This review summarizes some basic properties and distribution of angiotensin I converting enzyme (ACE). ACE is one of several biologically important ectoproteins that exists in both membrane-bound and soluble forms. Localized on the surface of various cells, ACE is inserted at the cell membrane via its carboxyl terminus. Human plasma ACE originates from endothelial cells while other body fluids may contain ACE that originates from epithelial, endothelial or germinal cells. The two isoforms of ACE, the two-domain somatic form and the single domain germinal form, convert angiotensin I to angiotensin II, and metabolize kinins and many other biologically active peptides, including substance P, chemotactic peptide and opioid peptides. The broad spectrum of substrates for ACE and its wide distribution throughout the body indicates that this enzyme, in addition to an important role in cardiovascular homeostasis, may be involved in additional physiologic processes such as neovascularization, fertilization, atherosclerosis, kidney and lung fibrosis, myocardial hypertrophy, inflammation and wound healing. Future research should explore the possible functions of tissue ACE and its systemic role as a pressor agent. ACE inhibitors have achieved widespread use in the treatment of hypertension and the protection of end-organ damage in cardiovascular and renal diseases. Potential problems related to side effects and compliance of such therapy need to be addressed. A safer way of producing therapeutic effects is promised by the delivery of the ACE antisense sequences by a vector producing a permanent inhibition of ACE and long-term control of blood pressure in hypertensive patients.

Adult male Sprague-Dawley rats were irradiated to the right hemithorax with a range of total doses delivered in 10 equal daily fractions of 4 MeV X rays. Half of each dose group consumed control feed, and half consumed feed containing the angiotensin-converting enzyme inhibitor captopril (50 mg/kg/day) continuously after the last irradiation. High-resolution computed tomography (CT) of the entire thorax was performed at 4 and 8 weeks after the last irradiation, and the findings with CT were correlated with hemodynamic data, heart weight, and pulmonary histopathology. Rats exposed to 20 or 40 Gy in 10 fractions exhibited no acute changes in right lung density. After 60 Gy in 10 fractions, however, right lung density in rats on the control diet increased significantly at 4 weeks, and then returned to normal at 8 weeks. Captopril-treated rats exposed to 60 Gy/10 fractions did not exhibit this transient increase in right lung density. After 80 Gy/10 fractions, right lung density increased to 0.60-0.65 g/cm3 at 4 weeks regardless of diet. At 8 weeks after 80 Gy/10 fractions, right lung density increased further in rats given the control diet, but decreased to near normal levels in captopril-treated animals. The density of the shielded left lung based on the CT was independent of both contralateral radiation dose and diet. Histological examination of the irradiated lungs indicated that these acute changes detected by CT were associated with the exudative and edematous phases of radiation pneumonitis, and that captopril reduced the severity of these changes. Irradiated (40-80 Gy/10 fractions) animals fed the control diet exhibited a significant increase in central venous and pulmonary artery pressure, and cardiac right ventricular hypertrophy. Captopril prevented or attenuated these hypertensive reactions. These data demonstrate that high-resolution CT can detect radiation reactions in rat lung within 4 weeks after 60 Gy/10 fractions, and that captopril spares these acute changes detected by CT. The mechanism of captopril action is not clear, but may be due in part to a reduction in pulmonary arterial pressure, resulting in less severe edema in the irradiated lung.

Beneficial effects of angiotensin converting enzyme inhibitors (ACEI) and angiotensin type 1 receptor (AT1) blockers in patients with cardiovascular and renal diseases have been clearly demonstrated in numerous large outcomes studies. In patients with heart failure (HF), ACEI have been shown to reduce overall mortality, mortality from cardiovascular causes, to increase life expectancy, as well as to preserve the renal function (CONSENSUS, SAVE, TRACE, AIRE, AIREX, CATS trials). In addition, in the PROGRESS study ACEI substantially decreased the risk of stroke and transient ischemic attacks in patients with cerebrovascular disorders. The HOPE and EUROPA studies confirmed that long term therapy with ACEI provides significant survival benefit in patients with broad range of atherosclerotic cardiovascular diseases. After these large and well designed clinical studies, ACEI have become standard therapy for routine secondary prevention in all patients with cardiovascular diseases, unless contraindicated. AT1 receptor blockers have been recently added to the cardiovascular therapeutic armamentarium. They are believed to provide additional protection by inhibition of locally synthesized angiotensin II on the level of AT1 receptor. The ELITE II, ValHeFT and CHARM studies have shown that AT1 receptor blockers are equally effective as ACEI in reduction of mortality and morbidity in patients with HF. Importantly, they may be used together with ACEI, or as alternative treatment in ACEI intolerant patients. Renal protection is another important effect of both ACEI and AT1 blockers that has been confirmed in several large clinical trials. The North American Microalbuminemia Study group and EUCLID group demonstrated significant reduction in progression of diabetic nephropathy in patients with insulin dependent diabetes mellitus (IDDM) treated with ACEI. AT1 receptor blockers are mainly studied in the non-insulin dependent diabetes mellitus (NIDDM) nephropathy. Four recent clinical trials (IRMA-2, DETAIL, RENAAL and IDNT) examined the effect of AT1 receptor blockers in patients with NIDDM nephropathy. These studies confirmed the beneficial effect of AT1 receptor blockers in patients with NIDDM nephropathy that was extended beyond the blood pressure reduction. Ongoing studies (ONTARGET, TRANSCEND and PROTECTION) should provide us with additional insights about cardiovascular, renal and other end-organ protective effects of these therapeutics.

This review summarizes physiology of circulating and local renin-angiotensin system (RAS), enzymatic properties and mechanism of action of angiotensin I converting enzyme inhibitors (ACEIs) on RAS, and implications of ACEIs in anesthetic management of patients treated with these drugs. ACEIs, through their effect on RAS, may improve cardiovascular functions, pulmonary dynamics, and body fluid homeostasis. Thus, ACEIs have become an integral part of management of patients with hypertension, congestive heart failure (CHF) and chronic renal disease. ACEIs, due to differences in their chemical structure, exert different pharmacological actions and can have protective or occasional damaging effects on different organs. The anesthesiologists are commonly involved in the management of patients treated with ACEIs. Thus, the role of ACEIs and their possible interaction with anesthetic agents must be an integral part of clinical decision-making during anesthesia Hemodynamic variation during anesthesia is mainly related to specific effects of anesthetic agents on sympathetic nervous system. Those with preoperative fasting, volume depletion and extended sympathetic blockade can have reduced vascular capacitance resulting in decreased venous return, reduced cardiac output and severe arterial hypotension. Angiotensin II (ANG2) a potent vasoconstrictor may counterbalance such hypotensive effect. During ACE inhibition ANG2 cannot counterbalance this hypotension. Thus, induction of anesthesia may cause severe hypotension in hypovolemic patients specifically in those receiving diuretics as a complement to ACEIs. Recent advances in RAS and the pharmacology of ACEIs have identified some predisposing factors and risks associated with anesthesia in patients treated with ACEIs. Practitioners should be vigilant, and readily have vasopressors, necessary fluids and other resuscitative measures for treatment of unexpected hemodynamic instability during anesthesia and surgery.

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