Grassi, Bruno, L. Bruce Gladden, Michele Samaja, Creed M. Stary, and Michael C. Hogan. Faster adjustment of O 2 delivery does not affect V O 2 on-kinetics in isolated in situ canine muscle. J. Appl. Physiol. 85(4): 1394-1403, 1998.-The mechanism(s) limiting muscle O 2 uptake (V O 2 ) kinetics was investigated in isolated canine gastrocnemius muscles (n ϭ 7) during transitions from rest to 3 min of electrically stimulated isometric tetanic contractions (200-ms trains, 50 Hz; 1 contraction/2 s; 60-70% of peak V O 2 ). Two conditions were mainly compared: 1) spontaneous adjustment of blood flow (Q ) [control, spontaneous Q (C Spont)]; and 2) pump-perfused Q , adjusted ϳ15 s before contractions at a constant level corresponding to the steady-state value during contractions in C Spont [faster adjustment of O 2 delivery (Fast O 2 Delivery)]. During Fast O 2 Delivery, 1-2 ml/min of 10 Ϫ2 M adenosine were infused intra-arterially to prevent inordinate pressure increases with the elevated Q . The purpose of the study was to determine whether a faster adjustment of O 2 delivery would affect V O 2 kinetics. Q was measured continuously; arterial (Ca O 2 ) and popliteal venous (Cv O 2 ) O 2 contents were determined at rest and at 5-to 7-s intervals during contractions; O 2 delivery was calculated as Q ·Ca O 2 , and V O 2 was calculated as Q · arteriovenous O 2 content difference. Times to reach 63% of the difference between baseline and steady-state V O 2 during contractions were 23.8 Ϯ 2.0 (SE) s in C Spont and 21.8 Ϯ 0.9 s in Fast O 2 Delivery (not significant). In the present experimental model, elimination of any delay in O 2 delivery during the rest-tocontraction transition did not affect muscle V O 2 kinetics, which suggests that this kinetics was mainly set by an intrinsic inertia of oxidative metabolism. gas exchange kinetics; muscle oxidative metabolism; submaximal exercise IT HAS BEEN KNOWN FOR DECADES that on a step transition from rest to exercise, or from a lower to a higher workload, O 2 uptake (V O 2 ) lags behind the power output increase (12), following a time course usually termed V O 2 on-kinetics. The mechanism(s) determining this kinetics has been a matter of considerable debate, mainly between those who consider it mainly related to the rate of adjustment of O 2 delivery to the exercising muscles (13-15) and those who support the concept that V O 2 on-kinetics is mainly set by an inertia of intramuscular oxidative metabolism (3, 32).An experimental approach to discriminate between the two conflicting hypotheses would be to increase the rate of adjustment of O 2 delivery to muscles and then determine whether the V O 2 on-kinetics becomes faster or not. Unfortunately, previous studies conducted following this approach yielded conflicting results. Hughson and co-workers (14), for example, described a significantly faster V O 2 on-kinetics when their subjects cycled in a supine position during the application of lower body negative pressure, which presumably enhanced the rate of O 2 delivery to the exercis...

In CHF, improvement in exercise ventilation and aerobic efficiency with sildenafil is sustained and is significantly related with an endothelium-mediated attenuation of exercising muscle oversignaling. Chronic sildenafil seems to be a remedy based on CHF pathophysiology and devoid of remarkable adverse effects.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells following binding with the cell surface ACE2 receptors, thereby leading to coronavirus disease 2019 (COVID-19). SARS-CoV-2 causes viral pneumonia with additional extrapulmonary manifestations and major complications, including acute myocardial injury, arrhythmia, and shock mainly in elderly patients. Furthermore, patients with existing cardiovascular comorbidities, such as hypertension and coronary heart disease, have a worse clinical outcome following contraction of the viral illness. A striking feature of COVID-19 pandemics is the high incidence of fatalities in advanced aged patients: this might be due to the prevalence of frailty and cardiovascular disease increase with age due to endothelial dysfunction and loss of endogenous cardioprotective mechanisms. Although experimental evidence on this topic is still at its infancy, the aim of this position paper is to hypothesize and discuss more suggestive cellular and molecular mechanisms whereby SARS-CoV-2 may lead to detrimental consequences to the cardiovascular system. We will focus on aging, cytokine storm, NLRP3/inflammasome, hypoxemia, and air pollution, which is an emerging cardiovascular risk factor associated with rapid urbanization and globalization. We will finally discuss the impact of clinically available CV drugs on the clinical course of COVID-19 patients. Understanding the role played by SARS-CoV2

Maximal exercise at extreme altitudes was studied during the course of the American Medical Research Expedition to Everest. Measurements were carried out at sea level [inspired O2 partial pressure (PO2) 147 Torr], 6,300 m during air breathing (inspired PO2 64 Torr), 6,300 m during 16% O2 breathing (inspired PO2 49 Torr), and 6,300 m during 14% O2 breathing (inspired PO2 43 Torr). The last PO2 is equivalent to that on the summit of Mt. Everest. All the 6,300 m studies were carried out in a warm well-equipped laboratory on well-acclimatized subjects. Maximal O2 uptake fell dramatically as the inspired PO2 was reduced to very low levels. However, two subjects were able to reach an O2 uptake of 1 l/min at the lowest inspired PO2. Arterial O2 saturations fell markedly and alveolar-arterial PO2 differences increased as the work rate was raised at high altitude, indicating diffusion limitation of O2 transfer. Maximal exercise ventilations exceeded 200 l/min at 6,300 m during air breathing but fell considerably at the lowest values of inspired PO2. Alveolar CO2 partial pressure was reduced to 7-8 Torr in one subject at the lowest inspired PO2, and the same value was obtained from alveolar gas samples taken by him at rest on the summit. The results help to explain how man can reach the highest point on earth while breathing ambient air.

Milano G, Morel S, Bonny C, Samaja M, von Segesser LK, Nicod P, Vassalli G. A peptide inhibitor of c-Jun NH2-terminal kinase reduces myocardial ischemia-reperfusion injury and infarct size in vivo.

Previous studies of the erythropoietic response to hypoxia in high-altitude natives suggest that the hematocrit and hemoglobin values in Himalayan natives (Sherpas) are lower than expected for the altitude, perhaps because of a genetic adaptation. However, differences in sampling techniques and experimental methods make comparisons difficult. Our studies were carried out to compare the erythropoietic response with the same altitude in age-matched natives of the Himalayas and Andes by the same experimental techniques. Healthy male subjects were selected in Ollagüe, Chile (n = 29, 27.3 +/- 5.9 yr) and in Khunde, Nepal (n = 30, 24.7 +/- 3.8 yr). Both of these villages are located at 3,700 m above sea level. Hematologic measurements confirmed lower hematocrit values in Nepal (48.4 +/- 4.5%) than in Chile (52.2 +/- 4.6%) (P less than 0.003). When subjects were matched for hematocrit, erythropoietin concentrations in Chile were higher than in Nepal (P less than 0.01). Detailed measurements of blood O2 affinity in Nepal showed no differences in shape or position of the O2 equilibrium curve between Sherpas and Western sojourners. Our results indicate that although Quechua Indians have higher hematocrits than Sherpas living at the same altitude, nevertheless they may be functionally anemic.

We describe a new form of mechanical pulmonary ventilation, low-frequency positive pressure ventilation with extracorporeal CO2 removal (LEPPV-ECCO2R). In a series of animal studies the rate of mechanical ventilation was 0.66, 1, 2, and 4 min-1 at a tidal volume of 3, 10, and 15 ml kg-1. We were able to maintain normal blood gases and normal lung volumes and lung mechanics even at the lowest ventilator rate with tidal volumes of 10 or 15 ml kg-1. Each experiment lasted 7 hours. Our data suggest a possible new dimension in the management of a difficult patient on mechanical pulmonary ventilation.

Chronic hypoxia (CH) is believed to induce myocardial protection, but this is in contrast with clinical evidence. Here, we test the hypothesis that repeated brief reoxygenation episodes during prolonged CH improve myocardial tolerance to hypoxia-induced dysfunction. Male 5-week-old Sprague-Dawley rats (n = 7–9/group) were exposed for 2 weeks to CH (F1O2 = 0.10), intermittent hypoxia (IH, same as CH, but 1 hr/day exposure to room air), or normoxia (N, F1O2 = 0.21). Hearts were isolated, Langendorff perfused for 30 min with hypoxic medium (Krebs-Henseleit, PO2 = 67 mmHg), and exposed to hyperoxia (PO2 = 670 mmHg). CH hearts displayed higher end-diastolic pressure, lower rate-pressure product, and higher vascular resistance than IH. During hypoxic perfusion, anaerobic mechanisms recruitment was similar in CH and IH hearts, but less than in N. Thus, despite differing only for 1 hr daily exposure to room air, CH and IH induced different responses in animal homeostasis, markers of oxidative stress, and myocardial tolerance to reoxygenation. We conclude that the protection in animals exposed to CH appears conferred by the hypoxic preconditioning due to the reoxygenation rather than by hypoxia per se.