No abstract

Angiotensin II, when given in low doses, raises blood pressure slowly. When tested in vitro on vascular smooth muscle cells, it has mitogenic and trophic effects; it is not known if it has these effects in vivo. Our purpose was to determine whether vascular hypertrophy develops during slow pressor infusion of angiotensin II and, if so, whether it is pressure induced. Three experiments were done in rats infused subcutaneously with angiotensin II (200 ng/kg/min) by minipump for 10-12 days. Experiment 1: Angiotensin II gradually raised systolic blood pressure (measured in the tail) from 143±2 to 208±8 mm Hg (mean±SEM), significantly suppressing plasma renin and increasing threefold (NS) plasma angiotensin II. There was no loss of peptide in the pump infusate when tested at the end of the experiment. Experiment 2: In the perfused mesenteric circulation, vasoconstrictor responses to norepinephrine, vasopressin, and KC1 were enhanced in rats given a slow pressor infusion of angiotensin II, but sensitivity of responses was not altered. This combination of changes suggests that vascular hypertrophy develops during slow pressor infusion of angiotensin II. Experiment 3: Vessel myography was done after angiotensin II infusion with and without a pressor response. Angiotensin II raised systolic blood pressure, increased heart weight, and produced myographic changes of vascular hypertrophy in the mesenteric circulation, increasing media width, media cross-sectional area, and media/lumen ratio. Hydralazine given with angiotensin II prevented the rise of pressure and the cardiac effect but not the vascular changes. Two-way analysis of variance showed that angiotensin II significantly increased media width, media cross-sectional area, and media/lumen ratio, all independent of hydralazine. Thus, although hydralazine inhibits the pressor and cardiac effects of angiotensin II, suggesting a pressor mechanism for the cardiac change, it does not inhibit structural vascular change, which suggests that at least part of the effect has a non-pressor mechanism. (Hypertension 1991;17:626-635)

Growth or altered metabolism of nonmyocyte cells (cardiac fibroblasts, vascular smooth muscle and endothelial cells) alters myocardial and vascular structure (remodeling) and function. However, the precise roles of circulating and locally generated factors such as angiotensin II, aldosterone and endothelin that regulate growth and metabolism of nonmyocyte cells have yet to be fully elucidated. Trials of pharmacologic therapy aimed at preventing structural remodeling and repairing altered myocardial structure to or toward normal in the setting of hypertension, heart failure and diabetes are reviewed. It is proposed that these are therapeutic goals that may reduce cardiovascular morbidity and mortality. Although this hypothesis remains unproved the primary goal of therapy should be to preserve or restore tissue structure and function.

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The purpose of the present study was to determine the cellular basis for the increased ratio of media thickness to lumen diameter (media-lumen ratio) consistently found in the peripheral resistance arteries from patients with essential hypertension using an unbiased stereological principle (the "disector"). Segments of subcutaneous resistance arteries (approximately 200 fim internal diameter) were isolated from gluteal biopsies of skin and subcutaneous fat taken from 16 untreated patients with essential hypertension and 16 age-and sex-matched normotensive control subjects. Measured under standardized conditions (ie, relaxed and under controlled mechanical conditions) on an isometric myograph, vessels from hypertensive patients had a significant (P<.05) reduction in lumen diameter and an increase in media-lumen ratio (P<.05) compared with vessels from normotensive control subjects. These changes were not associated with alterations in the estimated media volume per segment length. After these measurements had been made, the arteries were fixed, serial sectioned, and stained. The volume fraction of smooth muscle cells within the media was estimated by point counting on photomicrographs of the vessels. Using the disector principle, we determined the numerical density (number per unit volume) of smooth muscle cells within the media of each vessel and calculated the average smooth muscle cell volume (1775±122 [mean±SEM] and 1532±112 /im 5 , hypertensive and normotensive, respectively, P>.0S) on the basis of these measurements. Furthermore, by a combination of the myograph measurements and the histological estimates, the number of smooth muscle cells per unit segment length (4.61 ±0.55 and 5.81 ±0.57 /im' 1 , hypertensive and normotensive, respectively, P>.05) also was calculated. These results suggest that the reduction in lumen diameter and the increase in media-lumen ratio observed in essential hypertension are brought about primarily by a rearrangement of smooth muscle cells within the medial layers of the arterial wall. The nonsignificant increase in individual cell size would indicate that myocyte hypertrophy may occur in the circulation at this level but is less important than remodeling in human hypertension. (Hypertension. 1993^2:523-526.) KEY WORDS • hypertension, essential • arteries • muscle, smooth, vascular • hypertrophy • hyperplasia E stablished human essential hypertension is characterized by an increase in total peripheral resistance, 1 and hemodynamically it has been shown that this is present at maximal vasodilatation. 1 ' 2 This indicates that the increased resistance is structurally determined rather than attributable to functional changes in the vasculature. Histological investigations on autopsy material support this by demonstrating a decreased lumen diameter 3 and an increased ratio of media thickness to lumen diameter (media-lumen ratio) 3 -4 in arteries from essential hypertensive patients. In these investigations the structural changes were mainly confined to small arteries that ar...