of activating these pathways, two potent natural vasoconstrictors are released into the circulation: norepinephrine and angiotensin II (AII). These hormones bind to receptors in arterioles and veins, where they cause vascular smooth muscle contraction. Initially, such vasoconstriction is beneficial in heart failure because it maximizes left ventricular preload (increased venous tone enhances venous return) and helps to maintain systemic blood pressure (because of arterial constriction).
However, venous constriction may ultimately cause excessive venous return to the heart, with a rise in the pulmonary capillary hydrostatic pressure and development of pulmonary congestion. In addition, excessive arteriolar constriction increases the resistance against which the left ventricle must contract and therefore ultimately impedes forward cardiac output. Vasodilator therapy is directed at modulating the excessive constriction of veins and arterioles, thus reducing pulmonary c ongestion and augmenting forward cardiac output.
Vasodilators are also useful antihypertensive drugs. Recall from Chapter 13 that blood pressure is the product of cardiac output and total peripheral resistance (BP = CO X TPR). Vasodilator drugs decrease arteriolar resistance and therefore lower elevated blood pressure.
Individual vasodilator drug classes act at specifi c vascular sites. Nitrates, for example, are primarily venodilators, whereas hydralazine is a pure arteriolar dilator. Some drugs, such as the ACE inhibitors, b -blockers, sodium nitroprusside, and nesiritide, are balanced vasodilators that act on both sides of the circulation.
Angiotensin-Converting Enzyme Inhibitors
The renin–angiotensin system plays a critical role in cardiovascular homeostasis. The major effector of this pathway is AII, which is formed by the cleavage of angiotensin I by ACE. All the actions of AII known to affect blood pressure control are mediated by its binding to AII receptors of the angiotensin II type 1 (AT1) subtype. Interaction with this receptor generates a series of intracellular reactions that causes, among other effects, vasoconstriction and the adrenal release of aldosterone, which promotes Na reabsorption from the distal nephron. As a result of these actions on vascular tone and sodium homeostasis, AII plays a major role in blood pressure and blood volume regulation. By blocking the formation of AII, ACE inhibitors decrease the systemic arterial pressure, facilitate natriuresis (e.g., by decreasing aldosterone production and reducing Na reabsorption from the distal nephron), and reduce adverse ventricular remodeling.
Another action of ACE inhibitors, which likely contributes to their hemodynamic effects, is related to bradykinin (BK) metabolism. The natural vasodilator BK is normally degraded to inactive metabolites by ACE. Because ACE inhibitors impede that degradation, BK accumulates and contributes to the antihypertensive effect, likely by stimulating the endothelial release of nitric oxide and biosynthesis of vasodilating prostaglandins.
Clinical Uses
HypertensionIn hypertensive patients, ACE inhibitors lower blood pressure with little change in cardiac output
or heart rate. One might assume that because this class of drug interferes with the renin– angiotensin system, it would be effective only in patients with “high-renin” hypertension, but that is not the case. Rather, they are effective in most hypertensive patients, regardless of serum renin levels. The reason for this is not clear but may relate to the additional antihypertensive effects of BK and vasodilatory prostaglandins previously described. In addition, renin– angiotensin activity has been demonstrated within tissues outside the circulation, including the walls of the vasculature, where ACE inhibitors may exert a vasodilatory effect independent of the circulating renin concentration.
ACE inhibitors increase renal blood fl ow,
usually without altering the glomerular filtration rate (GFR), because of dilation of both the afferent and efferent glomerular arterioles. Used alone, ACE inhibitors show similar antihypertensive efficacy as diuretics and -blockers, but unlike the latter drugs, they do not adversely affect serum glucose or lipid
concentrations. ACE inhibitors are often recommended therapy in diabetic hypertensive patients, because the drugs slow the development of diabetic nephropathy (a syndrome of progressive renal deterioration, proteinuria, and hypertension) through favorable effects on intraglomerular pressure.
Heart Failure
In heart failure, ACE inhibitors reduce peripheral vascular resistance (decrease afterload), reduce cardiac fi lling pressures (decrease preload), and increase cardiac output. The rise in cardiac output usually matches the fall in peripheral resistance such that blood pressure tends not to fall (remember, BP = CO x TPR), except in patients with intravascular volume depletion as might result from overly vigorous diuretic therapy. The augmented cardiac output reduces the drive for compensatory neurohormonal stimulation in CHF, such that elevated levels of norepinephrine fall. In addition, clinical trials have shown that ACE inhibitors signifi cantly improve survival in patients with chronic heart failure and following myocardial infarction. Some studies have shown that ACE inhibition also reduces
the risk of myocardial infarction and death in patients with chronic vascular disease, including coronary artery disease (CAD), even if left ventricular function is not impaired. The primary excretory pathway of most of these agents is through the kidney, so their dosages should generally be reduced in patients with renal dysfunction.
Adverse Effects
HypotensionThis is a rare side effect when ACE inhibitors are used to treat hypertension. It is more likely to occur in heart failure patients in whom intravascular volume depletion has resulted from vigorous diuretic use. Such patients have significant activation of the renin–angiotensin system; therefore, blood pressure is largely maintained by the vasoconstricting actions of circulating AII. The administration of an ACE inhibitor in that setting may result in hypotension because of the sudden reduction of AII levels. This side effect is avoided by temporarily reducing the diuretic regimen and starting the ACE inhibitor at a low dosage.
Hyperkalemia
Because ACE inhibitors indirectly reduce the serum aldosterone concentration, the serum potassium concentration may rise, but only rarely into the clinically important hyperkalemic range. Conditions that can further increase serum potassium levels and may result in dangerous hyperkalemia during ACE
inhibitor use include renal insuffi ciency, diabetes (owing to hyporeninemic hypoaldosteronism, a condition often present in elderly diabetics), and concomitant use of potassium-sparing diuretics.
Renal Insufficiency
Administration of an ACE inhibitor to patients with intravascular volume depletion may result
in hypotension, decreased renal perfusion, and azotemia. Correction of volume depletion, or reduction of the ACE inhibitor dosage, usually corrects this complication.
ACE inhibitor therapy can also precipitate renal failure in patients with bilateral renal artery stenosis because such patients rely on high efferent glomerular arteriolar resistance (which is highly dependent on AII) to maintain intraglomerular pressure and filtration. Administering an ACE inhibitor abruptly decreases efferent arteriolar tone and glomerular hydrostatic pressure and may therefore worsen GFR in this setting.
Cough
Irritation of the upper airways resulting in a dry cough is reported in up to 20% of patients receiving ACE inhibitor therapy. Its mechanism has not been established but may relate to the
increased BK concentration provoked by ACE inhibitors. This side effect may last weeks after
the drug is discontinued.
Other Effects
Very rare adverse reactions to ACE inhibitors include angioedema and agranulocytosis. ACE
inhibitors should not be used in pregnancy because they have been shown to cause fetal injury.
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