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.

It is now established that all of the components necessary for the local formation of angiotensin II (ANG II) coexist in the kidney and can alter local ANG II production rate. However, data on ANG II concentrations in different compartments within the kidney are limited. Recently, proximal tubule fluid ANG II concentrations in the nanomolar range were reported. Using an ANG II radioimmunoassay procedure with enhanced sensitivity, we performed experiments to explore proximal tubular fluid ANG II levels further and to determine the source of the ANG II. Total free-flow proximal tubular fluid samples (n = 11) had an average ANG II concentration of 13 +/- 2 nM. These concentrations were similar (10 +/- 2 nM) in samples collected into pipettes containing the inhibitors enalaprilat and EDTA (n = 17). Fluid collected from blocked proximal tubules that were perfused with artificial tubular fluid showed similar ANG II concentrations both in the presence (22 +/- 3 nM) and absence (22 +/- 4 nM) of the angiotensin-converting-enzyme inhibitor, enalaprilat, in the perfusate. Plasma ANG II concentrations were much lower and averaged 155 +/- 26 pM. Isotonic saline expansion lowered plasma ANG II levels to 30 +/- 5 pM (P < 0.01) but did not significantly decrease intraluminal ANG II (8 +/- 1 nM). These data provide further evidence that intratubular ANG II concentrations are in the nanomolar range and are regulated independently of the plasma ANG II levels. The data obtained from perfused tubules indicate that the proximal tubule adds substantial amounts of ANG II or a precursor into the tubular lumen.

Introduction. Transgenic rats with inducible angiotensin II (Ang II)-dependent hypertension (strain name: TGR[Cyp1a1-Ren2]) were generated by inserting the mouse Ren2 renin gene, fused to the cytochrome P450 1a1 (Cyp1a1) promoter, into the genome of the rat. The present study was performed to characterise the changes in plasma and kidney tissue Ang II levels and in renal haemodynamic function in Cyp1a1-Ren2 rats following induction of either slowly developing or malignant hypertension in these transgenic rats. Materials and Methods. Arterial blood pressure (BP) and renal haemodynamics and excretory function were measured in pentobarbital sodium-anaesthetised Cyp1a1-Ren2 rats fed a normal diet containing either a low dose (0.15%, w/w for 14-15 days) or high dose (0.3%, w/w for 11-12 days) of the aryl hydrocarbon indole-3-carbinol (I3C) to induce slowly developing and malignant hypertension, respectively. In parallel experiments, arterial blood samples and kidneys were harvested for measurement of Ang II levels by radioimmunoassay. Results. Dietary I3C increased plasma renin activity (PRA), plasma Ang II levels, and arterial BP in a dose-dependent manner. Induction of different fixed levels of renin gene expression and PRA produced hypertensive phenotypes of varying severity with rats developing either mild or malignant forms of hypertensive disease. Administration of I3C, at a dose of 0.15% (w/w), induced a slowly developing form of hypertension whereas administration of a higher dose (0.3%) induced a more rapidly developing hypertension and the clinical manifestations of malignant hypertension including severe weight loss. Both hypertensive phenotypes were characterised by reduced renal plasma flow, increased filtration fraction, elevated PRA, and increased plasma and intrarenal Ang II levels. These I3C-induced changes in renal haemodynamics, PRA and kidney Ang II levels were more pronounced in Cyp1a1-Ren2 rats with malignant hypertension. Chronic administration of the AT 1 -receptor antagonist,

Renal tissue angiotensin I (Ang I) and II (Ang II) content and angiotensin converting enzyme activity were assessed in both kidneys during initial (7 days) and maintenance (25 days) phases of two-kidney, one clip hypertension in rats. At 7 and 25 days, systolic arterial pressure was 146±2 and 170±7 mm Hg, respectively. After 7 days, Ang I content of clipped kidneys was 64% and 70% higher (p< 0.001) than in nonclipped and sham-operated kidneys, respectively, when compared with levels in kidneys from sham-operated rats. In kidneys harvested 25 days after clipping one renal artery, Ang I and Ang II contents in clipped kidneys were increased 102% and 24% (p<0.01), respectively. Ang II content was also 32% higher in nonclipped kidneys. Angiotensin converting enzyme activity in nonclipped kidneys was greater (/?<0.05) than that in either clipped (46% higher) or sham-operated kidneys (57% higher). Plasma Ang I and Ang II levels were elevated at 7 days bat were not different at 25 days in clipped rats. These results demonstrate a dissociation between intrarenal and circulating levels of Ang I and Ang II and suggest that qualitatively different mechanisms may be responsible for the elevated intrarenal Ang II levels during the initial and maintenance phases of renal hypertension. (Hypertension 1992^0:763-767) KEY WORDS • renin-angjotensin system • hypertension, renal • hypertension, renovascnlar • angiotensin I • angiotensin II • kininase II T here is now considerable evidence demonstrating a close relation between the renin-angiotensin system (RAS) and the development of hypertension in the two-kidney, one clip (2K1C) Goldblatt hypertensive rat model.

In hypertension caused by unilateral renal artery stenosis, the nonstenotic kidney becomes renin depleted but fails to prevent hypertension. The nonstenotic kidney mysteriously develops elevated intrarenal angiotensin II (ANG II) content. Rats chronically infused with ANG II exhibit a similar hypertensive process. The augmentation of intrarenal ANG II is due to receptor-mediated internalization and continued ANG II formation, which provide a hypertensinogenic stimulus.