md_a
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- Aug 31, 2015
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I found this thesis and I think it is worth reading for the link between the AT1 receptor already popular with Covid, and the body's resistance to exertion by blocking the AT1 receptor. I copied a small part, it being long, and I attached the pdf format to the end.
..............
INACTIVATION OF AT1a RECEPTORS ATTENUATE LACTATE ACCUMULATION AND IMPROVE CARDIAC PERFORMANCE AND ACID-BASE HOMEOSTASIS DURING ENDURANCE EXERCISE
A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science
By
AHMAD M. ALHAJOJ
B. Pharm, King Khalid University, Abha, Saudi Arabia
2014
Wright State University
Exercise tolerance
The relationship between exercise performance and low RAS activity in the circulation
was discussed in the introduction of this thesis. Another important objective of the
current study was to identify the role of angiotensin II receptor in exercise tolerance.
Results suggested lower lactate levels in AT1a deficit mice as compared to WT during
wheel running exercise. This observation could justify the over activity of AT1aKO mice
reported in Mistlberger et al., 2001 during wheel running exercise, and in Murphy et al.,
2012 in response to rotarod exercise test. Lactate accumulates in lower levels in AT1a
deficit mice which blunt acceleration in metabolic acidosis and delays muscle fatigue
onset leading to improvement in the physical performance. Moreover, since angiotensin
II is the main peptide in RAS system cascade, our finding is consistent with the concepts
that relate the exercise performance improvement to lower ACE activity in the circulation
(Gayagay et al., 1998; Saul et al., 1999; Montgomery et al., 1999; Montgomery et al.,
1998). In order to confirm the role of AT1a receptor in minimizing metabolic acidosis
resulting from exercise-induced lactic acidosis, blood pH was assessed post- sacrifice.
Interestingly, finding reported lower blood pH in WTEX as compared to WT control and
to AT1aKOEX groups. The exact mechanism through which AT1a receptor inactivation
reduces lactic acidosis and resists changes in blood pH during exercise needs further investigation. However, lactic acid generated during physical activity buffered mainly by
bicarbonate buffer (HCO3-) system (as mentioned in the introduction). Therefore,
electrolyte analysis (including bicarbonate) was performed after sacrifice. Higher
bicarbonate buffer was observed in exercise AT1aKO blood mice. This observation was
associated with low level of blood chloride ion (CL-) in exercise AT1aKO. Bicarbonate
penetrates the erythrocyte cell membrane through exchange with intracellular chloride
ion, a process called Cl–/HCO3- shift. Consequently, Bicarbonate buffer and chloride ion
results could be explanation for the low levels of lactic acid and higher blood pH in mice
lacking AT1a receptors during exercise training. Ingestion of sodium bicarbonate
(NaHCO3) or exercising under alkaline condition improves exercise performance and
capacity (Price et al., 2003). To the author knowledge, however, this is the first data
evaluate lactate levels, blood pH, and electrolytes in exercise AT1a deficit mice. Glucose
measurements were also taken during exercise and the results suggested greater blood
glucose in WTEX at 60 and 10 min of wheel running as compared to AT1aKOEX at the
same time. In contrast, blood glucose levels were not significantly affected during
exercise in AT1aKO group. The role of AT1a receptor in maintaining almost stable blood
glucose noted in this experiment need to be identified. Nevertheless, since the absence of
AT1a receptor associated with enhanced physical performance, skeletal muscle required
to utilize more glucose to keep continues energy supply. This clarification is consistent
with a study suggested that RAS-inhibition could increase skeletal muscle-glucose uptake
and glucose transport system during exercise training(Henriksen and Jacob et al 1995)
which may lead to maintain stable blood glucose levels.
Quadriceps Skeletal muscle collagen assessments results indicated greater collagen levels
in WTEX as compared to WT control group. Elevated collagen levels could be an
indication for skeletal muscle tissue damage or fibrosis (Lorts et al 2012). This
observation could be a consequence of metabolic acidosis and the impairment in
metabolic efficiency reported in the above findings. Absence of AT1a receptor is
associated with increase in skeletal muscle strength up to 25% and enhancement in the
exercise performance and the whole body function (Murphy et al 2012). Collectively,
improvement in exercise tolerance reported in this study is attributed to enhancement in
metabolic efficiency and skeletal muscle mechanical efficiency in mice lacking AT1a
receptor.
The way that the reduction of RAS is associated with improvement in exercise capacity
and performance has not been fully understood. One explanation, depending on our
finding, is that inhibition of AT1a receptor can increase the level of bicarbonate buffer
(the first line buffer for lactic acid) during exercise training which minimize the level of
blood lactate accumulation leading to reduction in metabolic acidosis and delay or
prevent muscle fatigue onset. Bicarbonate buffer, in the form of sodium bicarbonate, has
been shown to be effective in increasing exercise endurance in human and recommended
to be used in youth athletes to improve performance for high intensity competitions
(Zajac et al 2009). Another possible clarification is that inhibition of AT1a receptor
would decrease vascular resistance (Gašaninet al 2013), and hence, increase cardiac
output and blood flow to the skeletal muscle. Our echocardiography investigation showed
higher left ventricular ejection fraction in AT1aKOEX animal which indicated greater
blood supply to the target organs and that would enhance the exercise performance. In
heart failure patients, muscle fatigue considered one of the most common symptoms that
need to be resolved as a part of heart failure therapy. However, some investigators
reported that skeletal muscle fatigue in heart failure patients is not related mainly to
reduction in the cardiac output, but it might attributed to skeletal muscle metabolic
inefficiency and the consequence muscle mechanical abnormality( Montgomery and
Brull et al 2000; Harridge et al et al 1996). Regular physical training improves the
symptoms of heart failure by enhancement of skeletal muscle performance and metabolic
efficiency (Montgomery and Brull et al 2000). Evidence suggested that skeletal muscle
metabolic efficiency could be impaired by of Ang II administration in animal model
(Brink et al.1996). Moreover, Ang II could also interfere with mitochondrial respiration
and impaired mitochondrial efficiency. RAS inhibition, by ACE inhibitor (ramipril) has
been reported to be effective in minimizing lactate production and increasing levels of
ATP and creatine phosphate (an important source of ATP) in ischemic heart animal (Linz
et al 1986).
Inflammation and exercise
Several studies reported that physical activity may reduce inflammation in human
subjects (Abramson et al 2002; Ford et al 2002). In the current study, however, two
inflammatory markers out of twelve cytokines were expressed in higher levels in WTEX
plasma: interlukin1-a (mIL-1a) and the chemokine murine growth-regulated alpha protein
(mKC). Ang II is an important mediator for inflammation and plays a crucial role in
inflammatory response (Suzuki et al 2003). Therefore, a possible explanation for
expression of (mIL-1a) and (mKC) inflammatory markers could be related to elevated
Ang II in the circulation during exercise in WTEX. In addition, these inflammatory
markers could be also related to the impairment in metabolic process and to the cardiac
remodeling and hypertrophy observed in WTEX group.
Effect of exercise on stress response
Conflict data are available regarding the relationship between exercise training and stress
management. While several studies suggested that regular physical activity may play a
role in stress reduction (Starzec et al 1983; Hare et al 2013), other investigators reported
an opposite role of exercise on stress levels (Girard and Garland et al 2001; Hu et al
1998; Härkönen et al 1990). A study suggested that involuntary and/or forced exercise is
associated with elevation in corticosterone response while there was no effect of
voluntary exercise in corticosteron levels (Ke et al., 2011). Ang II has been reported as an
important stress mediator and has a role in stimulation of corticosterone synthesis
(Rainey et al 1991; Saavedra et al 2007). The current study was reported lower plasma
corticosterone in both exercise groups as compared to control. However, no effect was
noticed for AT1a receptors in plasma corticosterone response to exercise. These results
support the concept that regular physical activity may improve stress management. In
contrast, urinary corticosterone was greater in both exercise groups following 2 hours of
exercise compared to the baseline at the week 7 of experiment. It is important to note that
plasma cortecosterone in this study was compared to control groups (different animal),
while urine corticosterone was taken at rest and after two hours of wheel running exercise
for the same animals. In addition, corticosteron measurement in urine sample before and
after the cage change reported no differences between groups.
Conclusion
Angiotensin Type 1 (AT1) receptors are involved in cardiovascular pathology.
Lozartan, the AT1 receptor blocker, in combination with exercise has been shown to be
effective in improving cardiac performance. Accumulated evidence reported the
relationship between exercise tolerance improvement and lower RAS in the circulation.
In the current study AT1aKO mice exhibited improved cardiac performance without
myocardium hypertrophy, greater exercise endurance, and enhanced metabolic activity
and skeletal muscle mechanical efficiency in response to chronic exercise. These results
suggest that the AT1a receptor is an important mediator of exercise induced cardiac
dysfunction and acid-base imbalance during exercise training. To the author knowledge,
this study was the first in estimating exercise endurance (lactate assessment) blood pH,
and electrolytes analysis in normotensive exercise AT1a receptors deficit mice. AT1a
receptors may also prevent expression of inflammatory proteins resulting from chronic
exercise. Regular physical activity could provide a positive effect in stress reduction as
shown by lower plasma coticosterone in exercise animal.
..............
INACTIVATION OF AT1a RECEPTORS ATTENUATE LACTATE ACCUMULATION AND IMPROVE CARDIAC PERFORMANCE AND ACID-BASE HOMEOSTASIS DURING ENDURANCE EXERCISE
A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science
By
AHMAD M. ALHAJOJ
B. Pharm, King Khalid University, Abha, Saudi Arabia
2014
Wright State University
Exercise tolerance
The relationship between exercise performance and low RAS activity in the circulation
was discussed in the introduction of this thesis. Another important objective of the
current study was to identify the role of angiotensin II receptor in exercise tolerance.
Results suggested lower lactate levels in AT1a deficit mice as compared to WT during
wheel running exercise. This observation could justify the over activity of AT1aKO mice
reported in Mistlberger et al., 2001 during wheel running exercise, and in Murphy et al.,
2012 in response to rotarod exercise test. Lactate accumulates in lower levels in AT1a
deficit mice which blunt acceleration in metabolic acidosis and delays muscle fatigue
onset leading to improvement in the physical performance. Moreover, since angiotensin
II is the main peptide in RAS system cascade, our finding is consistent with the concepts
that relate the exercise performance improvement to lower ACE activity in the circulation
(Gayagay et al., 1998; Saul et al., 1999; Montgomery et al., 1999; Montgomery et al.,
1998). In order to confirm the role of AT1a receptor in minimizing metabolic acidosis
resulting from exercise-induced lactic acidosis, blood pH was assessed post- sacrifice.
Interestingly, finding reported lower blood pH in WTEX as compared to WT control and
to AT1aKOEX groups. The exact mechanism through which AT1a receptor inactivation
reduces lactic acidosis and resists changes in blood pH during exercise needs further investigation. However, lactic acid generated during physical activity buffered mainly by
bicarbonate buffer (HCO3-) system (as mentioned in the introduction). Therefore,
electrolyte analysis (including bicarbonate) was performed after sacrifice. Higher
bicarbonate buffer was observed in exercise AT1aKO blood mice. This observation was
associated with low level of blood chloride ion (CL-) in exercise AT1aKO. Bicarbonate
penetrates the erythrocyte cell membrane through exchange with intracellular chloride
ion, a process called Cl–/HCO3- shift. Consequently, Bicarbonate buffer and chloride ion
results could be explanation for the low levels of lactic acid and higher blood pH in mice
lacking AT1a receptors during exercise training. Ingestion of sodium bicarbonate
(NaHCO3) or exercising under alkaline condition improves exercise performance and
capacity (Price et al., 2003). To the author knowledge, however, this is the first data
evaluate lactate levels, blood pH, and electrolytes in exercise AT1a deficit mice. Glucose
measurements were also taken during exercise and the results suggested greater blood
glucose in WTEX at 60 and 10 min of wheel running as compared to AT1aKOEX at the
same time. In contrast, blood glucose levels were not significantly affected during
exercise in AT1aKO group. The role of AT1a receptor in maintaining almost stable blood
glucose noted in this experiment need to be identified. Nevertheless, since the absence of
AT1a receptor associated with enhanced physical performance, skeletal muscle required
to utilize more glucose to keep continues energy supply. This clarification is consistent
with a study suggested that RAS-inhibition could increase skeletal muscle-glucose uptake
and glucose transport system during exercise training(Henriksen and Jacob et al 1995)
which may lead to maintain stable blood glucose levels.
Quadriceps Skeletal muscle collagen assessments results indicated greater collagen levels
in WTEX as compared to WT control group. Elevated collagen levels could be an
indication for skeletal muscle tissue damage or fibrosis (Lorts et al 2012). This
observation could be a consequence of metabolic acidosis and the impairment in
metabolic efficiency reported in the above findings. Absence of AT1a receptor is
associated with increase in skeletal muscle strength up to 25% and enhancement in the
exercise performance and the whole body function (Murphy et al 2012). Collectively,
improvement in exercise tolerance reported in this study is attributed to enhancement in
metabolic efficiency and skeletal muscle mechanical efficiency in mice lacking AT1a
receptor.
The way that the reduction of RAS is associated with improvement in exercise capacity
and performance has not been fully understood. One explanation, depending on our
finding, is that inhibition of AT1a receptor can increase the level of bicarbonate buffer
(the first line buffer for lactic acid) during exercise training which minimize the level of
blood lactate accumulation leading to reduction in metabolic acidosis and delay or
prevent muscle fatigue onset. Bicarbonate buffer, in the form of sodium bicarbonate, has
been shown to be effective in increasing exercise endurance in human and recommended
to be used in youth athletes to improve performance for high intensity competitions
(Zajac et al 2009). Another possible clarification is that inhibition of AT1a receptor
would decrease vascular resistance (Gašaninet al 2013), and hence, increase cardiac
output and blood flow to the skeletal muscle. Our echocardiography investigation showed
higher left ventricular ejection fraction in AT1aKOEX animal which indicated greater
blood supply to the target organs and that would enhance the exercise performance. In
heart failure patients, muscle fatigue considered one of the most common symptoms that
need to be resolved as a part of heart failure therapy. However, some investigators
reported that skeletal muscle fatigue in heart failure patients is not related mainly to
reduction in the cardiac output, but it might attributed to skeletal muscle metabolic
inefficiency and the consequence muscle mechanical abnormality( Montgomery and
Brull et al 2000; Harridge et al et al 1996). Regular physical training improves the
symptoms of heart failure by enhancement of skeletal muscle performance and metabolic
efficiency (Montgomery and Brull et al 2000). Evidence suggested that skeletal muscle
metabolic efficiency could be impaired by of Ang II administration in animal model
(Brink et al.1996). Moreover, Ang II could also interfere with mitochondrial respiration
and impaired mitochondrial efficiency. RAS inhibition, by ACE inhibitor (ramipril) has
been reported to be effective in minimizing lactate production and increasing levels of
ATP and creatine phosphate (an important source of ATP) in ischemic heart animal (Linz
et al 1986).
Inflammation and exercise
Several studies reported that physical activity may reduce inflammation in human
subjects (Abramson et al 2002; Ford et al 2002). In the current study, however, two
inflammatory markers out of twelve cytokines were expressed in higher levels in WTEX
plasma: interlukin1-a (mIL-1a) and the chemokine murine growth-regulated alpha protein
(mKC). Ang II is an important mediator for inflammation and plays a crucial role in
inflammatory response (Suzuki et al 2003). Therefore, a possible explanation for
expression of (mIL-1a) and (mKC) inflammatory markers could be related to elevated
Ang II in the circulation during exercise in WTEX. In addition, these inflammatory
markers could be also related to the impairment in metabolic process and to the cardiac
remodeling and hypertrophy observed in WTEX group.
Effect of exercise on stress response
Conflict data are available regarding the relationship between exercise training and stress
management. While several studies suggested that regular physical activity may play a
role in stress reduction (Starzec et al 1983; Hare et al 2013), other investigators reported
an opposite role of exercise on stress levels (Girard and Garland et al 2001; Hu et al
1998; Härkönen et al 1990). A study suggested that involuntary and/or forced exercise is
associated with elevation in corticosterone response while there was no effect of
voluntary exercise in corticosteron levels (Ke et al., 2011). Ang II has been reported as an
important stress mediator and has a role in stimulation of corticosterone synthesis
(Rainey et al 1991; Saavedra et al 2007). The current study was reported lower plasma
corticosterone in both exercise groups as compared to control. However, no effect was
noticed for AT1a receptors in plasma corticosterone response to exercise. These results
support the concept that regular physical activity may improve stress management. In
contrast, urinary corticosterone was greater in both exercise groups following 2 hours of
exercise compared to the baseline at the week 7 of experiment. It is important to note that
plasma cortecosterone in this study was compared to control groups (different animal),
while urine corticosterone was taken at rest and after two hours of wheel running exercise
for the same animals. In addition, corticosteron measurement in urine sample before and
after the cage change reported no differences between groups.
Conclusion
Angiotensin Type 1 (AT1) receptors are involved in cardiovascular pathology.
Lozartan, the AT1 receptor blocker, in combination with exercise has been shown to be
effective in improving cardiac performance. Accumulated evidence reported the
relationship between exercise tolerance improvement and lower RAS in the circulation.
In the current study AT1aKO mice exhibited improved cardiac performance without
myocardium hypertrophy, greater exercise endurance, and enhanced metabolic activity
and skeletal muscle mechanical efficiency in response to chronic exercise. These results
suggest that the AT1a receptor is an important mediator of exercise induced cardiac
dysfunction and acid-base imbalance during exercise training. To the author knowledge,
this study was the first in estimating exercise endurance (lactate assessment) blood pH,
and electrolytes analysis in normotensive exercise AT1a receptors deficit mice. AT1a
receptors may also prevent expression of inflammatory proteins resulting from chronic
exercise. Regular physical activity could provide a positive effect in stress reduction as
shown by lower plasma coticosterone in exercise animal.
