Angiotensin has many different actions, most of which relate, either directly or indirectly, to the regulation of blood pressure, fluid, and electrolyte homeostasis (1, 2). In addition to potent vasoconstrictor effects, actions ofangiotensin on vasculature include the stimulation ofprostaglandin release (3), the modulation of angiotensin receptor number (4), and the stimulation of angiogenesis (5). Angiotensin also has important actions on the central and peripheral nervous systems, the adrenal, kidney, intestine, and heart (6-1 1). Given these multiple diverse actions of angiotensin, two important questions are (a) which of these actions represent normal physiological events, and (b) whether such actions may assume a pathogenic role. These questions have recently been placed in sharper focus by the clinical application of inhibitors of the renin-angiotensin system (RAS),' and in particular, the use of converting enzyme inhibitors (CEIs) for the treatment of hypertension. Any attempt to answer these questions requires an accurate concept ofthe RAS. The purpose of this review is to discuss new concepts concerning angiotensin production by the circulating RAS, how these relate to angiotensin production within tissues, and the possible mechanisms by which CEIs lower blood pressure. The study of tissue angiotensin systems is still at an early stage. In this review I have attempted to synthesize a coherent model of the interaction between the circulating and tissue angiotensin systems, which might assist in the interpretation of new developments in this area.

/pdf/circulating-and-tissue-angiotensin-systems-43t6kf1z4q.pdf

Circulating and tissue angiotensin systems.

To define the role of local synthesis of angiotensinogen in tissue angiotensin production, we have quantitated angiotensinogen messenger RNA (mRNA) levels in 17 different tissues of four groups of rats: control rats, nephrectomized rats, rats given dexamethasone, ethynylestradiol, and triiodothyronine, and nephrectomized rats given dexamethasone, ethynylestradiol, and triiodothyronine. Angiotensinogen mRNA was identified in 12 tissues: liver, kidney, brain, spinal cord, aorta, mesentery, atria, lung, adrenal, large intestine, stomach, and spleen. Angiotensinogen mRNA was not identified in pituitary, ventricle, testis, small intestine, or pancreas. When expressed per gram tissue wet weight, angiotensinogen mRNA levels of extrahepatic tissues were less than 4% of hepatic levels. However, when expressed per milligram total RNA, angiotensinogen mRNA levels of brain, spinal cord, aorta, and mesentery were 26-42% of hepatic levels. Regulation of angiotensinogen mRNA levels was tissue specific. This demonstration of a widespread tissue distribution of angiotensinogen mRNA may indicate a similarly widespread distribution of local angiotensin systems that are independent of the circulating renin-angiotensin system.

/pdf/angiotensinogen-gene-is-expressed-and-differentially-5d8qdoz1pt.pdf

Angiotensinogen gene is expressed and differentially regulated in multiple tissues of the rat.

The missing link in the evidence for an active endogenous renin angiotensin system in the brain has been the demonstration of local angiotensin synthesis in the central nervous system in vivo. In this report the extraction and characterization of angiotensin I and angiotensin II from the brain of rats is described. The accumulation of angiotensin I was enhanced in hypertensive rats when the conversion to angiotensin II was blocked in vivo by the converting enzyme inhibitor captopril.

https://science.sciencemag.org/content/sci/221/4613/869.full.pdf

Angiotensin synthesis in the brain and increased turnover in hypertensive rats

https://www.gastrojournal.org/article/S0016-5085(03)00695-4/pdf

Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II☆

In adult mammalian kidney, cyclooxygenase-2 (COX-2) expression is found in a restricted subpopulation of cells. The two sites of renal COX-2 localization detected in all species to date are the mac...

Physiological regulation of cyclooxygenase-2 in the kidney

The localization of renin, converting enzyme (CE) and angiotensin II (ANG II) in the kidneys of rats and mice was investigated with immunocytochemical methods. According to the presence and specific intrarenal localization of these components of the renin-angiotensin-system (RAS) our results suggest that in addition to the well known systemic effects of the RAS, there are interactions of its components inside the kidney. These interactions may lead to the generation of an extra portion of ANG II in the renal blood stream with its target cells determined by the localization of CE at the luminal side of well defined endothelial areas. These intrarenal-intravasal reactions may or may not reinforce the action of “systemic” ANG II, generated prerenally. In addition, the existence of true intrarenal-interstitial interactions, with the different components and actions of this intrarenal RAS restricted entirely to the kidney is suggested by our results, particularly the demonstration of ANG II within epitheloid cells and the dissociation of systemic renin and ANG II from their local concentrations in renal hypertensive rats.

The intrarenal renin-angiotensin-system. An immunocytochemical study on the localization of renin, angiotensinogen, converting enzyme and the angiotensins in the kidney of mouse and rat.

I. Lockwald

Papers

The intrarenal renin-angiotensin-system. An immunocytochemical study on the localization of renin, angiotensinogen, converting enzyme and the angiotensins in the kidney of mouse and rat.