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Antihistamines Cause A 27% Reduction Of Gene Response After Exercise.
Antihistamines May Block The Beneficial Effects Of Exercise On Glucose Metabolism.
Antihistamines Block The Post-Exercise Reduction In Blood Pressure.
Antihistamines Block The Energizing Effects Of Exercise.
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References:
Loy, Bryan D., and Patrick J. O'Connor. "The effect of histamine on changes in mental energy and fatigue after a single bout of exercise." Physiology & behavior 153 (2016): 7-18.
Pellinger, Thomas K., et al. "Local histamine H1-and H2-receptor blockade reduces postexercise skeletal muscle interstitial glucose concentrations in humans." Applied Physiology, Nutrition, and Metabolism 35.5 (2010): 617-626.
Pellinger, Thomas K., Breanna R. Dumke, and John R. Halliwill. "Effect of H1‐and H2‐histamine receptor blockade on postexercise insulin sensitivity." Physiological reports 1.2 (2013): e00033.
Pickles, Sam. The Effect of Intensity on Post-Exercise Hypotension: Is Post-Exercise Hypotension different following high intensity interval exercise when compared to continuous exercise and do antihistamines blunt the hypotensive response?. Diss. Cardiff Metropolitan University, 2015.
Romero in "Antihistamines affect exercise recovery, may or may not be a problem." Medical Press, April 14, 2016
Romero, Steven A., et al. "Evidence of a broad histamine footprint on the human exercise transcriptome." The Journal of Physiology (2016).
After vigorous exercise, some 3,000 genes go to work to aid recovery by boosting muscles and blood vessels, but in the presence of high doses of antihistamines almost 27 percent of the gene response is blunted, according to University of Oregon researchers.
Whether the antihistamine effect on 795 affected genes might suggest a problem for competitive athletes and devoted exercisers, however, is not known, said John R. Halliwill, professor of human physiology. He was one of 10 co-authors of the study now online ahead of print in the Journal of Physiology.
Histamine is a substance in the body that responds to pollens, molds, animal dander, insect bites and other allergens. Too much response in some people fuels uncomfortable allergic reactions, prompting the use of antihistamines.
Halliwill discovered in 2005 that histamines also relax blood vessels, increasing blood flow that aids post-exercise recovery. That emerged from his original focus on why some people, including athletes, pass out after vigorous physical exertion. He later found a link between an over-activation of two histamine receptors to drops in blood pressure.
The new study—led by doctoral student Steven A. Romero and in collaboration with Hans Dreyer, a departmental colleague who studies muscle physiology—expanded the research to a wider genetics level. Researchers sequenced RNA, molecules essential for protein synthesis and signaling among genes, with state-of-the-art equipment in the UO's Genomics Core Facility.
"We were looking for pathways associated with the growth of new blood vessels," said Halliwill, who is director of the department's Exercise and Environmental Physiology Lab. "We saw evidence of that, but we also saw gene expression associated with glucose uptake by muscles, restructuring of muscle in response to exercise, immune responses and intercellular communications."
In the research, 10 men and six women, all 23-25 years old, physically fit and active, performed an hour of knee-extension exercise at 60 percent of their peak power, about 45 kicks per minute. Biopsies were done before and three hours after exercise to obtain samples of the quadriceps (vastulus lateris), skeletal muscles on the side of the thighs.
Eight participants took 540 milligrams of fexofenadine and 300 milligrams of ranitidine—levels nearly three times the recommended dosages of the over-the-counter antihistamines. Each target one of the two known histamine receptors involved in recovery responses.
During exercise, blood flow, blood pressure and heart rate were monitored. The three-hour recovery window allowed the team to study gene transcription slightly beyond previous work that had found histamine improved blood flow for two hours after exercise.
The antihistamines had no effect prior to exercise and little influence on gene expression at the conclusion of the workout. Three hours after exercise 88 percent of the 795 genes affected by the antihistamines mostly responded with lower levels of expression.
"Histamine, a substance that we typically think of negatively and is most often associated with seasonal allergies, is an important substance contributing to the normal day-to-day response to exercise in humans," said Romero, who is now at the University of Texas Southwestern Medical Center in Dallas on a postdoctoral fellowship from the National Institutes of Health.
In their conclusion, the authors noted that the research highlighted only a small fraction of genes likely involved in signaling pathways influenced by histamine receptors activation during recovery.
"Our data really highlight that there remain many unanswered questions regarding the use of exercise to promote beneficial adaptations in humans, Romero added. "Integrative physiologists from across the world have spent a great deal of effort conducting elegant studies in humans and yet we still have much work left to do."
A key question is whether people should avoid taking antihistamines when they exercise. It's too early to make that call, Halliwill said.
"We've got more work that we have to do," he said. "We need to do a training study in which we put people on histamine blockers and see if their adaptations to exercise training are as robust or diminished. There are a lot of redundancies in physiological systems. I wouldn't be surprised if blocking histamine receptors ends up being overcome by something else, but I also wouldn't be surprised if we can demonstrate that some responses to exercise training do become blunted if you take high doses of histamine blockers."
Whether the antihistamine effect on 795 affected genes might suggest a problem for competitive athletes and devoted exercisers, however, is not known, said John R. Halliwill, professor of human physiology. He was one of 10 co-authors of the study now online ahead of print in the Journal of Physiology.
Histamine is a substance in the body that responds to pollens, molds, animal dander, insect bites and other allergens. Too much response in some people fuels uncomfortable allergic reactions, prompting the use of antihistamines.
Halliwill discovered in 2005 that histamines also relax blood vessels, increasing blood flow that aids post-exercise recovery. That emerged from his original focus on why some people, including athletes, pass out after vigorous physical exertion. He later found a link between an over-activation of two histamine receptors to drops in blood pressure.
The new study—led by doctoral student Steven A. Romero and in collaboration with Hans Dreyer, a departmental colleague who studies muscle physiology—expanded the research to a wider genetics level. Researchers sequenced RNA, molecules essential for protein synthesis and signaling among genes, with state-of-the-art equipment in the UO's Genomics Core Facility.
"We were looking for pathways associated with the growth of new blood vessels," said Halliwill, who is director of the department's Exercise and Environmental Physiology Lab. "We saw evidence of that, but we also saw gene expression associated with glucose uptake by muscles, restructuring of muscle in response to exercise, immune responses and intercellular communications."
In the research, 10 men and six women, all 23-25 years old, physically fit and active, performed an hour of knee-extension exercise at 60 percent of their peak power, about 45 kicks per minute. Biopsies were done before and three hours after exercise to obtain samples of the quadriceps (vastulus lateris), skeletal muscles on the side of the thighs.
Eight participants took 540 milligrams of fexofenadine and 300 milligrams of ranitidine—levels nearly three times the recommended dosages of the over-the-counter antihistamines. Each target one of the two known histamine receptors involved in recovery responses.
During exercise, blood flow, blood pressure and heart rate were monitored. The three-hour recovery window allowed the team to study gene transcription slightly beyond previous work that had found histamine improved blood flow for two hours after exercise.
The antihistamines had no effect prior to exercise and little influence on gene expression at the conclusion of the workout. Three hours after exercise 88 percent of the 795 genes affected by the antihistamines mostly responded with lower levels of expression.
"Histamine, a substance that we typically think of negatively and is most often associated with seasonal allergies, is an important substance contributing to the normal day-to-day response to exercise in humans," said Romero, who is now at the University of Texas Southwestern Medical Center in Dallas on a postdoctoral fellowship from the National Institutes of Health.
In their conclusion, the authors noted that the research highlighted only a small fraction of genes likely involved in signaling pathways influenced by histamine receptors activation during recovery.
"Our data really highlight that there remain many unanswered questions regarding the use of exercise to promote beneficial adaptations in humans, Romero added. "Integrative physiologists from across the world have spent a great deal of effort conducting elegant studies in humans and yet we still have much work left to do."
A key question is whether people should avoid taking antihistamines when they exercise. It's too early to make that call, Halliwill said.
"We've got more work that we have to do," he said. "We need to do a training study in which we put people on histamine blockers and see if their adaptations to exercise training are as robust or diminished. There are a lot of redundancies in physiological systems. I wouldn't be surprised if blocking histamine receptors ends up being overcome by something else, but I also wouldn't be surprised if we can demonstrate that some responses to exercise training do become blunted if you take high doses of histamine blockers."
There's not just one, but there are two studies that indicate that using H1 blockers may impair the post-exercise increase in insulin sensitivity / glucose metabolism in general. There's Pellinger's 2010 study that found that the use of histamine H1-and H2-inhibiting drugs reduces not just the postexercise skeletal muscle interstitial glucose accumulation, but also the hyperemia (=increased blood flow to the muscles) and may thus in fact slow down the recovery from exercise.
The second study is a bit more concrete (Pellinger. 2013). It comes from the same group of researchers. This time, however, the scientists tested the logical follow-up question, whether the previously observed effects would also affect the increase in insulin sensitivity following exercise. To this ends the scientists had 20 healthy young subjects (12 exercise; eight nonexercise sham) randomly consume either control or H1‐ and H2‐blockers (fexofenadine and ranitidine) days. To assess the effects of the drugs on the glucose metabolism post exercise, the subjects then cycled at 60% of their VO2 peak for 60 min. Afterwards, the scientists conducted postexercise whole‐body insulin sensitivity tests (Matsuda insulin sensitivity index) and found that the former was reduced by 25% with H1‐ and H2‐receptor blockade (P < 0.05).
Interestingly enough, the "pro-diabetic" effect is limited to exercised individuals. In a sham trial, where the subjects simply sat around for 60 minutes, a similar effect on insulin sensitivity was not observed. So, the scientists are right to conclude that their "results indicate that insulin sensitivity following exercise is blunted by H1‐ and H2‐receptor blockade." Since this ill effect is probably mediated by the previously observed blunting of the exercise-induced skeletal muscle vasodilatation, it is only logical that the same effect was not observed in the sham trial.
The second study is a bit more concrete (Pellinger. 2013). It comes from the same group of researchers. This time, however, the scientists tested the logical follow-up question, whether the previously observed effects would also affect the increase in insulin sensitivity following exercise. To this ends the scientists had 20 healthy young subjects (12 exercise; eight nonexercise sham) randomly consume either control or H1‐ and H2‐blockers (fexofenadine and ranitidine) days. To assess the effects of the drugs on the glucose metabolism post exercise, the subjects then cycled at 60% of their VO2 peak for 60 min. Afterwards, the scientists conducted postexercise whole‐body insulin sensitivity tests (Matsuda insulin sensitivity index) and found that the former was reduced by 25% with H1‐ and H2‐receptor blockade (P < 0.05).
Interestingly enough, the "pro-diabetic" effect is limited to exercised individuals. In a sham trial, where the subjects simply sat around for 60 minutes, a similar effect on insulin sensitivity was not observed. So, the scientists are right to conclude that their "results indicate that insulin sensitivity following exercise is blunted by H1‐ and H2‐receptor blockade." Since this ill effect is probably mediated by the previously observed blunting of the exercise-induced skeletal muscle vasodilatation, it is only logical that the same effect was not observed in the sham trial.
Closely related (mechanistically) to the previously cited effects on glucose metabolism are the results Sam Pickles presented in his 2015 undergraduate degree thesis.
In the corresponding study, Pickles had his young healthy subjects perform 4x4 minutes of interval training at 85% VO2max or 30 min of continous exercise at 75% of VO2max - both either with or without antihistamine ingestion. And guess what!? Yes, you're right: The ingestion of the antihistamines redued the post-exercise hypotensive effect (PEH) of both types of exercise by ~3.7/ 3.2 mmHg, a measurable, but not a statistically significant. (p=0.177 and 0.183, for interval and continuous training, respectively) difference, and still: since the mechanism (reduced hyperemia) appears to be clear, the results are relevant and Pickles is right to point out that "further research is required to determine the clinical implications of the interaction between antihistamines and the scale of PEH when prescribing antihistamines for patients using exercise as an intervention for hypertension" (Pickles. 2015).
In the corresponding study, Pickles had his young healthy subjects perform 4x4 minutes of interval training at 85% VO2max or 30 min of continous exercise at 75% of VO2max - both either with or without antihistamine ingestion. And guess what!? Yes, you're right: The ingestion of the antihistamines redued the post-exercise hypotensive effect (PEH) of both types of exercise by ~3.7/ 3.2 mmHg, a measurable, but not a statistically significant. (p=0.177 and 0.183, for interval and continuous training, respectively) difference, and still: since the mechanism (reduced hyperemia) appears to be clear, the results are relevant and Pickles is right to point out that "further research is required to determine the clinical implications of the interaction between antihistamines and the scale of PEH when prescribing antihistamines for patients using exercise as an intervention for hypertension" (Pickles. 2015).
In another 2016 study, Loy et al. tested the effect of histamine on changes in mental energy and fatigue after a single bout of exercise in 20 women with low vigor and high fatigue.
The subjects received the H1 antagonist drug doxepin hydrocholoride (6 mg | aka SINEQUAN, an anti-histamine that's prescribed for depression and anxiety) in tomato juice and tomato juice alone (placebo) in a randomized, double-blinded, cross-over experiment before performing 30 min of light intensity cycling exercise and completing energy, fatigue, sleepiness, and motivation scales, and cognitive tasks.
After exercise, mental fatigue increased for the doxepin condition (p = 0.014) but not placebo (p = 0.700), while mental energy decreased for both PLA and DOX (p < 0.001) and cognitive task performance was unaffected.
Reason enough for the authors to infer that "histamine binding to H1 receptors in the brain has a role in exercise-induced reductions in mental fatigue, but not increases in energy" (Loy. 2016) - a logical conclusion, but we are still far from understanding histamine and its various physiological effects on the body.
The subjects received the H1 antagonist drug doxepin hydrocholoride (6 mg | aka SINEQUAN, an anti-histamine that's prescribed for depression and anxiety) in tomato juice and tomato juice alone (placebo) in a randomized, double-blinded, cross-over experiment before performing 30 min of light intensity cycling exercise and completing energy, fatigue, sleepiness, and motivation scales, and cognitive tasks.
After exercise, mental fatigue increased for the doxepin condition (p = 0.014) but not placebo (p = 0.700), while mental energy decreased for both PLA and DOX (p < 0.001) and cognitive task performance was unaffected.
Reason enough for the authors to infer that "histamine binding to H1 receptors in the brain has a role in exercise-induced reductions in mental fatigue, but not increases in energy" (Loy. 2016) - a logical conclusion, but we are still far from understanding histamine and its various physiological effects on the body.
References:
Loy, Bryan D., and Patrick J. O'Connor. "The effect of histamine on changes in mental energy and fatigue after a single bout of exercise." Physiology & behavior 153 (2016): 7-18.
Pellinger, Thomas K., et al. "Local histamine H1-and H2-receptor blockade reduces postexercise skeletal muscle interstitial glucose concentrations in humans." Applied Physiology, Nutrition, and Metabolism 35.5 (2010): 617-626.
Pellinger, Thomas K., Breanna R. Dumke, and John R. Halliwill. "Effect of H1‐and H2‐histamine receptor blockade on postexercise insulin sensitivity." Physiological reports 1.2 (2013): e00033.
Pickles, Sam. The Effect of Intensity on Post-Exercise Hypotension: Is Post-Exercise Hypotension different following high intensity interval exercise when compared to continuous exercise and do antihistamines blunt the hypotensive response?. Diss. Cardiff Metropolitan University, 2015.
Romero in "Antihistamines affect exercise recovery, may or may not be a problem." Medical Press, April 14, 2016
Romero, Steven A., et al. "Evidence of a broad histamine footprint on the human exercise transcriptome." The Journal of Physiology (2016).