Myocardial and plasma renin-angiotensinogen dynamics during pressure-induced cardiac hypertrophy

Abstract

Plasma and left ventricular (LV) renin and angiotensinogen concentrations were assessed in a rat model of pressure-overload cardiac hypertrophy to determine if myocardial levels remained proportional to plasma levels over time. Three days after subdiaphragmatic aortic constriction (AC), LV hypertrophy was evident and renin concentrations in both plasma and LV, although not significantly elevated, were positively correlated with relative cardiac mass. After 42 days AC, LV hypertrophy remained, plasma and LV renin and angiotensinogen levels were not different from shams, and there was no correlation between renin and relative cardiac mass. Furthermore, LV renin and angiotensinogen concentrations remained at ∼25 and 4%, respectively, of those in plasma throughout the experiment. Myocytes from 3-day AC and sham-treated rats contained little renin as did LV from 48-h anephric rats. Incubations using calculated concentrations of myocardial interstitial renin and angiotensinogen revealed significant angiotensin I generation. These data suggest that LV renin in this model varies directly with plasma renin, is confined to the interstitial space, and can generate significant intramyocardial angiotensin I.

Angiotensin II and the Heart

“…Indeed, decreased rather than increased angiotensinogen levels were found in failing human hearts, 62 whereas in infarcted rat hearts or in rat hearts that had been exposed to pressure overload, no changes in angiotensinogen content were observed. 60,74 Finally, with regard to ACE, the findings on changes in mRNA levels in diseased hearts are in full agreement with the findings on changes in its protein levels under these conditions. Cardiac tissue ACE increases after myocardial infarction as well as during pressure and volume overload-induced left ventricular hypertrophy.…”

“…58,59 Therefore, it appears that the renin responsible for cardiac angiotensin generation is renin of renal origin that reaches the heart via the circulation. Renin may enter the heart either through diffusion in the interstitial space 56,60 or through binding to renin receptors. [61][62][63][64] The source of angiotensinogen in the heart is currently unknown.…”

“…The angiotensinogen concentrations present in cardiac tissue are compatible with the idea that angiotensinogen diffuses freely from the blood compartment into the interstitial space. 47,60 Studies in a modified version of the rat Langendorff-perfused heart, allowing the separate collection of coronary effluent and interstitial transudate, showed that angiotensinogen, when added to the perfusion buffer, rapidly entered the interstitial space. 56 At steady state, its levels in interstitial fluid and coronary effluent were comparable.…”

“…Ang II, through its effect on prostaglandin synthesis, 73 will affect this response. Detailed information on myocardial renin-angiotensinogen dynamics during pressure overload-induced cardiac hypertrophy and after myocardial infarction has been obtained by Heller et al 60 and Hirsch et al 74 They found cardiac renin to vary directly with plasma renin under all circumstances. Similarly, the rise in cardiac renin occurring in subjects with end-stage heart failure was accompanied by a parallel increase in plasma renin.…”

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

“…Therefore, the heart must sequester renin from the circulation to synthesize ANG II locally. Renin may diffuse into the interstitial space (18,28) or bind to renin receptors and/or renin-binding proteins (8,46,53). Because renin in blood is predominantly present in the form of its inactive precursor prorenin (11), it is also conceivable that the heart sequesters prorenin instead of renin.…”