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Institute of Physiology and Pharmacology, Department of Physiology, Göteborg University, Sweden; and Clinical and Experimental Research Laboratory, Lung and Heart Institute, Sahlgrenska University Hospital/Östra, Göteborg, Sweden
Address all correspondence and requests for reprints to: Göran Bergström, Institute of Physiology and Pharmacology, Department of Physiology, P.O. Box 432, 405 30 Göteborg, Sweden.
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Abstract |
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Mean arterial blood pressure was measured in conscious, unrestrained male and female bovine GH and littermate control mice during normal as well as high salt intake using telemetric devices. Structure in artificially perfused maximally dilated hindquarter vascular beds and vascular reactivity and endothelial function in small mesenteric vessels were studied in female bovine GH and control mice.
Mean arterial blood pressure was increased in female bovine GH transgenic (126 ± 3 mm Hg) and male bovine GH transgenic (129 ± 4 mm Hg) compared with female (109 ± 3 mm Hg, P < 0.05) and male (111 ± 3 mm Hg, P < 0.05) controls respectively. Increased salt intake had no effect on mean arterial blood pressure. Perfusion studies showed a significant decrease in the average diameter of the female bovine GH transgenic hindquarter vascular bed (P < 0.05). The responses of isolated resistance arteries to nor-epinephrine, potassium-induced depolarization, acetylcholine, or sodium-nitroprusside did not significantly differ between bovine GH transgenic and control mice.
We conclude that the phenotype of the bovine GH transgenic mice includes a salt-resistant form of hypertension. Furthermore, the increase in mean arterial blood pressure is accompanied by a significant structural narrowing of the resistance vasculature without changes in vascular reactivity or endothelial function. The results imply that hypertension in bovine GH transgenic mice is maintained mainly by a structurally based increase in peripheral vascular resistance.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hypertension is reported in 20–40% of all acromegalic patients with a possible predominance in females (1, 2). The mechanisms behind the development of the high blood pressure are poorly understood. Administration of GH to healthy volunteers is in most studies not associated with hypertension (2). However, sodium retention and edema have been observed (3), possibly explained by a rise in plasma aldosterone and renin levels (4, 5). GH treatment in humans also results in an increase in heart rate and stroke volume (2). Because GH does not appear to affect blood pressure in humans, peripheral resistance has to be reduced. However, there is no real consensus in the literature, and a few studies report increased MAP after GH administration to humans (2).
In normotensive experimental animal models, GH administration (injections or GH-secreting tumors) has failed to affect MAP or vascular reactivity (6, 7, 8, 9). However, cardiac hypertrophy has been observed, most likely of eccentric type with a large left ventricle and proportionally increased myocardium (10, 11). It has furthermore been shown that GH is needed for the development of high blood pressure and adaptive structural vascular changes in experimental renovascular hypertension (12).
Transgenic mice models, overexpressing GH, has been used in only a few studies of cardiovascular disease. Dilley and Schwartz (13) reported no difference in blood pressure but an increased media to lumen size in the mesenteric blood vessels of female transgenic C57/Bl6 mice overexpressing either rat GH or bovine GH (bGH). A recent study in a strain of C57Bl/6JxCBA kept in our laboratory, overexpressing bGH, with elevated serum GH (1000–1400 ng/ml) and IGF-I (700–770 ng/ml) levels (14), showed that systolic cardiac function in these mice were compromised showing signs compatible with eccentric left ventricular hypertrophy (11). To further explore the cardiovascular function of this strain of GH transgenic mice, we used telemetric technique to measure 24-h blood pressure in conscious unrestrained animals. We also measured the blood pressure reaction to a diet enriched in sodium. Furthermore, we evaluated both structure and function of the resistance vasculature using wire myo-graph technique and hindquarter perfusion of the mesenteric and skeletal vasculature, respectively.
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Materials and Methods |
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Animals were housed together with littermate controls during most parts of the studies. However, during telemetric studies all mice were housed individually. The environment of the animal rooms was controlled with a 12-h light, 12-h dark cycle (0730 h, with a 1-h dawn/sunset function), a relative humidity between 45–55% and a temperature of 20 C. The mice had free access to tap water and standard pellet chow (R-34, Lactamin, Vadstena, Sweden). The study was performed after prior approval from the local ethical committee for animal experimentation at the Göteborg University, Sweden.
Groups of 5- to 7-month-old transgenic and littermate controls were randomly chosen for the different study protocols outlined below. However, in the studies using telemetry slightly younger mice were used (3–5 months of age). Only female mice were used for the studies of vascular function.
Blood pressure measurements
MAP and heart rate (HR) were continuously measured in freely
moving bGH transgenic and littermate control mice of both sexes, using
telemetry.
Surgical implantation of telemetry transmitters
Radiotelemetry transmitters were implanted in all animals at
least 5 d before any experimentation. Mice were anesthetized using
medetomidine (Domitor, Orion Espoo, Finland, 0.005 mg/10 g, ip) and
ketamine (0,75 mg/10 g, ip). A telemetry transmitter catheter (OD 0.4
mm, Data Sciences International Inc., St. Paul, MN) was implanted into
the carotid artery as previously described by Carlson
(15). The transmitter (TA11PA-F20, weight 3 g) was
positioned sc in the right flank of the animal and the incision closed
with staples. Anesthesia was reversed by atipamezole (Antisedan, Orion
Espoo, 0.04 mg/10 g, p.o.). After at least 5–7 d of recovery,
the cage with the animal was placed on a receiver plate and the signal
collected using the Dataquest LabPRO Acquisition System (version 3.01,
Data Sciences international, Inc.). The following sampling parameters
were used; sampling frequency 500 Hz, sample duration 12 sec, save
period 2 min. The pressure signal was corrected for electronic
offset, the average of a measurement outside the animal before
implantation and after explantation.
Baseline telemetry MAP
Five to 7 d after implantation, MAP and HR were measured
for 2 consecutive d in an undisturbed environment.
Effect of high salt
Effect of high salt diet was tested in female mice. After
baseline recording of MAP and HR, the battery was turned off and the
mice were administered a diet containing 8% NaCl (wt/wt, AnalyCen,
Lidköping, Sweden) with free access to tap water. The mice were
kept on this diet for 7 d, after which MAP and HR were recorded
for another 2 d, still on high salt diet.
Renal function in conscious mice
Conscious renal function was measured in a sex-mixed group of
bGH transgenic (n = 3) and matched wild-type control mice (n
= 5). After anesthesia, a small mini-pump (ALZET, DURECT Corp.,
Cupertino, CA) was implanted sc, delivering a steady infusion of
Cr-EDTA (Amersham International, UK) for 24 h
(0.8 µCi/h). After 4 h recovery from anesthesia, the mice
received a bolus injection of Cr51-EDTA (5 µCi,
ip) and were placed in separate metabolic cages for 24-h collection of
urine. Blood samples were taken at the start and at the end of urine
collection and the plasma was analyzed for radioactivity using a
-counter (Packard 5019, Packard Co., Amana, IA).
Glomerular filtration rate (GFR) was calculated by standard formulas
(Urinary Cr51-EDTA/Plasma
Cr51-EDTA x urinary-flow).
Hemodynamic studies of maximally dilated hindquarters
Female mice were prepared for hindquarter perfusions with a
modified technique from that earlier described for rats
(12). Briefly, the abdomen was opened and the aorta and
vena cava cleared from tissue above the iliac bifurcation. The aorta
was cannulated (PE-25) and perfusion of the hindquarter started with a
2% human albumin perfusate at 37 C (wt/wt, Immuno, Vienna, Austria).
Temperature was maintained by an additional water jacket close to the
aortic inlet and a heating lamp. The vena cava was cut wide open to
minimize venous outflow resistance. The ionic composition of the
perfusate was Na+ 148, K+
4.9, Cl- 134,
HCO3- 25,
Mg2+ 0.83, Ca2+ 2.5,
H2PO4 0.6, and glucose 5.6
mmol. When bubbled with 5% CO2, the pH of the
solution was 7.40. The perfusion was done alternating transgenic mice
and their littermate controls. Baseline perfusion flow was set at 10
ml/100 g of hindquarter weight. The hindquarter was dissected out at
the end of the experiment and weighed. The perfusion protocol consisted
of random changes in the flow rate and simultaneous recordings of
perfusion pressure in a t-tube close to the aortic inlet. Individual
pressure-flow curves were established from which flow rates at
designated pressures was estimated (10, 20, 30, 40, 50, 60, 70, and 80
mm Hg, see Fig. 4
). We also tried to assess the maximal pressor
response by injecting a bolus-cocktail of angiotensin II,
phenylephrine, and vasopressin V1-agonist in
supraphysiological doses. However, due to technical problems with the
low perfusion volumes and in-homogeneity of the responses, the data
were impossible to interpret and are therefore not presented.
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The function of the endothelium was evaluated by the response to
acetylcholine (Ach) and compared with the response to the
endothelium-independent vasodilator sodium-nitroprusside (SNP). Ach
(range 10-9–10-6
M) and SNP (range
10-11–10-6
M) were administered in a cumulative way, on precontracted
vessels (NE, maximal contraction), increasing the concentrations in
half log steps every 4 min. A second dose-response relationship to Ach
was performed in the presence of the nitric oxide (NO)-synthase
inhibitor N[
]-nitro-L-arginine (L-NNA,
100 µM).
Statistics
Body-, heart-weights, and MAP before and after salt were
compared using t test. MAP from telemetry was compared using
an ANOVA followed by the Dunnett post hoc testing for differences from
control. Hind-quarter vascular resistance was compared using a repeated
measures ANOVA. Concentration-response relations in the Myo-graph were
analyzed with nonlinear regression (GraphPad Systems) giving Emax as the maximal
response and EC50 as the concentration giving
half-maximal response. Statistical analysis was performed by means of
t test for paired or unpaired observations. Probability
level of less than 0.05 is regarded as significant. Values are given as
means ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The increase in left ventricular
weight was in excess of the increase in body weight and also well in
excess of the observed increase in blood pressure (17%).
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, P < 0.01 for both).
When female mice were fed a diet enriched in sodium for 1 wk to test
for salt sensitive hypertension, neither bGH transgenic nor female
control mice responded with any significant change in MAP (Table 2). However, HR was significantly
decreased in both bGH transgenic and female littermate control mice
(P < 0.05, Table 2).
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Hemodynamic studies of maximally dilated hindquarters
Perfusion of the hindquarter at maximal dilatation revealed that
female bGH transgenic mice needed a higher flow to reach the same
perfusion pressure as the littermate control, i.e. a higher
resistance in the bGH transgenic mice hindquarter (Fig. 2). The higher resistance in the bGH
transgenic hindquarter is equivalent to a narrower average lumen
diameter in this vascular bed, compared with littermate control mice
(law of Poisuille’s).
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). However, the sensitivity of the
response to NE was significantly shifted to the right in the bGH
transgenic mice (EC50, P <
0.05), suggesting a decreased sensitivity of the bGH transgenic mice
vascular bed to the vasoconstrictor action of NE (Fig. 3).
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). Pretreatment with L-NNA
resulted in a reduction but not a complete abolishment of the
vasodilator action, suggesting that the action of Ach is mediated both
by release of) NO as well as endothelial hyperpolarizing factor (EDHF).
SNP resulted in similar vasodilator response in both female bGH
transgenic and littermate control mice (Fig. 4). |
Discussion |
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Blood pressure
We have shown that MAP was increased in female and male bGH
transgenic compared with littermate control mice. Human acromegaly is
associated with an increased prevalence of hypertension (20–40%);
however, results from animal studies are more controversial. When using
different injection techniques of GH or surgical implantation of
GH-producing tumors, the effect on MAP is not consistent between
studies (2), although most studies showing no effect of GH
on MAP.
The information on blood pressure levels of GH-transgenic mice is limited. Dilley and Schwartz (13) reported no increase in the systolic blood pressure of female GH-transgenic mice. Noteworthy is that they found systolic blood pressure, measured with tail-artery plethysmography, to be in the range of 90–95 mm Hg. This is remarkable low because the SBP recorded by telemetry in the control normotensive mice in our study was in the range of 130–150 mm Hg. Indeed, several studies have shown MAP of mouse to be in the same range as in other rodents. The low MAP in the study by Dilley (13) points to important methodological differences between our studies making comparisons difficult.
In the present study, we used sophisticated, state-of-the-art telemetry equipment to measure blood pressure. MAP was increased to the same extent in both sexes of bGH transgenic mice. Telemetric measurement of blood pressure in mice is a new technique (15) but must nevertheless be considered as the gold standard for MAP measurements. In a unique way, the technique allows us to measure the true, unrestrained MAP of mice in their normal environment. From the data in the present study, we conclude that both sexes of bGH transgenic mice of the studied strain are hypertensive.
Acute administration of human GH leads to salt and water retention (3). Furthermore, previous reports have shown a higher incidence of glomerulosclerosis in old bGH transgenic mice (17). Thus, it could be speculated that an impaired excretory capacity or a volume retaining action of GH could explain the high MAP. We therefore analyzed renal function in a subgroup of conscious male and female bGH transgenic mice. GFR in the bGH transgenic mice were unchanged, arguing against excretory failure as an explanation to the high MAP. Furthermore, MAP in the bGH transgenic mice were not affected by an approximately 10-fold increase of salt ingestion (8% in food); therefore, it is unlikely that the observed hypertension is salt dependent.
Vascular function studies
What might be the mechanisms behind the increased MAP in bGH
transgenic mice? In an attempt to answer this question, we analyzed
vascular structure and function in both the hindquarter vascular bed
(skeletal muscle) and in isolated vessels from the mesenteric bed of
female mice. The techniques complement each other and give important
insights in to the pathophysiology of bGH hypertension.
Hindquarter vascular resistance
The hemodynamic technique to study resistance in the maximally
dilated skeletal vascular bed of the hindquarter has been used
extensively in rats to deduce the structure of the vasculature
(18). With this technique, it has been established that
the hallmark of all forms of hypertension is an increased resistance of
the vascular bed at maximal dilatation (18, 19). This
corresponds to a decrease in the average lumen dimensions of the
vascular bed, which will have severe implications for blood pressure
control as reviewed previously (19). In the present
study, we found resistance to be increased, and thus we interpret this
as a decrease in the average lumen dimensions of the vascular bed of
the hindquarter. However, it is important to note that this finding
could both cause and be the result of the increased pressure
(18), and it is thus difficult to draw any firm
conclusions on the pathogenetic importance of these findings. The
finding is in apparent contrast to the finding by Dilley and Schwarz
(13) that the average lumen diameter was increased in
several vascular sections. However, it is important to note that the
whole organ perfusion technique used in the present study is averaging
the lumen diameters along the whole length of the vessel. The
morphological technique used by Dilley only gives a spot measurement at
one defined level of the vasculature. Furthermore, the vessels in the
study by Dilley (13) were fixed at the assumed
physiological pressure and not at maximal dilatation allowing for
sampling artifacts. The effect of GH injections on vascular structural
properties in hindquarters has previously been studied in rats
subjected to hypertension due to experimental renal artery stenosis
(12). This study pointed to a permissive role for GH in
the structural adjustment of the vasculature to an increased pressure
load. Furthermore, GH administration to hypophysectomized rats resulted
in encroachment of the vascular lumen in the hindquarter thus
confirming our results. It is thus possible that excess GH could be of
primary pathophysiological importance in the development of
hypertension in GH transgenic mice by remodeling the resistance
vasculature.
Mesenteric vascular function
We also studied vascular function and reactivity in isolated
segments of the mesenteric bed. Using this technique, we can estimate
the reactivity of the vascular bed to different agonists. In the
present study, we evoked vascular constriction both by the adrenergic
agonist, NE, and the unspecific, depolarizing effect of hyperkalemia.
We found no difference in the maximal constriction evoked by these two
substances between the bGH transgenic and the littermate control mice.
However, the sensitivity to applied NE was significantly reduced in the
bGH transgenic mice, with a rightward shift of the dose-response curve.
This implies down-regulation of NE-receptors or second messenger
systems but with an intact maximal contractile strength of the vessel.
One explanation for this finding could be a down-regulation of
adrenergic receptors secondary to an increased sympathetic drive. It is
interesting to speculate that hypertension in bGH transgenic mice is
caused by, or associated with, an increase in sympathetic drive, which
results in a decreased NE sensitivity in the vasculature (see below).
This hypothesis remains to be tested.
As discussed above, vascular reactivity is dependent on both the function of the smooth muscle cells and the geometry of the vessels, i.e. vessel-wall size in relation to lumen dimensions (18, 19). Thus, to be able to fully describe the function of the vasculature in the bGH transgenic mice, we would also need reliable data on wall-size in the vessels studied. Detailed future analyses of both the contractile properties of the bGH transgenics smooth muscle cells and a proper analysis of wall size in relation to lumen dimension could shed further light on the pathogenesis of the hypertension in bGH transgenic mice.
Human acromegaly is associated with both hypertension (20–40%) and diabetes (10–20%) (1). Both these disorders have been associated with endothelial dysfunction (20, 21) and could thus be an important pathogenetic component in development of bGH transgenic mice hypertension. Despite the very high serum levels of GH found in the bGH transgenic mice (14), blood glucose levels are similar in bGH transgenic and littermate control mice (22). However, even though no regular insulin sensitivity test has been performed, the insulin levels has been shown to be markedly higher in bGH transgenic mice compared with controls, suggesting a marked insulin resistance in these mice that could affect endothelial function (22). The myo-graph technique allows us to test the endothelial function of the vessel. Administration of Ach triggers release of two endothelium-dependent vasodilators: NO and EDHF (23). However, the similar results between the two experimental groups suggest that endothelial function is intact in the bGH transgenic mice. The vascular dilatation was substantially, but not totally, inhibited by a blocker of NO formation (L-NNA). This finding implies that most of the Ach-induced vascular dilatation was caused by NO release with a small contribution from EDHF. The administration of the direct NO donor, sodium nitroprusside, shows that the reactivity to NO is similar in bGH transgenic and littermate controls mice. Thus, we can conclude that endothelial dysfunction is not a major patho-genetic factor in bGH transgenic mice hypertension.
Integrative control of blood pressure in bGH transgenes
Our current data showing that an increased salt ingestion does not
result in an increase in MAP argues against a salt-sensitive form of
hypertension. In an earlier study using the same strain of bGH
transgenic, it was clear that despite cardiac hypertrophy in excess of
body weight increase (Table 1), the systolic cardiac function were
markedly compromised, showing signs compatible with eccentric left
ventricular hypertrophy (11). These changes were most
likely caused by a defect in energy handling in the cardiomyocytes
(11). Even though we cannot estimate cardiac output from
these studies, it is hard to reconcile the impaired systolic function
with an increase in MAP. However, together with the results in the
present study showing vascular narrowing of the hindquarter vascular
bed and a normal contractile strength of the mesenteric vasculature, it
is likely that the MAP in bGH transgenic mice is maintained by an
increase in peripheral vascular resistance based mainly on vascular
narrowing of the resistance vasculature. Furthermore, it has been
proposed that insulin can stimulate the activity of the sympathetic
nervous system and cause vasoconstriction and hypertension
(24). Thus, the high insulin levels observed in the bGH
transgenic mice (22) could stimulate the sympathetic
nervous system and be important pathogenetic factors contributing to
the increase in peripheral resistance and hypertension of the bGH
transgenic mice. Supporting the notion of an increase in sympathetic
tone is the observed decrease in NE sensitivity in the small mesenteric
vessels.
Conclusion
We have shown, using telemetric technique, that mice
overexpressing bGH irrespective of gender have an increased MAP that is
not salt sensitive. This increase in MAP is associated with a narrowed
lumen of the hindquarter vasculature. However, there was no difference
in the contractile strength of the mesenteric vascular wall, nor any
difference in endotheial function between bGH transgenic and littermate
control mice. The finding of a hypertensive phenotype suggests that the
bGH transgenic mice is a valid model for studies of cardiovascular
disease in human acromegaly. This implies that the hypertension in bGH
transgenic mice is maintained mainly by a structurally based
increase in peripheral vascular resistance, perhaps augmented by the
sympathetic stimulatory effect of hyperinsulinemia.
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Acknowledgments |
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Footnotes |
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Abbreviations: Ach, Acetylcholine; bGH, bovine GH; EDHF, endothelial hyperpolarizing factor; GFR, glomerular filtration rate; HR, heart rate; MAP, mean arterial blood pressure; NE, nor-epinephrine; NO, nitric oxide; SNP, sodium-nitroprusside.
Received November 28, 2000.
Accepted for publication April 3, 2001.
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, n = 8) and litter mate controls (n =
7–8), preconstricted with NE. The dilatory effect of Ach was blocked
to more than 50% by a blocker of NO-formation (L-NNA).
,
n = 5) as well as littermate controls (n = 4).