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Bosentan reduces blood pressure and the renal damage induced by high fructose diet in rats
POSTERS: Antihypertensive Drugs
AJH 1999;12:111A-138A
D001
D002
T H E A N T I H Y P E R T E N S I V E E F F E C T OF T H E
A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY OF THE EFFECTIVENESS AND SAFETY OF ORAL STEV1OS1DE IN HUMAN HYPERTENSION. Ju-Chi Liu*. Paul Chan*, Juei-Tang Cheng. Division o f Cardiovascular Medicine, Taipei Medical College and affiliated Taipei Wan Fang Hospital, Taipei, Taiwan, R.O.C. Stevioside is a natural plant glycoside isolated from the plant S t e v i a r e b a u d i a n a which has been commercialized as a sweetener in Japan for more than 20 years. Previous animal studies have shown that stevioside has an antihypertensive effect. To evaluate the effect of stevioside in human hypertension, a multicenter, randomized, double-blind, placebo-controlled study was undertaken. This study group consisted of I06 Chinese hypertensive subjects with diastolic blood pressure between 95110 m m H g and ages ranging from 28 to 75 years with 60 subjects (men 34, women 26; mean + SD, 54.1 _+3.8 years) allocated to active treatment and 46 (men 19, women 27; mean _+ SD, 53.7 4.1 years) to placebo treatment. Each subject was given capsules containing stevioside (250 mg) of placebo thrice daily and followed-up at monthly intervals for one year. After three months, the systolic and diastolic blood pressure of the stevioside group decreased significantly (systolic: 166.0 _+9.4 to 152.6 _+6.8 mmHg; diastolic: 104.7 + 5.2 to 90.3 _+3.6 mmHg, p < 0.05). Blood biochemistry parameters including lipid and glucose showed no significant changes. No significant adverse effect was observed and quality of life assessment showed no deterioration. This study shows that oral stevioside is a safe and effective modality that may be considered as an alternative or supplementary therapy for patients with hypertension.
B E R B E R I N E D E R I V A T I V E 6 - P R O T O B E R B E R I N E IN S P O N T A N E O U S L Y H Y P E R T E N S I V E RATS. Wen-Pin Huang, Paul Chan*, Juei-Tang Cheng. Division o f Cardiovascular Medicine, Taipei Medicine College and affiliated Taipei W a n - F a n g Hospital, Taipei, Taiwan, R.O.C. Berberine is a natural isoquinoline alkaloid found in plants o f the R a n u n c u l a c e a e and Berberidaceae families. Extracts f r o m berberine-containing plants h a v e been used as traditional Chinese folk remedies for centuries. The antihypertensive effects o f the berberine derivative, 6protoberberine (PTB-6) w e r e studied in spontaneously hypertensive rats (SHRs). In conscious SHRs, PTB-6 lowered the systemic arterial blood pressure in a dosedependent m a n n e r ( 6 - P T B 5 m g / k g , -31.1 + 1 . 6 m m H g ; 6PTB 10mg/kg, -42.4_+ 3.1 m m H g ) . Cardiac output using the thermodilution m e t h o d was reduced in P T B - 6 treated anesthetized S H R s with a tendency to decrease in heart rate. Injection o f P T B - 6 into the intracerebral ventricles o f SHRs lowered the systemic arterial blood pressure and heart rate. The berberine derivative P T B - 6 is an effective antihypertensive agent. The m e c h a n i s m o f antihypertensive effect o f P T B - 6 is probably through a central sympatholytic effect.
Koy Words:
Berberine, Protoberberine, Spontaneously hypertensive rats
Key Words:
compliance, hypertension, stevioside
D003
D004
BOSENTAN REDUCES BLOOD PRESSURE AND THE RENAL D A M A G E INDUCED BY HIGH FRUCTOSE DIET IN RATS. Cosenzi A, Bernobich E, Plazzotta N, Seculin P, Bonavita M, Costacurta C, Bellini G. lstituto di Medicina Clinic&, University of Trieste - Trieste -ITALY Bnsantan (13) is a non selective antagonist of Et receptors. B is effective in reducing blood pressure (BP) in some animal models of hypertension and in essential hypertensives. Rats fed high fructose diet (HFD) develop hyperinsniinemia, hypertriglyceridemla, hypertension (H). In the kidney, hypcrfiltration, glomerolar hypertrophy and deposition of collagen and fibronectin have been observed. The aim of this study was to evaluate whether B was effective not only in decreasing BP but also in reducing the renal damage induced by HFD. Forty WKY male rats were divided into 4 groups (Gr): Gr.l and Gr.2 received HFD, Gr.3 and Gr.4 standard diet (SD) for one month. Thereafter the following treatments were administered: Gr.l HFD plus B 100mg/kg/die, Gr.2 HFD plus placebo, Gr.3 SD plus B 100mg/kg/die, Gr.4 SD plus placebo. After one-month treatment all animals were sacrificed. A morphometric analysis was performed by examining 100 glomernli for each animal. Renal deposits of fibronectin (F) collagen I and IV (C. I and C. IV) were dersnnstrated by means of immunechemistry. The remits were compared by one-way Anova and Scheff6 range. At the end of the study B significantly reduced BP in rats fed HFD but not in rats with SD. Moreover, B reduced GH and the deposits of i C. I and C. IV. HFD+Bin HFD+ PI SD + Bol SD+PI BPbaseline (mmHg) 119±5 118±4 121+-5 120+-5 BP lmo~th (nmlHg) 150±4' 150+8' 127+4 126+-5 BP 2mo~lth (mmHg) 131±3 151+-4" 132±4 132+4 Total~l~-n.area (~) 10052+-404* 123S5± 421'* 8911± S00 9052+586 Glome~lartm~(/2) 9187+-455" 10170+483** 8027+-798 8156+-582 ~(pa) 865±128 2213±381' 884±276 896+-126 Collage~I(~ore) 1.1+0.2 2.4+-0.6* 1.1+- 0.2 1.0~ 0.1 CollagmIV (score) 1.9± 0.6 2.7 + 0.3* 1.7± 0.5 1.54-0.4 Fibrone~n(e~t'e) 2.7 4.0.6* 3.4 4-0.4** 1.54-0.6 1.54-0.7 * or ** denote groupa wtth sta~sneat d~fferemes Sisnifioan~ level F < 0.0001 Our study shows that B has a veay favoarable effect on BP levels increased by HFD and on the renal damage. These data further suggest that Et antagonism could be considered a new target in the treatment of hypertension and in the prevention of its complications.
BOSENTAN REDUCES THE DEPOSITION DF COLLAGEN HI IN THE LEFT VENTRICLE OF RATS WITH HYPERTENSION INDUCED BY HIGH FRUCTOSE DIET. Plazzotta N, Cmenzi A, Bemobich E, Seeulin P, Bonavita M, Guidone B, BeHini G. lstituto di MedJcina Clinica, University of Trieste - Trieste -ITALY LeR ventricular hypertrophy (LVH) is characterised not only by myocites hypertrophy, but also by interstitial alterations. There is a progressive collagen deposition, starting from the perivascnlar spaces. In hypertensive patients, who present an early characteristic alteration of diastolic function, interstitial modifications play an important role to increase left ventrifular stiffness. The authors have prewously demonstrated that in rats fed high fructose diet (HFD), hypertension is combined with an increase of collagen deposits in left ventricnlar extracellnlar matrix. Bosentan 03) is a non selective antagonist of Et receptors. This drug is effective in reducing blood pressure (BP) in some animal models of hypertension and in essential hypertensives. The aim of this study was to evaluate whether B was effective not only in reducing BP but also in preventing the deposition of collagen IlI in the left ventricle induced by HFD Forty WKY male rats were divided into 4 groups (Gr): Gr.l and Gr.2 received HFD. Gr.3 and Gr.4 standard diet (SD) for one month. Thereafter the following treatments were administered: Gr.1 HFD plus B 100mg/kg/die, Gr.2 HFD plus placebo, Gr.3 SD plus B 100mg/kg/die, Gr.4 SD pins placebo. After one month of treatment all animals were sncrificed. LeR ventricnlar deposits of collagen Ill (Coll. Ill) were demonstrated by means of immuaechamistW. The results were compared by one-way Anova and Scheff6 range. At the end of the study B significantly reduced BP in rats fed HFD but not in rats with SD; moreover, the drug decreased the cardiac deposits of Coil. HI in these rats. HFD+Boa HFD+ Pl SD+Bm SD+PI BPbaeline (mmHg) 119±$ 118+4 121+5 120±5 BP Imocth (mnIHi0 150+4" 150+-8' 127±4 126+5 BP~m'~h (mmHg) 131+-3 151±4" 132±4 132+-4 Collasenm (scetl) 2.4+- 0.6 3.14. 0.3* 1,0± 0.1 1.4+-0.5 * dcnot~ groupt wCthltatlaffcnl d ~ m ~ c ~ a Significancelevel F < 0.000I LVH is an important negative prognostic factor in the hypertensive patients; this study demonstrates that B reduces the deposition of CIII observed in LVH, thus suggesting a role for endothelin antagonism in t ~ e P ~ n r ~ f n of the cardiac complications of hypertension.
Key Words: fructose, hypertension, bosentan, kidney
fructose, hypertension, b n s a t a n , heart
AJH 1999;12:111A-138A
D001
D002
T H E A N T I H Y P E R T E N S I V E E F F E C T OF T H E
A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY OF THE EFFECTIVENESS AND SAFETY OF ORAL STEV1OS1DE IN HUMAN HYPERTENSION. Ju-Chi Liu*. Paul Chan*, Juei-Tang Cheng. Division o f Cardiovascular Medicine, Taipei Medical College and affiliated Taipei Wan Fang Hospital, Taipei, Taiwan, R.O.C. Stevioside is a natural plant glycoside isolated from the plant S t e v i a r e b a u d i a n a which has been commercialized as a sweetener in Japan for more than 20 years. Previous animal studies have shown that stevioside has an antihypertensive effect. To evaluate the effect of stevioside in human hypertension, a multicenter, randomized, double-blind, placebo-controlled study was undertaken. This study group consisted of I06 Chinese hypertensive subjects with diastolic blood pressure between 95110 m m H g and ages ranging from 28 to 75 years with 60 subjects (men 34, women 26; mean + SD, 54.1 _+3.8 years) allocated to active treatment and 46 (men 19, women 27; mean _+ SD, 53.7 4.1 years) to placebo treatment. Each subject was given capsules containing stevioside (250 mg) of placebo thrice daily and followed-up at monthly intervals for one year. After three months, the systolic and diastolic blood pressure of the stevioside group decreased significantly (systolic: 166.0 _+9.4 to 152.6 _+6.8 mmHg; diastolic: 104.7 + 5.2 to 90.3 _+3.6 mmHg, p < 0.05). Blood biochemistry parameters including lipid and glucose showed no significant changes. No significant adverse effect was observed and quality of life assessment showed no deterioration. This study shows that oral stevioside is a safe and effective modality that may be considered as an alternative or supplementary therapy for patients with hypertension.
B E R B E R I N E D E R I V A T I V E 6 - P R O T O B E R B E R I N E IN S P O N T A N E O U S L Y H Y P E R T E N S I V E RATS. Wen-Pin Huang, Paul Chan*, Juei-Tang Cheng. Division o f Cardiovascular Medicine, Taipei Medicine College and affiliated Taipei W a n - F a n g Hospital, Taipei, Taiwan, R.O.C. Berberine is a natural isoquinoline alkaloid found in plants o f the R a n u n c u l a c e a e and Berberidaceae families. Extracts f r o m berberine-containing plants h a v e been used as traditional Chinese folk remedies for centuries. The antihypertensive effects o f the berberine derivative, 6protoberberine (PTB-6) w e r e studied in spontaneously hypertensive rats (SHRs). In conscious SHRs, PTB-6 lowered the systemic arterial blood pressure in a dosedependent m a n n e r ( 6 - P T B 5 m g / k g , -31.1 + 1 . 6 m m H g ; 6PTB 10mg/kg, -42.4_+ 3.1 m m H g ) . Cardiac output using the thermodilution m e t h o d was reduced in P T B - 6 treated anesthetized S H R s with a tendency to decrease in heart rate. Injection o f P T B - 6 into the intracerebral ventricles o f SHRs lowered the systemic arterial blood pressure and heart rate. The berberine derivative P T B - 6 is an effective antihypertensive agent. The m e c h a n i s m o f antihypertensive effect o f P T B - 6 is probably through a central sympatholytic effect.
Koy Words:
Berberine, Protoberberine, Spontaneously hypertensive rats
Key Words:
compliance, hypertension, stevioside
D003
D004
BOSENTAN REDUCES BLOOD PRESSURE AND THE RENAL D A M A G E INDUCED BY HIGH FRUCTOSE DIET IN RATS. Cosenzi A, Bernobich E, Plazzotta N, Seculin P, Bonavita M, Costacurta C, Bellini G. lstituto di Medicina Clinic&, University of Trieste - Trieste -ITALY Bnsantan (13) is a non selective antagonist of Et receptors. B is effective in reducing blood pressure (BP) in some animal models of hypertension and in essential hypertensives. Rats fed high fructose diet (HFD) develop hyperinsniinemia, hypertriglyceridemla, hypertension (H). In the kidney, hypcrfiltration, glomerolar hypertrophy and deposition of collagen and fibronectin have been observed. The aim of this study was to evaluate whether B was effective not only in decreasing BP but also in reducing the renal damage induced by HFD. Forty WKY male rats were divided into 4 groups (Gr): Gr.l and Gr.2 received HFD, Gr.3 and Gr.4 standard diet (SD) for one month. Thereafter the following treatments were administered: Gr.l HFD plus B 100mg/kg/die, Gr.2 HFD plus placebo, Gr.3 SD plus B 100mg/kg/die, Gr.4 SD plus placebo. After one-month treatment all animals were sacrificed. A morphometric analysis was performed by examining 100 glomernli for each animal. Renal deposits of fibronectin (F) collagen I and IV (C. I and C. IV) were dersnnstrated by means of immunechemistry. The remits were compared by one-way Anova and Scheff6 range. At the end of the study B significantly reduced BP in rats fed HFD but not in rats with SD. Moreover, B reduced GH and the deposits of i C. I and C. IV. HFD+Bin HFD+ PI SD + Bol SD+PI BPbaseline (mmHg) 119±5 118±4 121+-5 120+-5 BP lmo~th (nmlHg) 150±4' 150+8' 127+4 126+-5 BP 2mo~lth (mmHg) 131±3 151+-4" 132±4 132+4 Total~l~-n.area (~) 10052+-404* 123S5± 421'* 8911± S00 9052+586 Glome~lartm~(/2) 9187+-455" 10170+483** 8027+-798 8156+-582 ~(pa) 865±128 2213±381' 884±276 896+-126 Collage~I(~ore) 1.1+0.2 2.4+-0.6* 1.1+- 0.2 1.0~ 0.1 CollagmIV (score) 1.9± 0.6 2.7 + 0.3* 1.7± 0.5 1.54-0.4 Fibrone~n(e~t'e) 2.7 4.0.6* 3.4 4-0.4** 1.54-0.6 1.54-0.7 * or ** denote groupa wtth sta~sneat d~fferemes Sisnifioan~ level F < 0.0001 Our study shows that B has a veay favoarable effect on BP levels increased by HFD and on the renal damage. These data further suggest that Et antagonism could be considered a new target in the treatment of hypertension and in the prevention of its complications.
BOSENTAN REDUCES THE DEPOSITION DF COLLAGEN HI IN THE LEFT VENTRICLE OF RATS WITH HYPERTENSION INDUCED BY HIGH FRUCTOSE DIET. Plazzotta N, Cmenzi A, Bemobich E, Seeulin P, Bonavita M, Guidone B, BeHini G. lstituto di MedJcina Clinica, University of Trieste - Trieste -ITALY LeR ventricular hypertrophy (LVH) is characterised not only by myocites hypertrophy, but also by interstitial alterations. There is a progressive collagen deposition, starting from the perivascnlar spaces. In hypertensive patients, who present an early characteristic alteration of diastolic function, interstitial modifications play an important role to increase left ventrifular stiffness. The authors have prewously demonstrated that in rats fed high fructose diet (HFD), hypertension is combined with an increase of collagen deposits in left ventricnlar extracellnlar matrix. Bosentan 03) is a non selective antagonist of Et receptors. This drug is effective in reducing blood pressure (BP) in some animal models of hypertension and in essential hypertensives. The aim of this study was to evaluate whether B was effective not only in reducing BP but also in preventing the deposition of collagen IlI in the left ventricle induced by HFD Forty WKY male rats were divided into 4 groups (Gr): Gr.l and Gr.2 received HFD. Gr.3 and Gr.4 standard diet (SD) for one month. Thereafter the following treatments were administered: Gr.1 HFD plus B 100mg/kg/die, Gr.2 HFD plus placebo, Gr.3 SD plus B 100mg/kg/die, Gr.4 SD pins placebo. After one month of treatment all animals were sncrificed. LeR ventricnlar deposits of collagen Ill (Coll. Ill) were demonstrated by means of immuaechamistW. The results were compared by one-way Anova and Scheff6 range. At the end of the study B significantly reduced BP in rats fed HFD but not in rats with SD; moreover, the drug decreased the cardiac deposits of Coil. HI in these rats. HFD+Boa HFD+ Pl SD+Bm SD+PI BPbaeline (mmHg) 119±$ 118+4 121+5 120±5 BP Imocth (mnIHi0 150+4" 150+-8' 127±4 126+5 BP~m'~h (mmHg) 131+-3 151±4" 132±4 132+-4 Collasenm (scetl) 2.4+- 0.6 3.14. 0.3* 1,0± 0.1 1.4+-0.5 * dcnot~ groupt wCthltatlaffcnl d ~ m ~ c ~ a Significancelevel F < 0.000I LVH is an important negative prognostic factor in the hypertensive patients; this study demonstrates that B reduces the deposition of CIII observed in LVH, thus suggesting a role for endothelin antagonism in t ~ e P ~ n r ~ f n of the cardiac complications of hypertension.
Key Words: fructose, hypertension, bosentan, kidney
fructose, hypertension, b n s a t a n , heart