Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis.

Abstract

The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of reninangiotensin system components in the heart with the levels in blood plasma in healthy pigs and 30 hours after nephrectomy. Angiotensin I (Ang I)-generating activity of cardiac tissue was identified as renin by its inhibition with a specific active site-directed renin inhibitor. We took precautions to prevent the ex vivo generation and breakdown of cardiac angiotensins and made appropriate corrections for any losses of intact Ang I and II during extraction and assay. Tissue levels of renin (n=ll) and Ang I (n=7) and II (n=7) in the left and right atria were higher than in the corresponding ventricles (P< .05). Cardiac renin and Ang I levels (expressed per gram wet weight) were similar to the plasma levels, and Ang II in cardiac tissue was higher than in plasma (P<.05). The presence of these renin-angiotensin system components in cardiac tissue therefore cannot be accounted for by trapped plasma or simple diffusion from plasma into the interstitial fluid. Angiotensinogen levels (n=ll) in cardiac tissue were 10% to 25% of the A ngiotensin I (Ang I) is produced in the circulating / \ blood by the action of renin from the kidney on -Z A . angiotensinogen produced by the liver. Ang I is converted to Ang II, a potent vasoconstrictor, by angiotensin-converting enzyme (ACE) located on the luminal surface of the vascular endothelium. It is now well established that Ang I and II are not only produced in the blood compartment but also locally in tissues. Recent evidence suggests that complete local reninangiotensin systems (RAS) are present in a number of organs, for instance, kidney, adrenal gland, and ovary. 13In such local RAS, the production of Ang I and II is thought to depend on in situ synthesized renin rather than plasma-derived renin.A local cardiac RAS has also been postulated. 4 ' 5 However, direct evidence for Ang I and II production in the heart by in situ synthesized renin is still lacking. Renin mRNA levels in the heart are usually low and can be detected only by polymerase chain reaction. 68 Early studies showed Ang I-generating activity in left ventric-

Biochemical properties of renin and prorenin binding to the (pro)renin receptor

“…The (P)RR mRNA has been reported to express in many organs, for example the kidney, heart, brain, eye, adipose tissue and vascular smooth muscle cells, 25,34 and thus it may help to accumulate renin and prorenin locally in tissues even though lacking components of RAS, that is, in the heart and vasculature wall. 36,37 Therefore, receptor-associated both renin and prorenin have been proposed to potentially activate tissue-specific RAS in an angiotensin-II-dependent manner ( Figure 1). As plasma prorenin level is higher than renin, thus it is suggested that prorenin may have a major role in this regard.…”

Blocking the tissue renin-angiotensin system: the future cornerstone of therapy

“…Although it is still controversial whether active renin is derived directly from the kidney or synthesised locally in the heart or blood vessels, 40,41 all other major components of the RAS have been localised in the heart and blood vessels. Thus, both circulating and tissue angiotensins play important roles in cardiovascular homeostasis.…”

“…The cascade induced by phospholipase D leads to the formation of fatty acids such as arachidonic acid, which is a precursor of leukotrienes and prostaglandins. 40 In addition, angiotensin II-induced cell hypertrophy and hyperplasia are both mediated through the AT 1 receptor. Protein kinase C as well as elevated intracellular calcium levels have been shown to promote growth-related inducible transcriptional factors such as c-fos, c-myc and c-jun involved in the stimulation of mitogenesis.…”

High-affinity prorenin binding to cardiac man-6-P/IGF-II receptors precedes proteolytic activation to renin

“…Although initially it was thought that this generation depends on the de novo synthesis of renin in the heart, it is now well established that such synthesis does not occur either under normal circumstances (13,24,34,35,40,56) or under pathological conditions (14,31,50). Therefore, the heart must sequester renin from the circulation to synthesize ANG II locally.…”