B F , was r e d u c e d s i g n i f i c a n t l y to 46% o f c o n t r o l levels w i t h nipradilol, a l t h o u g h p r o p r a n o l o l elevated vascul a r r e s i s t a n c e by 39%. These results suggest t h a t n i p r a d i l o l dilates p e r i p h e r a l vessels, possibly t h r o u g h the a c t i o n o f its n i t r o e s t e r residue o r by c o n c o m i t a n t alphas-blocking activity. INTRODUCTION
Beta-adrenergic blocking agents have been used extensively as first-line hypotensive drugs. The mechanism underlying the reduction of blood pressure by beta-blockers has been primarily attributed to a decrease in cardiac output based on a negative inotropic action on the heart. 1'2 In fact, propranolol, a nonselective beta-blocker without intrinsic sympathomimetic activity (ISA), has been reported to decrease cardiac output, while increasing total peripheral resistance. 1'2 This might be one of the reasons why beta-blockers are contraindicated in cases of congestive heart failure Address correspondence to: Shigehiro Katayama, M.D., The Fourth Department of Medicine, Saitama Medical School,38 Morohongo, Moroyama-cho,Iruma-gun, Saitama 350-04, Japan. Received for publication on July 23, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted. 587
0011-393x/92/$3.50
INCREASED FOREARM BLOOD FLOW BY NIPRADILOL
or peripheral circulatory insufficiency, especially in the elderly. However, there is evidence t h a t beta-blockers with ISA are different from those without ISA in t h a t they lower blood pressure by reduction of elevated peripheral resistance. 3-5 A new nitroester-containing beta-blocker, nipradilol, has been introduced, which has been reported to be a nonselective beta-blocker without ISA, but with a weak antagonistic activity for alphaladrenergic receptors. 6-s Using venous occlusion plethysmography we examined whether or not nipradilol has a vasodilative action on forearm blood vessels in patients with essential hypertension. PATIENTS
AND METHODS
The study was performed on seven inpatients (mean age, 51.6 -- 6.7 years) with essential hypertension. Diagnosis of essential hypertension was based on a blood pressure of over 160 m m H g and/or 95 m m H g after excluding secondary hypertension. Written informed consent was obtained from all participants at the time of enrollment. All medications were withdrawn and dietary sodium intake was adjusted to 7 gm/day. Two weeks later, the subjects were randomly assigned to receive either 6 mg of nipradilol on the first day followed by 20 mg propranolol on the third day or propranolol on the first day and nipradilol on the third day. One of the patients was unable to complete the propranolol study. Blood pressure, heart rate, and forearm blood flow (FBF) were determined at room temperature (22 -+ 2 °C) in a recumbent position after overnight fasting, as well as 2 hours after oral administration of a beta-blocker. FBF was measured by venous occlusion plethysmography with strain gauges (Vasculab, Medasonics, Mountain View, California) as reported previously. 9'1° In brief, the cuff just above the elbow was rapidly inflated to 50 mmHg, while h a n d circulation was excluded with another wrist blood pressure cuff inflated to 200 mmHg. FBF was obtained from the forearm volume change (ml/100 ml/min), and forearm vascular resistance (FVR) was calculated by dividing m e a n blood pressure by FBF (mmHg/ml/100 ml/min). The average of three determinations during three minutes was used. Data are expressed as mean - SEM. Statistical differences were evaluated by paired Student's t test and considered to be significant at P < 0.05. RESULTS
Blood pressure was significantly decreased 2 hours after oral administration of both beta-blockers, as illustrated in Figure 1. Heart rate tended to decrease after beta-blockade by nipradilol or propranolol (not significant). As a result, the product of systolic blood pressure and heart rate was 588
S. AKABANE ET AL.
[ ~ P < 0.05 7
220-
~
80
r ~ N S ~
NS
200 -
~-P < 0.05. 18070160E vE a.
140a. 120-
v P < 0.01 7
0ot t
w00~
8o 5O
60: T
i Before
i 2 hr
Nipradilol
i Before
T
.i 2 hr
I
Before
Propranolol
I
2 hr
Nipradilol
J Before
mean -I- S E M , 2 hr
Propranolol
Figure 1. Systolic (SBP) or diastolic blood pressure (DBP) and pulse rate (PR) before and 2 hours after oral administration of 6 mg nipradilol (left column) or 20 mg propranolol (right column). N S = not significant.
significantly decreased (P < 0.05) from 10,086 -+ 630 mmHg- beats/min to 8,719 -+ 578 mmHg • beats/min after nipradilol administration and from 10,448 +- 1,178 mmHg. beats/min to 9,290 -+ 1,143 mmHg. beats/min after propranolol administration. As shown in Figure 2, nipradilol significantly augmented FBF with a significant decrease in FVR. However, propranolol produced a significant decrease in FBF with a slight, but not significant, increase in FVR. Table I shows changes in these parameters. Although changes in systolic or diastolic blood pressure and heart rate did not differ between the two groups, the response of FBF and FVR to nipradilol was significantly different from propranolol. DISCUSSION
The present study demonstrated that nipradilol has the same hypotensive potency as propranolol, although heart rate was not significantly decreased. As evidenced by a decrease in the product of systolic blood pressure and heart rate after nipradilol treatment, the blood pressure lowering effect may be primarily dependent on a decrease in cardiac output, which was previously demonstrated by Tsukiyama and coworkers, using radiocardiography with 131I-labeled human serum albumin. 11 However, the present study demonstrated that nipradilol almost doubled the FBF and decreased the FVR by 50%, indicating that nipradilol also has a direct vasodilative effect. A previous study in pithed rats pretreated with dihy589
I N C R E A S E D FOREARM BLOOD FLOW BY NIPRADILOL
FP < 0.053
3.0
[ P < O,O2]
I P < O'O2]
300-
\
? ~ 2.0
200-
~NS~
1
E E
E IJ.
u_ 1.0¸
LL
1002
J I Before
I 2hr
Nipradilol
I Before
mean ± SEM t 2 hr
Propranolol
I Before
I 2hr
Nipradilol
I Before
L mean ± SEM 2hr
Propranolol
Figure 2. Forearm blood flow (FBF) or forearm vascular resistance (FVR) before and 2 hours after oral administration of 6 mg nipradilol or 20 mg propranolol. NS = not significant.
droergotamine also demonstrated that nipradilol dilates venous capacitance vessels. 12 FBF, which was determined in the present study, reflects muscular arteriolar resistance. 13 Therefore, nipradilol may dilate not only capacitance vessels but also resistance vessels. This is in marked contrast to beta-blockers without ISA such as propranolol, which have been reported to increase peripheral resistance. In fact, propranolol elevated FVR with a significant 26% decrease in FBF in the present study. On the other hand, beta-blockers with ISA such as pindolol have been found to exert a direct vasodilatory action through beta2-adrenergic receptors. 5 However, nipradilol does not have ISA. The nitrates of nipradilol may act on vascular beds or NO2- released from the molecule m a y play some role in dilat-
Table. Changes in systolic (SBP) and diastolic blood pressure (DBP), pulse rate (PR), forearm blood flow (FBF), and forearm vascular resistance (FVR) 2 hours after oral administration of 6 mg nipradilol or 20 mg propranolol.
Nipradilol (n = 7) SBP (mmHg) DBP (mmHg) PR (beats/ram) FBF (ml/100 ml/min) FVR (mmHg/ml/100 ml/min)
-5.7 -4.6 -6.9 0.94 -85.8
_+ 2.3 -+ 1.3 -+ 3.5 +_ 0.28 _+ 29.8
Each value represents the mean _+ SEM. 590
P NS NS NS <0.01 <0.01
Propranolol (n = 6) -7.7 -5.7 -4.8 -1.25 56.0
+- 3.9 _+ 1.9 _+ 2.5 _+ 0.08 -- 25.3
S. AKABANEET AL.
ing blood vessels. However, the latter possibility is unlikely since plasma concentrations of nipradilol or its non-nitroester metabolite (4 or 10 ng/ml after one week oral administration of 6 mg twice daily) 14 are less than those of isosorbide dinitrate, which has been reported to reach about 8 ng/ml. Its metabolites, the 2- and 5-isosorbide mononitrates, also reached very high plasma concentrations of over 30 and 150 ng/ml, respectively. 15 Alternatively, the vasodilative action of nipradilol may be attributed at least in part to its concomitant alphal-blocking action. 1 In clinical trials, nipradilol has proven to be effective not only in hypertensive patients as a hypotensive agent, 16 but also in patients with angina pectoris. 17 Whatever the mechanism, its vasodilative action may add further support to its use in hypertensive patients with complications such as decreased peripheral circulation or angina pectoris.
Acknowledgment The authors express their gratitude to Kowa Company Ltd. for supporting this study. References: 1. Lydtin H, Kusus T, Daniel W, et al. Propranolol therapy in essential hypertension. A m Heart J 1972; 83:589-595. 2. Tarazi RC, Dustan HP. Beta-adrenergic blockade in hypertension. Practical and theoretical implications of long-term hemodynamic variations. A m J Cardiol 1972; 29:633640. 3. Atterhog JH, Duner H, Pernow B. Hemodynamic effect of long-term treatment with pindolol in essential hypertension with special reference to the resistance and capacitance vessels of the forearm. Acta Med Scand 1977; 202:517-521. 4. Manin't Veld AJ, Schlekamp MADH. How intrinsic sympathomimetic activity modulates the haemodynamic responses to beta-adrenoceptor antagonist. A clue to the nature of their antihypertensive mechanism. Br J Clin Pharmacol 1982; 13(Suppl. 2):245S-257S. 5. Chang PC, van Brummelen P, Vermeij P. Acute vasodilator action of pindolol in humans. Hypertension 1985; 7:146-150. 6. Uchida Y, Nakamura M, Shimizu S, et al. Vasoactive and beta-adrenergic blocking properties of 3,4-dihydro-8-(-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-1benzopyran (K-351), a new antihypertensive agent. Arch Int Pharmacodyn Ther 1982; 262:132-149. 7. Asada H, Nanjo T, Itoh T, et al. Effects of 3,4-dihydro-8-(-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-l-benzopyran (K-351) on smooth muscle cells and neuromuscular transmission in guinea pig vascular tissues. J Pharmacol Exp Ther 1982; 223:560-572. 8. Kou K, Ibengwe J, Suzuki H. Effects of alpha adrenoceptor antagonist on electrical and mechanical response of the isolated dog mesenteric vein to perivascular nerve stimulation and exogenous noradrenaline. Naunyn-Schmiedeberg's Arch Pharmacol 1984; 326: 7-13. 591
INCREASEDFOREARMBLOODFLOWBYNIPRADILOL
9. Ide M, Katayama S, Akabane S, et al. Effect of alphal-blockade on diminished forearm blood flow in diabetics. Diabetes Res Clin Pract 1991; 12:157-162. 10. Kodama J, Katayama S, Tanaka K, et al. Effect of captopril on glucose concentration: Possible role of augmented postprandial forearm blood flow. Diabetes Care 1990; 13: 1109-1111. 11. Tsukiyama H, Otsuka K, Higuma K. Hemodynamic effects of short-term treatment with nipradilol in essential hypertension. Ther Res 1985; 3:1121-1129. (In Japanese with English abstract) 12. Shirasawa Y, Fujii M, Nakamura M. Venodilating action of nipradilol (K-351) in the pithed rat pretreated with dihydroergotamine. Jpn J Pharmacol 1985; 39:77-82. 13. Wood JE. The veins: Normal and abnormal function. Boston: Little Brown and Company, 1965. 14. Yoshimura M, Kojima J, Itoh A, Suzuki J. Pharmacokinetics of nipradilol (K-351), a new antihypertensive agent, in human. Jpn J Clin Pharmacol Ther 1985; 16:679-691. 15. Chasseaud LF. Newer aspects of the pharmacokinetics of organic nitrates. Z Kardiol 1983; 72(Suppl. 3):20-23. 16. Kaneko Y, Shionoiri H, Iimura O, et al. Antihypertensive effects and clinical safety of long-term administration of nipradilol (K-351) on essential hypertension. Ther Res 1986; 5:135-154. 17. Ueda H, Kato K, Uchida H, et al. Effects of nipradilol on angina pectoris. Rinsho to Kenkyu 1986; 63:4109-4124. (In Japanese)
592
EFFECTS OF NIPRADILOL, A NEW NITROESTER-CONTAINING BETA-BLOCKER, ON FOREARM BLOOD FLOW SHIGEKI AKABANE, SHIGEHIRO KATAYAMA, AKIRA ITABASHI, MUNEMICHI INABA, YOSHIKO MARUNO, HIDEYUKI KASHIWABARA, SHINGO SANESHIGE, TAKAYOSHI SENDA, AND JUN ISHII The Fourth Department of Medicine, Saitama Medical School, Saitama, Japan
ABSTRACT B e t a - b l o c k e r s w i t h o u t i n t r i n s i c s y m p a t h o m i m e t i c a c t i o n have been r e p o r t e d to p r o d u c e an increase in p e r i p h e r a l v a s c u l a r resistance. The p r e s e n t s t u d y was designed to d e t e r m i n e t h e effects o f a new b e t a - b l o c k e r , n i p r a d i l o l (3,4-dihydro-8-(-hydroxy-3-isopropylamino) p r o p o x y - 3 - n i t r o x y - 2 H - l - b e n z o p y r a n ) , on f o r e a r m blood flow ( F B F ) in seven p a t i e n t s ( m e a n age, 51.6 -+ 6.7 y e a r s ) w i t h e s s e n t i a l hypertension. A f t e r o v e r n i g h t fasting, F B F was d e t e r m i n e d u s i n g venous occlusion s t r a i n - g a u g e p l e t h y s m o g r a p h y before a n d two h o u r s a f t e r oral a d m i n i s t r a t i o n o f 6 m g n i p r a d i l o l or 20 m g p r o p r a n o l o l . B o t h betab l o c k e r s p r o d u c e d a significant decrease in blood pressure, and h e a r t r a t e also t e n d e d to decrease. As a result, t h e p r o d u c t o b t a i n e d by m u l t i p l y i n g systolic blood p r e s s u r e by h e a r t r a t e was r e d u c e d a f t e r b o t h n i p r a d i l o l a n d p r o p r a n o l o l . N i p r a d i l o l i n c r e a s e d F B F f r o m 0.78 -+ 0.10 ml/100 m l / m i n to 1.72 - 0.28 ml/100 m l / m i n ( P < 0.02), while p r o p r a n o l o l d e c r e a s e d F B F (from 0.99 -+ 0.29 ml/100 m l / m i n to 0.73 0.24 ml/100 ml/min, P < 0.02). V a s c u l a r resistance, c a l c u l a t e d by dividing m e a n blood pressure by F B F , was r e d u c e d s i g n i f i c a n t l y to 46% o f c o n t r o l levels w i t h nipradilol, a l t h o u g h p r o p r a n o l o l elevated vascul a r r e s i s t a n c e by 39%. These results suggest t h a t n i p r a d i l o l dilates p e r i p h e r a l vessels, possibly t h r o u g h the a c t i o n o f its n i t r o e s t e r residue o r by c o n c o m i t a n t alphas-blocking activity. INTRODUCTION
Beta-adrenergic blocking agents have been used extensively as first-line hypotensive drugs. The mechanism underlying the reduction of blood pressure by beta-blockers has been primarily attributed to a decrease in cardiac output based on a negative inotropic action on the heart. 1'2 In fact, propranolol, a nonselective beta-blocker without intrinsic sympathomimetic activity (ISA), has been reported to decrease cardiac output, while increasing total peripheral resistance. 1'2 This might be one of the reasons why beta-blockers are contraindicated in cases of congestive heart failure Address correspondence to: Shigehiro Katayama, M.D., The Fourth Department of Medicine, Saitama Medical School,38 Morohongo, Moroyama-cho,Iruma-gun, Saitama 350-04, Japan. Received for publication on July 23, 1992. Printed in the U.S.A. Reproduction in whole or part is not permitted. 587
0011-393x/92/$3.50
INCREASED FOREARM BLOOD FLOW BY NIPRADILOL
or peripheral circulatory insufficiency, especially in the elderly. However, there is evidence t h a t beta-blockers with ISA are different from those without ISA in t h a t they lower blood pressure by reduction of elevated peripheral resistance. 3-5 A new nitroester-containing beta-blocker, nipradilol, has been introduced, which has been reported to be a nonselective beta-blocker without ISA, but with a weak antagonistic activity for alphaladrenergic receptors. 6-s Using venous occlusion plethysmography we examined whether or not nipradilol has a vasodilative action on forearm blood vessels in patients with essential hypertension. PATIENTS
AND METHODS
The study was performed on seven inpatients (mean age, 51.6 -- 6.7 years) with essential hypertension. Diagnosis of essential hypertension was based on a blood pressure of over 160 m m H g and/or 95 m m H g after excluding secondary hypertension. Written informed consent was obtained from all participants at the time of enrollment. All medications were withdrawn and dietary sodium intake was adjusted to 7 gm/day. Two weeks later, the subjects were randomly assigned to receive either 6 mg of nipradilol on the first day followed by 20 mg propranolol on the third day or propranolol on the first day and nipradilol on the third day. One of the patients was unable to complete the propranolol study. Blood pressure, heart rate, and forearm blood flow (FBF) were determined at room temperature (22 -+ 2 °C) in a recumbent position after overnight fasting, as well as 2 hours after oral administration of a beta-blocker. FBF was measured by venous occlusion plethysmography with strain gauges (Vasculab, Medasonics, Mountain View, California) as reported previously. 9'1° In brief, the cuff just above the elbow was rapidly inflated to 50 mmHg, while h a n d circulation was excluded with another wrist blood pressure cuff inflated to 200 mmHg. FBF was obtained from the forearm volume change (ml/100 ml/min), and forearm vascular resistance (FVR) was calculated by dividing m e a n blood pressure by FBF (mmHg/ml/100 ml/min). The average of three determinations during three minutes was used. Data are expressed as mean - SEM. Statistical differences were evaluated by paired Student's t test and considered to be significant at P < 0.05. RESULTS
Blood pressure was significantly decreased 2 hours after oral administration of both beta-blockers, as illustrated in Figure 1. Heart rate tended to decrease after beta-blockade by nipradilol or propranolol (not significant). As a result, the product of systolic blood pressure and heart rate was 588
S. AKABANE ET AL.
[ ~ P < 0.05 7
220-
~
80
r ~ N S ~
NS
200 -
~-P < 0.05. 18070160E vE a.
140a. 120-
v P < 0.01 7
0ot t
w00~
8o 5O
60: T
i Before
i 2 hr
Nipradilol
i Before
T
.i 2 hr
I
Before
Propranolol
I
2 hr
Nipradilol
J Before
mean -I- S E M , 2 hr
Propranolol
Figure 1. Systolic (SBP) or diastolic blood pressure (DBP) and pulse rate (PR) before and 2 hours after oral administration of 6 mg nipradilol (left column) or 20 mg propranolol (right column). N S = not significant.
significantly decreased (P < 0.05) from 10,086 -+ 630 mmHg- beats/min to 8,719 -+ 578 mmHg • beats/min after nipradilol administration and from 10,448 +- 1,178 mmHg. beats/min to 9,290 -+ 1,143 mmHg. beats/min after propranolol administration. As shown in Figure 2, nipradilol significantly augmented FBF with a significant decrease in FVR. However, propranolol produced a significant decrease in FBF with a slight, but not significant, increase in FVR. Table I shows changes in these parameters. Although changes in systolic or diastolic blood pressure and heart rate did not differ between the two groups, the response of FBF and FVR to nipradilol was significantly different from propranolol. DISCUSSION
The present study demonstrated that nipradilol has the same hypotensive potency as propranolol, although heart rate was not significantly decreased. As evidenced by a decrease in the product of systolic blood pressure and heart rate after nipradilol treatment, the blood pressure lowering effect may be primarily dependent on a decrease in cardiac output, which was previously demonstrated by Tsukiyama and coworkers, using radiocardiography with 131I-labeled human serum albumin. 11 However, the present study demonstrated that nipradilol almost doubled the FBF and decreased the FVR by 50%, indicating that nipradilol also has a direct vasodilative effect. A previous study in pithed rats pretreated with dihy589
I N C R E A S E D FOREARM BLOOD FLOW BY NIPRADILOL
FP < 0.053
3.0
[ P < O,O2]
I P < O'O2]
300-
\
? ~ 2.0
200-
~NS~
1
E E
E IJ.
u_ 1.0¸
LL
1002
J I Before
I 2hr
Nipradilol
I Before
mean ± SEM t 2 hr
Propranolol
I Before
I 2hr
Nipradilol
I Before
L mean ± SEM 2hr
Propranolol
Figure 2. Forearm blood flow (FBF) or forearm vascular resistance (FVR) before and 2 hours after oral administration of 6 mg nipradilol or 20 mg propranolol. NS = not significant.
droergotamine also demonstrated that nipradilol dilates venous capacitance vessels. 12 FBF, which was determined in the present study, reflects muscular arteriolar resistance. 13 Therefore, nipradilol may dilate not only capacitance vessels but also resistance vessels. This is in marked contrast to beta-blockers without ISA such as propranolol, which have been reported to increase peripheral resistance. In fact, propranolol elevated FVR with a significant 26% decrease in FBF in the present study. On the other hand, beta-blockers with ISA such as pindolol have been found to exert a direct vasodilatory action through beta2-adrenergic receptors. 5 However, nipradilol does not have ISA. The nitrates of nipradilol may act on vascular beds or NO2- released from the molecule m a y play some role in dilat-
Table. Changes in systolic (SBP) and diastolic blood pressure (DBP), pulse rate (PR), forearm blood flow (FBF), and forearm vascular resistance (FVR) 2 hours after oral administration of 6 mg nipradilol or 20 mg propranolol.
Nipradilol (n = 7) SBP (mmHg) DBP (mmHg) PR (beats/ram) FBF (ml/100 ml/min) FVR (mmHg/ml/100 ml/min)
-5.7 -4.6 -6.9 0.94 -85.8
_+ 2.3 -+ 1.3 -+ 3.5 +_ 0.28 _+ 29.8
Each value represents the mean _+ SEM. 590
P NS NS NS <0.01 <0.01
Propranolol (n = 6) -7.7 -5.7 -4.8 -1.25 56.0
+- 3.9 _+ 1.9 _+ 2.5 _+ 0.08 -- 25.3
S. AKABANEET AL.
ing blood vessels. However, the latter possibility is unlikely since plasma concentrations of nipradilol or its non-nitroester metabolite (4 or 10 ng/ml after one week oral administration of 6 mg twice daily) 14 are less than those of isosorbide dinitrate, which has been reported to reach about 8 ng/ml. Its metabolites, the 2- and 5-isosorbide mononitrates, also reached very high plasma concentrations of over 30 and 150 ng/ml, respectively. 15 Alternatively, the vasodilative action of nipradilol may be attributed at least in part to its concomitant alphal-blocking action. 1 In clinical trials, nipradilol has proven to be effective not only in hypertensive patients as a hypotensive agent, 16 but also in patients with angina pectoris. 17 Whatever the mechanism, its vasodilative action may add further support to its use in hypertensive patients with complications such as decreased peripheral circulation or angina pectoris.
Acknowledgment The authors express their gratitude to Kowa Company Ltd. for supporting this study. References: 1. Lydtin H, Kusus T, Daniel W, et al. Propranolol therapy in essential hypertension. A m Heart J 1972; 83:589-595. 2. Tarazi RC, Dustan HP. Beta-adrenergic blockade in hypertension. Practical and theoretical implications of long-term hemodynamic variations. A m J Cardiol 1972; 29:633640. 3. Atterhog JH, Duner H, Pernow B. Hemodynamic effect of long-term treatment with pindolol in essential hypertension with special reference to the resistance and capacitance vessels of the forearm. Acta Med Scand 1977; 202:517-521. 4. Manin't Veld AJ, Schlekamp MADH. How intrinsic sympathomimetic activity modulates the haemodynamic responses to beta-adrenoceptor antagonist. A clue to the nature of their antihypertensive mechanism. Br J Clin Pharmacol 1982; 13(Suppl. 2):245S-257S. 5. Chang PC, van Brummelen P, Vermeij P. Acute vasodilator action of pindolol in humans. Hypertension 1985; 7:146-150. 6. Uchida Y, Nakamura M, Shimizu S, et al. Vasoactive and beta-adrenergic blocking properties of 3,4-dihydro-8-(-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-1benzopyran (K-351), a new antihypertensive agent. Arch Int Pharmacodyn Ther 1982; 262:132-149. 7. Asada H, Nanjo T, Itoh T, et al. Effects of 3,4-dihydro-8-(-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-l-benzopyran (K-351) on smooth muscle cells and neuromuscular transmission in guinea pig vascular tissues. J Pharmacol Exp Ther 1982; 223:560-572. 8. Kou K, Ibengwe J, Suzuki H. Effects of alpha adrenoceptor antagonist on electrical and mechanical response of the isolated dog mesenteric vein to perivascular nerve stimulation and exogenous noradrenaline. Naunyn-Schmiedeberg's Arch Pharmacol 1984; 326: 7-13. 591
INCREASEDFOREARMBLOODFLOWBYNIPRADILOL
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