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Dúvidas [email protected] Arquivo SOHERJ-2004.ppt Site www.gdenucci.com. Ativadores de guanilato ciclase solúvel: uma nova classe de agentes anti-hipertensivos. NO-cGMP Biochemistry. ODQ. (-). L-NAME. GTP. sGC. (-). cGMP. NOS. PDE5. 5’GMP. (-). L-ARGININE. NO. PDE5

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d vidas denucci@gdenucci com arquivo soherj 2004 ppt site www gdenucci com
Dúvidas

[email protected]

Arquivo

SOHERJ-2004.ppt

Site

www.gdenucci.com

no cgmp biochemistry
NO-cGMP Biochemistry

ODQ

(-)

L-NAME

GTP

sGC

(-)

cGMP

NOS

PDE5

5’GMP

(-)

L-ARGININE

NO

PDE5

inhibitors

slide6

NO synthase

NO donors

YC – 1

BAY 58-2667

argine

NO

guanylyl cyclase

cGMP-regulated Ion channels

GTP

cGMP

cGMP-dependent protein kinases

cGMP-regulated phosphodiesterases

cellular effects

slide7

NO

guanylyl cyclase

GTP

cGMP

GMP

cGMP

cGMP-dependent protein kinase

phospho

diesterase 5

P

Cellular effects

slide8

Tail-cuff pressure

mmHg

Weeks

Basic Res Cardiol 91, 1996

classification
Classification

+1 or 2 foci of N or F (<500 mm)

++ >2 non-confluent (<500 mm)

+++ confluent N or F (>500 mm)

heart ischemia
Heart ischemia
  • L-NAME
  • 2K-1C

100

75

%

50

25

0

2w

4w

8w

EPJ 287, 1995

effect of enalapril pre treatment 2 weeks on l name induced hypertension
Effect of enalapril pre-treatment (2 weeks) on L-NAME-induced hypertension

175

*

*

*

*

*

*

*

150

TCP (mmHg)

125

100

B

1

2

3

4

5

6

7

8

9

10

Weeks

  • Control

L-NAME

 L-NAME + Enalapril

  • Enalapril
heart ischemia1
Heart ischemia

100

75

%

50

25

0

8w

  • L-NAME
  • Enalapril

EPJ 287, 1995

no hypertension
NO hypertension

Accompanied by kidney and heart disease Hypertension sensitive to ACE inhibitors Kidney disease sensitive to ACE inhibitors

Heart ischemia not sensitive to ACE inhibitors

slide15

- NO and cGMP are involved in vasodilatation mechanism;

- Glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO;

- NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC);

- BAY 41-2272 is a pyrazolopyridine compound that potently stimulates sGC through this site by a mechanism that is independent of NO (Stasch et al., 2001).

BAY 41-2272 (MW 360.40)

slide16

HO

O

N

N

Bay 58-2667

N

OH

O

O

O

O

O

OH

N

N

N

YC-1

3-(5’-Hidroxymethyl-2’-furyl-1-1benzylindazole)

ODQ

1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one

slide17

Coronary blood flow

Mean arterial blood pressure

(ml min-1)

(mm Hg)

50

40

30

20

10

0

0

-5

-10

-15

-20

-25

-30

3 10 30 100

3 10 30 100

Dose (μg kg-1 i.v.)

Dose (μg kg-1 i.v.)

Heart rate

Oxygen saturation in coronary sinus

(beats min-1)

(%)

30

25

20

15

10

5

15

10

5

0

3 10 30 100

3 10 30 100

Dose (μg kg-1 i.v.)

Dose (μg kg-1 i.v.)

anaesthetised rat i v bay 41 8543
Anaesthetised rat (i.v.) BAY-41-8543

Control 3 μg kg-1 i.v.

10 μg kg-1 i.v. 30 μg kg-1 i.v.

100 μg kg-1 i.v. 300 μg kg-1 i.v.

Control 3 μg kg-1 i.v.

10 μg kg-1 i.v. 30 μg kg-1 i.v.

100 μg kg-1 i.v. 300 μg kg-1 i.v.

100

80

60

40

20

0

-20

-40

-60

-80

-100

40

20

0

-20

-40

-60

-80

Deviation in heart rate (beats/min)

Deviation in mean blood pressure (mmHg)

0 5 10 15 20 25 30 35

0 5 10 15 20 25 30 35

Time (min)

Time (min)

anaesthetised rat per os
Anaesthetised rat (per os)

Control 0,1 mg kg-1 p.o.

0,3 mg kg-1 p.o. 1 mg kg-1 p.o.

Control 0,1 mg kg-1 p.o.

0,3 mg kg-1 p.o. 1 mg kg-1 p.o.

20

10

0

-10

-20

-30

-40

-50

-60

100

80

60

40

20

0

-20

-40

-60

-80

-100

Deviation in heart rate (beats / min)

Deviation in mean blood pressure (mmHg)

0 20 40 60 80 100 120 140

0 20 40 60 80 100 120 140

Time (min)

Time (min)

no hypertension1
NO hypertension

Accompanied by kidney and heart disease Hypertension sensitive to ACE inhibitors Kidney disease sensitive to ACE inhibitors

Heart ischemia not sensitive to ACE inhibitors

slide21

Aims

“ Evaluate the effects of BAY 41-2272 on the arterial blood pressure (MABP), heart weight index (HWI), left ventricular weight index (LVWI) and cardiomyocyte hypertrophy (Vv) induced by chronic L-NAME treatment in rats.”

slide23

Methods

  • Implant of radiotelemetry device into descending aorta;
  • Mean Arterial Blood Pressure (MABP) and Heart Rate acquired twice a week for 90 seconds during 8 weeks;
  • Heart and Left Venctricle Weight Indexes (HWI and LVWI) and cardiomyocyte volume density (Vv) were analysed to determine the cardiac and cardiomyocyte hypertrophy, respectively.
slide24

Animal groups

- Control

- L-NAME (20mg/rat per day)

- L-NAME + BAY

- BAY (10mg/kg per day)

 BAY was dissolved in DMSO 80% and administered by diary oral gavage.

Control and L-NAME groups received DMSO 80% as a vehicle.

(20mg/rat per day + 10mg/kg per day)

slide25

Effect of BAY 41-2272co-treatment on L-NAME-induced hypertension

 p<0.05 and  p<0.01 compared to Control group

## p<0.01 compared to L-NAME group.

slide26

L-NAME +

Control

L-NAME

BAY

BAY

Heart Rate (

bmp)

377

+

12

362

+

18

401

+

15

431

+

25*

Body Weight

338.8

+

13.6

301.0

+

9.3*

324.0

+

15.1

295.7

+

16.0*

Heart Weight

#

Index (HWI ; mg/g)

2.39

+

0.18

2.81

+

0.13*

2.46

+

0.21

2.48

+

0.26

Left Ventricle

#

Weight Index

1.12

+

0.15

2.08

+

0.19*

1.22

+

0.59

1.23

+

0.48

(LVWI ; mg/g)

Heart Rate, Body Weight, Heart and Left Ventricle Weight Indexes after 8 weeks

 p<0.05 compared to Control group

# p<0.01 compared to L-NAME group.

slide27

Left Ventricle Photomicrography

 - area of repairing fibrosis

slide28

Conclusion

“ BAY 41-2272 significantly reduced arterial hypertension, cardiomyocyte hypertrophy and myocardial fibrosis induced by a 8-week treatment with L-NAME.”

slide29

Sildenafil

(MW 474.46)

BAY 41-2272

(MW 360.40)

BAY 41-2272 induces HCC relaxation

pEC50

Emax

6.71  0.05

111  5

6.85  0.06

117  5

slide30

0

BAY

BAY + ODQ

GTN

40

% Relaxation

GTN + ODQ

80

120

-8

-7

-6

-5

log [BAY 41-2272] (M)

0

BAY

BAY + ODQ

GTN

40

% Relaxation

GTN + ODQ

80

120

-8

-7

-6

-5

log [BAY 41-2272] (M)

BAY 41-2272 induces CC relaxation

Human

Rabbit

slide31

Conclusão

Ativadores da enzima guanilato ciclase solúvel apresentam interessante potencial terapêutico para tratamento de hipertensão arterial, isquemia miocárdica e disfunção erétil.

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