Invited Symposium: Hypertension I: Structure of Small Arteries in Hypertension
Small or resistance arteries are vessels with a lumen diameter of 100 to 300 um that are a major site of resistance to blood flow. Abnormalities of small arteries in hypertension may participate in elevation of blood pressure or in the complications of hypertension such as cerebral infarction and renal failure. Ischemic cardiac events in hypertensive patients, although the result of plaque fissure or rupture and coronary artery obstruction of larger epicardial arteries, may be influenced by disease of the coronary microcirculation.
Endothelial dysfunction or structural changes of small arteries may modulate the consequences of upstream events (plaque rupture and epicardial artery obstruction) on myocardial tissue. In favor of this hypothesis is the finding that treatment of moderate to severe hypertension, or of mild hypertension, succeeds in reducing the incidence of stroke and heart or renal failure, but is less effective in decreasing coronary ischemic events and mortality thereof. We have hypothesized that the lack of improvement found in cardiac ischemia could be due to persistent alterations in structure and function of the coronary small vessels in patients treated with the older antihypertensive drugs that are the ones employed in multicenter randomized clinical trials to date. In order to improve outcome in hypertensive patients, it may be necessary to induce a regression of vascular remodeling and functional changes, rather than only lowering blood pressure.
Small arteries in hypertension
Small arteries of hypertensive patients present what has recently been defined as "eutrophic remodeling", that is a reduction in the lumen and external diameter with normal media cross-section (or volume of the media per unit length). They have the same number of smooth muscle cells and little evidence of cell hypertrophy. Cells are restructured around the lumen of the blood vessel resulting in a smaller lumen and outer diameter. How this re-arrangement occurs is unknown, but may result from changes in cell adhesion molecules or intercellular matrix deposition or spatial arrangement of fibrillar material.
As well, the function of small blood vessels is altered in hypertensive patients. Active media stress developed in response to most vasoconstrictors is reduced, except perhaps for angiotensin II. Despite blunted responses to vasoconstrictors, the structural abnormalities of resistance arteries will enhance constrictor responses, contributing thus to elevated vascular tone. Endothelium is dysfunctional in hypertension, as shown by reduction in the relaxation induced by acetylcholine acting on pre-contracted vessels, first demonstrated in experimental animals and also shown in humans with essential hypertension. The impaired endothelium-dependent relaxation found in hypertension may be due to deficient production of nitric oxide, or increased degradation of nitric oxide, perhaps as a consequence of enhanced oxidative stress and increased production of free radicals. It may also be a consequence of production of endoperoxides with potent contractile properties (endothelium-derived contracting factor or EDCF). Several factors have been implicated in the induction of the structural changes present in small arteries in hypertension. Hyperplasia or cell hypertrophy in response to angiotensin II, other vasoactive peptides, or other agents such as catecholamines may play a role. Angiotensin II and endothelin-1 act via calcium-mediated pathways, and therefore calcium may act as a common pathway for angiotensin and endothelin, both functional and growth-related.
It has accordingly been speculated that treatment with antihypertensive agents that interfere with these signaling pathways might alter remodeling of arteries in hypertensive patients. The mechanisms involved in the production of functional changes in small arteries remain unclear. Decreased contraction in response to vasoconstrictors may obey different mechanisms, including receptor downregulation (potentially for endothelin responses) or impaired excitation contraction coupling . Endothelial vasorelaxant dysfunction may involve as already mentioned reduced nitric oxide production or enhanced degradation of nitric oxide due to effects of superoxide anions, or excess production of vasoconstrictor endoperoxides (EDCF).
Effects of antihypertensives in rats
Spontaneously hypertensive rats (SHR) exhibit alterations in the structure and function of small arteries of the heart, kidney, and brain that resemble those described in hypertensive humans in studies of subcutaneous gluteal small arteries. These vessels present eutrophic or hypertrophic remodeling. We have recently shown that the ratio of collagen to elastin is increased in the media of small arteries of SHR, and that expression of some integrins is enhanced. Constrictors elicit reduced media stress responses (except for angiotensin II). Endothelium dependent relaxation is reduced as a result of acetylcholine induced contractions through production of endothelium-derived contracting factor (EDCF). Treatment of SHR with calcium channel antagonists, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, resulted in correction of abnormal endothelial function and regression of vascular remodeling, including the collagen/elastin ratio and expression of integrins. The effects of ACE inhibition may be due to inhibition of angiotensin II generation resulting in less hypertrophic remodeling and collagen deposition, or to the effect of accumulation of bradykinin, which could beneficially influence endothelial function.
In the case of angiotensin receptor antagonists like losartan or others, the blockade of the AT1 receptor that is responsible for the angiotensin II-induced growth responses, probably plays the major role. The absence of protection of the AT2 receptor in presence of elevated angiotensin II concentrations found under the effects of AT1 antagonists could as well play a role. The AT2 receptor may stimulate nitric oxide production and thus favorably affect the endothelium. Calcium channel blockade inhibits elevation of intracellular calcium levels mediated via voltage dependent calcium channels, and blunts responses to different agents, including the vasoactive peptides, catecholamines, etc. The similarity of results obtained with the three classes of agents (ACE inhibitors, AT1 antagonists and calcium channel antagonists) may suggest that intracellular calcium may be a common pathway in the intracellular signaling which participates in the development of the structural and functional abnormalities of small arteries in hypertension. Finally, some calcium channel antagonists have antioxidant properties, which could contribute to the beneficial effects found with these agents on endothelial dysfunction, since endothelium is devoid of L-type voltage-dependent calcium channels.
Effect of antihypertensives in humans
Randomized prospective studies have been performed in essential hypertensive patients examining small arteries obtained from gluteal subcutaneous biopsies and comparing the effects of treatment with beta blockers and ACE inhibitors (cilazapril for 1 and 2 years, or perindopril in a 1 year trial). Regression to normal of structure of small arteries was observed under the action of the ACE inhibitors cilazapril and perindopril, whereas no improvement occurred under the beta blocker atenolol. Contractile function, particularly in response to endothelin-1, was depressed in small arteries of untreated hypertensive patients, and was normalized by treatment with the ACE inhibitor but not the beta blocker. This may indicate an improvement of the smooth muscle phenotype, or alternatively, but still only hypothetically, an upregulation of dowregulated endothelin receptors as increased endothelial endothelin-1 expression is reduced with normalization of blood pressure and improvement in the state of the endothelium.
Endothelial function as measured by acetylcholine-induced relaxation, improved under the ACE inhibitor cilazapril but not with atenolol. In contrast, in studies in which endothelial function was evaluated by acetylcholine-induced relaxation measured by changes in forearm blood flow, no improvement was noted in short-term studies with the ACE inhibitor enalapril or with cilazapril by other investigators. However, improvement of endothelial function of coronary arteries was shown with quinapril using coronary angiography in the TREND study.
Well-controlled hypertensive patients treated for a prolonged time (i.e. more than one year) with the once-a-day extended release formulation of the dihydropyridine calcium channel antagonist nifedipine (nifedipine GITS) were compared to an equally well-controlled group of essential hypertensive patients treated for a similar duration of time with the beta blocker atenolol, in a case-control study design. Patients had not received in the past any antihypertensive agent but a beta-blocker, or in the case of nifedipine GITS-treated patients, they might have been treated previously with either beta-blockers or calcium channel blockers. The structure and function of resistance arteries isolated from biopsies of gluteal subcutaneous tissue from these two groups of essential hypertensive patients were compared to those of age- and sex-matched normotensive subjects and of untreated essential hypertensive patients. The media to lumen ratio of small arteries from patients treated with nifedipine GITS was similar to that of normotensives, indicating complete regression of structural alterations under treatment, and significantly smaller than in atenolol-treated, who presented persistent small artery changes, or untreated hypertensive patients. Contraction responses of small arteries to maximum concentrations of norepinephrine were similar in normotensives and nifedipine GITS-treated hypertensive patients, whereas in untreated and atenolol-treated hypertensive patients, response to norepinephrine was reduced. Endothelium-dependent relaxation responses were similar in normotensive controls and in nifedipine GITS-treated patients, whereas they were significantly smaller in vessels from atenolol-treated patients, and in the latter they resembled those found in untreated hypertensive patients.
The reversal of structural and functional abnormalities of small arteries under antihypertensive treatment in SHR and other models of hypertension in the rat correlates with the lowering of blood pressure, and may be independent of the antihypertensive agent used. However, normalization of endothelial function may occur particularly when hypertensive rats are treated with calcium channel antagonists or with ACE inhibitors. In contrast, studies in hypertensive patients show that vascular remodeling of small arteries, either structural or functional, regresses differently depending on the agent used to normalize blood pressure. In equally well-controlled hypertensive patients, different results were found when patients treated with beta blockers such as atenolol were compared to patients treated with either ACE inhibitors or with long acting calcium channel antagonists. Atenolol-treated patients presented persistent abnormalities of small artery structure and function, whereas ACE inhibitor or calcium channel antagonist-treated patients presented normalized structure, and reversal of altered endothelial and smooth muscle cell responses toward normal
The structural parameter that most studies have examined is the media to lumen ratio of small arteries, which is highly reproducible in this type of study. The media to lumen ratio of resistance arteries has major hemodynamic significance, and in gluteal subcutaneous small arteries it has recently been shown to correlate closely with minimal vascular resistance at maximal vasodilatation measured in forearm blood flow studies of normotensive and hypertensive subjects. This underscores the significance of the correction of this abnormal parameter by treatment with ACE inhibitors or calcium channel antagonists.
The pathophysiological significance of the effects of ACE inhibitors and calcium channel antagonists on gluteal subcutaneous small arteries of hypertensive patients may in part be clarified by the studies which have been performed in SHR. The changes detected on gluteal subcutaneous small arteries in hypertensive humans are essentially the same ones found in hypertensive rats in more pathophysiologically critical vascular beds, such as in coronary and renal small arteries. Treatment with the calcium channel antagonists mibefradil or amlodipine, with the ACE inhibitors perindopril or cilazapril, or with AT1 angiotensin receptor antagonists, resulted in regression of these changes, including a diminution of media collagen deposition, in all vascular beds examined in parallel with normalization of blood pressure. It is known that hypertensive patients present abnormalities of the coronary microcirculation. Treatment with enalapril has recently been shown to improve coronary reserve, and this is presumably an expression of the regression of structural and functional (possibly endothelial) changes in the coronary microcirculation. Thus, 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, angiotensin antagonists and calcium channel blockers 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 treatment of hypertensive patients with beta-blockers results in a vasoconstrictor effect. This could be another reason contributing in part to the differential effects of these antihypertensive agents. Treatment with specific antihypertensive drugs such as some of the newer antihypertensive agents (ACE inhibitors, angiotensin antagonists and calcium channel antagonists), but not beta-blockers like atenolol, may result in reversal of the structural and functional alterations of small arteries in essential hypertensive patients. This may be particularly true with respect to cardiac events, and could result in benefits additional to blood pressure lowering, with a reduction of hypertension-induced morbidity and mortality. The latter remains to be demonstrated.
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.
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|Schiffrin, EL; (1998). Arterial Structure, Endothelial Dysfunction and Effects of Antihypertensive Treatment.. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/mulvany/schiffrin0304/index.html|
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