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Randomized Controlled Trial
. 2024 Mar 1;326(3):H705-H714.
doi: 10.1152/ajpheart.00783.2023. Epub 2024 Jan 19.

Hemorheological, cardiorespiratory, and cerebrovascular effects of pentoxifylline following acclimatization to 3,800 m

Andrew R Steele  1 , Connor A Howe  1 , Travis D Gibbons  1   2 , Katharine Foster  3   4 , Alexandra M Williams  5 , Hannah G Caldwell  1 , L Madden Brewster  1 , Jennifer Duffy  1 , Justin A Monteleone  1 , Prajan Subedi  3   4 , James D Anholm  3   4 , Mike Stembridge  6 , Philip N Ainslie  1 , Joshua C Tremblay  6
Affiliations
Randomized Controlled Trial

Hemorheological, cardiorespiratory, and cerebrovascular effects of pentoxifylline following acclimatization to 3,800 m

Andrew R Steele et al. Am J Physiol Heart Circ Physiol. .

Abstract

Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m. Participants (6 males/10 females; age, 27 ± 4 yr old) received either a placebo or 400 mg of pentoxifylline orally the night before and again 2 h before testing. We assessed arterial blood gases, venous hemorheology (blood viscosity, red blood cell deformability, and aggregation), and inflammation (TNF-α) in room air (end-tidal oxygen partial pressure, ∼52 mmHg). Global cerebral blood flow (gCBF), ventilation, and pulmonary artery systolic pressure (PASP) were measured in room air and again after 8-10 min of isocapnic hypoxia (end-tidal oxygen partial pressure, 40 mmHg). Pentoxifylline did not alter arterial blood gases, TNF-α, or hemorheology compared with placebo. Pentoxifylline did not affect gCBF or ventilation during room air or isocapnic hypoxia compared with placebo. However, in females, PASP was reduced with pentoxifylline during room air (placebo, 19 ± 3; pentoxifylline, 16 ± 3 mmHg; P = 0.021) and isocapnic hypoxia (placebo, 22 ± 5; pentoxifylline, 20 ± 4 mmHg; P = 0.029), but not in males. Acute pentoxifylline administration in lowlanders at 3,800 m had no impact on arterial blood gases, hemorheology, inflammation, gCBF, or ventilation. Unexpectedly, however, pentoxifylline reduced PASP in female participants, indicating a potential effect of sex on the pulmonary vascular responses to pentoxifylline.NEW & NOTEWORTHY We conducted a double-blind, placebo-controlled study on the rheological, cardiorespiratory and cerebrovascular effects of acute pentoxifylline in healthy lowlanders after 11-14 days at 3,800 m. Although red blood cell deformability was reduced and blood viscosity increased compared with low altitude, acute pentoxifylline administration had no impact on arterial blood gases, hemorheology, inflammation, cerebral blood flow, or ventilation. Pentoxifylline decreased pulmonary artery systolic pressure in female, but not male, participants.

Keywords: cerebral blood flow; chemoreflex; high altitude; hypoxic pulmonary vasoconstriction; red blood cell.

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Conflict of interest statement

No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Figure 1.
Figure 1.
Schematic of the experimental design. Participants were given 400 mg of pentoxifylline or placebo the night prior and again 2 h before testing began. The experiment began with participants laying in supine and resting state quietly for ∼10 min before collections of resting venous blood samples and radial artery blood samples. Following this, we assessed carotid body chemoreflex-mediated inhibition of ventilation (hyperoxia carotid body test) using a Douglas bag. Thereafter, we assessed carotid body chemoreflex-mediated activation of ventilation (isocapnic hypoxia test) participants using an end-tidal forcing system to maintain end-tidal carbon dioxide partial pressure (PETCO2) at baseline values, while being exposed to 2 progressive hypoxic stages [end-tidal partial pressure of oxygen (PETO2) = 45 and 40 mmHg]. Echocardiography and cerebral blood flow were measured at both baseline and during the final minute of the last stage of isocapnic hypoxia.
Figure 2.
Figure 2.
Global cerebral blood flow (gCBF) with placebo (blue) and pentoxifylline (PTX; red) during room air (n = 16) and isocapnic hypoxia (40 mmHg; n = 14). Closed dots are individual responses, and bar graphs are group means. Paired 2-tailed Student’s t tests were used for the room air comparisons, and a Wilcoxon matched-pairs signed-rank test was used for the hypoxia comparisons.
Figure 3.
Figure 3.
Carotid body tonic activity and sensitivity to hypoxia during placebo and pentoxifylline (PTX) conditions. A: carotid body tonic activity was assessed as the minute ventilation (V̇e) in response to transient hyperoxia reported as a relative reduction from baseline during placebo (blue) and PTX (red) (n = 15). B: carotid body sensitivity to hypoxia was assessed using isocapnic hypoxia during placebo and PTX (n = 14). To create a sensitivity slope, the minute ventilation of the last minute of each hypoxic stage (room air, end-tidal partial pressure of oxygen of 45 mmHg and end-tidal partial pressure of oxygen of 40 mmHg) was collected, and a linear slope between minute ventilation and arterial oxygen saturation was used to determine the acute hypoxic ventilatory response. Closed dots are individual responses, and bar graphs are group means.
Figure 4.
Figure 4.
Pulmonary artery systolic pressure with placebo (blue) and pentoxifylline (PTX; red) during room air (n = 14) and isocapnic hypoxia (40 mmHg; n = 12). Closed dots are individual responses, and bar graphs are group means. Paired 2-tailed Student’s t tests were used for the statistical comparisons.
Figure 5.
Figure 5.
Pulmonary artery systolic pressure (PASP) sensitivity to isocapnic hypoxia (40 mmHg). The delta increase in PASP divided by the delta decrease in the end-tidal partial pressure of oxygen (PETO2) with placebo (blue) and pentoxifylline (PTX; red). Closed dots are individual responses, and bar graphs are group means. Paired 2-tailed Student’s t tests were used for the statistical comparisons (n = 12).
Figure 6.
Figure 6.
Pulmonary artery systolic pressure with placebo (blue) and pentoxifylline (PTX; red) during room air and isocapnic hypoxia (40 mmHg) in females (A) (room air and isocapnic hypoxia, n = 8) and males (B) (room air, n = 6; isocapnic hypoxia, n = 4). Closed dots are individual responses, and bar graphs are group means. Paired 2-tailed Student’s t tests were used for the statistical comparisons. *P < 0.05, placebo vs. PTX.
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