Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions‐parallels and contrasts.

Abstract

1 The emergence of diuretic drugs and angiotensin converting enzyme (ACE) inhibitors ranks amongst the major therapeutic advances of modern medicine. The discovery of these drug groups arose largely by chance, yet each has dramatically influenced the treatment of congestive cardiac failure and arterial hypertension. 2 The central role which diuretics have had in the management of both oedema and hypertension hinges on their ability to induce a net renal excretion of solute and water by selective interference with either active or passive ion transport processes in different segments of the nephron. Irrespective of sites of action, the continued antihypertensive action of diuretics is characterized by a reduction in plasma volume and extracellular fluid (ECF) volume that lasts for as long as the diuretic is given. The mechanism of this effect remains unclear but may involve autoregulatory reactions that leave cardiac output unaltered but maintain a sustained reduction in total peripheral resistance. 3 ACE inhibitors also lower blood pressure by decreasing total peripheral resistance, leaving cardiac output, plasma volume and ECF volume unchanged. The detailed way these haemodynamic changes are achieved remains unknown but inhibition of converting enzyme present not only in the kidney but also in many extrarenal tissue sites, appears important. In both hypertension and cardiac failure, however, the kidney acts as a key target organ for ACE inhibitors. The increased renal vascular resistance and inappropriate renal salt excretion are reversed with enhanced renal blood flow and saluresis. Both angiotensin II (All) and vasopressin-mediated contraction of glomerular mesangial cells is inhibited, making glomerular filtration more efficient. Reduced aldosterone secondary to blockade of AII formation contributes to saluresis whilst encouraging positive potassium balance. ACE inhibition also impairs breakdown of kinins which may contribute to intrarenal and peripheral vasodilation either on their own or via release of prostaglandins and other vasoactive substances.4 The hypotensive actions of diuretics are potentiated by ACE inhibition primarily through blockade of AII formation and prevention of secondary aldosteronism. In combination, these drugs permit low doses to be used because of their synergistic effects. 5 Caution has to be exercised whenever ACE inhibition is used, without and especially with diuretics, in the management of renovascular hypertension and other low-perfusion states. In these circumstances, AII plays an important autoregulatory role in preserving glomerular filtration through an increase in post-glomerular resistance. Suppression of angiotensin formation with an ACE inhibitor can cause a critical reduction in glomerular perfusion. On the other hand, with careful titration, the dual actions of low-dose loop diuretics and an ACE inhibitor may be highly efficacious in treating severe heart failure and totally prevent such serious metabolic sequelae as azotaemia and hyponatraemia. 6 Unlike the experien...

Antihypertensive effects of nitrendipine and cilazapril alone, and in combination in hypertensive patients with chronic renal failure.

“…However, changes in ECC do not necessarily reflect an influence of cilazapril on glomerular filtration rate since tubular secretion of creatinine may be influenced by ACE inhibitors (Bauer & Reams, 1985). In accordance with the known natriuretic properties of calcium antagonists (Zanchetti & Leonetti, 1985;Sluiter et al, 1987b) and ACE inhibitors (Lant, 1987;Todd & Heel, 1986) we observed a slight reduction in body weight during nitrendipine, cilazapril, and during the combination of these two drugs. In our study dry cough was the most important side effect observed during cilazapril.…”

The Evolution of Renin-Angiotensin Blockade: Angiotensin-Converting Enzyme Inhibitors as the Starting Point

“…Although it took close to 40 years from the discovery of the clinical effectiveness of organomercurials as diuretics to the arrival of the first orally active diuretic chlorothiazide, it took only 5 years (1971-1976) to succeed in developing an oral ACE inhibitor as a successor to the parenterally effective nonapeptide ACE inhibitor teprotide [2]. The first orally active ACE inhibitor was the drug captopril, which was commercially released in 1981.…”

Treating Stage 2 Hypertension

“…27 Diuretics are believed to lower BP generally by stimulation of diuresis-natriuresis, resulting in reduction of plasma fluid, extracellular fluid volume, and sodium. 19,28 Long-term diuretic therapy is also associated with a reduction in total peripheral resistance of unclear mechanism, contributing to its antihypertensive effect. 19,28 The main physiologic basis for adding a diuretic to an ACE inhibitor is that the sodium depletion induced by the diuretic will trigger counterregulatory activation of the RAS that will make BP more dependent on angiotensin II, and thus potentiate the efficacy of the ACE inhibitor.…”

“…19,28 Long-term diuretic therapy is also associated with a reduction in total peripheral resistance of unclear mechanism, contributing to its antihypertensive effect. 19,28 The main physiologic basis for adding a diuretic to an ACE inhibitor is that the sodium depletion induced by the diuretic will trigger counterregulatory activation of the RAS that will make BP more dependent on angiotensin II, and thus potentiate the efficacy of the ACE inhibitor. 29,30 The blunting of this counterregulatory response with ACE inhibition, particularly the inhibition of aldosterone release, also enhances the antihypertensive efficacy of the diuretic.…”

“…29,30 The blunting of this counterregulatory response with ACE inhibition, particularly the inhibition of aldosterone release, also enhances the antihypertensive efficacy of the diuretic. 26,28,29 Furthermore, the mild natriuretic effect of ACE inhibitors adds to the sodium-and fluid-volume reduction of diuretics. 29,30 Multiple studies have shown that adding a diuretic to an ACE inhibitor provides significant BP reduction compared to placebo 31,32 and adds significantly greater antihypertensive efficacy than component monotherapy, while reducing Thiazide-type diuretics for most; may consider ACEI, ARB, βB, CCB, or combination…”