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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 agentes anti-hipertensivos.

ODQ

(-)

L-NAME

GTP

sGC

(-)

cGMP

NOS

PDE5

5’GMP

(-)

L-ARGININE

NO

PDE5

inhibitors


NO synthase agentes anti-hipertensivos.

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


NO agentes anti-hipertensivos.

guanylyl cyclase

GTP

cGMP

GMP

cGMP

cGMP-dependent protein kinase

phospho

diesterase 5

P

Cellular effects


Tail-cuff pressure agentes anti-hipertensivos.

mmHg

Weeks

Basic Res Cardiol 91, 1996


Classification
Classification agentes anti-hipertensivos.

+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 agentes anti-hipertensivos.

  • 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 L-NAME-induced hypertension

100

75

%

50

25

0

8w

  • L-NAME

  • Enalapril

EPJ 287, 1995


No hypertension
NO hypertension L-NAME-induced 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


- NO and cGMP are involved in vasodilatation mechanism; L-NAME-induced hypertension

- 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)


HO L-NAME-induced hypertension

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


Coronary blood flow L-NAME-induced hypertension

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 L-NAME-induced hypertension

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) L-NAME-induced hypertension

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 L-NAME-induced 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


Aims L-NAME-induced hypertension

“ 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.”


Structure bay 41 2272

N L-NAME-induced hypertension

N

F

N

N

N

NH2

STRUCTURE BAY 41-2272


Methods L-NAME-induced hypertension

  • 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.


Animal groups L-NAME-induced hypertension

- 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)


Effect of L-NAME-induced hypertensionBAY 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.


L-NAME + L-NAME-induced hypertension

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.


L-NAME-induced hypertension

Left Ventricle Photomicrography

 - area of repairing fibrosis


Conclusion L-NAME-induced hypertension

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


Sildenafil L-NAME-induced hypertension

(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


0 L-NAME-induced hypertension

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


Conclusão L-NAME-induced hypertension

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


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