Endothelial regulation: Understanding RAS Content Points: There are 2 renin-angiotensin systems (RASs) that regulate endothelial function.6,7 The system illustrated in the slide is the classic or circulating RAS. The RAS is thought to be responsible for acute BP regulation. The first step in regulation occurs in the kidneys. When the volume or flow of blood through the kidneys changes, cells within the kidneys detect the change and release renin. Sodium or volume depletion, shock, hemorrhage, heart failure or renal damage can change flow or volume of blood. This leads to conversion of angiotensinogen to angiotensin I (A I) and, with the help of angiotensin-converting enzyme (ACE), A I is converted to A II. A II is a potent vasoconstrictor and thus raises BP to compensate for the decrease in blood volume or flow. This increase in flow or volume then decreases renin production through a feedback mechanism.8

Circulating vs tissue ACE Content Points: Only about 10% of the ACE in the body circulates in the plasma. As shown in the previous slide, the circulating ACE is responsible for acute BP changes. Approximately 90% of the ACE is found in tissues: for example, blood vessels, the heart, and the central nervous system.9,10,11 In this system circulating or local A I is converted to A II by local ACE. This local production of A II by vascular ACE is thought to be involved in vascular and cardiac structure and function over the long term.6,7,12,13

Circulating and tissue RAS influence cardiovascular system Content Points: The circulating endocrine RAS has both short-term and long-term effects on the CV system.12 Short-term effects include facilitating sodium and water reabsorption, blood vessel constriction, positive chronotropic effects and arrhythmogenic effects. The hemodynamic effects of the circulating RAS increase BP. It is believed that the circulating RAS is activated during CV compensation, including dehydration, hemorrhage, and heart failure. Long-term changes in vascular tone are caused by tissue RAS that creates changes in vascular structure and function. These effects are involved in the pathophysiology of hypertension, vascular disease, and heart failure

Vasculoprotective effects of tissue ACE inhibition Content Points: Inhibition of ACE results in a decrease in A II levels and an increase in bradykinin levels. Elevation of bradykinin levels facilitates release of NO, which leads to relaxation of smooth muscle around blood vessels.14 ACE inhibition appears to improve endothelial function by a variety of mechanisms including: reducing vascular smooth muscle growth and cell migration, decreasing platelet aggregation and PAI-1 levels, inhibiting matrix synthesis, and increasing t-PA levels.

Role of angiotensin II in atherogenesis Content Points: A number of studies indicate that A II plays a role in atherogenesis. Several conditions such as hypertension, dyslipidemia, and elevated insulin levels lead to endothelial dysfunction that seems to be at least partially mediated by A II.15,16 A II is an influential factor in hypertension. It causes an increase in vascular wall thickness by facilitating smooth muscle proliferation.17,18

ACE inhibitors and fibrinolysis Content Points: The RAS19 works with the fibrinolytic system to maintain a smoothly functioning CV system.20 Bradykinin increases t-PA and decreases PAI-1. This action promotes breakdown of fibrin. A II has the opposite function. It is logical that ACE inhibitors may regulate the fibrinolytic system since they alter the RAS. The action of the ACE inhibitors to elevate bradykinin levels and decrease A II levels could be expected to promote higher levels of t-PA and thus fibrinolysis.

The fibrinolytic system Content Points: In a healthy individual, plasminogen activators facilitate the breakdown of plasminogen to plasmin. Plasmin is essential for the breakdown of fibrin into fibrin degradation products.20 To balance the effects of plasminogen activators, PAI-1 inhibits the degradation of plasminogen. Another inhibitor, antiplasmin, halts the breakdown of fibrin. Maintenance of the balance prevents hemorrhage or thrombus formation.

Regulation of fibrinolysis: Fundamental contributions of balance between t-PA and PAI-1 Content Points: In health, the fibrinolytic system maintains a delicate balance. The viscosity of blood is regulated by plasminogen activators, such as t-PA, on the one hand and by plasminogen activator inhibitors, such as PAI-1, on the other hand. Both are produced by a variety of cell types including endothelial cells.21 Clot lysis is mediated by t-PA. In a healthy individual this prevents formation of a thrombus but excessive quantities of t-PA lead to hemorrhage. Clot formation is facilitated by PAI-1, which prevents hemorrhage in the normal state. Elevated levels of PAI-1 contribute to thrombus formation.