Review: AT 1-receptor blockade in experimental myocardial ischaemia/reperfusion

(1)

Journal of the Renin- Angiotensin-Aldosterone System

(Including other peptidergic systems)

March 2001 Volume 2

AT

1

-receptor blockade in experimental myocardial

ischaemia/reperfusion

Rainer Schulz, Gerd Heusch

Keywords: renin-angiotensin-aldosterone system, AT1-receptor,

AT2-receptor,

myocardial ischaemia, reperfusion

Abteilung für Pathophysiologie, Zentrum für Innere Medizin des Universitätsklinikums Essen,

Germany

Correspondence to: Professor Gerd Heusch Abteilung für Pathophysiologie, Zentrum für Innere Medizin,

Universitätsklinikum Essen,

Hufelandstraße 55, 45122 Essen, Federal Republic of Germany,

Tel: +49 201 723 4480 Fax: +49 201 723 4481 E-mail: gerd.heusch@ uni-essen.de

JRAAS2001;2

(suppl 1):S136-S140

Introduction

The renin-angiotensin-aldosterone system (RAAS)

is activated during myocardial ischaemia, and

angiotensin II (Ang II) is formed locally in

ischaemic hearts. At least two Ang II receptor

subtypes, the AT

1

- and the AT

2

-receptor, have been

identified. AT

1

-receptor blockade, like

angiotensin-converting enzyme (ACE) inhibition, limits infarct

size, improves functional recovery following

myocardial ischaemia and attenuates ventricular

remodelling post-myocardial infarction (MI) and

the resulting development of heart failure. The

potential mechanisms responsible for the

cardio-protection by AT

1

-receptor blockade remain to be

elucidated in detail, but appear to involve AT

2

-receptor activation and, like ACE inhibitors

(ACE-I), bradykinin potentiation. Combined treatment

with ACE-I and AT

1

-receptor blockers reduces

infarct size and improves fractional shortening of

myocytes from failing hearts more than either

monotherapy alone.

Renin-angiotensin system (RAS) in

myocardial ischaemia

Angiotensinogen and renin are secreted into the

circulation by the liver and kidney, respectively. The

decapeptide angiotensin I (Ang I), the product of

the renin-angiotensinogen reaction, is cleaved by

ACE in blood and endothelial cells, especially in the

lungs, to the vasoactive octapeptide, Ang II.

1

_Apart

from the systemic RAAS there is a local cardiac

renin-angiotensin system (RAS).

2,3

_{All RAS}

compo-nents are present in cardiac tissue, and both Ang I

and II are generated in the heart.

4

_{However, the}

renin for local cardiac angiotensin production

probably originates from the circulating pool.

4

The systemic RAS is activated in dogs

5

_and

patients

6

_{with acute MI, and local Ang II formation}

occurs in ischaemic canine hearts.

7

_{In addition to}

formation by ACE, chymase in human hearts

8

_{and a}

chymase-like protease in canine hearts,

7

_largely

contribute to cardiac Ang II formation.

9

_Apart

from the formation of Ang II, ACE is also

responsi-ble for the degradation of kinins; following ACE

inhibition, the concentration of kinins,

50

_{such as}

bradykinin, is increased.

10

At least two Ang II receptor subtypes, the AT

1

-and the AT

2

-receptor, have been identified. All the

cardiovascular effects of Ang II, i.e. vasoconstriction,

positive inotropy, cardiac hypertrophy,

noradrena-line and aldosterone release and renal sodium

reab-sorption, have been attributed to activation of the

AT

1

-receptor.

11,12

Despite its molecular

identifica-tion,

13

_{the physiological role of the AT}

2

-receptor

remains to be established in detail. Following AT

1

-receptor blockade, intravenous Ang II infusion

decreases mean arterial pressure; this decrease is

completely abolished by additional AT

₂

-receptor

blockade.

14

_{Mice lacking the AT}

2

-receptor have

increased vasoconstrictor responses during Ang II

infusion,

15

_{and their ACE activity is increased.}

16

_In

resting, non-stimulated coronary endothelial cells

from spontaneously hypertensive rats, Ang II

induces cell proliferation only following AT

₂

-receptor blockade.

17

_{Ang II inhibits endothelial cell}

proliferation following foetal growth factor (FGF)

stimulation; this effect is also abolished following

blockade of AT

₂

-receptors.

17

_{Thus, the AT}

2

-receptor

appears to counteract the effects of AT

1

-receptor

activation, in that it induces vasodilation and

inhibits cell proliferation. Blockade of the AT

1

-receptor increases Ang II concentrations through

feed-back disinhibition,

18

_{possibly leading to}

increased activation of the AT

₂

-receptor.

19,20

_AT

2

-receptor activation, in turn, increases nitric oxide

(NO) release

21,22

_{and cyclic guanosine}

3',5'-monophosphate formation;

20,22

_{these effects of AT}

1

-receptor blockade are abolished by blockade of

the bradykinin B

2

-receptor.

20,21

Activation of the

bradykinin B

₂

-receptor is known to mediate

coronary vasodilation

23

_{and infarct size reduction.}

24

Effects of AT

1

-receptor blockade on

reversible contractile dysfunction following

myocardial ischaemia (myocardial ‘stunning’)

The data from studies on myocardial stunning

with AT

1

-receptor blockade are controversial.

Pretreatment with the AT

₁

-receptor blocker

L-158338

25

_{or losartan}

26

_{increased coronary flow}

and cardiac output following 20 minutes global

ischaemia in isolated working rat hearts. In

addition, when added to the perfusate in isolated

rat hearts, losartan increased coronary flow, the

maximum of the first derivative of the left

ven-tricular pressure (dP/dt

max

) and peak systolic

pressure, following 60 minutes global ischaemia.

27

In contrast, however, losartan, when added to the

perfusate, did not improve the recovery of left

ventricular work following 30 minutes global

ischaemia in isolated rat hearts

28

_{and following 15}

minutes global ischaemia in isolated guinea pig

hearts.

29

_{Apart from different doses and time of}

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March 2001 Volume 2

In vivo, in anaesthetised open-chest dogs,

sub-jected to 15 minutes occlusion of the left

circum-flex coronary artery and 4 hours subsequent

reper-fusion, pretreatment with the AT

1

-receptor blocker,

candesartan, improved the functional recovery of

reperfused myocardium. After 4 hours of

reperfu-sion, systolic wall thickening was still depressed in

placebo-treated dogs (–1.5±3.4% vs. 17.7±5.6%

during control conditions, p<0.05), whereas it had

recovered in candesartan-treated dogs (11.4±3.7%

at 4 hours reperfusion vs. 18.3±2.7 during control

conditions, NS, p<0.05

vs. placebo-treated dogs).

This attenuation of myocardial stunning was not

based on more favourable systemic

haemodynam-ics or regional myocardial blood flow.

30

ACE-I also attenuate myocardial stunning,

1,31,32

these beneficial effects being mediated in dogs by

bradykinin and prostaglandins, but not by NO.

32

Supporting the concept that prostaglandins are

important in attenuating myocardial stunning,

stimulation of endogenous prostacyclin synthesis

also improves the post-ischaemic recovery of

myocardial contractile function in pigs.

33

Effects of AT

1

-receptor blockade on MI

Pretreatment with the AT

₁

-receptor blocker,

can-desartan, decreased the no-flow area

34

_{and creatine}

kinase release

35,36

_{during reperfusion following}

25–30 minutes global ischaemia in isolated rat hearts

(Table 1).

37,38

_{Losartan, when added to the perfusate,}

did not generally decrease creatine kinase release

during reperfusion

36

_{or infarct size}

39-41

_{in isolated rat}

or rabbit hearts following 25–30-minute ischaemia,

except in one study, in which creatine kinase

Table 1 Effects of AT1-receptor antagonists on cardiac ischaemia/reperfusion.37,38

Reference Model Occlusion Reperfusion AT1-receptor Treatment Creatine Creatine

antagonist started kinase kinase

placebo

35 Isolated rat 30 min global 30 min Candesartan 7 days prior <10 U* 25 U

heart (1 mg/kg) oral to ischaemia

27 Isolated rat 60 min global 30 min Losartan Prior to ischaemia 41 U* 73 U

heart (31°C) (182 mM)

36 Isolated rat 25 min global 45 min Candesartan Prior to ischaemia 29 U* 48 U

heart (10 nM)

36 Isolated rat 25 min global 45 min Losartan Prior to ischaemia 41 U 48 U

heart (3 µM)

Reference Model Occlusion Reperfusion AT1-receptor Treatment Infarct Infarct size

antagonist started size placebo

38 Isolated 30 min global 120 min Losartan Prior to ischaemia 25% 31%

rabbit heart (10 µM)

39 Isolated 40 min global 60 min Losartan Prior to ischaemia 29% 26%

rabbit heart (1 µM)

45 Rat in situ 30 min 120 min Losartan Prior to reperfusion 74% 79%

(10 mg/kg)

46 Rat in situ Permanent Losartan Prior to ischaemia 57% 65%

(15 mg/kg) oral

48 Rat in situ Permanent Losartan 10 weeks prior 34%* 44%*

(40 mg/kg) oral to ischaemia

37 Rabbit in situ 30 min 120 min Losartan Prior to reperfusion 41% 52%

(10 mg/kg) i.v.

76 Rabbit in situ 30 min 60 min L-158809 Stopped 24 hr 54% 52%

(1 mg/kg) oral prior to ischaemia

47 Dog in situ 90 min 240 min EXP3174 Prior to ischaemia 50% 37%

(0.1 mg/kg) i.v.

77 Dog in situ 60 min 180 min Irbesartan Prior to ischaemia 24.8% 26.9%

(10 mg/kg)

49 Dog in situ 90 min 90 min Losartan 7 days prior 22%* 54%

(10-15 mg/kg) oral to ischaemia

50 Pig in situ 60 min 120 min EXP3174 Prior to ischaemia 35%* 71%

(1 mg/kg) i.v.

43 Pig in situ 90 min 120 min Candesartan Prior to ischaemia 10%* 22%

low-flow (1 mg/kg) i.v.

40 Pig in situ 45 min 240 min Candesartan 5 min prior 40/35%* 78%

(2 and 20 µg/kg) to reperfusion coronary sinus

retroinfusion

(40 µg/kg) i.v.

42 Pig in situ 45 min 240 min Candesartan Prior to ischaemia <60%* 80%

(20 µg/kg) i.v.

low-flow (1 mg/kg) i.v.

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March 2001 Volume 2 Supplement 1

release following 60-minute global hypothermic

ischaemia was significantly reduced.

27

_The

differ-ence between these studies relates to the dose of

losartan used, which was 10,000 times higher in

this latter study than in other studies.

In vivo, candesartan significantly reduced

infarct size following coronary occlusion

42-44

_or

low-flow ischaemia

45,46

_{in pigs. The mechanisms}

underlying the protective effects of candesartan

on infarct size involve a signal cascade of AT

2

-receptor and bradykinin B

2

-receptor activation

and prostaglandins.

45

_{Again, the AT}

1

-receptor

blocker, losartan or its active metabolite, EXP3174,

had no significant effect on infarct size in rats

47,48

or dogs.

49

_{Explanations for the failure to reduce}

infarct size are related to the time of application

(prior to reperfusion

47

_{), the duration of ischaemia}

(permanent occlusion

48

_{) or the dosages used.}

47-49

Pre-ischaemic treatment with high doses of

losartan or EXP3174 decreased infarct size in

rats,

50

_dogs

51

_{and pigs.}

52

Pretreatment with ACE-I reduced infarct size

following 60-minute coronary occlusion in pigs,

52

90-minute low-flow ischaemia in pigs

46

_and

fol-lowing 90-minute

7

_{and 6-hour}

24

_coronary

occlu-sion in dogs. Infarct size was also reduced

follow-ing 6-hour coronary occlusion in dogs when the

treatment started 30 minutes after the onset of

ischaemia,

5

_{and following 30-minute coronary}

occlusion in rats

47

_{and rabbits}

53,54

_{even when the}

treatment started before reperfusion. In contrast,

ACE-I did not reduce infarct size following 24-hour

coronary occlusion in dogs when the treatment

started 40 minutes

55

_{or 10 minutes}

56

_{after the onset}

of ischaemia. The beneficial effects of ACE-I on

infarct size are mediated by bradykinin in dogs

7,24

and rabbits,

53

_{by prostaglandins in rats}

47

_{and also}

by NO in rats

47

_{and rabbits.}

54

The reduction of infarct size by ACE-I

53

_{and AT}

1

-receptor blockers

45,57,58

_{is thus mediated through}

bradykinin.AT

1

-receptor blockers increase the

for-mation of bradykinin and ACE-I reduce bradykinin

breakdown. Indeed, combined treatment with the

ACE-I ramiprilat and the AT

1

-receptor blocker,

can-desartan, reduced infarct size for a given ischaemic

blood flow to a greater extent than either drug

alone

46

_{(Figure 1). Once again, the decrease in}

infarct size was prevented by HOE140 and was

thus mediated by bradykinin.

46

Effects of AT

1

-receptor blockade on

ventricular remodelling following MI

In rat hearts, AT

1

-receptor blockade with losartan,

when given 24 hours following the onset of

ischaemia, did not affect infarct size, but the area

surrounding the infarcted zone, as an estimate of

scar thinning, was significantly reduced after four

weeks of treatment with losartan.

59

In AT

1A

-receptor knockout mice, left

ventricu-lar dilatation, left ventricuventricu-lar dysfunction and

cardiac fibrosis in the non-infarcted area were less

than in wild-type mice at four weeks following

MI.

60,61

_{Similarly, pharmacological blockade of the}

AT

1

-receptor with L-158809 or candesartan

atten-uated the post-infarction increase in left

ventricu-lar end-diastolic volume.

19,62,63

_{In addition, the}

increase in left ventricular end-systolic volume

was attenuated and ejection fraction increased.

19

Moreover,AT

₁

-receptor blockade increased

myocar-dial capillary density,

64

_{and decreased}

cardiomy-ocyte size

19

_{and ventricular weight.}

62,63,65-67

_{In rats,}

the development of interstitial fibrosis after MI was

abolished by losartan,

19,64

_{but not by valsartan.}

66

The beneficial effects of AT

1

-receptor blockade

on ventricular remodelling were abolished by the

AT

2

-receptor blocker, PD 123319 and, similar to

the effects of the ACE-I ramipril in the same study,

by the bradykinin B

2

-receptor blocker, HOE140.

19

Increasing cardiac bradykinin levels, by

applica-tion of an ACE-I and a neutral endopeptidase

antagonist, also attenuated left ventricular

hyper-trophy following MI in rats;

68

_{the effect of}

combined treatment was greater than either

monotherapy alone.The importance of bradykinin

for the functional and structural preservation of

the heart was further strengthened by studies in

bradykinin B

₂

-receptor knockout mice in which

left ventricular dilatation and fibrosis, as well as

loss of contractile function during ageing, were

accelerated compared with wild-type mice.

69

As described in MI, combined administration

of an ACE-I and an AT

1

-receptor blocker improved

left ventricular myocyte shortening,

70

_increased

ventricular function and decreased

neurohormon-al activation

71,72

_{in pacing-induced heart failure in}

pigs; the improvement in myocyte shortening

with combined treatment was greater than with

either monotherapy alone.

70

Clinical perspective

With respect to the infarct size reduction

Figure 1 Relationships between subendocardial blood flow at 5-minute ischaemia and infarct size in pigs. Subendocardial blood flow correlated inversely to infarct size in all groups of pigs. Infarct size for any given subendocardial blood flow was significantly reduced in pigs receiving ramiprilat (y=–212.6 y+20,7, n=10, r=–0.79) and candesartan (y=–276.9 y+24.5, n=10, r=–0.79) compared with placebo (y=–392.4 y+40.0, n=10, r=–0.94, p<0.05).The relationship between subendocardial blood flow and infarct size with combined drugs (y=–137.4 y+12.8, n=10, r=–0.71) was further shifted downwards and different from the relationships of all other groups (p≤0.05).Adapted from Weidenbach et al.44

Placebo Ramiprilat Candesartan

Ramiprilat + Candesartan p<0.05 vs_{. placebo}

p<0.05 vs. Ramiprilat or Candesartan

Infar

ct size (% ar

ea at risk)

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March 2001 Volume 2

provided by ACE-I, AT

1

-receptor blockers or

combined treatment with ACE-I and AT

₁

-receptor

blockers that has been demonstrated in pigs,

patients undergoing treatment with these drugs

for indications such as hypertension and post-MI

ventricular dilatation may also benefit from

improved prognosis in the event of an acute MI.

In pacing-induced heart failure in pigs,

combined ACE inhibition and AT

1

-receptor

blockade improves ventricular function and

myocardial blood flow and decreases

neurohor-monal activation.

71,72

_{In patients with heart failure,}

ACE-I

73,74

_{and AT}

1

-receptor blockers

75,76

reduce

mor-bidity and mortality. Again, the combined use of

ACE-I and AT

1

-receptor blockers appears to be

more beneficial in preventing left ventricular

dilatation and suppressing neurohormonal

activa-tion than ACE-I alone.

77

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