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ACE Inhibition and Vascular Protection in Hypertension

Introduction

Lüscher, Thomas F.

Editor(s): Lüscher, Thomas F.

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Journal of Cardiovascular Pharmacology: August 1999 - Volume 34 - Issue - p S1-S2
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High blood pressure has already been shown to be an important cardiovascular risk factor in the Framingham study. It remains important today, although we do have several pharmacological treatment modalities to reduce blood pressure. At the time of President Theodor Roosevelt, no effective drug was available and the President therefore succumbed to a cerebral hemorrhage in the middle of the historically important period towards the end of World War II; however, antihypertensive drugs became available in the 50s and 60s. These first-generation antihypertensive drugs were of moderate efficacy and exhibited a low tolerability. None of these compounds, with the exception of diuretics, have survived up to today. The development of more efficacious and better tolerable drugs in the 70s, in particular β-blockers, angiotensin converting enzyme (ACE) inhibitors and calcium antagonists have considerably enriched our choice in the treatment of patients with hypertension. More recently, other drugs have also become available, in particular the angiotensin receptor antagonists.

Although blood pressure can be lowered efficaciously with the drugs available today, the clinical effects are less than satisfactory. Indeed, several meta-analyses have shown that the effects of antihypertensive treatment on the prevention of stroke are rather impressive, with a reduction in events of around 40%, while those related to coronary artery disease (which is epidemiologically much more important) are modest with an average of 14-15% relative risk reduction. This discrepancy has led to a lot of research exploring possible causes for these differences. Obviously one of the possibilities is the target blood pressure. Was target blood pressure too low, leading to an increase in coronary events at the lowest levels? Or was blood pressure not reduced appropriately and hence the full benefit not achieved in those prone to coronary artery disease? The Hypertension Optimal Treatment (HOT) trial, along with others, definitively answered this question and excluded the J-curve argument. It is now clear that the optimal target blood pressure is probably in the range of 85 mmHg diastolic and 135 mmHg systolic. It is obvious, however, that this treatment goal, now officially recognized by the World Health Organization as well as the International Society of Hypertension, is not achieved in many patients. This is because of compliance of the physician as well as that of the patient, as many studies have shown that patients are not appropriately treated by physicians and/or are not taking the drugs prescribed.

There are additional problems, however, and they relate to the vessel wall. It is not hypertension per se which is the therapeutic goal but rather vascular protection. The concept of vascular protection has evolved in the last decade and focuses on the effects of high blood pressure on the function of the endothelium as well as vascular smooth muscles in the large conduit as well as the resistance arteries. It has been shown that hypertension does induce endothelial dysfunction with reduced endothelium-dependent vasodilation and, in some models at least, increased endothelin expression. Furthermore, hypertension is associated with an increased adherence of circulating monocytes, all events that may be important for the development of vascular disease in these patients. With these new concepts of vascular protection, the effects of various classes of drugs became of interest. The ACE inhibitors are of particular importance in this context as they exert important local vascular effects. ACE is located in the endothelial cell membrane where it converts angiotensin I into the biologically active angiotensin II. Angiotensin II then can activate receptors on endothelial cells as well as on vascular smooth muscle. Within the endothelium, angiotensin II stimulates endothelin production, the release of plasminogen activator inhibitor-1 and many other mediators. In addition, the octapeptide does have profound effects on vascular smooth muscle via AT1 receptors linked to vasoconstriction and proliferation. In contrast to angiotensin receptor antagonists, however, ACE inhibitors also exert effects on the bradykinin system. Bradykinin is released from endothelial cells as a response to shear stress and causes, via B1 bradykinin receptors, the release of nitric oxide and prostacyclin, both important local vascular mediators causing vasodilation and inhibition of platelet function. The breakdown of bradykinin is helped by an enzyme previously called kininase-II, which has now been recognized to be identical to ACE. Inhibition of the breakdown of bradykinin by ACE inhibitors leads to an increased local concentration of the kinin and, in turn, increased release of nitric oxide and prostacyclin which is considered to be beneficial for the vessel wall. Furthermore, ACE inhibitors stabilize the bradykinin receptor and hence make it more likely to be activated. These vascular protective effects of ACE inhibitors may provide additional clinical benefit beyond that exerted by the blood pressure lowering alone. This may be of particular importance, as indicated above, as there really is a great need to further improve the coronary protective effects of antihypertensive therapy.

In this supplement, a number of interesting articles related to this subject are presented. A first article elaborates on the concept of vascular protection in hypertension and the role of ACE inhibitors compared to other antihypertensive drugs. The second paper concentrates on the question of dosing. This may be important, particularly in this context since the dosage of ACE inhibitors used in clinical trials is, in general, much higher than that seen in clinical practice. A new ACE inhibitor, spirapril, is presented in two further contributions related to clinical studies in patients with varying degrees of hypertension. Finally, the importance of ACE inhibition in the renal circulation as well as in diabetic patients is reviewed.

It is the hope of the Editor that this comprehensive supplement interests the readers of the Journal of Cardiovascular Pharmacology and educates physicians in this clinically important area of vascular protection and hypertension.

Section Description

A Spirapril symposium held in Vienna, Austria, August 25, 1998

The symposium and the publication of this supplement were supported by an educational grant from ASTA Medica AG, Frankfurt am Main, Germany.

© 1999 Lippincott Williams & Wilkins, Inc.