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BackgroundSodium-ibuprofenate in hypertonic saline (NaIHS) administered directly to the lungs by nebulization and inhalation has antibacterial and anti-inflammatory effects with the potential to deliver these benefits to hypoxic patients. We describe a compassionate use program that offered this therapy to hospitalized COVID-19 patients.MethodsNaIHS (50 mg ibuprofen, tid) was provided in addition to standard of care to hospitalized Covid-19 patients until oxygen saturation levels of >94% were achieved on ambient air. Patients wore a containment hood to diminish aerosolization. Outcome data from participating patients treated at multiple hospitals in Argentina between April 04, 2020, through October 31, 2020 are summarized.Results383 patients were treated, including 327 not on mechanical ventilation at baseline (MV) and 56 ICU patients receiving MV. For those not on baseline MV (59±0.8 years), 64% were male, most with at least one recognized risk factor for disease severity, and mean NEWS2 score prior to treatment initiation of 7.0±0.1. The average length of stay (ALOS) was 11.5±0.3 days and length of treatment (LOT) 9.0±0.2 days. In patients on baseline MV (60.6±2.2 years), 69.9% were male, baseline mean NEWS2 Score was 8.8±0.4, ALOS 15.5±1.4 days and LOT 10.5±0.7 days. Reversal of deterioration in oxygenation and NEWS2 scores was observed acutely following initiation of therapy. Overall in-hospital mortality was 10.7% among patients not on MV at baseline, and 19.6% among patients receiving MV at baseline. No serious adverse events were considered related to ibuprofen therapy.ConclusionsTreatment of COVID-19 pneumonitis with inhalational nebulized NaIHS was associated with rapid improvement in hypoxia and vital signs, with no serious adverse events attributed to therapy. Nebulized NaIHS is worthy of further study in randomized, placebo-controlled trials.(ClinicalTrials.gov:NCT04382768).

Cardiovascular risk is very high in CRF, but the underlying mechanisms are not well understood. Traditional cardiovascular risk factors (RF) do not explain the increased risk, and observational studies have observed paradoxical or absent associations between classical RF and mortality in ESRD. CRF studies found that statin therapy does not reduce CV events; these may be the results of “resistant atherosclerosis” observed in these patients. We investigated if carotid total plaque area (TPA) is increased at progressively lower creatinine clearance and whether or not TPA progression is increased in CRF patients not on dialysis. Methods: The Blossom DMO Argentina ethics committee approved the study and informed consent was obtained from each participant. We performed a cohort study in 201 patients with Normal Renal Function (NRF), Stage 2 and 3 CRF. Clinical, laboratory tests and TPA were determined at time 0 and after 1 year. TPA was measured using carotid ultrasonography. Renal function (eGFR) was determined by the MDRD equation. The Study population was divided into quartiles of eGFR. Results: 1 st Quartile, (51±1yo, eGFR 89±2 ml/min) had a blood pressure (BP) of 136±2/81±1 mmHg, BMI 31±1, Total Chol (tChol) 196±6 mg/dl, HbA1c 6.7±0.4% and had the lowest Chol 192±5 mg/dl, HbA1c 6.2±0.1% and TPA 47±6mm 2 ; 3 rd Quartile, (59±1yo, eGFR 63±1 ml/min) BP 133±2/82±1, tChol 192±5 mg/dl, HbA1c 6.2±0.1% and TPA 47±6mm 2 ; 4 th Quartile (60±2yo, eGFR 52±1 ml/min) BP 140±3/84±1, tChol 209±5 mg/dl, HbA1c 6.2±0.1% and TPA 76±11mm 2 . After one year, the 4 th Quartile had the most progression of TPA ( p < 0.005); it was not influenced by age, hypertension, smoking, dyslipidemia or diabetic status. Conclusions: In CRF, TPA increases as renal function decreases; its progression is not associated with traditional risk factors. Other mechanisms are responsible for the observed excess of cardiovascular disease in CKD. Determination of TPA should be used to measure effects of antiatherosclerotic therapy to decrease the enormous cardiovascular event rate observed in this population.

Although the positive family history for premature cardiovascular events has been considered a putative risk factor for decades, it has not been incorporated along with other established risk factors such as hyperlipidemia, hypertension, and cigarette smoking in the daily clinical practice when physicians evaluates the cardiovascular risk of a patient. One of the reason may be the presence of multiple risk factors coexisting during these evaluations. The objective of this research was to investigate if patients with a family history of premature cardiovascular events have higher total plaque area than patients without it, in the absence of other classical risk factors. Design and method: Patients from the primary prevention database of Blossom DMO program were identified to have positive family history of premature cardiovascular events (FHPCVE). After apply excluding criteria (absence of any classical risk factor) 23 patients qualified. A control group was generated reaching same data in variables (blood pressure, age, body weight, LDL cholesterol), except carotid total plaque area which was reported at the end of groups formation, once both groups were formed. We used the same definition as the Framingham study (family history of Results: The group with FHPCVE was similar to the control group. Age 59±2 sv 60±1 yo, blood pressure 126±2/75±1 mmHg vs 127±1/74±1 mmHg, body mass index, 23±1 vs 24±1 Kg/cm 2 and LDL cholesterol 116±15 vs 139±20 mg/dl. When total plaque area was determined by Doppler, patients with FHPCVE had a TPA of 49±8 mm 2 while control group 33±4 mm 2 (p Conclusions: Our data indicates that patients with positive family history for premature cardiovascular events have larger total plaque area than patients without it, indicating enhanced risk to develop a cardiovascular event, even in the absence of other classical risk factor. Physicians should identify early and treat accordingly these patients to prevent arterial deterioration.

During hypertension kidney fails to maintain Na balance, leading to increased blood volume and blood pressure. It has been suggested that humoral defects and in the last decade in Na transport disorders have been described in different tubular segments. Our aim was to investigate the interaction between antidiuretic hormone (ADH) and angiotensin II (Ang II) in oxygen consumption (QO2, as a marker of Na transport ) in the loop of Henle , in normotensive and hypertensive animals. To do that we used suspensions of thick ascending limbs of the loop of Henle and and measured QO2, cAMP and superoxide production. We found that In normotensive animals, the basal QO2 was 112 ± 5 nmol O2/min/mg protein. ADH (1 nM) increased QO2 227% compared to baseline values. In the presence of ADH and Ang II (1 nM) initially decreased QO2 with a subsequent recovery (279 ± 17 nmol O2/min/mg protein). ADH increased cAMP levels, whereas Ang II decreased it. In contratst, ADH caused no effect in superoxide levels in thick ascending limbs of normotensive and increased after 3.3 minutes incubation. In hypertensive rats, the QO2 was stimulated by 98% after ADH. In these rats, and Ang II + ADH produced an initial decrease QO2 and a subsequent over-stimulation by ADH (184 % increase , p

Coronary heart disease (CHD) is the leading cause of death among women. Currently, global risk assessment derived by a Framingham risk equation is used to identify women at increased risk, but still we do not detect them early enough to decrease the rate of cardiovascular events. Perhaps we overestimate their protection during the premenopausal and early postmenopausal years, and overestimate the sensitivity of risk scores. Methods: A descriptive cross-sectional study in primary prevention in 1256 women (age 19-84) from Argentina. FRS with body mass index (FRSbmi) and PTP-TPA were used for the evaluation. TPA by ultrasound was determined as previously described by Spence et al (Stroke 2002;33;2916-2922). Patients were divided into DMII (n=293) and control groups (n=963) and then each group was divided according to age, Results: No difference was observed between the incidence of smoking, Hypertension or presence of early family cardiovascular event in DM II and control group. DM II patients had higher TPA vs. control group at all ages. FRSbmi was higher in the DM II group at all age groups. PTP-TPA score for DM II 60 groups were 10±3, 27±4, 48±3, 73±1 respectively while in control group were 3±1, 9±1, 23±1, and 50±1 respectively. These data indicate that DM II women in premenopausal or first years of menopausal age (40-50 years) are at intermediate or high risk to develop a cardiovascular event while non-diabetic women reach this PTP-TPA risk after age 50. CONCLUSION: In our population, diabetic women after age 40 should be considered at possibly high risk of cardiovascular events compared with a non-diabetic group. Direct assessment of atherosclerotic burden, such as TPA, should be used early in this population, even in the presence of menstrual cycles, instead of relying on traditional risk scores.

The onset of symptoms of coronary heart disease in women are displaced a decade compared with men after menopause, but currently there are reports in which 1 in 4 women is less than 59 years, suggesting that in the pre-menopausal period there is marked progression of vascular disease. Therefore we evaluated the presence of atherosclerotic disease in primary care menopausal women. Additionally, we hypothesized that the strict control of the traditional risk factors is not enough to prevent vascular disease progression. Methods, post-menopausal women without cardiovascular events from Argentina were evaluated. Framingham risk score with body mass index (FRSbmi) and carotid ultrasound were employed for the evaluation. Carotid total plaque area (TPA) by ultrasound was determined as previously described by Spence et al (Stroke 2002;33;2916-2922). Additionally, LDL cholesterol (LDL), triglycerides (Trig) and HbA1c were measured. All determinations were done on day 1 and after 8 months of treatment. Only patients who achieved all the therapeutic goals (blood pressure (BP) Conclusion, these results indicate that in the presence of controlled traditional risk factors, atherosclerosis may progress in some patients, including in menopausal women. Additional promoters of atherosclerosis should be evaluated in these progressive patients or possibly more intensive treatment should be used in such patients.

Nitric oxide (NO) reduces blood pressure in vivo by two mechanisms, vasodilation and increasing urinary volume: however, the exact mechanism by which it increases urinary volume is not clear. We hypothesized that NO inhibits antidiuretic hormone (ADH)-stimulated fluid reabsorption (J(r)) by the isolated rat cortical collecting duct (CCD) by decreasing water permeability (Pf) and sodium reabsorption (Jna). In the presence of 10(-11) MADH, Jv was 0.15 +/- 0.04 nl.min-1.mm-1; after 10(-6) M spermine nonoate (SPM) was added to the bath. Jv decreased to 0.06 +/- 0.03 nl.min-1.mm-1 (P < 0.03). To investigate whether the inhibition of Jv was the result of decreased Pf and/or Jna, we first tested the effect of SPM on ADH-stimulated Pf. Basal Pf was stimulated to 289.2 +/- 77.3 microns/s after 10(-11) M ADH was added to the bath (P < 0.01). SPM decreased Pf to 159.8 +/- 45.0 microns/s (P < 0.05). To ensure that this effect on Pf was due to NO release, we used another NO donor, nitroglycerin (NTG). Pf was initially -25.8 +/- 18.3 microns/s and increased to 133.9 +/- 30.5 microns/s after addition of 10(-11) M ADH (P < 0.002). NTG, 20 microM, lowered Pf to 92.4 +/- 18.4 microns/s (P < 0.02). In the presence of 10(-9) M ADH, NTG also decreased Pf(P < 0.04). Next we investigated the effect of SPM on ADH-stimulated JNa. In the presence of ADH, JNa was 37.8 +/- 7.3 pmol.min-1.mm-1. After SPM was added, it dropped to 24.3 +/- 5.1 pmol.min-1.mm-1 (P < 0.05). Time controls exhibited no change in ADH-stimulated Jv, Pf, or Jna. We concluded that 1) NO decreases ADH-stimulated water and sodium transport in the isolate CCD, and 2) water reabsorption is inhibited by a primary effect on Pf. A direct effect of NO on the CCD may explain its natriuretic and diuretic effects observed in vivo.

Indirect evidence suggests that nitric oxide inhibits sodium reabsorption by the collecting duct; however, direct evidence is lacking. It was hypothesized that endothelium-derived nitric oxide inhibits sodium flux in the cortical collecting duct by blocking amiloride-sensitive sodium channels. Tubules were obtained from Sprague-Dawley rats pretreated with deoxycorticosterone acetate (5 mg/rat i.m.) 5 to 9 days before the experiment. Nitric oxide was added to the system by either the addition of endothelial cells and the induction of the release of nitric oxide via acetylcholine (10(-7) M) or by the addition of nitric oxide donors. Acetylcholine-induced nitric oxide release from endothelial cells decreased lumen-to-bath sodium flux by 24 +/- 7% (N = 3; P < 0.05). The addition of the nitric oxide donor, spermine NONOate (10(-5) M), decreased net sodium flux 68% from 10.1 +/- 2.0 to 3.6 +/- 2 pmol/mm.min (N = 5; P < 0.025). To assure that the inhibition of sodium flux was due to nitric oxide, another donor, nitroglycerin (2 x 10(-5) M), was used, which decreased sodium flux by 43%. Luminal amiloride (10 microM) decreased net sodium flux by 83% (from 14.8 +/- 1.2 to 2.4 +/- 0.7 pmol/mm.min; N = 5; P < 0.025). The addition of nitric oxide via spermine NONOate to tubules decreased intracellular sodium levels by 26% (N = 6; P < 0.005). The Na(+)-K+ATPase activity of spermine NONOate-treated tubules was 14.7 +/- 3.2 pmol/mm.min compared with the control value of 10.2 +/- 2.0 pmol/mm.min. Nitroglycerin did not significantly affect pump activity either.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial natriuretic factor (ANF) inhibits fluid absorption (Jv) in the proximal straight tubule (PST) only after stimulation with angiotensin II (ANG II). To investigate ANF's dependency on ANG II for transport inhibition, we blocked and mimicked angiotensin's second messenger cascades and then examined ANF's ability to inhibit Jv. ANG II (10(-10) M)-stimulated Jv was 0.47 +/- 0.10 nl.mm-1. min-1. After ANF (10(-10) M) was added to the bath, Jv fell by approximately 40% (P < 0.05). ANG II stimulates Jv via activation of protein kinase C (PKC) and decreasing protein kinase A (PKA) activity. We inhibited PKA with H-89. In the presence of only H-89, Jv was 0.75 +/- 0.11 nl.mm-1.min-1. After ANF was added to the bath Jv fell by 30% (P < 0.05). Intracellular adenosine 3',5'-cyclic monophosphate content was not affected by ANF in the presence of ANG II. ANF could not inhibit Jv in the presence of ANG II and 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor. KT-5823, a guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase inhibitor, blocked the action of ANF on Jv (P > 0.30). PKC inhibition did not prevent the decrease in Jv induced by ANF. We conclude that ANF inhibits ANG II-induced stimulation of transport by a mechanism that requires phosphorylation mediated by cGMP-dependent protein kinase subsequent to a decrease of PKA activity.

Background: Ultrasound measurement of carotid plaque area (TPA) is a noninvasive method for identifying patients at higher risk of cardiovascular events. Previous studies demonstrated that intensive medical therapy reduces TPA. In this study we examined effects of less intensive therapy on TPA, and the usefulness of TPA in risk stratification. Methods. Baseline Framingham Risk Score (FRS), TPA, blood pressure (BP), body mass index and the post test probability using TPA (PtP TPA) were determined from patients at the primary care unit. TPA measurements were reported to primary physicians to encourage them to follow preventive guidelines. After 10±1 months patients were reevaluated to investigate changes from baseline. Results: among 140 patients enrolled between July 2009, and July 2011, 52% were male, BP was 142±1/81±1 mmHg, BMI 29±1 kg/m2, FRS 24±1, PtP TPA 50±2, and TPA 97±7 mm2. After 10±1 months of treatment, three groups were identified. Group 1 had a reduction of TPA (127±13 to 99±12 mm2, p Conclusions: Plaque measurement may be useful for targeting preventive therapy and evaluating new treatments and response to therapy, and may improve cost-effectiveness of secondary preventive treatment.

Abstract —The factor responsible for salt sensitivity of blood pressure in Dahl rats is unclear but presumably resides in the kidney. We tested the hypotheses that (1) thick ascending limbs of Dahl salt-sensitive rats (DS) absorb more NaCl than those of Dahl salt-resistant rats (DR) and (2) NO inhibits transport to a lesser extent in thick ascending limbs from DS. We found that basal chloride absorption (J Cl ) by thick ascending limbs from DR was 105.8±10.0 pmol · mm −1 · min −1 (n=6). Ten and 100 μmol/L spermine NONOate, an NO donor, decreased J Cl in DR to 65.8±8.5 and 46.8±7.0 pmol · mm −1 · min −1 , respectively. Basal J Cl in DS was 131.6±13.4 pmol · mm −1 · min −1 (n=7). In DS, 10 and 100 μmol/L spermine NONOate decreased J Cl to 111.5±12.8 and 46.8±6.2 pmol · mm −1 · min −1 , respectively. No difference was observed in basal or NO-inhibited Na absorption by cortical collecting ducts or in basal or NO-inhibited oxygen consumption by inner medullary collecting ducts. Because NO acts via generation of cGMP, we measured cGMP production by thick ascending limbs from DS and DR to see whether a difference in cGMP production could account for the difference in basal or NO-inhibited transport. Basal rates of cGMP production were similar between the 2 strains. Although NO increased cGMP production by thick ascending limbs from both strains, no difference existed between DS and DR. We concluded that the reduced ability of NO to block transport in thick ascending limbs in DS may account for at least part of the salt sensitivity of blood pressure in this strain.

Abstract Nitric oxide has a diuretic effect in vivo. We have shown that nitric oxide inhibits antidiuretic hormone–stimulated osmotic water permeability in the collecting duct; however, the mechanism by which this occurs is unknown. We hypothesized that inhibition of antidiuretic hormone–stimulated water permeability by nitric oxide in the collecting duct is the result of activation of cGMP-dependent protein kinase, which in turn decreases intracellular cAMP. To test this hypothesis, we microperfused cortical collecting ducts. Antidiuretic hormone–stimulated water permeability was 317±47 μm/s ( P P P P

The effect of angiotensin 1-7 (Ang 1-7) on the proximal tubule has not been well studied. It was hypothesized that Ang 1-7 has a biphasic effect on fluid absorption in the isolated rat proximal straight tubule. Proximal straight tubules were perfused at a rate of 5.81 +/- 0.44 nL/mm per minute and absorbed fluid at 0.98 +/- 0.10 nL/mm per minute. Bicarbonate absorption was 80.1 +/- 11.6 pmol/mm per minute. When 10(-12) M Ang 1-7 was added to the bath, fluid absorption increased to 1.47 +/- 0.10 nL/mm per minute (P0.013) and bicarbonate increased to 115.0 +/- 12.8 pmol/mm per minute (P0.004). Ang 1-7 had no effect on either the maximum rate of bicarbonate absorption (P0.90) or bicarbonate permeability (P0.60). Next, 10(-8) M Ang 1-7 was used. During the control period, fluid absorption was 0.90 +/- 0.09 nL/mm per minute. When 10(-8) M Ang 1-7 was added, fluid absorption decreased to 0.62 +/- 0.04 nL/mm per minute (P0.05). DuP 753, an AT1 receptor antagonist, blocked both effects induced by Ang 1-7, whereas PD 123319, an AT2 receptor antagonist, did not block the stimulatory effect. From these data, it was concluded that Ang 1-7 binds AT1 receptors and has a biphasic effect on fluid absorption, and at physiologic levels, the heptapeptide induces the stimulation of bicarbonate absorption.

The effect of endothelin-1 (ET-1) on the proximal tubule remains unclear. This may be due to a biphasic effect on transport in this segment. We hypothesized that ET-1 has a biphasic effect on fluid absorption (Jv) in the proximal straight tubule and that its inhibitory effect is superimposed on its stimulatory effect. ET-1 (10(-13) M) stimulated Jv from 0.68 +/- 0.07 to 1.11 +/- 0.20 nl/mm/min, a 60% increase (P < 0.04). 10(-12) and 10(-10) M ET-1 had no significant effect. 10(-9) M ET-1 reduced Jv from 0.81 +/- 0.19 to 0.44 +/- 0.15 nl/mm/min (P < 0.009). Staurosporine (STP, 10(-8) M) prevented both 10(-9) and 10(-13) M ET-1 from altering Jv significantly indicating that protein kinase C (PKC) is involved. Indomethacin (10(-5) M) blocked the inhibition produced by 10(-9) M ET-1. ETI (10(-6) M), a lipoxygenase inhibitor, also blocked ET-1 inhibition of Jv. Interestingly ET-1 (10(-9) M) stimulated Jv in the presence of both indomethacin and ETI. When 10(-9) M ET-1 was added in the presence of 10(-5) M quinacrine, a phospholipase (PL) inhibitor, Jv also increased from 1.02 +/- 0.20 to 1.23 +/- 0.22 nl/mm/min (P < 0.03). STP blocked this increase. We conclude that (a) 10(-13) M ET-1 stimulates fluid absorption by activating PKC; (b) 10(-9) M ET-1 decreases Jv by PKC-, PL-, cyclooxygenase-, and lipoxygenase-dependent mechanisms; and (c) the inhibitory effect of ET-1 on Jv is superimposed on the stimulatory effect.