Vasoconstriction.

Angiotensin II is a powerful vasoconstrictor. The compound acts directly on vascular smooth muscle (VSM) to cause contraction. Vasoconstriction is prominent in arterioles and less so in veins. As a result of angiotensin-induced vasoconstriction, blood pressure rises. In addition to its direct action on blood vessels, angiotensin II can cause vasoconstriction indirectly by acting on (1) sympathetic neurons to promote norepinephrine release, (2) the adrenal medulla to promote epinephrine release, and (3) the central nervous system to increase sympathetic outflow to blood vessels.

Release of aldosterone.

Angiotensin II acts on the adrenal cortex to promote synthesis and secretion of aldosterone, whose actions are discussed below. The adrenal cortex is highly sensitive to angiotensin II, and hence angiotensin II can stimulate aldosterone release even when angiotensin II levels are too low to induce vasoconstriction. Aldosterone secretion is enhanced when sodium levels are low and when potassium levels are high.

Alteration of cardiac and vascular structure.

Angiotensin II may cause pathologic structural changes in the heart and blood vessels. In the heart, it may cause hypertrophy (increased cardiac mass) and remodeling (redistribution of mass within the heart). In hypertension, angiotensin II may be responsible for increasing the thickness of blood vessel walls. In atherosclerosis, it may be responsible for thickening the intimal surface of blood vessels. And in heart failure and myocardial infarction, it may be responsible for causing cardiac hypertrophy and fibrosis. Known effects of angiotensin II that could underlie these pathologic changes include

Regulation of blood volume and blood pressure.

After being released from the adrenal cortex, aldosterone acts on distal tubules of the kidney to cause retention of sodium and excretion of potassium and hydrogen. Because retention of sodium causes water to be retained as well, aldosterone increases blood volume, which causes blood pressure to rise.

Pathologic cardiovascular effects.

Until recently, knowledge of aldosterone’s actions was limited to effects on the kidney. Now, however, we know that aldosterone can cause more harmful effects. Like angiotensin II, aldosterone can promote cardiac remodeling and fibrosis. In addition, aldosterone can activate the sympathetic nervous system and suppress uptake of norepinephrine in the heart, thereby predisposing the heart to dysrhythmias. Also, aldosterone can promote vascular fibrosis (which decreases arterial compliance) and it can disrupt the baroreceptor reflex. These adverse effects appear to be limited to states such as heart failure, in which levels of aldosterone can be extremely high.

Regulation of renin release.

Since renin catalyzes the rate-limiting step in angiotensin II formation, and since renin must be released into the blood in order to act, the factors that regulate renin release regulate the rate of angiotensin II formation.

As indicated in Figure 44–1, release of renin can be triggered by multiple factors. Release increases in response to a decline in blood pressure, blood volume, plasma sodium content, or renal perfusion pressure. Reduced renal perfusion pressure is an especially important stimulus for renin release, and can occur in response to (1) stenosis of the renal arteries, (2) reduced systemic blood pressure, and (3) reduced plasma volume (brought on by dehydration, hemorrhage, or chronic sodium depletion). For the most part, these factors increase renin release through effects exerted locally in the kidney. However, some of these factors may also promote renin release through activation of the sympathetic nervous system. (Sympathetic nerves increase secretion of renin by causing stimulation of beta₁-adrenergic receptors on juxtaglomerular cells.)

Release of renin is suppressed by factors opposite to those that cause release. That is, renin secretion is inhibited by elevation of blood pressure, blood volume, and plasma sodium content. Hence, as blood pressure, blood volume, and plasma sodium content increase in response to renin release, further release of renin is suppressed. In this regard, we can view release of renin as being regulated by a classic negative feedback loop.

Hypertension.

All ACE inhibitors are approved for hypertension. These drugs are especially effective against malignant hypertension and hypertension secondary to renal arterial stenosis. They are also useful against essential hypertension of mild to moderate intensity—although maximal benefits may take several weeks to develop.

In patients with essential hypertension, the mechanism underlying blood pressure reduction is not fully understood. Initial responses are proportional to circulating angiotensin II levels and are clearly related to reduced formation of that compound. (By lowering angiotensin II levels, ACE inhibitors dilate blood vessels and reduce blood volume; both actions help lower blood pressure.) However, with prolonged therapy, blood pressure often undergoes additional decline. During this phase, there is no correspondence between reductions in blood pressure and reductions in circulating angiotensin II. It may be that the delayed response is due to reductions in local angiotensin II levels—reductions that would not be revealed by measuring angiotensin II in the blood.

ACE inhibitors offer several advantages over most other antihypertensive drugs. In contrast to the sympatholytic agents, ACE inhibitors do not interfere with cardiovascular reflexes. Hence, exercise capacity is not impaired and orthostatic hypotension is minimal. In addition, these drugs can be used safely in patients with bronchial asthma, a condition that precludes the use of beta₂-adrenergic antagonists. ACE inhibitors do not promote hypokalemia, hyperuricemia, or hyperglycemia—side effects seen with thiazide diuretics. Furthermore, they do not induce lethargy, weakness, or sexual dysfunction—responses that are common with other antihypertensive agents. Most importantly, ACE inhibitors reduce the risk of cardiovascular mortality caused by hypertension. The only other drugs proved to reduce hypertension-associated mortality are beta blockers and diuretics (see Chapter 47).

Heart failure.

ACE inhibitors produce multiple benefits in heart failure. By lowering arteriolar tone, these drugs improve regional blood flow, and, by reducing cardiac afterload, they increase cardiac output. By causing venous dilation, they reduce pulmonary congestion and peripheral edema. By dilating blood vessels in the kidney, they increase renal blood flow, and thereby promote excretion of sodium and water. This loss of fluid has two beneficial effects: (1) it helps reduce edema and (2) by lowering blood volume, it decreases venous return to the heart, and thereby reduces right-heart size. Lastly, by suppressing aldosterone and reducing local production of angiotensin II in the heart, ACE inhibitors may prevent or reverse pathologic changes in cardiac structure. Although only seven ACE inhibitors are approved for heart failure (see Table 44–1), both the American Heart Association and the American College of Cardiology have concluded that the ability to improve symptoms and prolong survival is a class effect. The use of ACE inhibitors in heart failure is discussed further in Chapter 48.

Myocardial infarction.

ACE inhibitors can reduce mortality following acute MI (heart attack). In addition, they decrease the chance of developing overt heart failure. Treatment should begin as soon as possible after infarction and should continue for at least 6 weeks. In patients who develop overt heart failure, treatment should continue long term. As for patients who do not develop heart failure, there are no data to indicate whether continued treatment would be beneficial or not. At this time, only three ACE inhibitors—captopril, lisinopril, and trandolapril—are approved for patients with MI.

Diabetic and nondiabetic nephropathy.

ACE inhibitors can benefit patients with diabetic nephropathy, the leading cause of end-stage renal disease in the United States. In patients with overt nephropathy, as indicated by proteinuria of more than 500 mg/day, ACE inhibitors can slow progression of renal disease. In patients with less advanced nephropathy (30 to 300 mg proteinuria/day), ACE inhibitors can delay onset of overt nephropathy. These benefits were first demonstrated in patients with type 1 diabetes (insulin-dependent diabetes mellitus) and were later demonstrated in patients with type 2 diabetes (non–insulin-dependent diabetes mellitus). More recently, ACE inhibitors have been shown to provide similar benefits in patients with nephropathy unrelated to diabetes.

The principal protective mechanism appears to be reduction of glomerular filtration pressure. ACE inhibitors lower filtration pressure by reducing levels of angiotensin II, a compound that can raise filtration pressure by two mechanisms. First, angiotensin II raises systemic blood pressure, which raises pressure in the afferent arteriole of the glomerulus (Fig. 44–3). Second, it constricts the efferent arteriole, thereby generating back-pressure in the glomerulus. The resultant increase in filtration pressure promotes injury. By reducing levels of angiotensin II, ACE inhibitors lower glomerular filtration pressure, and thereby slow development of renal injury.

At this time, the only ACE inhibitor approved for nephropathy is captopril. However, the American Diabetes Association considers benefits in diabetic nephropathy to be a class effect, and hence recommends choosing an ACE inhibitor based on its cost and likelihood of patient adherence.

Can ACE inhibitors be used for primary prevention of diabetic nephropathy? No. This conclusion is based on the Renin-Angiotensin System Study (RASS), which evaluated the effects of an ACE inhibitor—enalapril [Vasotec]—and an ARB—losartan [Cozaar]—in patients with type 1 diabetes who did not have hypertension or any signs of early kidney disease. The result? Both drugs failed to protect the kidney: Compared with patients receiving placebo, those receiving enalapril or losartan developed the same degree of microalbuminuria (an early sign of kidney damage), the same decline in kidney function, and the same changes in glomerular structure (as shown by microscopic analysis of kidney biopsy samples). Hence, although ACE inhibitors may slow progression of established nephropathy, they do not protect against early kidney damage.

Prevention of MI, stroke, and death in patients at high cardiovascular risk.

One ACE inhibitor—ramipril [Altace]—is approved for reducing the risk of MI, stroke, and death (from cardiovascular causes) in patients at high risk for a major cardiovascular event—high risk being defined by (1) a history of stroke, coronary artery disease, peripheral vascular disease, or diabetes, combined with (2) at least one other risk factor, such as hypertension, high LDL cholesterol, low HDL cholesterol, or cigarette smoking. Ramipril was approved for this use based on results of the Heart Outcomes Prevention Evaluation (HOPE) trial, a large study in which patients at high cardiovascular risk took either ramipril (10 mg/day) or placebo. Follow-up time was 5 years. The result? The combined endpoint of MI, stroke, or death from cardiovascular causes was significantly lower in the ramipril group (14% vs. 18%)—a 22% reduction in risk. Possible mechanisms underlying benefits include reduced vascular resistance and protection of the heart, blood vessels, and kidneys from the damage that angiotensin II and aldosterone can cause over time.

Like ramipril, perindopril [Aceon, Coversyl] can reduce morbidity and mortality in patients at risk for major cardiovascular events. However, the drug is not yet approved for this use. Benefits were demonstrated in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA). Patients in EUROPA were at lower risk than those in HOPE.

Can ACE inhibitors other than ramipril and perindopril also reduce cardiovascular risk? Possibly. However, at this time there is insufficient evidence to say for sure.

Diabetic retinopathy.

The RASS trial showed that at least one ACE inhibitor—enalapril—can reduce the risk of diabetic retinopathy in some patients. Specifically, in patients with type 1 diabetes, who do not have hypertension, nephropathy, or established retinopathy, enalapril prevented or slowed development of retinal change. However, in patients with type 1 diabetes and established retinopathy, enalapril had no benefit. In patients with type 2 diabetes, enalapril had no benefit, regardless of retinopathy status.