(Hypertension. 1995;26:397-400.)
© 1995 American Heart Association, Inc.
Articles |
Vasodilator Response of Mesenteric Arterioles to Histamine in Spontaneously Hypertensive Rats
From the Department of Bioengineering and Institute for Biomedical Engineering, University of California–San Diego, La Jolla.
Correspondence to Dr Geert W. Schmid-Schönbein, 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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Abstract Recent evidence suggests that spontaneously hypertensive rats (SHR) exhibit an impaired response to inflammatory mediators. We designed this study to analyze the response of arterioles of SHR after stimulation with a proinflammatory agent, histamine, compared with the response of arterioles of normotensive Wistar-Kyoto (WKY) controls. We observed mesenteric arterioles by intravital microscopy in rats under general anesthesia and measured their lumen diameters after histamine superfusion. To compare the concentration-response curve with histamine, we also studied the effect of an endothelium-dependent vasodilator, acetylcholine, and an independent vasodilator, sodium nitroprusside. At the end of each experiment we applied papaverine topically to determine the maximal diameter for each vessel, from which we computed arteriolar tone. Arteriolar tone in SHR is set at a higher steady state level than in WKY. The concentration required for a 50% dilator response (EC50) of histamine in SHR was significantly higher than that in WKY. In SHR the arteriolar response showed the same refractory pattern to histamine as to acetylcholine. In contrast, the EC50 of sodium nitroprusside in SHR was similar to that in WKY. Our results indicate that SHR exhibit an impaired dilator response to histamine that is due to a blunted endothelium-dependent vasodilation.
Key Words: microcirculation • histamine • sodium nitroprusside • endothelium • acetylcholine
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Introduction |
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The progressive elevation of arterial blood pressure in the spontaneously hypertensive rat (SHR) is associated with a shift in hemodynamic resistance that is especially striking in small arterial or arteriolar segments of the microcirculation. Among the factors proposed to account for the increase in arteriolar resistance are smooth muscle medial hypertrophy,1 rarefaction,2 and elevation of tone in resistance arteries.3 An above-normal level of arteriolar tone in the skeletal muscle microcirculation of SHR can be demonstrated down to the smallest precapillary ramifications of the terminal arterioles (15 to 20 µm).4 The factors leading to this upward displacement of arteriolar tone in hypertensive individuals remain largely speculative.
The progression of the hypertensive syndrome is paralleled by an elevation of arterial blood pressure that is associated with elevation of total peripheral resistance as well as by a heightened response to vasoactive stimuli.5 6 In addition, a seemingly unrelated trend is seen in that there is a blunted response of the arterioles in skeletal muscles to locally derived dilators such as acetylcholine.7
We recently observed that there is a blunted response in SHR to recruit leukocytes after stimulation with a proinflammatory stimulus.8 9 10 11 At the same time we noted that there was a subnormal response of the arterioles to proinflammatory substances.9 Accordingly, we designed the present intravital microscopic study to explore details of the arteriolar response to histamine. Our objective was to analyze the changes induced in mesenteric arteriolar dilator responses after topical application of histamine as well as vasodilators with different sites of action. We used histamine as a local agent for two reasons: First, it is a naturally occurring proinflammatory vasodilator that has a wide variety of vascular reactions related to local hyperemia; second, the vasodilator effect of histamine appears to be mediated by an endothelial cell–dependent interaction with smooth muscle. Recent evidence indicates that the inflammatory response to histamine such as the leukocyte–endothelial cell interaction is suppressed in SHR tissues.10 11
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Methods |
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Rats
All animal procedures were previously reviewed and approved by the University of California–San Diego Animal Subject Committee. SHR (n=18) and Wistar-Kyoto rats (WKY, n=20) (13 to 14 weeks of age, Charles River Breeding Laboratories, Wilmington, Mass) were used for the study. The rats were maintained under general anesthesia with pentobarbital sodium (30 mg/kg IM) as part of the routine for in vivo microscopy and were arranged on a heating pad and covered with a blanket at 37°C. A catheter (PE-50 tubing, Clay Adams) was inserted into the femoral artery, and mean arterial pressure was measured.12 Blood pressure was continuously monitored during the entire period of microvascular observation, and average values were calculated. In a previous study11 we were able to show that mean arterial blood pressure exhibited only a modestly lower value (10% to 15%) after general anesthesia with pentobarbital sodium compared with levels prevailing after arterial catheterization under local anesthesia (4% lidocaine hydrochloride SC; Astra Pharmaceutical Products, Inc).
Intravital Microscopy
The abdomen was opened by a small midline incision for
exteriorization of the ileocecal portion of the mesentery, which was
draped over a plastic support for intravital microscopy, as described
previously.10 The preparation was kept at 37°C and
continuously superfused (1.0 mL/min) with a Krebs-Henseleit
bicarbonate-buffered solution saturated with a 95%
N2/5% CO2 gas mixture. Interruption of
the suffusion over the tissue was avoided because even short drying was
found to result in rapid cell injury as assessed previously by
intravital staining with propidium iodide.13
The mesenteric microcirculation was visualized through an intravital microscope (x55 water-immersion objective lens, Leitz) with the use of a CCD camera (model JE2362, Javelin). Three unbranched arterioles with diameters between 20 and 35 µm and approximately 150 µm in length were selected in each preparation. The images were stored on 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 a final magnification of x2000 on the TV monitor (CT-1383 VY, Panasonic).
After a 20-minute period to allow hemodynamic parameters to reach steady state, concentration-response curves were determined by addition of each vasodilator individually (histamine dihydrochloride, acetylcholine, sodium nitroprusside; Sigma Chemical Co) in 10-fold increments (10-8 to 10-3 mol/L) to the Krebs-Henseleit bicarbonate superfusate solution. The arterioles were observed at each concentration for 20 minutes. Separate sets of rats were used for each dilator. After the diameter response to the highest concentration was recorded, maximal vasodilation was induced by topical application of papaverine (1.0 mg/mL). This dilator has been 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 provided the values for steady state lumen diameter (dss). Measurements after application of papaverine provided maximal diameter values (dmax). The dose of 1.0 mg/mL papaverine was sufficient to eliminate evidence of active tone in the arterioles, as no further vessel dilation was observed at constant pressure with the addition of any other vasodilator.4 Topical application of papaverine had no effect on 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, tone 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.4 Steady state diameter (dss) was computed for vessels that exhibited vasomotion as the time average over at least 10 vasomotor cycles.
As a further precaution possible mast cell degranulation that 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. In the presence of the stain mast cells that show degranulation can be identified by the presence of metachromatic granules in the contiguous extracellular space.14 After toluidine blue staining the microscopic field under observation, together with three to four surrounding fields, was scanned for determination of the percentage of mast cells that exhibited degranulation. In tissues in which more than 10% of the mast cell showed degranulation, the data were discarded to minimize the influence of an unregulated cofactor on endogenous histamine release from the mast cells.
Statistical Analysis
Statistical differences between the two rat strains and
treatment modalities were determined by one-way layout ANOVA and
Scheffé-type multiple comparison test. All values are
expressed as mean±SD. Statistical significance was set at a value of
P<.05.
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Results |
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Mean arterial blood pressure of SHR under general anesthesia remained significantly above normal at 164±8.6 mm Hg compared with that of WKY (101.1±10.4 mm Hg).
The level of mesenteric arteriolar tone under steady state control conditions in SHR was significantly higher than in WKY (Fig 1, top). In the present experiment the arterioles within the same range of dmax value were sampled in two rat strains. It is noteworthy that the mean dmax value was not significantly different between WKY (31.3±3.3 µm) and SHR (31.0±4.0 µm) (Fig 1, bottom; P=.64), in line with previous measurements.4
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Topical application of histamine (Fig 2a) led to a stepwise decrease in steady state levels of tone in both WKY and SHR in a concentration-dependent manner, with the magnitude of the response in SHR being significantly lower throughout the concentration range between 10-8 and 10-4 mol/L. The EC50 value of histamine for tone response in SHR (2.3x10-4 mol/L) was approximately 90 times higher than that in WKY (2.5x10-6 mol/L) (P<.05). The arteriolar response to acetylcholine application (Fig 2b) followed a trend similar to that for histamine (Fig 2a), with a significantly higher level of tone in SHR. The EC50 (1.3x10-4 mol/L) of acetylcholine for tone response in SHR was approximately 200 times higher than that in WKY (3.7x10-6 mol/L) (P<.05).
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The concentration-dependent arteriolar tone response to sodium nitroprusside showed no difference between SHR and WKY (Fig 2c). The EC50 (8.3x10-7 mol/L) of sodium nitroprusside for tone in SHR was similar to that in WKY (7.1x10-7 mol/L).
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Discussion |
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SHR mesenteric arterioles were clearly refractory to the dilator action of histamine and acetylcholine (Fig 2). In contrast, there was no effect on an endothelium-independent vasodilator response (sodium nitroprusside) in SHR (Fig 2).
Separate studies in the literature have reported that vascular tone of arterioles is significantly elevated in several tissues in hypertension.4 15 Although a number of specific modalities have been advanced to explain the upward shift of steady state arteriolar tone in SHR, it appears that the condition may actually be the end result of several overlapping mechanisms acting in concert, such as an increased myogenic response to the elevated blood pressure,16 a suppression of endothelial cell–derived relaxation, or a shift in neurogenic stimulation,17 among others. Previous investigations dealing with the microcirculation of hypertensive individuals have reported morphological changes in the wall of arterioles18 as well as changes in the structure of the arteriolar network,2 19 20 which could account for the elevation in peripheral resistance. Although the question of whether such changes involve primarily the functional coupling between endothelial and smooth muscle cells in active tone of resistance vessels in hypertension remains open, much of the recent evidence supports the idea that an altered function of vascular endothelial cells is intimately involved in the development of particular models of hypertension.21
Despite uncertainties about the relevance of changes observed in the terminal vascular tree of the mesentery compared with those present in other major tissues and the necessity to maintain animals under general anesthesia, a feature that by itself can have an effect on vascular reactivity, the intravital approach provides unique information at the single-cell level concerning the integration of cellular mediators and systemic controls that cannot be measured by other physiological approaches. An important feature in this regard is the stability and reproducibility of exteriorized tissue preparations. In the present experiments we elected to use the rat ileocecal mesentery because of the substantial background of experimental evidence characterizing the behavior of the microvascular network with respect to cellular and physiological perturbations. The results presented on tone are based on in vivo measurements under well-controlled conditions. The anesthetic management of such experimental preparations has been carefully evaluated and standardized. In a previous study4 we weighed the influence of anesthesia on tone and found no significant distortion of arteriolar tone within the pentobarbital dose needed for general anesthesia.
Several studies have demonstrated that histamine-induced relaxations were endothelium dependent.22 23 24 Differences have been found in the endothelium-dependent vascular response between species and even between vessels in different tissues of the same species.25 The level of nitric oxide released by histamine in the guinea pig coronary circulation was sufficient to account for the increase in cGMP and the observed coronary vasodilation.26 In general, our observations together with those of previous workers26 27 tend to support the idea that the histamine-induced vasodilator response in rat mesenteric arterioles is endothelium dependent.
Many studies have shown that the arterioles in hypertensive SHR were refractory to acetylcholine at a concentration that usually produces a well-defined dilator response on topical application in skeletal muscle preparations.7 Along these lines it should be noted that the relaxation of arterial28 and arteriolar29 30 segments induced by acetylcholine can no longer be evoked in the absence of endothelium. These findings are in line with the data reported here in the mesentery (Fig 2). Our in vivo measurements are also compatible with in vitro studies on ring preparations of mesenteric arteries from hypertensive strains31 in which it was found that the responses to acetylcholine were blunted, whereas the dilation following endothelium-independent sodium nitroprusside remained unaltered. An impaired release of an endothelial cell–derived mediator at the level of microvessels in SHR is further supported by our finding that sodium nitroprusside continues to induce a significant decrease in steady state tone in hypertensive SHR arterioles (Fig 2).
In line with the suggestion by Ignarro et al32 that the modes of action of sodium nitroprusside and nitric oxide are similar, our data can be interpreted to suggest that nitric oxide release is decreased in hypertensive individuals. Evidence has been obtained that endothelial and smooth muscle cells from SHR are genetically modified to release less nitric oxide than cells from WKY.33 Thus, in young SHR the reduced arteriolar dilation in response to an increase in flow is apparently a consequence of the impairment of the nitric oxide–mediated portion of the flow-dependent dilatation.34 We have recently obtained direct evidence to suggest that SHR have enhanced levels of superoxide anion production in mesenteric arteriolar endothelial cells.35 In such a scenario, if endogenously produced nitric oxide were consumed by an overproduction of O2- in SHR, reactions involving an endothelium-derived nitric oxide–dependent vasodilator effect would be attenuated in SHR.
In conclusion, the blunted dilator response of the arterioles to histamine (an endothelium-dependent proinflammatory vasodilator) in the SHR mesenteric microcirculation may represent a factor that contributes to the atypical inflammatory response, including the attenuated hyperemia in this strain.
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Acknowledgments |
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This work was completed during the tenure of a Research Fellowship for Dr H. Suzuki from the American Heart Association, California Affiliate. The research was supported by US Public Health Service grant HL-10881.
Received March 24, 1995; first decision May 15, 1995; accepted June 2, 1995.
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