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PubMed1977

Blockade of renin or angiotensin for understanding human hypertension: a comparison of propranolol, saralasin and converting enzyme blockade.

To understand the role of the renin-angiotensin-aldosterone system in the pathogenesis of human hypertension, in serial studies we have blocked the system using three different pharmacologic probes: 1) reduction of renin secretion by administration of the beta receptor blocker, propranolol; 2) blockade of the action of angiotensin II by infusion of saralasin, a competitive antagonist of angiotensin II; and 3) blockade of the enzymatic conversion of angiotensin I to angiotensin II by infusing a nonapeptide competitive inhibitor. The depressor responses induced by either propranolol or the nonapeptide expose a significant to major involvement of excess renin--angiotensin in maintaining the hypertension of some 50 to 70% of common forms of hypertension including "essential" hypertension. This subgroup includes nearly all patients with high or "normal" renin--sodium profiles. The considerably lower estimates for a renin factor in essential hypertension suggested by saralasin testing now appear due to the partial agonism of this drug. Further studies are required to determine whether this relative or absolute excess of renin secretion is primarily involved in the hypertension and if not why it fails to shut itself off. Similar studies of normal subjects are also needed to determine whether renin support of blood pressure is proportionately greater or less than in hypertensive subjects. Meanwhile the validation provided by these three different pharmacologic probes portends a burgeoning clinical role for renin--sodium profiling not only in screening for renal and adrenal cortical hypertensions but also for characterizing the vasoconstrictor and volume elements involved in various individual patients and thus enabling more specific treatments of the various subtypes of essential hypertension.

Aldosterone↗
PubMedDate not supplied

[Properties and action specificity of carboxycathepsin (peptidyl dipepsidase) from bovine kidneys].

Carboxycathepsin from bovine kidney split the dipeptide fragments from the C-terminal part of peptides of different structure. Peptides containing the proline residue at the second position from the C-terminal amino acid residue and also peptides with substituted terminal alpha-carboxyl group were not hydrolyzed by carboxycathepsin. The enzyme was activated by Cl, Zn2+, Co2+ and Mn2+. The substances which formed the chelate complexes with ions of two-valent metals and also heavy metal ions, inhibited the enzymatic activity. Diisopropyl fluorophosphate did not inhibit carboxycathepsin. The homogeneous preparation of carboxycathepsin converted angiotensin 1 into angiotensin 11 and hydrolyzed bradikinine, splitting off C-terminal dipeptides consequentially.

Angiotensin II↗
PubMed1978

Antihypertensive activity in rats for SQ 14,225, an orally active inhibitor of angiotensin I-converting enzyme.

SQ 14,225 (D-3-mercapto-2-methylpropanoyl-L-proline) markedly lowered the blood pressure of the renin-dependent aortic-ligated and two-kidney Goldblatt hypertensive rat and failed to reduce blood pressure in the one-kidney Goldblatt hypertensive rat. In the two-kidney Goldblatt rat, SQ 14,225 (p.o.) was about 10 times as potent as teprotide, the nonapeptide SQ 20,881 (s.c.). Oral doses of SQ 14,225 moderately reduced the blood pressure of the Wistar-Kyoto spontaneously hypertensive rat but not that of the normotensive Wistar-Kyoto rat. Bilateral nephrectomy abolished the antihypertensive activity of SQ 14,225 in the spontaneously hypertensive rat. SQ 14,225 and SQ 20,881 elicited parallel dose-response curves in the two-kidney renal hypertensive rat. Post-treatment of spontaneously hypertensive rats with either agent failed to augment the antihypertensive effect produced by effective doses of the other agent. The results suggest that SQ 14,225 acts primarily by inhibiting the renin-angiotensin system to reduce elevated blood pressure, especially in presumably renin-dependent models of hypertension.

Administration, Oral↗
PubMed1977

The immediate pressor response to saralasin: a measure of the degree of angiotensin II vascular receptor vacancy.

(1) An immediate pressor response so saralasin, 10 microgram/kg/min, occurred in 52 of 57 (91%) hypertensive patients. (2) We propose that the amplitude of the immediate pressor response functions as an in vivo measure of the number of initially vacan angiotensin II vascular receptors. (3) The immediate pressor response to saralasin forecasts the subsequent sustained response, both of which are related to the renin-sodium profile. (4) The dual blood pressure responses to saralasin, immediate and sustained, make this drug useful for the pharmacological identification of high, normal, and low renin hypertensive patients as they are presently classified. (5) The ability of saralasin to elevate the BP immediately in most hypertensive patients shows the need for caution in its use. It is a safe drug from this standpoint if very small infusions (0.01-0.10 microgram/kg/min) are first tried in hypertensive patients whose PRA is unknown.

Angiotensin II↗
PubMed2025

Spike protein-induced VSIR-ISX signaling disrupts metabolic homeostasis and promotes COVID-19-related immune dysfunction.

COVID-19 has caused millions of deaths worldwide since 2019. Vaccination has reduced both transmission and disease severity. However, emerging viral variants have weakened vaccine effectiveness, highlighting the need for new antiviral therapies. This study examines how the SARS-CoV-2-Spike protein (SARS-2-S) induces the VSIR-ISX signaling pathway, leading to metabolic disturbances that may worsen disease progression. Using RNA sequencing, we found that SARS-2-S expression in pulmonary cells activates genes involved in tryptophan and arachidonic acid (AA) metabolism, altering bioactive mediators like kynurenine and prostanoids, which are crucial for inflammation and immune responses. Mechanistically, the ACE2-MYD88 pathway, activated by SARS-2-S, enhances the VSIR-ISX axis through NF-κB signaling, driving these metabolic disruptions. Chromatin immunoprecipitation and genome sequencing revealed that ISX, activated via VSIR-MAPK signaling, upregulates enzymes involved in AA metabolism by binding directly to their gene promoters. Notably, disrupting the VSIR-ISX axis using shRNA interference or NF-κB inhibitors effectively mitigated these metabolic disturbances. Our findings suggest that the VSIR-ISX pathway could be a promising therapeutic target for treating COVID-19 by addressing virus-induced metabolic disruptions.

Humans↗
PubMed2025

Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.

BACKGROUND & AIMS: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake. METHODS: Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus. RESULTS: We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib. CONCLUSION: Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

Humans↗
PubMed1976

Kinetic properties of pulmonary angiotensin-converting enzyme. Hydrolysis of hippurylglycylglycine.

Some of the kinetic properties of angiotensin-converting enzyme (peptidyl-dipeptide hydrolase, EC 3.4.15.1) purified from hog lung have been determined using hippurylglycylglycine as substrate. The effects of pH and ionic environment on enzyme activity are complex and interdependent. At 0.1 M NaCl, the pH-activity curve shows an abrupt decrease in V/Km as the pH rises from 6 to 6.5, implying that ionization of a group in the enzyme with a pK in this range aids in binding of the substrate. Chloride is required for enzyme activity; there are two phases in the effect of NaCl. At both pH 6 AND 8, THE FIRST PHASE (UP TO 0.1 M NaCl) is activation. The second phase (above 0.1 M) at pH 6 is inhibition, while at pH 8 there is further activation which appears to be dependent upon ionic strength rather than a specific Cl-effect. Activation by cobalt and inhibition by EDTA are somewhat more effective at pH 6 than at pH 8. The nonapeptide inhibitor less than Glu-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro is nearly equipotent at both pH 6 and 8, but Arg-Pro-Pro is more inhibitory at pH 8 than at pH 6.

Animals↗
PubMed2024

TMPRSS2-mediated SARS-CoV-2 uptake boosts innate immune activation, enhances cytopathology, and drives convergent virus evolution.

The accessory protease transmembrane protease serine 2 (TMPRSS2) enhances severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uptake into ACE2-expressing cells, although how increased entry impacts downstream viral and host processes remains unclear. To investigate this in more detail, we performed infection assays in engineered cells promoting ACE2-mediated entry with and without TMPRSS2 coexpression. Electron microscopy and inhibitor experiments indicated TMPRSS2-mediated cell entry was associated with increased virion internalization into endosomes, and partially dependent upon clathrin-mediated endocytosis. TMPRSS2 increased panvariant uptake efficiency and enhanced early rates of virus replication, transcription, and secretion, with variant-specific profiles observed. On the host side, transcriptional profiling confirmed the magnitude of infection-induced antiviral and proinflammatory responses were linked to uptake efficiency, with TMPRSS2-assisted entry boosting early antiviral responses. In addition, TMPRSS2-enhanced infections increased rates of cytopathology, apoptosis, and necrosis and modulated virus secretion kinetics in a variant-specific manner. On the virus side, convergent signatures of cell-uptake-dependent innate immune induction were recorded in viral genomes, manifesting as switches in dominant coupled Nsp3 residues whose frequencies were correlated to the magnitude of the cellular response to infection. Experimentally, we demonstrated that selected Nsp3 mutations conferred enhanced interferon antagonism. More broadly, we show that TMPRSS2 orthologues from evolutionarily diverse mammals facilitate panvariant enhancement of cell uptake. In summary, our study uncovers previously unreported associations, linking cell entry efficiency to innate immune activation kinetics, cell death rates, virus secretion dynamics, and convergent selection of viral mutations. These data expand our understanding of TMPRSS2's role in the SARS-CoV-2 life cycle and confirm its broader significance in zoonotic reservoirs and animal models.

SARS-CoV-2↗
PubMed1978

Canine pulmonary angiotensin-converting enzyme. Physicochemical, catalytic and immunological properties.

Antiontensin-converting enzyme (peptidyldipeptide hydrolase, EC 3.4.15.1) has been solubilized from canine pulmonary particles and purified to apparent homogeneity. A value of approx. 140000 was estimated for the molecular weight of the native and the reduced, denatured forms of the enzyme. No free NH2-terminal residue was detected by the dansylation procedure. Carbohydrate accounted for 17% of the weight of the enzyme, and the major residues were galactose, mannose and N-acetylglucosamine with smaller amounts of sialic acid and fucose. Removal of sialic acid residues with neuraminidase did not alter enzymatic activity. The enzyme contained one molar equivalent of zinc. Addition of this metal reversed stimulation and inhibition of activity observed in the presence of Co2+ and Mn2+, respectively. Immunologic homology of pure dog and rabbit enzymes was demonstrable with goat antisera. Fab fragments and intact IgG antibodies displayed similar inhibition dose vs. response curves with homologous enzyme, whereas the fragments were poor inhibitors of heterologous activity compared to the holoantibodies. The canine glycoprotein was much less active than the rabbit preparation in catalyzing hydrolysis of Hip-His-Leu. In contrast, the two enzymes exhibited comparable kinetic parameters with angiotensin I as substrate.

Amino Acid Sequence↗