Pharmacological Basis of Selective SBP Reduction

Many antihypertensive agents, such as dihydralazine, propanolol and diuretics in middle age [24, 33], have been shown to have no effect on arterial stiffness or wave reflections and cannot target the above-mentioned mechanisms. What follows is focused on antihypertensive drugs that have a potential direct effect on large artery structure and function.

Changes in Stiffness and Wave Reflections Induced by Nitrates

Two double-blind randomized placebo-controlled studies [31, 36] have investigated the effect of chronic isosorbide dinitrate (ISDN) in elderly subjects with isolated systolic hypertension. In one study, ISDN caused a significant decrease of SBP, from the 8th to the 12th week of treatment: -27 mm Hg with ISDN and -13 mm Hg with placebo. DBP and heart rate did not differ from placebo. The other study confirmed the reduction in office PP with ISDN after 8 weeks of treatment (ISDN: -18%; placebo: -5%) without a reduction in DBP (ISDN: 0%; placebo: -6%). In addition, ambulatory PP was also reduced with ISDN, while it did not change during placebo [36], During this study, no nitrate tolerance was observed. Similar findings have been reported in hypertensive subjects of middle age using transdermal nitroglycerin or the long-acting agent molsidomine [37, 38]. The fact that nitrates decrease PP without decreasing DBP suggests that these compounds act mainly on muscular conduit arteries without a substantial effect on small resistance vessels.

Investigations with the NO donor sinitrodil in young healthy volunteers [39] showed a dose-dependent increase in brachial artery compliance after a single oral dose. With sinitrodil 40 mg, brachial artery compliance increased by 27% while compliance was only increased 8% after ISDN 20 mg. In contrast, total peripheral resistance decreased by 11% after ISDN and only 7% after sin-itrodil. It therefore appears possible to develop drugs that act even more selectively on large arteries than nitrates. Drugs like the NO donor sinitrodil are presumed to be suitable candidates to decrease PP, thereby decreasing SBP without decreasing, or even increasing, DBP.

Apart from NO donors, enhancers of NO production/release might be of interest in the treatment of systolic hypertension in the elderly. Recent studies suggest that some compounds like the diuretic agent cicletanine [40, 41], the selective p1-blocker nebivolol [42] and even the selective atrial natriuretic peptides [43] act as enhancers of NO production and/or release with a resulting decrease of arterial stiffness. These examples offer some prospective views on the development of drugs acting specifically on systolic hypertension in the elderly. Recent studies in old hypertensive rats support the concept that NO dysfunction and/or related endothelial alterations involving oxidative stress may be important target mechanisms in the development of the age-related increase of PP and arterial stiffness [44]. In addition, clinical interference with gene polymorphisms related to NO synthase has been reported in humans to modulate the age-PP relationship [45].

Stiffness and Wave Reflection Changes Associated with Sodium and the

Renin-Angiotensin System

Since angiotensin II stimulates the production of various types of collagen fibers [46] together with a number of growth factors [47], converting enzyme inhibition and angiotensin II type I AT1 receptor blockade have been used as pharmacological tools to show that in vivo, the chronic inhibition of the effects of angiotensin II prevents the aortic accumulation of collagen in spontaneously hypertensive rats (SHRs) [48]. Antihypertensive doses of converting-enzyme inhibitor were shown to prevent the chronic accumulation of aortic col lagen, whereas this result was not observed with the non-specific vasodilator hydralazine for the same BP reduction. The collagen reduction was noted even with non-antihypertensive doses of converting enzyme inhibitor and paralleled the decrease of angiotensin-converting enzyme measured in the aortic tissue, but not in the plasma [48]. Further experiments clearly indicated that the collagen effects were not due to bradykinin but involved specifically the blockade of AT1 receptors of angiotensin II [49]. Finally, such findings were observed exclusively on a normal, but not a high sodium diet [50], a situation in which the production of transforming growth factor-^ is increased [51], Furthermore, when a diuretic and a converting enzyme inhibitor were studied in SHRs, the combination of the two agents was able to consistently prevent carotid collagen accumulation and, at the same time, decrease isobaric carotid stiffness [52]. Thus, it is important now to re-evaluate the possible links between sodium, diuretics, blockers of the renin-angiotensin system, and changes of extracellular matrix of arterial vessels in humans and rat models of hypertension.

Experimental data on sodium-induced changes of arterial structure and function have been mostly obtained in genetic strains of hypertensive rats, such as stroke-sensitive and -resistant SHRs and Dahl salt-sensitive rats [50, 53, 54]. In these models, increased sodium intake does not significantly modify intra-arterial BP (with the exception of Dahl salt-sensitive rats), but is associated with reduced isobaric carotid stiffness, increased aortic wall thickness and collagen accumulation. Such alterations are prevented by reduced sodium diet or administration of diuretics, without concomitant change of the intra-arterial BP level. Numerous findings in molecular biology have demonstrated the pressure-independent effect of sodium and/or diuretic compounds on the aortic and carotid vessel wall, leading to a loss or a reduction in the contractile properties of vascular smooth muscle cells and to an increase in their secretory properties [55].

In the clinical investigation of hypertensive humans, substantial links between arterial stiffness, sodium and blockade of the renin-angiotensin system have been reported. As in hypertensive rats, converting enzyme inhibitors are able to produce a pressure-independent increase of diameter, compliance and distensibility of peripheral muscular arteries [56]. Such changes are observed even in the presence of diuretic compounds. By contrast, diuretics alone, given to middle-aged hypertensive patients, cause little changes in arterial diameter and stiffness [57, 58], The REASON study in hypertensive patients [59] has shown that the combination of perindopril (Per) and indapamide (Ind) decreases brachial SBP and PP more than the ^-blocking agent atenolol for the same reduction of DBP (fig. 5). This result is even more obvious when BP is measured centrally, in the carotid artery and the thoracic aorta, and not in the

Fig. 5. REASON study [64]: in middle-aged hypertensive subjects, the indapamide/ perindopril combination reduces more SBP than the p-blocking agent atenolol for the same DBP reduction. Subsequently, PP is more reduced with the combined drug treatment, particularly at the site of central (carotid) arteries. B = Brachial; C = carotid; BP = blood pressure.

Fig. 5. REASON study [64]: in middle-aged hypertensive subjects, the indapamide/ perindopril combination reduces more SBP than the p-blocking agent atenolol for the same DBP reduction. Subsequently, PP is more reduced with the combined drug treatment, particularly at the site of central (carotid) arteries. B = Brachial; C = carotid; BP = blood pressure.

brachial artery. After 6 months of therapy, the hemodynamic pattern showed a change in central wave reflections, and at 1 year, a pressure-independent reduction of aortic stiffness. These findings, observed with Per/Ind, but not aten-olol, strongly suggest that structural changes of the vessels occur after 1 year of drug treatment, because, in the long term, drug treatment has limited effect on the thickness of elastic arteries [60], but does better on the structure of muscular arteries and arterioles [61, 62]. Therefore, the weight of evidence suggests a parallelism between the reduction of SBP and PP under Per/Ind and the regression of arteriolar structural changes, commonly observed under blockade of the renin-angiotensin system, but not with atenolol. The validity of this observation is strengthened by two modifications previously noted under drug treatment by converting enzyme inhibition (but not with P-blocking agents): a reduction in arteriolar peripheral reflection coefficients [63] and in the timing and/or amplitude of backward pressure wave [64, 65], responsible for the observed selective decrease in central SBP and PP (fig. 5). This interpretation is compatible with the finding by Rizzoni et al. [66] that, in hypertensive subjects, structural alterations of small resistance arteries predict CV risk, as well as increased PP level. Finally, taken together, these results suggest that drug treatment of hypertension to selectively reduce SBP and PP requires complex interactions between structure and function of small and large arteries.

Stiffness Changes Induced by Aldosterone Antagonists

In recent years, experimental studies in rats have shown that chronic al-dosterone administration might act on the mechanical properties of large vessels as well as on myocardial stiffness [67]. Immunohistochemical methods have shown that the intensity of staining of mineralocorticoid receptors within the vascular wall predominates in the aorta and decreases with the size of the arteries [68]. Endogenous vascular synthesis of aldosterone occurs in the rat mesenteric artery, even after adrenalectomy, and requires the presence of an intact endothelium [69, 70]. In this line of evidence, Benetos et al. [71, 72] have observed that, both in younger and older hypertensive rats, spironolac-tone prevents in vivo both myocardial and aortic collagen accumulation with minimal changes of intra-arterial BP. Conversely, long-term aldosterone infusion in the presence of high sodium intake increases the intrinsic rigidity of the aortic wall in rats [67]. This increased aortic rigidity is reversed in the presence of the selective aldosterone antagonist eplerenone [67]. In contrast, in hypertensive patients, studies of spironolactone administration for 2 weeks never produced a change in brachial artery stiffness [33], suggesting that long-term treatments may be needed to limit aortic stiffness.

Interestingly, in untreated hypertensive subjects, increased aortic stiffness and increased plasma aldosterone have been shown to be statistically associated [73]. In addition, in hypertensive subjects, a polymorphism of the aldo-synthase gene has been found to be associated with a pressure-independent increase of aortic stiffness with age [74]. Long-term studies are needed in subjects with hypertension, particularly in the elderly, to demonstrate a reduction of arterial stiffness and SBP following aldosterone antagonism, since recently it is commonly used in subjects with congestive heart failure.

Stiffness Changes and Mechanotransduction Mechanisms

Mechanical properties of the large arteries may be modified independently of mean arterial pressure not only through structural modifications of elastin and collagen, but also through the specific effects of interstitial molecules of the extracellular matrix, which are implicated in the cell-cell and cell-matrix attachments and thus in mechanotransduction [75]. In rats and in man, amino-guanidine and collagen breakers such as ALT711 decrease isobaric carotid stiffness without changing mean arterial pressure or the elastin and collagen contents of the arterial wall [76-78]. The stiffness improvement seems to be the consequence of blockade of collagen glycation with resulting changes in collagen cross-linking. On the other hand, diuretic compounds, such as inda-

pamide, have been shown to reduce aortic stiffness and to modify wave reflections in SHRs and in man, in association with changes in the proteoglycan-labeling patterns of the arterial wall [79, 80]. Finally, other antihypertensive compounds, as calcium-entry blockers (see p. 146) or mostly converting enzyme inhibitors, whether or not associated with atrial peptides, act mostly on fibronectin [81], a major component with integrins of mechanotransduction mechanisms within the arterial wall.

Finally, numerous substances, such as estrogens, have been proposed in the future to improve the mechanical properties of hypertensive large arteries independently of MBP changes.

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