(Circulation. 2000;101:1641.)
© 2000 American Heart Association, Inc.
Editorials |
Hypertension, Small Arteries, and Pathways for Angiotensin II Generation
"The Proper Study of Mankind is Man"*
From the Departments of Radiology and Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts.
Correspondence to Norman K. Hollenberg, MD, PhD, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115.
Key Words: Editorials • angiotensin • hypertension
In his seminal review, Folkow1 pointed out that recognition of structural cardiovascular changes in association with hypertension is longstanding: In 1836, Richard Bright described both left ventricular and aortic wall thickening in Bright’s disease. Moreover, George Johnson some 50 years later first reported wall thickening in arterioles, but the functional and hemodynamic consequences appear to have been overlooked until Folkow began to develop the theme some 30 years ago, a field of interest that has grown over the past 3 decades.
Until about 10 to 15 years ago, the underlying pathogenetic sequence seemed straightforward. Muscle hypertrophies in the face of an increased workload. An increase in arterial blood pressure represents an increase in workload for the heart and the arterial tree. Hypertrophy of the heart and vascular tree, then, not only come as no surprise but might have been anticipated.
If elevated blood pressure represents the central element in pathogenesis, why does control of blood pressure with the ß-blocking agent atenolol not reverse the hypertrophic process in the study by Schiffrin et al in this issue of Circulation and earlier studies?2 3 The ratio of small-artery wall thickness to lumen was as increased after a year of treatment with atenolol as it was at baseline. It has been common experience that it is much easier to normalize blood pressure than to normalize vascular structure in patients with essential hypertension4 5 6 and in animal models.7 8 9 The duration of treatment seems to be the crucial factor. In a long-term follow-up study, up to 6 years of antihypertensive treatment was required to achieve full normalization of forearm vascular resistance in patients with essential hypertension.10
The possibility that the renin-angiotensin system makes a special contribution to the pathogenesis of vascular structural changes has been the subject of substantial investigation over the past decade. Depending on the conditions, angiotensin II (AngII) can induce vascular smooth muscle hypertrophy and hyperplasia.11 12 Infusion of AngII can lead to an increase in thickness of the arterial media and in the ratio of media to lumen in resistance arteries, even when subpressor doses of AngII are used.13 In animal models, converting enzyme inhibitors are especially effective in preventing or reversing vascular hypertrophy.14 15 In a previous study, Schiffrin and coworkers2 showed that a converting enzyme inhibitor was more effective in reversing the vascular structural changes than the ß-blocker atenolol. That study was identical in duration to the present report in which an AngII antagonist was used.3 In the earlier study, as in this one, 1-year treatment with atenolol did nothing to modify the ratio of media to lumen, whereas the ACE inhibitor induced a significant reduction in that ratio.2 The possibility that factors other than a reduction in AngII generation were responsible for the response to the ACE inhibitor was clear, as is always the case when these drugs are used. ACE is also kininase-II, and so bradykinin accumulation due to decreased degradation and the consequent release of prostaglandins or nitric oxide could have played a pathogenetic role. Thus, the findings in the current study, in which an AngII antagonist replaced the ACE inhibitor, suggests that the ACE inhibitor in the earlier study actually acted via a reduction in AngII formation. A careful comparison of the findings from the 2 studies might provide additional insights into pathogenesis, insights with potentially important therapeutic implications.
There has been substantial recent interest in the possibility that non-ACE–dependent AngII generation makes a substantial contribution to overall AngII generation in the heart, kidneys, and arteries.16 17 18 19 20 Ordinarily, we depend on information from studies in animal models to tease out intimate relationships of this sort. Unfortunately, this is a setting in which there are crucial differences between species in the specific biochemistry of the enzyme chymase.18 19 20
In humans, chymase appears to have a single substrate, AngI, and a single product, AngII. Thus, it really ought to have been called angiotensin-converting enzyme, but that name was already taken by an enzyme that is responsible for all of the conversion of AngI to AngII in plasma but to a lesser degree in the tissues.17 In rats and rabbits, conversely, AngI is not the substrate, and AngII is not the product of chymase: rather, chymase acts on AngII to degrade it and thus has a very different function.18 19 For these reasons, a host of studies in such small-animal models in which converting enzyme inhibitors and AngII antagonists have been compared are potentially misleading, if one is really interested in predicting the response in humans. In small-animal models, AngII antagonists and ACE inhibitors have induced an identical response, as might have been anticipated if there was no non-ACE–dependent AngII generation.
In humans, the direct comparison of the renal hemodynamic response to AngII antagonists and ACE inhibitors has suggested that 30% to 40% of AngII generation is non-ACE dependent when the renin system is stimulated by a low-salt diet.20 This percentage is even higher when the renin system is suppressed by a high-salt diet (N.K.H., unpublished observation, 1999).
In the patient with hypertension, 2 other tissues in which non-ACE–dependent AngII generation could be important are the heart and the arteries. Although there have been substantial numbers of in vitro studies, there is no information available yet on the intact human being. Comparison of the 2 studies from Schiffrin’s laboratory raises the interesting possibility that a similar scenario exists in the arterial tree in hypertensives.2 3 Although comparison of studies performed at different times is tenuous, the studies were performed by the same investigators, in the same laboratory, in a similar patient population, and for an identical duration. In the study with the ACE inhibitor, the wall-lumen ratio improved but was not corrected. In the present study with an AngII antagonist, that correction was complete. The findings would favor a significant non-ACE–dependent pathway for AngII generation in the arteries, analogous to the findings in the kidney. Such a conclusion must be tentative until an AngII antagonist and an ACE inhibitor are compared head-to-head in a proper randomized trial.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
1 Alexander Pope: An Essay on Man. Epistle II,1,i. 
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