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(Hypertension. 1996;27:114-118.)
© 1996 American Heart Association, Inc.
Articles |
Glucocorticoid Modulates Vasodilator Response of Mesenteric Arterioles in Spontaneously Hypertensive Rats
From the Department of Bioengineering and Institute for Biomedical Engineering, University of California, San Diego, La Jolla.
Correspondence to Geert W. Schmid-Schönbein, PhD, Department of Bioengineering and Institute for Biomedical Engineering, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0412.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Abstract We previously reported that the response of the arterioles in spontaneously hypertensive rats (SHR) to histamine is blunted compared with that in normotensive control rats (Wistar-Kyoto rats [WKY]). The present study was designed to analyze the extent to which this blunted arteriolar response may be attributed in SHR to the concurrent elevation of circulating glucocorticoids through the use of adrenalectomy with and without dexamethasone supplementation. Mesenteric arterioles were observed by intravital microscopy under general anesthesia, and their lumen diameters were measured after histamine superfusion. The concentration-response curve with histamine was compared with that of an endothelium-independent vasodilator, sodium nitroprusside. At the end of each experiment, papaverine was applied topically to determine the maximal diameter for each vessel, from which a measure of arteriolar tone could be computed. The arteriolar tone in sham-operated SHR is set at a higher steady-state level than in sham-operated WKY. The concentration required for a 50% dilator response (EC50) of histamine in adrenalectomized SHR was restored to the level of WKY. Adrenalectomy did not significantly affect the EC50 of histamine in WKY. When adrenalectomized SHR received a supplement of dexamethasone, the arteriolar response was found to show the same refractory pattern to histamine as sham-operated SHR. In contrast, the EC50 of sodium nitroprusside in sham-operated and adrenalectomized SHR was similar to that in sham-operated WKY. Our results indicate that the impaired dilator response to histamine in SHR is related to an enhanced adrenal glucocorticoid secretion.
Key Words: microcirculation • histamine • sodium nitroprusside • adrenalectomy • dexamethasone
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The progressive development of hypertension in SHR is associated with a shift in hemodynamic resistance. During this period a greater than normal level of arteriolar tone in the skeletal muscle microcirculation of SHR can be demonstrated, to the smallest precapillary ramifications of the terminal arterioles (15 to 20 µm).1 Among the factors that have been proposed to account for the increase in arteriolar resistance are smooth muscle medial hypertrophy,2 rarefaction,3 and an elevation of tone in resistance arteries.4 The precise causal and temporal interrelation between the factors leading to this upward displacement of arteriolar tone and the hypertension per se remains largely speculative.
In light of the fact that circulating corticosteroid levels are markedly elevated in SHR5 6 7 8 it was proposed that various vascular manifestations of the hypertensive condition may involve glucocorticoid pathways.9 Ancillary evidence is provided by the facts that progression of the SHR syndrome is associated with a hypertrophy of the cortical zones of the adrenal glands10 and that the hypertensive state can be prevented by adrenalectomy or by hypophysectomy. The demonstration that corticosterone supplementation in SHR was found to restore hypertension after adrenalectomy further strengthens the possibility that glucocorticoids per se may be a key factor in the development of hypertension.11
We recently observed that recruitment of leukocytes in SHR is blunted when stimulated with proinflammatory stimuli.12 13 14 15 At the same time we noted a less striking response of the arterioles to such proinflammatory substances.13 In this context we reported that the blunted response under steady-state conditions to histamine treatment appeared to be mediated by way of an endothelial cell–dependent pathway in mesenteric arterioles of SHR.16
Accordingly, the present intravital microscopic protocol was designed to clarify the contribution of adrenal glucocorticoids to the atypical arteriolar response to histamine in SHR. In particular, the analysis is designed to measure mesenteric arteriolar dilator response after topical application of histamine, an endothelium-dependent mediator, compared with sodium nitroprusside, an endothelium-independent dilator. The behavior of the small arterioles (20 to 35 µm) was used as a framework for the following reasons. (1) The arterioles in this range are physically aligned separately from the adjacent venules or lymphatics so that a vasodilation independent of adjacent endothelium could be assessed. (2) The arterioles in such a hierarchical subdivision offer a clear image, and there are small differences in the intravascular pressure levels between SHR and WKY compared with large arterioles.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Rat Preparation
All rat procedures were previously reviewed and approved by the University of California, San Diego, Animal Subject Committee. SHR (n=18) and WKY (n=18) (Charles River Breeding Laboratories, Wilmington, Mass) were used for the study. Twelve SHR and 12 WKY were subjected to bilateral adrenalectomy, and 6 SHR and 6 WKY were subjected to sham surgery at 12 weeks and studied at 13 weeks.15 17 The cohort of adrenalectomized SHR and WKY was fed and watered ad libitum with standard rat chow and with saline in the drinking water and were maintained in a light-controlled holding facility for 1 week. The sham-operated SHR and WKY were fed and watered ad libitum standard rat chow and water.10 15 17 The animals appeared alert and in good health. All experiments were performed at the same time of day (11 AM to 2 PM). Completeness of the adrenalectomy was verified by postmortem examination of the suprarenal region. To explore the relation of adrenocortical secretions to the observed vascular sequelae, in SHR we resorted to adrenalectomy with and without replacement therapy.
Blood Pressure Measurement
Each rat was maintained under
general pentobarbital sodium
anesthesia (30 mg/kg IM) as part of the routine for in vivo
microscopy, arranged on a heating pad, and covered with a blanket
heated to 37°C. A catheter (polyethylene PE-50 tubing, Clay Adams)
was inserted into the femoral artery, and mean arterial
pressure was measured.18 Blood pressure was continuously
monitored during the entire period of microvascular observation from
which average values were calculated. In a previous
study15 we showed that the mean arterial blood
pressure exhibited an only modestly lower value (10% to 15%) after
general anesthesia with pentobarbital sodium compared with
levels prevailing after a catheterization under local
anesthesia (4% lidocaine hydrochloride SC, Astra
Pharmaceutical Products, Inc). Comparable minor reductions in blood
pressure were seen during general anesthesia in the four
groups used here (sham WKY, sham SHR, adrenalectomized WKY, and
adrenalectomized SHR).15 17
Intravital Microscopic Observation of Mesentery
The abdomen
was opened by a small midline incision. The
ileocecal part of the mesentery was exteriorized carefully and draped
over a plastic support for intravital microscopy as described
previously.14 The preparation was kept at 37°C and
continuously superfused (1.0 mL/min) with a Krebs-Henseleit
bicarbonate-buffered solution saturated with 95%
N2/5% CO2. Interruption of the
suffusion over the tissue was avoided, since even short drying was
found to result in rapid cell injury as assessed previously by
intravital staining with propidium iodide.19
The
mesenteric microcirculation was visualized through an intravital
microscope (x55 water immersion objective lens, Leitz) using a digital
color CCD camera (DEI-470, Optronics Engineering). Single, unbranched
arterioles with a diameter between 20 and 35 µm and a length of 
50
µm were selected for study. The images were stored in a videocassette
recorder (model AG-127OP, Panasonic) for playback analysis.
Vessel diameters were measured off-line with a video
image–shearing monitor (model 907 IPM). All diameters reported in
this study refer to inner lumen measurements at the magnification
provided by a x55 objective lens with final magnification x2000 on
the screen of the television monitor (CT-1383 VY, Panasonic).
After a 20-minute period was observed to allow hemodynamic parameters to reach steady state, concentration-response curves were determined by adding each vasodilator individually (histamine dihydrochloride and sodium nitroprusside, Sigma Chemical Co) in 10-fold increments (10-8 to 10-3 mol/L) to the Krebs-Henseleit bicarbonate superfusate solution.16 The arterioles were observed at each concentration for 20 minutes. Separate sets of rats were used for each dilator. After the diameter response at the highest concentration was recorded, maximal vasodilation was induced by topical application of papaverine 1.0 mg/mL. This dilator is used routinely for such measurements because it interacts directly with the smooth muscle cell and does not involve any specific receptor pathway. The initial measurements made for a particular concentration at steady state provided the values for dss. Measurements after application of papaverine provided dmax values. The 1.0-mg/mL dose of papaverine was sufficient to eliminate evidence of active tone in the arterioles because no further vessel dilation was observed at constant pressure with the addition of any other vasodilator.1 Topical application of papaverine did not affect the arterial blood pressure, which was monitored throughout the experimental protocol.
The level of arteriolar tone (T) was computed as T=(dmax-dss)/dmax. As such, T is a nondimensional parameter that serves to reflect the degree of active smooth muscle constriction such that T=0% in dilated vessels and T=100% in fully constricted vessels with an occluded lumen.1 dss was computed for vessels that exhibited vasomotion as a time average over at least 10 vasomotor cycles.
As a further precaution possible mast cell degranulation, which might have been caused by the surgical handling of the ileocecal mesentery, was evaluated at the end of each experiment by superfusion of 0.1% toluidine blue solution for 30 minutes. After staining is completed, mast cells that show degranulation can be identified by the presence of metachromatic granules in the contiguous extracellular space.20 After toluidine blue staining was completed, the microscopic field under observation together with 3 to 4 surrounding fields was scanned to determine the percentage of mast cells that were degranulated. In tissues in which >10% of the mast cells showed degranulation the data were discarded to minimize the influence of an unregulated cofactor on endogenous histamine release from the mast cells.
Steroid Intervention
To assess the effects of glucocorticoids
on blood pressure and
arteriolar behavior in the adrenalectomized rats,15
dexamethasone 21-acetate (Sigma Chemical Co) was injected
into a separate group of rats at a dose of 0.5 mg/kg body wt per day IM
for 5 days, in line with a previous
method.6 15 17
Statistical Analysis
Statistical differences between the two
animal strains and
treatment modalities were determined by one-way layout ANOVA and
Scheffé's-type multiple comparison test. All values are
expressed as mean±SD. Statistical significance was set at
P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Sham-operated SHR under general anesthesia were used as a point of departure because mean arterial blood pressure remained significantly higher than normal, at a level of 166±9.3 mm Hg compared with 102.0±11.1 mm Hg for the sham-operated WKY (Table 1
).
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In the present experiment arterioles with the same range of
dmax values were sampled in two strains. We emphasize that
the average dmax value was not significantly different
among the groups (Table 2), in line with previous
measurements.1 17
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A concentration-dependent reduction of arteriolar tone occurred in
response to topical histamine in sham-operated as well as
adrenalectomized SHR both with and without dexamethasone
supplementation (Fig 1). The magnitude of the response
in sham-operated SHR was significantly less than in
sham-operated WKY for all concentrations between
10-8 and
10-4 mol/L (Fig 1). The EC50
value of histamine with respect to the tone response in
sham-operated SHR (2.8x10-4 mol/L,
Fig 1, bottom, 
) was 40 times higher than in
sham-operated
WKY (6.8x10-6 mol/L, Fig 1, top,
)(P<.05).
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P<.05 compared with
adrenalectomy groups.
After adrenalectomy, the elevated EC50 value of histamine
for the tone response in SHR decreased significantly
(4.4x10-6 mol/L, Fig 1
, bottom,
)(P<.05), to the level characteristic of
sham-operated WKY. Such a decrease in the EC50 values
in the adrenalectomized SHR could be prevented by supplementation with
dexamethasone (1.0x10-3
mol/L, Fig 1, bottom, 
) (P<.05). The
EC50
value of histamine for the tone response in the adrenalectomized WKY
and dexamethasone-supplemented, adrenalectomized WKY
groups was 3.3x10-6 mol/L and
2.8x10-6 mol/L. A comparable range
of values was present in the sham-operated WKY (Fig 1,
top).
When the endothelium-independent dilator sodium
nitroprusside was used, the arteriolar tone response in SHR and WKY did
not show the same trend as the response to histamine (Fig 2).
There were no differences in the EC50
value between the sham-operated SHR
(1.0x10-6 mol/L, Fig 2, bottom, )
and sham-operated WKY (2.0x10-6
mol/L, Fig 2, top, ). In both adrenalectomized cohorts the
EC50 values for sodium nitroprusside fell into the same
range (WKY, 2.0x10-6 mol/L; SHR,
1.7x10-6 mol/L, ). No significant
differences were seen in the EC50 values between
adrenalectomized, dexamethasone-supplemented WKY
(1.2x10-6 mol/L, Fig 2, top, ) and
dexamethasone-supplemented, adrenalectomized SHR
(1.0x10-6 mol/L, Fig 2, bottom,
).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present results indicate that the mesenteric arterioles of SHR are refractory to the dilator action of histamine but not to sodium nitroprusside. Although a refractory state was no longer evident after bilateral adrenalectomy, this state could be restored with glucocorticoid supplementation (Fig 1
). Several studies in the literature have reported that the vascular tone of arterioles is significantly elevated in hypertensive individuals.1 21 Although several specific modalities have been advanced to explain the upward displacement of steady-state arteriolar tone in SHR, this condition is likely to actually be the end result of several overlapping mechanisms acting in concert, including an increased myogenic response to elevated blood pressure,22 suppression of endothelial cell–derived relaxation,23 and a shift in neurogenic stimulation,24 among others. Previous investigations dealing with the microcirculation of hypertensive patients also reported morphological changes in the wall of arterioles25 and changes in the development of the arteriolar network,3 26 27 which the authors of these reports thought could account for the elevation in peripheral resistance. In a recent report we showed that adrenalectomy served to prevent the development of the hypertension per se as well as enhanced arteriolar tone in SHR and that glucocorticoid but not mineralocorticoid supplementation served to restore increased blood pressure and arteriolar tone, emphasizing the importance of glucocorticoids in the development of hypertension (H.S., B.W.Z., G.W.S.-S. unpublished results, 1995).
Although intravascular pressure in the smaller mesenteric arterioles of SHR and WKY has not been reported, according to the report of Bohlen28 of the arterioles of the wall of the intestine, the intravascular micropressures in the 20- to 35-µm mesenteric arterioles in SHR are moderately higher than those in WKY. Compared with the large difference in systemic blood pressure between SHR and WKY, however, the significance of this difference of intravascular pressures at this branching level between two strains is not as great. A myogenic effect due to the somewhat higher intravascular pressure is likely to be associated with the higher tone in SHR arterioles.
A series of studies has demonstrated that histamine-induced relaxations were endothelium dependent.29 30 31 We emphasize that there are differences in the endothelium-dependent vascular response among species and even between vessels in different tissues of the same species.32 For example the level of NO released by histamine in the guinea pig coronary circulation alone is believed to be sufficient to account for the increase in cGMP and the observed coronary vasodilation.33 In general our observations,16 in line with those of previous workers,33 34 support the idea that the histamine-induced vasodilator response in the rat mesenteric arterioles is an endothelium-dependent phenomenon.
In line with the proposal by Ignarro et al35 that the
modes of action of sodium nitroprusside and NO are similar, the
present measurements suggest that the actual release of NO is
decreased in hypertensive individuals. Endothelial
cells and smooth muscle cells from SHR vessels apparently are modified
to release less NO than cells from WKY.23 Thus, the
increase in flow associated with reduced arteriolar dilation in young
SHR could be interpreted to be a consequence of an impairment of the
NO-mediated part of the flow-dependent dilation.36
Such a sequela is in line with the observation that the arterioles in
the SHR mesentery are refractory to
endothelium-dependent vasodilators (histamine and
acetylcholine).16 Although an enhanced level of superoxide
anion production in mesenteric arteriolar
endothelial cells of SHR is no longer present after
adrenalectomy, an elevated level of oxidative stress can be reinstated
by dexamethasone supplementation.17 In line
with such a scenario, if endogenously produced NO in SHR
was in turn consumed by an overproduction of superoxide
anion, reactions involving an endothelium-derived
NO-dependent vasodilator effect would in turn be attenuated. The
activity of xanthine oxidase, a key enzyme associated with
microvascular oxidative stress in SHR,17 is increased in
SHR myocardium compared with that of WKY.37
Interestingly, epithelial cell gene expression of xanthine
dehydrogenase and xanthine oxidase are enhanced by glucocorticoid
application.38 Glucocorticoids also blunt the induction of
nitric oxide synthesis in smooth muscle.39 Because in the
absence of a source of adrenal glucocorticoids the suppressed
vasodilator response of the SHR arterioles to histamine is no longer
evident (Fig 1, bottom), the present results provide additional
indirect evidence for a link between glucocorticoids and the altered
production of endothelium-derived
vasoactive agents.
In conclusion, the mechanism by which the dilator response of the arterioles to agents such as histamine is blunted in the SHR mesenteric microcirculation appears to be related to an elevation of adrenal glucocorticoid secretion in this genetic model of the hypertension syndrome.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The research was supported by US Public Health Service grant HL-10881. This work was completed during the tenure of a Research Fellowship for Dr H. Suzuki from the American Heart Association, California Affiliate.
Received July 27, 1995; first decision August 25, 1995; accepted October 2, 1995.
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