Evidence for renal vascular remodeling in angiotensin II-induced hypertension :

There has been an explosive growth of interest in the multiple interacting paracrine systems that influence renal microvascular function. This review first discusses the membrane activation mechanisms for renal vascular control. Evidence is provided that there are differential activating mechanisms regulating pre- and postglomerular arteriolar vascular smooth muscle cells. The next section deals with the critical role of the endothelium in the control of renal vascular function and covers the recent findings related to the role of nitric oxide and other endothelial-derived factors. This section is followed by an analysis of the roles of vasoactive paracrine systems that have their origin from adjoining tubular structures. The interplay of signals between the epithelial cells and the vascular network to provide feedback regulation of renal hemodynamics is developed. Because of their well-recognized contributions to the regulation of renal microvascular function, three major paracrine systems are discussed in separate sections. Recent findings related to the role of intrarenally formed angiotensin II and the prominence of the AT1 receptors are described. The possible contribution of purinergic compounds is then discussed. Recognition of the emerging role of extracellular ATP operating via P2 receptors as well as the more recognized functions of the P1 receptors provides fertile ground for further studies. In the next section, the family of vasoactive arachidonic acid metabolites is described. Possibilities for a myriad of interacting functions operating both directly on vascular smooth muscle cells and indirectly via influences on endothelial and epithelial cells are discussed. Particular attention is given to the more recent developments related to hemodynamic actions of the cytochrome P-450 metabolites. The final section discusses unique mechanisms that may be responsible for differential regulation of medullary blood flow by locally formed paracrine agents. Several sections provide perspectives on the complex interactions among the multiple mechanisms responsible for paracrine regulation of the renal microcirculation. This plurality of regulatory interactions highlights the need for experimental strategies that include integrative approaches that allow manifestation of indirect as well as direct influences of these paracrine systems on renal microvascular function.

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 KCl 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.

In this paper I have presented two closely related themes both of which seem to be fundamental in understanding the pathophysiology of hypertension. The first theme is the dominant role of the volume-excretion function of the kidneys in setting the long-term arterial pressure level. That is, each person in general has a rather steady intake of salt, water, and those other constituents that make up extracellular fluid. When the arterial pressure is normal, the kidney excretion of these constituents is exactly the correct amount to balance the intake of each of them. When the pressure is too great, there is more loss than gain, and the body fluid volume decreases; therefore, the pressure falls until the exact balance point is reached again; it is only at this balance point that the loss and gain are equal. At any pressure below the balance point, volume gain is greater than loss, and the pressure will continue to rise until the exact balance level is again reached. This capability of the kidney mechanism to return the pressure all-the-way back to the level of balance between input and output--not merely part-way back--is called the "infinite gain" characteristic of this pressure control system, and the level to which the pressure is controlled is called the "set-point" of the system. In pathophysiological states, the set-point for pressure control can be increased to hypertensive levels as a result of (1) a pathophysiological change in renal function or (2) increased salt and volume intake; then hypertension will ensue. Other abnormalities of circulatory function that do not affect one of these two factors cannot cause chronic hypertension because of the infinite gain feature of the renal-volume mechanism for pressure control. One such condition that does not cause hypertension without some concurrent abnormality that affects renal function is a primary increase in total peripheral resistance. The second theme is that whole-body autoregulation causes the blood flow in all parts of the body to return or remain near to normal when high arterial pressure tries to increase the flow. It does this by increasing the resistance in all parts of the peripheral arterial tree. Therefore, in effect, autoregulation converts any tendency to high cardiac output hypertension into high resistance hypertension. Yet, in so far as is now known, the pressure level will be the same with or without autoregulation.(ABSTRACT TRUNCATED AT 400 WORDS)