Role of the Renin Angiotensin System

1
Role of the Renin Angiotensin System

• In SAVE, captopril was associated with 25
  reduction in risk for recurrent MI, 24 reduction
  n risk of death from cardiovascular events,
  severe heart failure, or MI
• In SOLVD, enalapril was associated with an 18
  reduction in risk of death from cardiovascular
  events, 28 reduction in risk of death from MI
• These benefits in the prevention of ischemic
  events cannot be explained easily or solely by
  the hemodynamic and cardioprotective effects of
  these agents
• The endothelium serves as the link between the
  fibrinolytic system and the RASMancini, G.B.,
  Role of Angiotensin-Converting Enzyme Inhibition
  in Reversal of Endothelial Dysfunction in
  Coronary Artery Disease, The American Journal
  of Medicine, vol. 105 (1A), July 6, 1998,
  pp.40S-47S Vaughan, D., Endothelial Function,
  Fibrinolysis, and Angiotensin-Converting Enzyme
  Inhibition, Clinical Cardiology, Nov., 1997,
  vol. 20 (Suppl. II), II-34-II-37.

2
Role of the Renin-Angiotensin System

• Pathophysiologic Effects of Ang II
• Expression of proliferative autocrine factors
  such as PDGF, bFGF and of antiproliferative
  factors, e.g TGFb1, leading to hypertrophy,
  hyperplasia
• Expression of endothelin - vasoconstriction
• Increased PAI-1 levels, favoring thrombosis
• Increased oxidative stress due to formation of
  free radical superoxide anion
• Stimulates NFkB

Pepine, C., et. al., Vascular Health as as
Therapeutic Target in Cardiovascular Disease,
Vascular Biology Working Group, University of
Florida, 1998 Gibbons, G., Vasculoprotective
and Cardioprotective Mechanisms of
Angiotensin-Converting Enzyme Inhibition The
Homeostatic Balance Between Angiotensin II and
Nitric Oxide, Clinical Cardiology, vol. 20
(Suppl. II), II-18-II-25 (1997).
3
Fibrinolysis RAS

• In human subjects, infusion of physiologic
  concentrations of angiotensin II resulted in
  rapid, dose-dependent, significant increases in
  PAI-1 levels without significant changes in TPA
  levels
• A recently identified angiotensin binding site,
  the angiotensin IV receptor (AT4) appears to be
  the receptor that mediates PAI-1 expression (Ang
  receptor blockers type 1 2 fail to prevent
  endothelial production of PAI-1
• In human subjects with HTN, graded doses of
  bradykinin were associated with dose-dependent
  increases in plasma TPA levels during concomitant
  ACE-I administration
• Bradykinin is a potent stimulus for release of TPA

Vaughan, D., Endothelial Function, Fibrinolysis,
and Angiotensin-Converting Enzyme Inhibition,
Clinical Cardiology, vol. 20 (Suppl. II),
II-34-II37 (1997).
4
Improvement in Endothelial Function with ACE-I

• Mechanism appears largely related to inhibition
  of kininase II of the kallikrein-kinin system
  which inactivates bradykinin
• Kinins (e.g., bradykinin) have a very short
  biological half-life because of proteolytic
  inactivation
• ACE inhibitors lead to the accumulation of kinin
  at the surface of the endothelium with an
  attendant increase in NO production via
  activation of the B2-kinin receptor and
  subsequent activation of eNOS (endothelial NO
  synthase)
• Potent vasodilator effects ensue
• ACE-I augments circulating levels of
  thevasodilator Angiotensin-(1-7)
• Several studies have reported a potentially
  important synergism between Ang-(1-7) and the
  kinin system with respect to vascular relaxation

Mancini, G.B., Role of Angiotensin-Converting
Enzyme Inhibition in Reversal of Endothelial
Dysfunction in Coronary Artery Disease, The
American Journal of Medicine, vol. 105 (1A), July
6, 1998, pp.40S-47SZhang, X., et. al., ACE
Inhibitors Promote Nitric Oxide Accumulation to
Modulate Myocardial Oxygen Consumption,
Circulation, vol. 95, no. 1, Jan 7, 1997, pp.
176-182Iyer, S., et. al., Angiotensin-(1-7)
Contributes to the Antihypertensive Effects of
Blockade of the Renin-Angiotensin System,
Hypertension, Suppl., vol. 31, no.1, part2, Jan.,
1998, pp. 356-361.
5
TREND Study

• 129 patients with documented CAD undergoing a
  nonsurgical revascularization procedure were
  randomized in double-blind manner to receive 6
  months of oral quinapril 40 mg or placebo once
  daily after baseline assessment of endothelial
  function
• Repeat angiography in 6 months with acetylcholine
  challenge study medication was stopped 3 days
  prior to angiography
• Endothelial dysfunction defined as either a
  definite constrictive response (gt/5 reduction
  in mean lumen diameter) or no response to
  acetylcholine (lt5 change in mean lumen diameter)

Mancini,G., et. al., Angiotensin-Converting
Enzyme Inhibition with Quinapril Improves
Endothelial Vasomotor Dysfunction in Patients
with Coronary Artery Disease, Circulation, vol.
94, no. 3, August 1, 1996, pp. 258- 265.