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Inhibition of prostaglandin synthesis: A possible mechanism for stress-induced hypertension
Medical Hypotheses 10: 445-449,
INHIBITION OF PROSTAGLANDIN STRESS-INDUCED HYPERTENSION Christopher Indiana
L.
Melby,
1983
SYNTHESIS:
PEHRS Dept.,
A POSSIBLE
Purdue
University,
MECHANISM
W.
FOR
Lafayette,
47906 ABSTRACT
while considered to be idiopathic, may Essential hypertension, be due to a variety of physiologic and/or psychologic factors, including stress. A possible mechanism for stress-induced hypertension is the inhibition of prostaglandin (PG) synthesis by the PGQ release of corticoids in the stereotypical stress response. and PGE2, acting as vasodilators are important antagonists to the pressor effects of norepinephrine. However, a decreased synthes i s of these PGs due to higher cortisol levels associated with stress, would negate their vasodilatory action, thus favoring vasoconstricPGF2a, a tion due to vascular suprasensitivity to norepinephrine. vasoconstrictor thought to be synthesized in the brain in response to a stressor, hypertension.
may also
play
a key
role
in
the
pathogenesis
of
INTRODUCTION
is
An increase a characteristic
in
blood acute
pressure response
(BP) of a normotensive individual to a stressor. The increased
cardiac output and increased peripheral vessel resistance, mediated through the release of catecholamines are mainly responsible for blood pressure elevation when an individual perceives himself to be in a “stressful” situation. The response is transient, normal, and non-pathologic. However, essential (primary) hypertension is a pathologic condition, with the chronic hypertensive state producing various detrimental changes in normal tissues and physiology, which predispose Essential hypertension is considered to cardiovascular pathology. to be idiopathic, but may be due to various physiologic factors including mineral corticoid excess, overactivity of the reninand increased sympatho-adrenal response or angiotensin system, The common characteristic is elevated BP (> 16O/g5) sensitivity. which indicates the problem is without increased cardiac output,
445
mainly
due
to
increased
total
peripheral
resistance
in
the
vascular
system. Stress is considered to be a factor in the development of essential hypertension (I). This association is not clearly understood, but it is known that hypertensive individuals can lower their BP by learning to relax. Recent studies have begun to shed some light on the relationship of stress and hypertension, specifically looking at the effects of stress on pressor hormones and prostaglandins. This paper will highlight some of the current findings on this topic of stress, prostaglandins, and hypertension. PROSTAGLANDINS Prostaglandins (PGs) are hormone-like substances mainly producing effects close to their site of release and are usually metabolized reaching circulation. Their effects vary greatly depending upon the type of prostaglandin and the tissue location (2). They are not stored in a preformed state but are synthesized and released as needed from specific polyunsaturated fatty acids found incorporated into cellular phospholipids. Once released from tissue lipids, the fatty acid precursors undergo a series of reactions which transform them into specific prostaglandins, designated as series 1, 2, and 3 based on the number of double bonds in their respective alkyl side chains Series 1 PGs are synthesized from dihomo-y-linolenic acid (C20:3w6), (2). their before
arachidonic acid series 3 PGs are
(C20:4w6) derived
is from
the precursor eicosapentaenoic
for
the acid
paper will examine the possible relationship between and series 2 PGs, although the 1 and 3series tension, of substantial importance.
series 2 PGs, and (C20:5w3). This stress, hyperPGs may also
be
PGs synthesized in the walls of blood vessels can act directly to or indirectly by either altermodify smooth muscle vascular tension, ing vessel responsiveness to vasoactive substances or by altering the levels of adrenergic neurotransmitters (2). Thus they contribute to PGt2 regulation of peripheral vascular resistance and BP control. with the former being the primary and PGE are vasodilators, The main vasoconstrictive arachidznate metabolite of blood vessels. PGs are TXA2 synthesized known to be produced in the stress response (3). Possible
in the
Mechanisms
blood brain
for
vessels and platelets, and a possible first
Stress-Induced
and PGF2a, mediator of
Hypertension
The effects of stress on the synthesis and release of PGs are specific stressors evoke different not well understood. Most likely, PG responses and one cannot conclude that there is a stereotyped PG However, based upon current research, response to al 1 stressors. some hypotheses have been developed which seek to explain the indue to an imbalance of PGs, possibly ducement of pathologic conditions initiated and/or mediated by stressors.
446
In
the
stereotypical
the stressor stimulates resulting inthe release lates the adrenal cortex a number elevated
stress
response
as
of responses, this discussion is cortisol levels on the biosynthesis
Rascher, through pathetic
et
al
(5)
corticosterone nervous system
the development tative increase
of of
proposed
by
Selye
(4),
the psyche at the hypothalamic level, of ACTH from the pituitary which stimuto produce cortiocoids. While these elicit
produced injection and its
hypertension norepinephrine
limited of
hypertension
in
to PGs. male
and studied their modulation by PGs. to
the
effects
Wistar
of
rats
peripheral symThey discovered
be associated not with a quanti(NE), but rather an increased
vessel wall sensitivity to NE resulting in vasoconstriction of perThis “supersensitivity” of the resistance ipheral blood vessels. vessels to NE can be explained. The increased level of circulating cortiocosteroid has been found to inhibit the release of the PG precursor, arachidonic acid from cellular phospholipids (6). Thus, within the blood vessel, PGl2 (vasodilator) cannot be synthesized to oppose the vasoconstrictive effect of sympathetic NE, and the latter has a comparatively greater effect in increasing vascular There is a failure in the important countervailing resistance. force lower
of PGl2 synthesis BP and counteract II .
.
.
.
the
inhibition
and the of
causes a supersensitivity which may be the trigger of
levels stress
hypertension”
release, effect
of
which NE.
PG biosynthesis
studies
by corticosterone
of resistance mechanism for
vessels to NE, the development
(5:237,).
Since continuous exposure to stressors inthe stress response, it could be induces hypertension by inhibiting Other
would normally act to The authors conclude:
give
some
credence
to
will elevate cortisol hypothesized that chronic the release of PG12. this
hypothesis.
Adrener-
gic has
stimulation, which is an integral aspect of the stress response, Serneri , et al been shown to affect PG12 production over time. (7) took 8 healthy male subjects and carried out adrenergic stimulation by immersing a foot of each individual in ice-water for two This initial stress of cold application induced a signifiminutes. cant rise in circulating PG12, but subsequent close periods of the same adrenergic stimulation caused the exhaustion of PGl2 production. It might therefore be argued that chronic stress could limit the synthesis of PGI thus reducing its effect as an antagonizing vasodilatory force to2;tress-induced adrenergic vasoconstriction. If this deficiency in PG production via increased cortisol levels initiates or exaggerates hypertension, then chronic administration of PG synthesis inhibitors should result in elevated BP. Although hypertension has not been reported in arthritics using nonwhich inhibit cycle-oxygenas steroidal anti-inflammatory drugs (NSAID),
447
and thus block PG synthesis, acute administrationof indomethacin can produce hypertension (8). Also, indomethacin-induced hypertension in anaesthetized dogs resembles that of essential hypertension elevated BP with no change in cardiac output, but a significant increase in vascular resistance (9). Possibly individuals using NSAlDs are not taking doses high enough to reach the 80% level of PG synthesis
inhibition
believed
to
be
required
to
produce
(8).
hypertension
Other studies have also provided support for stress-induced hypertension via PG modulation, Weber, et al (lo), in his study of hypertensive humans found an impaired capacity of the kidney to activate the Kallikrein-Kinin system. This system normally acts to produce vascular vasodilation with its activation possibly stimulated by PGs. Its effect is greatly augmented by the release of PGE2 in the kidney (8). With inhibition of PG synthesis by a stress-induced blood cortisol increase, the effect of the Kallikrein-Kinin system would be lessened, with a reduced counteractionofthe vasoconstrictive comangiotensin II and NE (ll), resulting in an increased pressor pounds, reponse to these stimuli. Thus, stress may be associated with hypertension by blocking the effect of PGl2 via synthesis inhibition, or by limiting the synergistic effect of PGE2 and bradykinin in lowering BP.
levels
Ignatowska, et al (12) found were higher in hypertensive
that PGF2~ individuals
(a
vasoconstrictor) than normotensives
prior to engaging in a mental stress activity, and believe the difference to be due to a greater anticipatory response to the stressor by the hypertensives. This “pre-test” anxiety would also increase since PGF2cl is believed to be synthesized cortisol levels. However, primarily in the brain in response to stress, the cortisol would not Thus the increased reach the tissue due to the blood brain barrier. blood cortisol would not inhibit the synthesis of PGF2d, and the It is stress-induced synthesis of PGF2e would raise blood pressure. possible that continua1 stress or inadequate coping responses lead to chronically striction and
high levels hypertension.
of
PGF2d
which
contribute
to
vascular
con-
PGs also influence renal physiology, and are involved in sodium metabolism - key aspects of hypertension pathophysiology. There is yet a wealth of information to be uncovered in this area, and much research is presently being undertaken to discover and specify the While definitive mechanisms of PG physiology related to hypertension. there is some indication that stress information is still lacking, is an important factor in the genesis and/or exacerbation of hypertension via inhibition of vasodilatory PGs, or the synthesis of PGF2a and TXA 2’
448
References 1.
2.
Jannsen, cause of Armstrong
et al. raised
Prolonged exposure to blood pressure in man.
J. et al. a metabolite vessels.
l!;“ISd;ld
stressful Lancet
stimulus :
86,
as
a
1977
Cardiovascular actions of prostacyclin of arachidonic acid which is synthesized Circulation Research 43,; Suppl l:l-112,
1978 3.
Olley PM and Conceani 134:688, 1980
4.
Selye entist,
5.
6.
The
H.
evolution
61:692,
SL and
from cells costeroids. U.S.A.
as
The
of
prostaglandins.
the
stress
concept.
Am J Dis
Child
American
Sci-
1973
Rascher, WR, et by prostaglandins Clinical rats. Hong,
F.
Modulation
al.
Levine
L.
Inhibition
the biochemical Proceedings of
73:1730,
of
sympathetic
in corticosterone-induced Science 57:235s, 1979 of
vascular hypertension
arachidonic
action of the National
acid
tone in
release
anti-inflammatory cortiAcademy of Sciences,
1976
7.
Neri Serneri, GG, et al. Prostacyclin, thromboxane, and ischemic heart disease. p. 138 in Prostaglandins and Cardiovascular Disease (Ruth Hegyel i, ed) Raven Press, New York, 1981
8.
McGiff JC and cardiovascular cular Disease
9.
Lonigro glandin
Quilley J. Prostaglandins, hypertension, and the p. 101 in Prostaglandins and Cardiovassystem. (Ruth Hegyeli, ed) Raven Press, New York, 1981
AJ, et al. synthesis
in
Dependency the dog.
of renal Circulation
blood flow Research
on prosta32:712,
1973 10.
Weber tial
11.
PC,
et
al.
hypertension.
Urinary Clinical
prostaglandins Science
and 57:259s,
kallikrein
in
essen
1979
Scholkens B, Steinbach R, and Ganten D. Blood pressure effects of endogenous brain angiotensin in rats are increased by inhiClinical Science 57:27ls, bition of prostaglandin biosynthesis. 1979
12.
lgnatowska H, Klonowicz T, and Feltynowski T. mental stress on prostaglandin F2c1 in patients hypertension and in healthy subjects. Clinical 1979
449
The effect of with essential Science 57:275s,
INHIBITION OF PROSTAGLANDIN STRESS-INDUCED HYPERTENSION Christopher Indiana
L.
Melby,
1983
SYNTHESIS:
PEHRS Dept.,
A POSSIBLE
Purdue
University,
MECHANISM
W.
FOR
Lafayette,
47906 ABSTRACT
while considered to be idiopathic, may Essential hypertension, be due to a variety of physiologic and/or psychologic factors, including stress. A possible mechanism for stress-induced hypertension is the inhibition of prostaglandin (PG) synthesis by the PGQ release of corticoids in the stereotypical stress response. and PGE2, acting as vasodilators are important antagonists to the pressor effects of norepinephrine. However, a decreased synthes i s of these PGs due to higher cortisol levels associated with stress, would negate their vasodilatory action, thus favoring vasoconstricPGF2a, a tion due to vascular suprasensitivity to norepinephrine. vasoconstrictor thought to be synthesized in the brain in response to a stressor, hypertension.
may also
play
a key
role
in
the
pathogenesis
of
INTRODUCTION
is
An increase a characteristic
in
blood acute
pressure response
(BP) of a normotensive individual to a stressor. The increased
cardiac output and increased peripheral vessel resistance, mediated through the release of catecholamines are mainly responsible for blood pressure elevation when an individual perceives himself to be in a “stressful” situation. The response is transient, normal, and non-pathologic. However, essential (primary) hypertension is a pathologic condition, with the chronic hypertensive state producing various detrimental changes in normal tissues and physiology, which predispose Essential hypertension is considered to cardiovascular pathology. to be idiopathic, but may be due to various physiologic factors including mineral corticoid excess, overactivity of the reninand increased sympatho-adrenal response or angiotensin system, The common characteristic is elevated BP (> 16O/g5) sensitivity. which indicates the problem is without increased cardiac output,
445
mainly
due
to
increased
total
peripheral
resistance
in
the
vascular
system. Stress is considered to be a factor in the development of essential hypertension (I). This association is not clearly understood, but it is known that hypertensive individuals can lower their BP by learning to relax. Recent studies have begun to shed some light on the relationship of stress and hypertension, specifically looking at the effects of stress on pressor hormones and prostaglandins. This paper will highlight some of the current findings on this topic of stress, prostaglandins, and hypertension. PROSTAGLANDINS Prostaglandins (PGs) are hormone-like substances mainly producing effects close to their site of release and are usually metabolized reaching circulation. Their effects vary greatly depending upon the type of prostaglandin and the tissue location (2). They are not stored in a preformed state but are synthesized and released as needed from specific polyunsaturated fatty acids found incorporated into cellular phospholipids. Once released from tissue lipids, the fatty acid precursors undergo a series of reactions which transform them into specific prostaglandins, designated as series 1, 2, and 3 based on the number of double bonds in their respective alkyl side chains Series 1 PGs are synthesized from dihomo-y-linolenic acid (C20:3w6), (2). their before
arachidonic acid series 3 PGs are
(C20:4w6) derived
is from
the precursor eicosapentaenoic
for
the acid
paper will examine the possible relationship between and series 2 PGs, although the 1 and 3series tension, of substantial importance.
series 2 PGs, and (C20:5w3). This stress, hyperPGs may also
be
PGs synthesized in the walls of blood vessels can act directly to or indirectly by either altermodify smooth muscle vascular tension, ing vessel responsiveness to vasoactive substances or by altering the levels of adrenergic neurotransmitters (2). Thus they contribute to PGt2 regulation of peripheral vascular resistance and BP control. with the former being the primary and PGE are vasodilators, The main vasoconstrictive arachidznate metabolite of blood vessels. PGs are TXA2 synthesized known to be produced in the stress response (3). Possible
in the
Mechanisms
blood brain
for
vessels and platelets, and a possible first
Stress-Induced
and PGF2a, mediator of
Hypertension
The effects of stress on the synthesis and release of PGs are specific stressors evoke different not well understood. Most likely, PG responses and one cannot conclude that there is a stereotyped PG However, based upon current research, response to al 1 stressors. some hypotheses have been developed which seek to explain the indue to an imbalance of PGs, possibly ducement of pathologic conditions initiated and/or mediated by stressors.
446
In
the
stereotypical
the stressor stimulates resulting inthe release lates the adrenal cortex a number elevated
stress
response
as
of responses, this discussion is cortisol levels on the biosynthesis
Rascher, through pathetic
et
al
(5)
corticosterone nervous system
the development tative increase
of of
proposed
by
Selye
(4),
the psyche at the hypothalamic level, of ACTH from the pituitary which stimuto produce cortiocoids. While these elicit
produced injection and its
hypertension norepinephrine
limited of
hypertension
in
to PGs. male
and studied their modulation by PGs. to
the
effects
Wistar
of
rats
peripheral symThey discovered
be associated not with a quanti(NE), but rather an increased
vessel wall sensitivity to NE resulting in vasoconstriction of perThis “supersensitivity” of the resistance ipheral blood vessels. vessels to NE can be explained. The increased level of circulating cortiocosteroid has been found to inhibit the release of the PG precursor, arachidonic acid from cellular phospholipids (6). Thus, within the blood vessel, PGl2 (vasodilator) cannot be synthesized to oppose the vasoconstrictive effect of sympathetic NE, and the latter has a comparatively greater effect in increasing vascular There is a failure in the important countervailing resistance. force lower
of PGl2 synthesis BP and counteract II .
.
.
.
the
inhibition
and the of
causes a supersensitivity which may be the trigger of
levels stress
hypertension”
release, effect
of
which NE.
PG biosynthesis
studies
by corticosterone
of resistance mechanism for
vessels to NE, the development
(5:237,).
Since continuous exposure to stressors inthe stress response, it could be induces hypertension by inhibiting Other
would normally act to The authors conclude:
give
some
credence
to
will elevate cortisol hypothesized that chronic the release of PG12. this
hypothesis.
Adrener-
gic has
stimulation, which is an integral aspect of the stress response, Serneri , et al been shown to affect PG12 production over time. (7) took 8 healthy male subjects and carried out adrenergic stimulation by immersing a foot of each individual in ice-water for two This initial stress of cold application induced a signifiminutes. cant rise in circulating PG12, but subsequent close periods of the same adrenergic stimulation caused the exhaustion of PGl2 production. It might therefore be argued that chronic stress could limit the synthesis of PGI thus reducing its effect as an antagonizing vasodilatory force to2;tress-induced adrenergic vasoconstriction. If this deficiency in PG production via increased cortisol levels initiates or exaggerates hypertension, then chronic administration of PG synthesis inhibitors should result in elevated BP. Although hypertension has not been reported in arthritics using nonwhich inhibit cycle-oxygenas steroidal anti-inflammatory drugs (NSAID),
447
and thus block PG synthesis, acute administrationof indomethacin can produce hypertension (8). Also, indomethacin-induced hypertension in anaesthetized dogs resembles that of essential hypertension elevated BP with no change in cardiac output, but a significant increase in vascular resistance (9). Possibly individuals using NSAlDs are not taking doses high enough to reach the 80% level of PG synthesis
inhibition
believed
to
be
required
to
produce
(8).
hypertension
Other studies have also provided support for stress-induced hypertension via PG modulation, Weber, et al (lo), in his study of hypertensive humans found an impaired capacity of the kidney to activate the Kallikrein-Kinin system. This system normally acts to produce vascular vasodilation with its activation possibly stimulated by PGs. Its effect is greatly augmented by the release of PGE2 in the kidney (8). With inhibition of PG synthesis by a stress-induced blood cortisol increase, the effect of the Kallikrein-Kinin system would be lessened, with a reduced counteractionofthe vasoconstrictive comangiotensin II and NE (ll), resulting in an increased pressor pounds, reponse to these stimuli. Thus, stress may be associated with hypertension by blocking the effect of PGl2 via synthesis inhibition, or by limiting the synergistic effect of PGE2 and bradykinin in lowering BP.
levels
Ignatowska, et al (12) found were higher in hypertensive
that PGF2~ individuals
(a
vasoconstrictor) than normotensives
prior to engaging in a mental stress activity, and believe the difference to be due to a greater anticipatory response to the stressor by the hypertensives. This “pre-test” anxiety would also increase since PGF2cl is believed to be synthesized cortisol levels. However, primarily in the brain in response to stress, the cortisol would not Thus the increased reach the tissue due to the blood brain barrier. blood cortisol would not inhibit the synthesis of PGF2d, and the It is stress-induced synthesis of PGF2e would raise blood pressure. possible that continua1 stress or inadequate coping responses lead to chronically striction and
high levels hypertension.
of
PGF2d
which
contribute
to
vascular
con-
PGs also influence renal physiology, and are involved in sodium metabolism - key aspects of hypertension pathophysiology. There is yet a wealth of information to be uncovered in this area, and much research is presently being undertaken to discover and specify the While definitive mechanisms of PG physiology related to hypertension. there is some indication that stress information is still lacking, is an important factor in the genesis and/or exacerbation of hypertension via inhibition of vasodilatory PGs, or the synthesis of PGF2a and TXA 2’
448
References 1.
2.
Jannsen, cause of Armstrong
et al. raised
Prolonged exposure to blood pressure in man.
J. et al. a metabolite vessels.
l!;“ISd;ld
stressful Lancet
stimulus :
86,
as
a
1977
Cardiovascular actions of prostacyclin of arachidonic acid which is synthesized Circulation Research 43,; Suppl l:l-112,
1978 3.
Olley PM and Conceani 134:688, 1980
4.
Selye entist,
5.
6.
The
H.
evolution
61:692,
SL and
from cells costeroids. U.S.A.
as
The
of
prostaglandins.
the
stress
concept.
Am J Dis
Child
American
Sci-
1973
Rascher, WR, et by prostaglandins Clinical rats. Hong,
F.
Modulation
al.
Levine
L.
Inhibition
the biochemical Proceedings of
73:1730,
of
sympathetic
in corticosterone-induced Science 57:235s, 1979 of
vascular hypertension
arachidonic
action of the National
acid
tone in
release
anti-inflammatory cortiAcademy of Sciences,
1976
7.
Neri Serneri, GG, et al. Prostacyclin, thromboxane, and ischemic heart disease. p. 138 in Prostaglandins and Cardiovascular Disease (Ruth Hegyel i, ed) Raven Press, New York, 1981
8.
McGiff JC and cardiovascular cular Disease
9.
Lonigro glandin
Quilley J. Prostaglandins, hypertension, and the p. 101 in Prostaglandins and Cardiovassystem. (Ruth Hegyeli, ed) Raven Press, New York, 1981
AJ, et al. synthesis
in
Dependency the dog.
of renal Circulation
blood flow Research
on prosta32:712,
1973 10.
Weber tial
11.
PC,
et
al.
hypertension.
Urinary Clinical
prostaglandins Science
and 57:259s,
kallikrein
in
essen
1979
Scholkens B, Steinbach R, and Ganten D. Blood pressure effects of endogenous brain angiotensin in rats are increased by inhiClinical Science 57:27ls, bition of prostaglandin biosynthesis. 1979
12.
lgnatowska H, Klonowicz T, and Feltynowski T. mental stress on prostaglandin F2c1 in patients hypertension and in healthy subjects. Clinical 1979
449
The effect of with essential Science 57:275s,