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Remodeling of Resistance Arteries in Hypertensive Patients: Effects of Antihypertensive Therapy

Ernesto L. Schiffrin, M.D.
MRC Multidisciplinary Research Group on Hypertension,
Clinical Research Institute of Montreal
University of Montreal
Montreal, Quebec, Canada

Abstract

Alterations in structure and function of small (resistance-size) arteries that occur in hypertensive patients and in experimental hypertensive models may contribute to blood pressure elevation and to the complications of hypertension. Treatment of spontaneously hypertensive rats (SHR) with angiotensin converting enzyme (ACE) inhibitors, calcium channel antagonists and angiotensin receptor antagonists results in regression of the altered structure of small arteries in different vascular beds. Endothelium-dependent relaxation is also improved. Several studies in hypertensive patients have now shown that treatment with some ACE inhibitors (cilazapril, perindopril, lisinopril) or extended release calcium channel antagonists (nifedipine GITS) induces similar effects in small arteries obtained from gluteal subcutaneous biopsies: both structure and endothelium-dependent relaxation are significantly improved. In contrast, treatment with the beta blocker atenolol did not result any improvement in the structure of small arteries or in endothelial function in hypertensive patients with equally well-controlled blood pressure in 3 different studies. Thus, treatment for at least one year with some ACE inhibitors and extended release calcium channel antagonists corrects the structure and endothelium-dependent relaxation of gluteal subcutaneous small arteries. It still remains to be determined whether this apparently beneficial effect beyond blood pressure lowering of these and other agents with vascular protective properties will result in reduced morbidity and mortality in hypertensive patients.

Introduction

Small or resistance arteries are vessels with a lumen diameter of 100 to 300 µm [1-3] that are a major site of resistance to blood flow [4]. Since elevated peripheral resistance is the hallmark of essential hypertension, alterations of small arteries participate in mechanisms of elevation of blood pressure. Abnormalities of these small arteries also play an important role in the complications of hypertension such as cerebral infarction [5] and renal failure [6]. Myocardial ischemic events in hypertensive patients result like in normotensive subjects from plaque fissure or rupture and coronary artery obstruction of the larger epicardial arteries [7]. However, in hypertensive patients the extent and consequences of ischemia may be influenced importantly by disease of the coronary microcirculation [7,8]. Endothelial dysfunction or structural changes of small arteries modulate the myocardial consequences of upstream events (plaque rupture and epicardial artery obstruction) [7]. Treatment of moderate to severe hypertension [9], or of mild hypertension [10-13], reduces the incidence of stroke and heart or renal failure as expected from cohort studies for the degree of blood pressure lowering (5-6mmHg) in clinical trials. Nevertheless, it is less effective in decreasing coronary ischemic events and mortality thereof [14,15]. The reduced benefit in cardiac ischemia derved from lower blood pressure could be due to persistent alterations in coronary microcirculation structure and function in patients treated with the older antihypertensive drugs, the ones employed in multicenter randomized clinical trials [9-13]. To improve outcome in hypertensive patients, it may indeed be necessary to induce a regression of vascular remodeling and functional changes, not only lower blood pressure.

Structural remodeling and functional changes in small arteries in hypertension

The first manisfestation of target organ damage present in mild hypertension in humans before development of cardiac hypertrophy, increased carotid intima-media thickness or microalbuminuria and nephroangiosclerosis is the remodeling of small arteries. Small arteries of hypertensive patients exhibit a reduction in the lumen and external diameter, normal or increased media thickness and increased media-to-lumen ratio but normal media cross-section (or volume of the media per unit length) [16-18]. This is what has recently been defined as "eutrophic remodeling" [19]. These vessels have the same number of smooth muscle cells and little evidence of cell hypertrophy [16]. Cells are re-arranged around a smaller vessel lumen but it is unknown how this restructuring occurs. It may result in part from changes in cell adhesion molecules [20] or extracellular matrix deposition or spatial arrangement of fibrillar material. We have recently shown in both spontaneously hypertensive rats (SHR) [20,21] and in human resistance arteries from hypertensive patients [22] that collagen deposition is enhanced.

The function of small blood vessels is also altered in hypertensive patients. The media stress developed in response to angiotensin II is increased or sometimes normal, whereas reponses to most vasoconstrictors are reduced [17,23,24]. The structural abnormalities of resistance arteries however enhance vasoconstrictor responses [1], contributing to elevated vascular tone. Endothelial function is impaired in hypertension: vasodilatory responses to acetylcholine in pre-contracted vessels are blunted both in hypertensive animals [25] and humans [26,27]. Endothelial dysfunction may be due to deficient generation of nitric oxide or increased degradation of nitric oxide, the latter perhaps a consequence of enhanced oxidative stress in the vascular wall [28]. Endothelium-derived endoperoxides (EDCF) have also been implicated [26,29].

Pathogenesis of small artery changes in hypertension

Smooth muscle cell hyperplasia or hypertrophy in response to angiotensin II [30], to endothelin or other vasoactive peptides, or to catecholamines, may be involved in growth contributing to remodeling of small arteries. This may be combined with collagen deposition in the media [20-22]. It is possible that apoptosis offsets the growth to result in eutrophic remodeling. Indeed, angiotensin II-induced growth may be associated with secondarily enhanced apoptotic rates in the muscular media [31]. Angiotensin II and endothelin-1 act via a complex array of signaling mechanisms inside the cell including MAP kinases and others, that interact with intracellular calcium at different molecular steps [32]. Thus, calcium may be a common pathway for angiotensin, endothelin, even catecholamines to induce contractile and growth effects. Antihypertensive agents that interfere with these signalling pathways could alter remodeling of arteries in hypertensive patients. Decreased contraction in response to vasoconstrictors may result from receptor downregulation or impaired excitation-contraction coupling [17,23,24]. Endothelial dysfunction may involve reduced nitric oxide production or enhanced degradation resulting from increased vascular oxidative stress [28], or production of EDCF [26,29].

Effects of calcium channel antagonists, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists on small arteries in hypertensive rats

The structure and function of small arteries of the heart and kidney [33-35], and the brain of SHR [35,36] resemble those described of subcutaneous gluteal small arteries of hypertensive humans [16,17,23], and present eutrophic or hypertrophic remodeling [37]. Endothelium-dependent relaxation is blunted because acetylcholine induces contractions via generation of EDCF [26,29]. SHR treated with calcium channel antagonists [34,38], angiotensin converting enzyme inhibitors (ACEI) [34,39,40,41] or angiotensin II receptor antagonists [42,43], showed correction of abnormal endothelial function and regression of vascular remodeling, including the excess collagen deposition [20,21]. Effects of ACEI may be the result of inhibition of angiotensin II generation or of accumulation of bradykinin, both of which could also beneficially influence endothelial function (angiotensin II reduction by attenuation of oxidative stress, bradykinin via stimulation of nitric oxide). Angiotensin receptor antagonists like losartan or others probably act via blockade of angiotensin II-induced growth. The absence of blockade of AT2 receptors stimulated by the elevated angiotensin II concentrations found under treatment with AT1 antagonists may stimulate nitric oxide production, which has anti-growth and proapoptotic effects, and also would correct the nitric oxide deficiency. Calcium channel antagonists block the elevation of intracellular calcium via voltage-dependent calcium channels, blunting responses to vasoactive peptides, catecholamines, etc. The similarity of results obtained with the three classes of agents (calcium channel antagonists, ACEI, and AT1 antagonists) suggests that intracellular calcium may be a common pathway with which all these antihypertensive agents interfere. Some calcium channel antagonists have antioxidant properties, which could contribute as in the case of blockade of angiotensin II, to the beneficial effects on endothelial dysfunction and the correction of structural remodeling.

Effect of ACE inhibitors versus beta blockers on small artery structure and function in hypertensive patients

We performed a randomized prospective comparison of treatment with an ACEI compared to a beta blocker to assess whether in essential hypertensive patients small artery structure would be corrected by the former. Patients were treated with the ACEI cilazapril or the beta blocker atenolol for 1 and 2 years [44,45] or by other investigators with perindopril in a 1 year trial [46], and small arteries obtained from gluteal subcutaneous biopsies were evaluated. The structure of small arteries under the action of the ACE inhibitors cilazapril [44,45] and perindopril [46] was corrected, whereas under the beta blocker atenolol there was no improvement. Endothelial function measured by acetylcholine-induced relaxation improved under the ACE inhibitor cilazapril but not with atenolol [45,47]. In a retrospective study, treatment with lisinopril for 3 years also resulted in improved structure and endothelial-dependent relaxation of small subcutaneous arteries of hypertensive patients [48]. It is of interest that in normotensive subjects with coronary artery disease, treatment for 6 months with another ACEI, quinapril,resulted in improvement of endothelial function of coronary arteries as shown by coronary angiography in the TREND study [49].

Effect of calcium channel antagonists versus beta blockers on small artery structure and function in hypertensive patients

In a case-control study design [50], hypertensive patients whose blood pressure was well controlled for a long period of time (i.e. more than one year) with the once-a-day extended release formulation of the dihydropyridine calcium channel blocker nifedipine (nifedipine GITS) were compared to equally well controlled essential hypertensive patients treated for a similar duration of time with the beta blocker atenolol. Patients had not received in the past any antihypertensive agent but a beta blocker, or a calcium channel antagonist, the latter only for patients treated with nifedipine GITS. The media to lumen ratio of small arteries from the nifedipine GITS treated-patients was similar to that of normotensives, indicating a complete regression of structural alterations under treatment, and significantly smaller than in atenolol-treated subjects, who presented the same small artery abnormalities as untreated hypertensive patients. A six-month treatment with amlodipine induced a significant reduction in minimal forearm minimal vascular resistance [51]. The same authors demonstrated that there was a close correlation between forearm minimal vascular resistance and media to lumen ratio of small arteries from gluteal biopsies from the same patients [52]. Endothelium-dependent relaxation responses in normotensive subjects and nifedipine GITS-treated patients were similar, whereas they were significantly reduced in vessels from atenolol-treated patients and in untreated hypertensive patients. After 6 months of treatment with amlodipine or enalapril, blunted responses of forearm blood flow to intra-arterial infusion of the nitric oxide synthase inhibitor NG-nitro-monomethyl-L-arginine (L-NMMA), suggesting impaired endothelial function, were normalized [53]. This suggested correction of endothelial dysfunction in the patients treated with the calcium channel blocker or the ACE inhibitor.

Discussion

Reversal of structural and functional abnormalities of small arteries under antihypertensive treatment in SHR and other models of hypertension in the rat correlates with lowering of blood pressure [34,35]. Correction of structure in hypertensive rat models may be independent of the antihypertensive agent used. However, endothelial function may be normalized particularly when hypertensive rats are treated with calcium channel antagonists or with ACE inhibitors [34,38], and may precede structural correction [54]. In hypertensive patients in contrast, structural or functional remodeling of small arteries regresses differently according to the agent used to normalize blood pressure. In equally well controlled hypertensive patients, atenolol-treated patients present persistent abnormalities of small artery structure and function, whereas ACE inhibitor or calcium channel antagonist-treated patients exhibit normalized structure, and reversal of altered endothelial and smooth muscle cell responses toward normal [44,45-47,50].

The media to lumen ratio of small arteries is independent of lumen diameter within the range examined in these studies (150-350µm) and is highly reproducible within and between patients in this type of study [45,55]. It also has major hemodynamic significance [1-3]. Moreover, media to lumen ratio of gluteal subcutaneous small arteries correlates closely with forearm minimal vascular resistance at maximal vasodilatation in normotensive and hypertensive subjects [52]. Finally, the changes detected on gluteal subcutaneous small arteries in hypertensive humans are the same ones found in hypertensive rats in more pathophysiologically critical vascular beds, such as in coronary and renal small arteries [33-35]. Hypertensive patients present abnormalities of the coronary microcirculation [8]. Treatment with the ACE inhibitor enalapril has recently been shown to improve coronary reserve, a manifestation of the regression of structural and functional (possibly endothelial) changes in the coronary microcirculation [56,57]. Thus, media to lumen ratio of small arteries is representative of systemic resistance arteries, and as the structure and function of subcutaneous small arteries is normalized, a similar improvement may occur in coronary small arteries in hypertensive patients treated with ACE inhibitors or calcium channel antagonists, which could potentially have a major favorable impact on cardiovascular morbidity in hypertension.

The mechanism of action whereby ACE inhibitors and calcium channel antagonists result in correction of structural and functional changes in small arteries has not been elucidated. Calcium plays a central role in the effects of angiotensin II, and thus it is not unexpected to find that ACE inhibitors and calcium channel antagonists induce similar effects on the structure and function of small vessels in experimental hypertensive animals and in essential hypertension in humans. The effects of ACE inhibitors may result from inhibition of generation of angiotensin II, but inhibition of degradation of kinins or hemodynamic effects may also play a role. Both ACE inhibitors and calcium channel antagonists are vasodilators, whereas beta blockers induce a vasoconstrictor effect [58], which could contribute in part to the differential effects of these antihypertensive agents.

Conclusion

Treatment with specific antihypertensive drugs such as some of the newer antihypertensive agents (calcium channel antagonists and ACE inhibitors, and perhaps AT1 receptor antagonists), but not beta blockers like atenolol, may result in reversal of the structural and functional alterations of small arteries in essential hypertensive patients. The protective effect on the vasculature of ACE inhibitors, and extended release or long-acting calcium channel antagonists, and perhaps AT1 receptor antagonists, may result in improved clinical outcomes. This may be particularly true with respect to cardiac events, and could produce benefits in addition to blood pressure lowering, with a reduction of hypertension-induced morbidity and mortality. The latter remains to be demonstrated.

Acknowledgments

The work from the author's laboratory reported in this manuscript was supported by a group grant from the Medical Research Council of Canada to the Multidisciplinary Research Group on Hypertension, and grants from Hoffmann-LaRoche Canada, Bayer Canada and Merck-Frosst Canada.

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