Author + information
- Received November 10, 1995
- Revision received May 2, 1996
- Accepted May 13, 1996
- Published online October 1, 1996.
- CLIVE ROSENDORFF*
- ↵*Address for correspondence: Dr. Clive Rosendorff, Medical Service, Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, New York 10468.
In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
The control of arterial blood pressure depends on a complex interaction of many factors—neural, endocrine and metabolic. Neuroendocrine components maintain a balance between vasoconstrictor and vasodilator substances. Generally, hormonal systems that are vasoconstrictor are also antinatriuretic, whereas those that are vasodilator are natriuretic.
Vasoconstrictor and antinatriuretic systems include the renin-angiotensin system, the sympathoadrenal system, endothelin, vasopressin, thromboxane and serotonin. Among the vasodilator and natriuretic agents are atrial natriuretic peptide, prostaglandin E2 and I2 (prostacyclin), the endothelium-derived relaxing factor nitric oxide, the kallikrein-kinin system and dopamine. Clearly, those systems that are vasoconstrictor and antinatriuretic could be implicated in the pathogenesis of hypertension, and of those so identified, the most solid evidence supports a major role for the renin-angiotensin system in several animal models of genetic and experimental hypertension and in human hypertension [1–6].
Recently, there has been an increasing awareness of yet another characteristic that seems to be shared by many of the vasoconstrictor-antinatriuretic hormones—namely, that they may operate as growth factors in the myocardium and in vascular smooth muscle, affecting growth-related genes in such a way as to promote cell hyperplasia or hypertrophy, or both. At least some of the vasodilator-natriuretic hormones have the opposite effect, namely, they inhibit cellular proliferative and growth processes.
Of all these systems, perhaps the most important, and certainly the most intensively studied, is the renin-angiotensin system. Its actions on resistance vessels are complex: it acts as an endocrine system and as a local tissue hormonal system through its paracrine and autocrine effects, and it is a neuromodulator, particularly of sympathetic actions on vascular smooth muscle.
The actions of angiotensin II can be regarded as immediate, intermediate and long term. Angiotensin II is a vasoconstrictor, increasing total peripheral vascular resistance and thereby increasing left ventricular afterload, intramyocardial wall tension and myocardial oxygen demand . Through its stimulation of aldosterone release, angiotensin II is an antinatriuretic and antidiuretic agent. Its long-term action is through the regulation of the expression of genes that activate and drive cell growth and replication in the cardiovascular system, which may result in hypertrophy of the myocardium and hypertrophy or hyperplasia of resistance vessels in certain subjects.
This review summarizes several independent and complementary lines of evidence suggesting that angiotensin II stimulates vascular hypertrophy or hyperplasia and that angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists are vasoprotector, which is related to their direct antiproliferative effects, antiatherogenic properties and favorable effects on arterial compliance.
1 The Renin-Angiotensin System
The components of the renin-angiotensin system are angiotensinogen, renin, angiotensin I, ACE and angiotensin II (Fig. 1).
Angiotensinogen is a large globular protein derived mainly from the pericentral zone of liver lobules . the glycoproteolytic enzyme renin cleaves a leucine-valine bond in the N-terminal region of human angiotensinogen or a leucine-leucine bond in the angiotensinogens of other species, to produce the decapeptide angiotensin I [6, 8]. The major source of renin is the juxtaglomerular cells of the afferent arteriole of the kidney. Translation of renin mRNA in these cells produces pre-prorenin, which in turn is converted by the removal of a single peptide and glycosylation to prorenin. Some prorenin to renin conversion takes place in the juxtaglomerular cells, and both are secreted. However, prorenin is the more abundant circulating form of renin, and the major site of conversion of prorenin to renin is unknown . Prorenin mRNA is expressed at very low levels  or is absent  in blood vessels, but there is avid uptake of prorenin by vascular tissue, which suggests that blood vessels may be the primary site of formation of renin from circulating prorenin. An important debate in this area relates to whether renin is synthesized to any significant extent in cardiovascular tissue or whether the renin in tissues is derived entirely from plasma uptake.
Angiotensin-converting enzyme is a dipeptidyl-carboxy-peptidase that converts angiotensin I to angiotensin II, and also inactivates bradykinin, a potent vasodilator. Although most research interest has focused on the role of ACE in catalyzing the formation of angiotensin II, the inactivation of bradykinin has been suggested as the reason for a number of phenomena. These include ACE inhibitor-induced cough  and the role of ACE inhibitors in normalizing endothelial function in hypertension and atherosclerosis . Bradykinin can stimulate the release of both vasodilating prostaglandins  and nitric oxide [13, 14].
Angiotensin-converting enzyme is ubiquitous and has been described in nearly all mammalian tissues. There is conflicting evidence regarding whether vascular ACE is increased in experimental hypertension. Some reports have shown an increase of vascular ACE in two-kidney, one-clip hypertensive rats [15, 16], but this has not been confirmed in the spontaneously hypertensive rat (SHR) [17, 18].
Enzymatic pathways independent of ACE have been described, which may contribute to the generation of angiotensin II in many tissues, including the blood vessel wall . Angiotensin II can be cleaved directly from angiotensinogen, bypassing the angiotensin I step, by cathepsin G and elastase in neutrophils, by tissue plasminogen activator in vascular tissue and by tonin [19, 20]. Several enzymes other than ACE can also generate angiotensin II from angiotensin I in vitro. These are tissue plasminogen activator, tonin and cathepsin G [21, 22]. Also, a chymostatin-sensitive angiotensin II generating enzyme has been described in aortic tissue from the dog, monkey and human , and chymase has been found in the heart .
The importance of these pathways remains obscure. It is not known whether these non-ACE pathways are present in vivo, nor whether they are activated only when the conventional ACE pathway is blocked. Many studies have shown that with chronic ACE inhibition, the angiotensin II levels, initially undetectable, rise, suggesting either incomplete ACE inhibition or the activation of an alternate pathway . The concept of incomplete ACE inhibition is suggested by the finding that ACE inhibitors induce expression of tissue ACE and increase total tissue and serum ACE concentrations . So far there is little or no experimental evidence that the ACE-independent pathways contribute substantially to angiotensin II biosynthesis or to vascular hypertrophy.
2 Angiotensin II Receptors
The development of angiotensin II antagonists has provided new pharmacologic tools for the classification of angiotensin II receptors. We now recognize two angiotensin II receptor subtypes—AT1 and AT2[26, 27]. The AT1 receptors are found in vascular and many other tissues and are almost certainly the receptors that transduce angiotensin II-mediated cardiovascular actions.
The AT2 receptors are more enigmatic. The AT2 binding sites are much more abundant in fetal and neonatal than in adult tissue, suggesting some role in development [28–32]. Localization is mainly in the brain [29–31]. It is therefore likely that AT2 receptors have little or nothing to do with the acute cardiovascular actions of angiotensin II. Also, as described later, most if not all of the growth-promoting effects of angiotensin II on arteries seem to be mediated through AT1 receptors, although there is a report of involvement of the AT2 isoform of the angiotensin II receptor in myointimal hyperplasia after vascular injury . However, expression of AT2 is upregulated in quiescent vascular smooth muscle cells that have been growth suppressed by serum depletion; in contrast, stimulation of growth by growth factors such as platelet-derived growth factor, epidermal growth factor or serum rapidly downregulates AT2[5, 34]. These results suggest that AT2 receptor expression parallels the suppression of vascular smooth muscle cell growth, the reverse of AT1 receptors. How these effects balance each other and how this balance is upset in angiotensin II atherogenesis is a new and potentially important area of research.
3 Angiotensin II: Signal Transduction in Vascular Smooth Muscle Cells
Activation of the AT1 receptor by angiotensin II sets in motion a specific and linear sequence of events that are the functional links between the membrane-bound receptor and intracellular effectors—namely, the contractile proteins and the nuclear mechanisms of growth and proliferation  (Fig. 2).
Stimulation of the AT1 receptor by angiotensin II activates a guanine nucleotide-binding regulatory protein (G protein), which in turn activates phospholipase C (PLC). Phospholipase C catalyzes the hydrolysis of the membrane phospholipid phosphatidylinositol bisphosphate, to produce two important intracellular messengers, 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) . The latter binds to the IP3 receptor on the endoplasmic reticulum to mobilize Ca2+ from intracellular stores, which activates Ca2+-dependent shortening of the contractile proteins of the cell .
The production of DAG is biphasic. There is an early phase derived from activation of phosphoinositide-specific PLC, whereas a later sustained and larger accumulation of DAG is derived from the phospholipase D-catalyzed hydrolysis of phosphatidylcholine. Diacylglycerol activates protein kinase C (PKC) and ultimately Na+/H+ exchange, leading to intracellular alkalinization. Both angiotensin II and other exogenous activators of PKC, such as phorbol esters, stimulate a sustained contraction of vascular smooth muscle tissue . Thus, the contractile response to angiotensin II seems to involve calcium mobilization from intracellular stores, rapid and transient by means of the IP3 mechanism, and slower and more sustained by the formation of DAG by PLC and phospholipase D.
The angiotensin II signal transduction pathway that results in growth or proliferation of vascular smooth muscle is poorly defined. Activation of the PLC-PKC-Ca2+ mobilization pathway is associated with cell growth in many systems . Angiotensin II activation of PKC in vascular smooth muscle cells leads to increased expression of c-fos and to stimulation of mitogen-activated protein (MAP) kinases [39, 40]. Activation of MAP kinases is known to induce the phosphorylation of nuclear proteins; thus, the PKC-MAP kinase pathway could represent a plausible signaling system linking angiotensin II activation of cell surface receptors to changes in nuclear activity .
There are other possibilities, for which there are tantalizing snippets of information. Angiotensin II also stimulates a PKC-independent tyrosine protein kinase, producing phosphorylation of several proteins of undetermined function . Angiotensin II increases cytosolic pH in vascular smooth muscle cells through activation of the Na+/H+ exchanger , a common response evoked by many mitogenic agents. Furthermore, several studies of cultured vascular smooth muscle cells have shown that angiotensin II stimulates the synthesis of several growth factors: platelet-derived growth factor-A-chain (PDGF-A), transforming growth factor-beta 1 (TGF-beta 1) and basic fibroblast growth factor (bFGF), suggesting an indirect autocrine mechanism for the growth response of vascular smooth muscle to angiotensin II [43–47].
4 Atherogenic Effects of Angiotensin II
The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia); which one seems to depend on the nature of the vascular smooth muscle cell target . For example, cells from normotensive rats become hypertrophied when incubated with angiotensin II [49, 50], whereas angiotensin II induces a proliferative response in cells from SHRs [45, 51, 52]. The data from whole animal studies (i.e., animal models of experimental hypertension) are consistent with the cell culture results. Hypertrophy of vascular smooth muscle cells has been reported in renal hypertension (angiotensin II dependent)  and angiotensin II-induced hypertension . However, in genetic models of hypertension such as in SHRs , in essential hypertension in humans  and in transgenic rats containing the ren-2 mouse renin gene , there are normal-sized vascular smooth muscle cells. Thus, in genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia, as in SHRs , or remodeling (redistribution of existing cells) , as in human essential hypertension and in transgenic rats.
Naftilan et al.  and Gibbons et al.  have published evidence for another interesting hypothesis. Angiotensin II-treated vascular smooth muscle cells in culture express increased levels of PDGF-A, bFGF and TGF-beta 1, as well as cause hypertrophy of the cells, as measured by RNA and protein synthesis, but not proliferation. However, the presence of anti-TGF antibody markedly enhances angiotensin II-stimulated DNA synthesis . The idea is that there may be a balance between the proliferative effects of PDGF-A and bFGF and a proposed antiproliferative action of TGF-beta 1, as in hypertrophic vessels in hypertension, whereas an imbalance in favor of PDGF-A and bFGF may result in cellular hyperplasia, as is seen in vascular injury [5, 59].
In atherogenesis, there are also changes in the extracellular matrix, characterized by increases in the amounts of elastin, collagen and glycosaminoglycans . Inflammatory cells invade the vessel wall and secrete cytokines, proteases and growth factors. There is endothelial dysfunction, with loss of some vasodilator capacity and of the ability to inhibit platelet aggregation and platelet and leukocyte adhesion. Vascular smooth muscle cells migrate into the subintimal space, causing thickening of the wall and a reduction in the lumen area. Limitation of vasodilator capacity, lipid and calcium deposition, fibrosis and thrombosis complete the atherosclerotic process.
Angiotensin II, like endothelin-1, another peptide vasoconstrictor, has a profound effect on the composition of the extracellular matrix of vascular smooth muscle cells, including effects on the synthesis and secretion of thrombospondin, fibronectin and tenascin. These effects are linked to the activity of autocrine feedback loops involving complex interrelation, as yet undetermined, between angiotensin II, endothelin-1, TGF-beta 1 and PDGF-A .
Very little is known about the molecular mechanisms by which vascular smooth muscle cell mitogens such as angiotensin II regulate gene expression to cause vascular smooth muscle growth or proliferation in hypertension and atherosclerosis. These may include the activation of proto-oncogenes such as c-fos[62, 63] or c-jun, a characteristic of many mitogenic agents, of the enhancer element activator protein-1 (AP-1)  or of growth factors such as PDGF-A and bFGF [43–47, 59]. The signal transduction system that links angiotensin II receptors and proto-oncogenes or growth activation almost certainly involves the phosphoinositide pathway, PKC and intracellular calcium mobilization [39, 66], and can be blocked by ACE inhibition .
Angiotensin II activates human peripheral blood monocytes, determined by both the release of tumor necrosis factor-alpha from monocytes and their adhesion to monolayers of human endothelial cells . This implies that angiotensin II is an important candidate stimulus for the subendothelial infiltration of monocytes observed in atherogenesis and hypertension.
It has also been suggested that angiotensin II promotes thrombosis. Angiotensin II increases plasminogen activator inhibitor type 1 in rat aortic smooth muscle cells  and in humans in vivo . This raises the possibility that angiotensin II is prothrombotic, with all of the implications for thrombin-related acceleration of atherosclerosis, and that ACE inhibitors or angiotensin II antagonists may exert some protective effect through this mechanism.
5 Structural Effects of ACE Inhibitors on Arteries
It has been almost a quarter of a century since Brunner et al.  described an epidemiologic association between measured levels of plasma renin activity and the incidence of myocardial infarction and stroke in 219 hypertensive patients. It was therefore postulated that angiotensin II might act as an independent risk factor and may enhance the risk of myocardial infarction by inducing vascular lesions. In 1991, Alderman et al.  reported the results of a prospective study of 1,717 patients with mild to moderate hypertension with a mean follow-up of 8.3 years. Again, there was a clear association between plasma renin activity and the incidence of myocardial infarction.
These types of studies have served to focus attention on the role of angiotensin II as a stimulus of both myocardial hypertrophy and neointimal proliferation in larger arteries. There are many reports demonstrating that angiotensin II may be implicated in the pathogenesis of left ventricular hypertrophy in a variety of conditions and that it is proatherosclerotic in a variety of animal models. These effects can be inhibited or even reversed by ACE inhibitors and by angiotensin II receptor antagonists, and, in humans, ACE inhibitors have a beneficial effect on arterial wall thickness and compliance.
In hypertension there are consistent and major changes in the functional and structural properties of arteries [73–76]. These mechanisms may explain the increase in arterial resistance and stiffness during hypertension. The mechanisms include 1) altered wall thickness, with medial hypertrophy, myointimal proliferation and an increase in collagen content; 2) increased passive stiffness of the vessel wall, probably due to the increase in collagen and smooth muscle mass of the arterial wall; and 3) increased active vascular muscle tone, due to a variety of local and extrinsic metabolic and neurohormonal factors.
For example, two-kidney, one-clip Goldblatt hypertensive rats developed increased aortic impedance, decreased arterial compliance and thickening of these vessels owing to smooth muscle cell hypertrophy, all reversed by the ACE inhibitor perindopril [77, 78]. Long-term treatment of SHRs before and after birth with captopril prevented the development of hypertension, structural and functional alterations of mesenteric arteries and cardiac hypertrophy . Perindopril completely reversed the aortic medial hypertrophy and arterial stiffening seen in two-kidney, one-clip renovascular hypertensive rats, characterized by increased renin-angiotensin activity, as well as in adult SHRs , in which plasma levels of renin activity, angiotensin II and renal renin content are not different from normotensive Wistar Kyoto control rats [81, 82]. Similar results were found with cilazapril .
Is the prevention of vascular hypertrophy by ACE inhibitors in animal models of hypertension unique to this class of antihypertensive agents, or is it a nonspecific consequence of blood pressure reduction? Pure vasodilators such as hydralazine (which increase the plasma level of angiotensin II) [84–86] do not prevent vessel wall thickening in SHRs, despite the normalization of blood pressure , and ACE inhibition has been shown to be more effective than other mechanisms of blood pressure lowering (beta-blockade, vasodilators) in decreasing vascular hypertrophy, despite similar decreases in blood pressure . Not all investigators have been able to confirm this, however, Hajdu et al.  reported that both cilazapril and hydralazine were effective in reducing vascular hypertrophy in stroke-prone SHRs.
Chronic hypertension is accompanied not only by hypertrophy of the vessel wall, but also by a reduction of the vessel wall's external diameter, both of which result in lumen encroachment, a process known as remodeling. Indeed, it is possible to reduce the internal diameter of vessels with little or no vascular hypertrophy by reducing the external diameter. In stroke-prone SHRs, cilazapril but not hydralazine increased internal and external diameters, whereas hydralazine reduced hypertrophy, but with little increase in the external diameter .
Christensen et al.  approached the question of the specificity of ACE inhibitors in reducing vascular hypertrophy or remodeling in a different way. They treated young SHRs (4 to 24 weeks old) with five different drugs: perindopril, captopril, hydralazine, isradipine and metoprolol. At 24 weeks the media/lumen ratio was reduced significantly by use of perindopril; somewhat by captopril, hydralazine and isradipine; and not at all by metoprolol. This may not mean very much, however, because the blood pressure values at the end of the treatment period were very different, with the greatest pressure fall in the perindopril-treated group. After withdrawal of treatment the rats previously treated with the ACE inhibitors perindopril and captopril maintained a normal blood pressure and the improved vascular structure. In rats treated with the other drugs, withdrawal of therapy resulted in a brisk return of blood pressures to previous hypertensive levels, and the media/lumen ratio increased in parallel.
Do the various ACE inhibitors differ in their ability to prevent or reverse vascular hypertrophy or remodeling? Frohlich and Horinaka  found in SHRs and Wistar Kyoso rats that six ACE inhibitors (captopril, CGS-16617, cilazapril, enalapril, utibapril and quinapril) had similar effects on systemic hemodynamic variables. However, there was considerable variability among the drugs in their ability to affect left ventricular mass and performance, as well as aortic hypertrophy and distensibility. These differences could reflect their pharmacodynamic (e.g., enzyme inhibition) and pharmacokinetic (e.g., cell penetration) actions, as well as their different efficacies on vascular smooth muscle cell processes mediating growth and proliferation.
Recently, it was shown that the ACE inhibitor perindopril, in addition to inhibiting neointimal proliferation in the balloon-injured rabbit aorta, reduced the expression of the proto-oncogenes c-jun and c-fos but not c-myc. This, together with the solid data linking angiotensin II with proto-oncogene expression, establishes a plausible hypothesis that the inhibition of proto-oncogene expression underlies the vasoprotective action of ACE inhibitors in hypertension.
The role, if any, of bradykinin in the regression of vascular hypertrophy by ACE inhibitors has not been determined. An obvious experiment would be to establish whether selective bradykinin B2 receptor antagonists, such as HOE 140, attenuate the antihypertrophic action of ACE inhibitors. One such study  has shown that the beneficial effects of ramipril on atherosclerosis in cholesterol-fed rabbits and on neointimal formation and vascular smooth muscle cell proliferation and migration after endothelial denudation in rats was abolished by the use of HOE 140. A possible mechanism of this effect is bradykinin-induced release, from endothelial cells, of nitric oxide, which is known to have an antiproliferative effect.
6 Angiotensin Inhibition and Vascular Structure and Function in Human Hypertension
Schiffrin et al.  recently published the results of an important study comparing the action of the ACE inhibitor cilazapril with the beta-blocker atenolol administered for 2 years to two groups of hypertensive patients. The media/lumen ratios of resistance vessels were measured directly from small subcutaneous arteries obtained by gluteal fat biopsy before and at the end of the 2-year period. Cilazapril normalized the ratio, although there was no change with atenolol. Another study by Thybo et al. , also using gluteal biopsy, showed that treatment of hypertensive patients for 12 months with perindopril resulted in an increase in small artery diameter and a reduction in the ratio of media thickness/lumen diameter, but no change in the media cross-sectional area, suggesting that the change was due to “remodeling.” A posteriori, it would seem that gluteal biopsy is unlikely to be more popular than noninvasive methods for studying this problem. However, studies in humans are severely limited by the relatively poor resolution of noninvasive technologies for visualizing arterial wall thickness, by the unavailability of any noninvasive method for assessing the morphology of small arteries and, in the physiologic domain, by having to make inferences about morphology from estimates of compliance from pulsed Doppler flowmetry or ultrasound echocardiographic tracking devices.
Nevertheless, because the questions relating to drug-induced regression of vascular hypertrophy are so important, there have been several studies of this type, despite methodologic problems. These have usually involved measurement of vascular compliance, occasionally wall thickness, in hypertensive patients before and after a period of treatment with antihypertensive drugs.
One of the most consistent findings in hypertension, whatever the stage of the disease or the method or site of measurement, is a decrease in arterial compliance. Systemic arterial compliance is diminished in borderline hypertension with a normal cardiac output (but not in the subgroup with a high cardiac output) [96, 97], in sustained hypertension in middle-aged patients  and in systolic hypertension in older people [99, 100]. Safer et al. , Simon et al. [102, 103] and Levenson et al.  first demonstrated an increase in brachial artery diameter and compliance in hypertensive patients treated with the ACE inhibitors captopril, enalapril and fosinopril. They later showed, using perindopril, that these actions were not due simply to flow-dependent dilation, but involved a drug-related relaxation of arterial smooth muscle [105, 106].
Because of the difference in loading of elastin and collagen in the walls of large arteries, the pressure-volume relation in those vessels is not linear . Thus, the pressure-diameter curve (which is measured) and the pressure-compliance curve (which is derived) are nonlinear; the higher the pressure, the lower the compliance. Therefore, all drugs that lower blood pressure increase compliance, as a simple mechanical consequence of pressure reduction. However, some but not all antihypertensive drugs increase compliance by amounts greater than can be predicted on the basis of their pressure-lowering effect. That is to say, the pressure-compliance curve is shifted upward. Essentially, this means that all antihypertensive drugs reduce arterial blood pressure by reducing arteriolar resistance, but only some dilate large arteries as well.
Generally, ACE inhibitors [103–105, 108] and calcium channel blockers [109, 110] improve large-artery compliance in hypertension, whereas the thiazide diuretic drugs [104, 108] urapidil , ketanserin  and clonidine  do not. One group of investigators [114, 115], using a new high precision ultrasound device, measured radial artery compliance in normotensive subjects before and after 8 days of treatment with placebo, atenolol, nitrendipine or lisinopril. Only lisinopril shifted the compliance-pressure curve upward.
An alternative approach to the assessment of the resistance of smaller precapillary resistance vessels has been available for several decades . This approach uses forearm and hand venous occlusion plethysmography to measure maximal blood flow after ischemia, from which forearm minimal resistance can be calculated. Using this technique, several workers have described decreases in minimal resistance after 6 months of therapy with pindolol, captopril or nitrendipine [117–119]. In a double-blind, randomized, parallel study, Dahlöf and Hansson  showed that after 6 months of therapy, captopril reduced forearm minimal resistance, whereas hydrochlorothiazide did not.
There have been far fewer studies of the regression of vascular structural changes than of arterial compliance. The reason for this must be the relatively poor resolution and sensitivity of the noninvasive methods available, usually B-mode ultrasound, to measure wall thickness in large arteries. Nevertheless, a number of studies are ongoing. One such study is the Perindopril Regression of Vascular Thickening European Community Trial (PROTECT), which will compare, over a 2-year period, the effectiveness of perindopril with that of hydrochlorothiazide on changes in the ultrasound-proven increase in intimal-medial thickness of the common carotid artery in young to middle-aged patients with mild to moderate essential hypertension . Another study, the Plaque Hypertension Lipid Lowering Italian Study (PHYLLIS), has as a stated objective the assessment of the efficacy of fosinopril versus hydrochlorothiazide, pravastatin versus diet or fosinopril plus pravastatin, in slowing the rate of progression of carotid artery atherosclerosis in hypercholesterolemic hypertensive patients over a 3-year period .
7 Angiotensin II Receptor Antagonists
A major advance in antihypertensive drug therapy has been the development of nonpeptide angiotensin II receptor antagonists, of which losartan (DuP 753) is the prototype. Losartan is a competitive antagonist of the AT1 receptor subtype, which mediates most of the established actions of angiotensin II in the cardiovascular system. The mitogenic or growth-promoting effect of angiotensin II seems also to be mediated by AT1 receptors and is blocked selectively by losartan at various levels. Losartan, but not PD 123177, an AT2 receptor antagonist, blocked angiotensin II-induced DNA and protein synthesis and intracellular Ca2+ mobilization in cultured aortic smooth muscle cells from the rat . Angiotensin II-induced increases in cell size, protein content and c-fos induction in cultured arterial smooth muscle cells were inhibited by losartan but not by CGP 42112A, an AT2 receptor blocker . Losartan blocks angiotensin II stimulation of DNA synthesis , c-fos expression  and the phosphoinositide-signaling system .
In intact animals, results with losartan have been consistent with those from cell culture. Losartan administered to growing SHRs for 6 weeks caused a reduction of aortic and mesenteric medial cross-sectional areas . Losartan but not hydralazine reduced aortic and tail artery medial thickness in 24-week old SHRs after only 2 weeks of treatment . After 10 weeks of treatment of 3-week old SHRs with losartan or captopril, there was a reduction in the mesenteric resistance artery media/lumen ratio .
In an interesting study, Morishita et al.  transfected the human ACE gene into intact rat carotid arteries. An increase in local ACE activity was associated with a parallel increase in DNA synthesis, protein content and wall/lumen ratio, all abolished by the administration of losartan. These effects of locally generated angiotensin II, and their reversal by losartan, occurred without any changes of circulating angiotensin II or arterial blood pressure, supporting the concept that increased autocrine/paracrine angiotensin II can directly cause vascular hypertrophy, independent of systemic factors and hemodynamic effects.
It is clear that some interventions will increase compliance or reduce wall thickness of large arteries, especially ACE inhibitors, calcium channel blockers and lipid-lowering agents. What is not clear is the significance of these measurements. Does compliance tell us about wall thickness due to vascular smooth muscle hypertrophy or a change in the elastin-collagen matrix, or both? Are wall thickness changes due to regression of early atherosclerotic lesions, to remodeling of the hypertrophied media, to a decrease in the size or number of individual smooth muscle cells or to any combination of these? To what extent do these changes reflect those that may or may not be occurring in smaller resistance arteries and arterioles, beyond the reach of conventional ultrasound? Last, and perhaps most important, can we extrapolate from wall thickness and compliance data obtained from the brachial and common carotid arteries to the coronary, intracerebral and intrarenal arteries? Put another way, are these therapy-induced changes in surrogate end points related to positive clinical outcomes?
There is no doubt that in hypertensive patients blood pressure reduction greatly reduces the risk of stroke and renal failure, and substantially reduces the risk of coronary events. These data were derived from very large clinical trials using antihypertensive drugs, mainly thiazide diuretics and beta-adrenoceptor blockers, which we now know have less effect on large artery compliance and morphology than ACE inhibitors and calcium channel antagonists. The current interest in these newer agents is based on the assumption that it is advantageous to increase vascular compliance and reverse vascular (and left ventricular) hypertrophy, to a greater extent than can be expected on the basis of the blood pressure fall alone. Although these are intuitively attractive premises, there is no experimental proof, and much work remains to be done in this area. The ultimate study design is one that compares representatives of the major classes of antihypertensive agents in a large, long-term, randomized, double-blind trial, with mortality as the major end point. One such study, the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), is already under way.
A.1 Abbreviations and Acronyms
ACE = angiotensin-converting enzyme
bFGF = basic fibroblast growth factor
DAG = 1,2-diacylglycerol
IP3 = inositol 1,4,5-trisphosphate
MAP = mitogen-activated protein
PDGF-A = platelet-derived growth factor-A-chain
PKC = protein kinase C
PLC = phospholipase C
SHR = spontaneously hypertensive rat
TGF-beta 1 = transforming growth factor-beta 1
- Received November 10, 1995.
- Revision received May 2, 1996.
- Accepted May 13, 1996.
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- 1 The Renin-Angiotensin System
- 2 Angiotensin II Receptors
- 3 Angiotensin II: Signal Transduction in Vascular Smooth Muscle Cells
- 4 Atherogenic Effects of Angiotensin II
- 5 Structural Effects of ACE Inhibitors on Arteries
- 6 Angiotensin Inhibition and Vascular Structure and Function in Human Hypertension
- 7 Angiotensin II Receptor Antagonists
- 8 Conclusions
- Appendix A