RAA System

ACE is a rather nonspecific peptidase that can cleave C-terminal dipeptides from various peptides (dipeptidyl carboxypeptidase). As kininase 11, it contributes to the inactivation of kinins, such as bradykinin. ACE is also present in blood plasma however, enzyme localized in the luminal side of vascular endothelium is primarily responsible for the formation of angiotensin 11. The lung is rich in ACE, but kidneys, heart, and other organs also contain the enzyme. 

Angiotensin 11 can raise blood pressure in different ways, including (1) vasoconstriction in both the arterial and venous limbs of the circulation (2) stimulation of aldosterone secretion, leading to increased renal reabsorption of NaCl and water, hence an increased blood volume (3) a central increase in sympathotonus and, peripherally, enhancement of the release and effects of norepinephrine. 

ACE inhibitors, such as captopril and enalaprilat, the active metabolite of enalapril, occupy the enzyme as false substrates. Affinity significantly influences efficacy and rate of elimination. 

Enalaprilat has a stronger and longer-Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

Lowering of an elevated blood pressure is predominantly brought about by diminished production of angiotensin 11. Impaired degradation of kinins that exert vasodilating actions may contribute to the effect 

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Renin-angiotensin-aldosterone (RAA) system (see also Chapter 8)... 

The other hormone of note synthesized by kidney is erythropoietin (EPO), a glycosylated peptide hormone (molecular weight approximately 50 000), which promotes red blood cell formation and is secreted in response to poor oxygen perfusion (hypoxia) of the kidney. This, along with the control of blood pressure via the RAA system illustrates the importance of the kidney in regulating aspects of the blood vascular system. Further details of EPO can be found in Chapter 5. 

Counter-regulation in acute hypotension due to vasodilators (B). Increased sympathetic drive raises heart rate (reflex tachycardia) and cardiac output and thus helps to elevate blood pressure. Patients experience palpitations. Activation of the renin-angioten-sin-aidosterone (RAA) system serves to increase blood volume, hence cardiac output. Fluid retention leads to an increase in body weight and, possibly, edemas. These counter-regulatory processes are susceptible to pharmacological inhibition ( 3-blockers, ACE inhibitors, ATI-antagonists, diuretics). 

Undesired effects. The magnitude of the antihypertensive effect of ACE inhibitors depends on the functional state of the RAA system. When the latter has been activated by loss of electrolytes and water (resulting from treatment with diuretic drugs), cardiac failure, or renal arterial stenosis, administration of ACE inhibitors may initially cause an excessive fall in blood pressure. In renal arterial stenosis, the RAA system may be needed for maintaining renal function and ACE inhibitors may precipitate renal failure. Dry cough is a fairly frequent side effect, possibly caused by reduced inactivation of kinins in the bronchial mucosa. Rarely, disturbances of taste sensation, exanthema, neutropenia, proteinuria, and angioneurotic edema may occur. In most cases, ACE inhibitors are well tolerated and effective. Newer analogues include lisinopril, perindo-pril, ramipril, quinapril, fosinopril, benazepril, cilazapril, and trandolapril. 

Adverse effects Renal function may deteriorate with the decreased circulating fluid volume, especially after the addition of another diuretic drug acting on the RAAS system, and careful monitoring of serum creatinine is essential. Serum potassium should be monitored within one week of initiation and at least every four weeks for the first three months and every three months thereafter. It should also be monitored at any dose change in spironolactone or if there is a change in concomitant medications that affects the potassium balance. The spironolactone dose (standard 25 mg per day) should be reduced if potassium levels are <5.4 mEq/L, and treatment should be discontinued if painful gynecomastia or serious renal dysfunction or hyperkalemia result. 

The natriuretic peptide family has three members, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP is stored mainly in the right atrium, whereas BNP is found mainly in the ventricles. Both are released in response to pressure or volume overload. CNP is found mainly in the brain and has very low plasma concentrations. ANP and BNP plasma concentrations are elevated in patients with heart failure and are thought to balance the effects of the RAA system by causing natriuresis, diuresis, vasodilation, decreased aldosterone release, decreased hypertrophy, and inhibition of the SNS and the RAA system. 

Activation of the SNS, the RAA system, AVP, and other mediators all cause vasoconstriction and increased SVR. In patients with heart failure, stroke volume varies inversely with SVR such that an increase in peripheral resistance leads to a severe decline in stroke volume and cardiac output (see Fig. 14—1). 

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