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Bioactive plant peptides have received considerable interest as potential antihypertensive agents with potentially fewer side effects than antihypertensive drugs. Here, the blood pressure-lowering effects of the Bowman-Birk protease inhibitor, BTCI, and its derived peptides, PepChy and PepTry, were investigated using normotensive (Wistar-WR) and spontaneously hypertensive rats (SHR). BTCI inhibited the proteases trypsin and chymotrypsin, respectively, at 6 µM and 40 µM, a 10-fold greater inhibition than observed with PepTry (60 µM) and PepChy (400 µM). These molecules also inhibited angiotensin converting enzyme (ACE) with IC 50 values of 54.6 ± 2.9; 24.7 ± 1.1; and 24.4 ± 1.1 µM, respectively, occluding its catalytic site, as indicated by molecular docking simulation, mainly for PepChy and PepTry. Gavage administration of BTCI and the peptides promoted a decrease of systolic and diastolic blood pressure and an increase of renal and aortic vascular conductance. These effects were more expressive in SHR than in WR. Additionally, BTCI, PepChy and PepTry promoted coronary vasodilation and negative inotropic effects in isolated perfused hearts. The nitric oxide synthase inhibitor blunted the BTCI and PepChy, with no cardiac effects on PepTry. The findings of this study indicate a therapeutic potential of BTCI and its related peptides in the treatment of hypertension.

This study was undertaken to delineate the mechanism of the effect of diphenylhydantoin (DPH) on renal renin release. DPH at a dose of 0.18 mg X kg-1 X min-1 was infused for 30 min into the renal artery of anesthetized dogs with acute unilateral renal denervation. In the innervated kidney, DPH infusion increased renin secretion rate (RSR) from 189 +/- 54 to 939 +/- 279 ng ANG I X h-1 X min-1. In the contralateral denervated kidneys, RSR did not change. An identical study was done in a second group of dogs in which unilateral renal denervation was done 24 h prior to DPH infusion. In this group, DPH infusion increased RSR from 63 +/- 57 to 643 +/- 180 ng ANG I X h-1 X min-1 in the innervated kidneys. In the contralateral denervated kidneys, RSR did not change. In a separate group of indomethacin-treated nondenervated dogs, intrarenal infusion of DPH increased RSR from 131 +/- 32 to 452 +/- 88 ng ANG I X h-1 X min-1. The percent increase in RSR in the indomethacin-treated dogs was not significantly different from the non-indomethacin-treated dogs. These data suggest that the stimulatory effect of DPH on renin release is mediated by or requires the presence of renal nerves. The step(s) after the renal nerves is (are) not mediated by prostaglandins.

Background: Individuals born preterm present left ventricle changes and increased risk of cardiac diseases and heart failure. The pathophysiology of heart disease after preterm birth is incompletely understood. Mitochondria dysfunction is a hallmark of cardiomyopathy resulting in heart failure. We hypothesized that neonatal hyperoxia in rats, a recognized model simulating preterm birth conditions and resulting in oxygen-induced cardiomyopathy, induce left ventricle mitochondrial changes in juvenile rats. We also hypothesized that humanin, a mitochondrial-derived peptide, would be reduced in young adults born preterm. Methods: Sprague-Dawley pups were exposed to room air (controls) or 80% O 2 at postnatal days 3 to 10 (oxygen-induced cardiomyopathy). We studied left ventricle mitochondrial changes in 4 weeks old males. In a cohort of young adults born preterm (n=55) and age-matched term (n=54), we compared circulating levels of humanin. Results: Compared with controls, oxygen-exposed rats showed smaller left ventricle mitochondria with disrupted integrity on electron microscopy, decreased oxidative phosphorylation, increased glycolysis markers, and reduced mitochondrial biogenesis and abundance. In oxygen-exposed rats, we observed lipid deposits, increased superoxide production (isolated cardiomyocytes), and reduced Nrf2 gene expression. In the cohort, left ventricle ejection fraction and peak global longitudinal strain were similar between groups however humanin levels were lower in preterm and associated with left ventricle ejection fraction and peak global longitudinal strain. Conclusions: In conclusion, neonatal hyperoxia impaired left ventricle mitochondrial structure and function in juvenile animals. Serum humanin level was reduced in preterm adults. This study suggests that preterm birth–related conditions entail left ventricle mitochondrial alterations that may underlie cardiac changes perpetuated into adulthood. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03261609.