PubMed · 14081167
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A G BONFANTE, C J VIETTI. 1963-05-10. [SHOCK; PHYSIOPATHOLOGIC CONSIDERATIONS].. https://pubmed.ncbi.nlm.nih.gov/14081167/
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Much of our knowledge of the influence of the sympathetic nervous system on the control of blood pressure is built on experimental approaches that focus very much on time scales <24 h. Although direct recordings of sympathetic nerve activity (SNA) over short time scales provide important information, it is difficult to place their relevance over the longer term where the development of chronic changes in blood pressure are likely to be a mixture of hormonal, renal, and neural influences. Recently new experimental approaches are now revealing a possible role for arterial baroreceptors in the chronic regulation of SNA. These studies reveal that chronic increases in blood pressure are associated with chronic changes in SNA that may be due to nonresetting of the blood pressure-SNA baroreflex relationship. This review discusses the implications of such information, highlighting new technologies for long-term recording of SNA that appear to hold much promise for revealing the role of SNA to the kidney for the long-term control of blood pressure.
N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural substrate for the N-terminal active site of angiotensin-converting enzyme (ACE). We previously reported that Ac-SDKP prevented cardiac fibrosis in rats with renovascular or aldosterone-salt hypertension. However, it is not clear whether Ac-SDKP reverses cardiac fibrosis in hypertension, nor the mechanism(s) involved. In the present study, we tested the hypothesis that Ac-SDKP reversal of hypertension-induced cardiac fibrosis involves a decrease in transforming growth factor-beta (TGF-beta) and/or connective tissue growth factor (CTGF). In 2-kidney, 1-clip (2K-1C) hypertensive rats, Ac-SDKP at 400 or 800 microg/kg per day SC was started 8 weeks after hypertension and cardiac fibrosis were established and was continued for 8 weeks. Left ventricular (LV) collagen in rats with 2K-1C plus vehicle at 8 and 16 weeks after clipping was similar but higher than in the sham group (P<0.05). Ac-SDKP at 400 and 800 microg/kg per day, which increased plasma Ac-SDKP 2- and 5-fold, respectively, reversed the increase in LV collagen in a dose-dependent manner. The mechanism by which Ac-SDKP reverses LV fibrosis does not appear to depend on ACE inhibition by Ac-SDKP, since we found that Ac-SDKP at various doses did not affect blood pressure responses to exogenous angiotensin I or bradykinin. However, Ac-SDKP reversed the increase in LV TGF-beta and CTGF compared with rats with 2K-1C plus vehicle (P<0.005). We concluded that in hypertension, Ac-SDKP reverses cardiac fibrosis, perhaps due in part to a decrease in TGF-beta and CTGF in the heart.
Beneficial effects of angiotensin II inhibition during inflammatory renal disease may involve both hemodynamic and nonhemodynamic mechanisms. To analyze whether angiotensin II inhibition has protective effects on lupus-like, autoimmune-mediated renal damage in MRL/lpr mice, four groups of mice were treated orally for 6 weeks with: 1) vehicle, 2) enalapril (3.0 mg/kg per day), 3) candesartan cilexetil (5.0 mg/kg), or 4) amlodipine (10 mg/kg) as a blood pressure control (n = 9-12/group). All antihypertensive treatments lowered blood pressure to a similar level compared with vehicle group (enalapril: 99.8 +/- 8.3 mm Hg; candesartan: 101 +/- 9 mm Hg; amlodipine: 103.8 +/- 6.7 mm Hg; vehicle: 113.5 +/- 4.6 mm Hg). Vehicle-treated mice developed a moderate glomerular injury with albuminuria (35.1 +/- 39.0 microg/mg of creatinine). Glomerular lesions consisted of immune complex deposition and mesangial expansion with increased mesangial cell proliferation. Amlodipine treatment had no significant protective effects. In contrast to vehicle- and amlodipine-treated mice, those subjected to angiotensin II blockade with enalapril or candesartan had reduced albuminuria, glomerular expansion, and mesangial proliferation. This was associated with significantly reduced renal chemokine mRNA expression compared with vehicle treatment. Our results show that inhibition of angiotensin II has protective effects on the glomerular damage of MRL/lpr mice that extend beyond hemodynamics and involve down-modulation of glomerular inflammation, reduction of mesangial cell proliferation, and decrease in chemokine expression.