PubMed · 6749415
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L D Dworkin, B M Brenner. 1982. Hormonal influences on glomerular function.. https://doi.org/10.1159/000407062
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Congestive heart failure (CHF) is characterized by sympathetic activation and parasympathetic withdrawal, and the magnitude of sympathoneural activation is associated with adverse outcome. Angiotensin-converting enzyme inhibitor therapy has been shown to reduce mortality and improve prognosis in patients with CHF, but whether this therapy improves cardiac autonomic control is not well known. This double-blind, placebo-controlled, crossover study examines the effects of enalapril on autonomic control in 12 patients with mild to moderate CHF by heart rate variability analysis. Compared with placebo, enalapril increased the SD of all normal RR intervals (SDNN) from 39 +/- 13 to 48 +/- 15 ms (p < 0.01), the SD of the average RR intervals for all 5-minute segments from 33 +/- 12 to 42 +/- 15 ms (p < 0.01), and the mean of the SDs of all RR intervals for all 5-minute segments (SDNN index) from 19 +/- 5 to 23 +/- 6 ms (p < 0.01). The root-mean-square successive differences and the percent differences between adjacent RR intervals > 50 ms were also increased from 17 +/- 8 to 21 +/- 8 ms (p < 0.01) and from 1.1 +/- 2.1 to 2.8 +/- 2.9% (p < 0.05). In addition, total, low-frequency, and high-frequency power were increased from 560 +/- 349 to 786 +/- 504 ms2/Hz (p < 0.01), from 125 +/- 107 to 179 +/- 135 ms2/Hz (p < 0.01), and from 46 +/- 32 to 94 +/- 78 ms2/Hz (p < 0.01), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
BACKGROUND: Chronic activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Increasing evidence indicates that other than the circulating RAS, a local RAS exists in several tissues, including the heart. The present study was carried out to quantify cardiac, renal, and pulmonary mRNA levels of renin, angiotensin-converting enzyme (ACE), and types 1 and 2 angiotensin II receptors (AT-1 and AT-2), in rats with different severities of heart failure. METHODS AND RESULTS: Heart failure was induced by the creation of an aortocaval fistula below the renal arteries. Rats with aortocaval fistula either compensate and maintain a normal sodium balance or decompensate and develop severe sodium retention. Six days after placement of the aortocaval fistula, heart weight (normalized to body weight) increased 35% (P < .05) in compensated and 65% in decompensated rats compared with control rats. Plasma renin activity increased 45% (P < .05) in rats in sodium balance and 127% in sodium-retaining rats. Total RNA was extracted from the heart, kidneys, and lungs, followed by reverse transcription-quantitative polymerase chain reaction. Renin mRNA levels in the heart, after 40 cycles, increased 68% (P < .01) and 140% in rats with either compensated or decompensated heart failure, respectively. Renal renin-mRNA levels also increased 130% (P < .05) in decompensated and only 52% (P < .05) in compensated animals. ACE-mRNA increased in a similar pattern in the heart but not in either the kidneys or lungs. Moreover, pulmonary, renal, and cardiac ACE immunoreactivity levels, assessed by Western blot analysis, showed the same trend. AT-1 receptor mRNA levels decreased 54% (P < .05) only in the myocardium of decompensated rats, whereas AT-2 receptor mRNA did not change in any tissue studied. CONCLUSIONS: The development of heart failure is associated with a remarkable increase in the expression of a local RAS in the heart, which may contribute to the pathogenesis of this clinical syndrome.
A series of 4-(heteroarylthio)-2-biphenylyltetrazoles was prepared, and the compounds were examined for their ability to displace [3H]AII from angiotensin II receptors. Analogues that exhibited significant receptor binding affinities at less than 10 microM were investigated further for potential antagonism of angiotensin II-mediated contraction of rabbit isolated aortic rings. Three 4-(heteroarylthio)-2-biphenylyltetrazoles were identified that exhibited sub-micromolar angiotensin II receptor binding affinities. These compounds and two reference agents, saralasin and losartan (DUP-753), exhibited concentration-dependent reversal of angiotensin II contraction in isolated aortic rings parallel to their receptor binding affinities. Molecular modeling studies were conducted to examine the conformational effects of the novel sulfide bridging unit contained in these 4-(heteroarylthio)-2-biphenylyltetrazoles. The biological effects of the sulfide bridge as well as alterations in the heteroaromatic moiety were investigated, and the resulting structure--activity relationships are discussed.