Structural and Functional Properties of Isolated, Pressurized, Mesenteric Resistance Arteries From a Vasopressin-Deficient Rat Model of Genetic Hypertension
Abstract In this study we examined the structural and functional properties of mesenteric resistance arteries isolated from normotensive and hypertensive vasopressin-deficient rats. Hypertensive rats had a significantly higher mean arterial pressure (176±3 mm Hg) than normotensive controls (121±2 mm Hg). First- and second-order mesenteric resistance arteries were set up in a pressure myograph and pressurized to the mean arterial pressure of the rat from which they had been isolated. Vessels were fixed with glutaraldehyde, embedded in Araldite, sectioned, and examined histologically. First- and second-order mesenteric resistance arteries from hypertensive rats displayed a reduced internal diameter and increased media-to-lumen ratio compared with their normotensive controls. However, there was no evidence for an increased media content, indicating that the reduced internal diameter of hypertensive arteries was consequent to either remodeling of similar amounts of wall material or a reduced artery distensibility but not vascular growth. Pressurized arteries were also examined with respect to their responsiveness to the vasoconstrictors norepinephrine and arginine vasopressin and to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator papaverine. Both first- and second-order mesenteric arteries from hypertensive rats displayed enhanced sensitivity to norepinephrine compared with their normotensive controls. This effect was specific for norepinephrine, because responses to arginine vasopressin were similar in vessels isolated from normotensive and hypertensive rats. No evidence was found for an impaired endothelium-dependent vasodilatation in arteries from hypertensive rats. Indeed, in hypertensive vasopressin-deficient rats responses to acetylcholine were increased in first-order arteries compared with those from normotensive rats. Responses to papaverine were similar in arteries isolated from either normotensive or hypertensive rats. These observations indicate that increased blood pressure in this genetic model of hypertension may result from an altered structure of resistance arteries and/or an increased sensitivity to norepinephrine rather than from impaired endothelium-dependent vasodilatation.
Small arteries (<500 μm) contribute substantially to vascular resistance.1 The properties of these blood vessels are therefore of particular interest in attempting to understand the causes and consequences of hypertension. Direct study of the structure and function of small arteries has been made possible with the introduction of in vitro techniques.2 3 In particular, isometric recording systems have been used extensively for examination of the properties of arteries isolated from hypertensive animals compared with their normotensive controls.4 The isometric wire myograph technique involves passing two mounting wires through the lumen of a ring segment of a blood vessel. For assessment of vascular structure the vessel is stretched to a length equated with a chosen pressure, and the diameter at this length is calculated. It is thereafter possible to focus closely on the vascular wall and measure media thickness. These two measurements allow determination of the relationship between the vascular wall and artery diameter. With the use of this approach it has been reported that marked alterations occur in small artery structure in many different models of hypertension, as outlined in a number of recent reviews.4 5 6 7 8 9 10 11 Data from many studies have indicated that the internal diameter of arteries from hypertensive animals is smaller than that of equivalent vessels from normotensive controls. This has been suggested to be consequent to vascular growth, stimulated by high blood pressure per se11 or by humoral agents,5 or to be due to a mechanism whereby vascular diameter is reduced, not by an increase in media thickness (hypertrophy) but by a remodeling of existing wall material.6
More recently, the technique of pressure myography has been used for examination of the properties of isolated resistance arteries.3 This method allows pressurization of cannula-mounted small arteries such that they assume the conformational structure they would achieve in vivo; hence, this approach is more physiological than the wire myograph.12 13 However, there are only a limited number of studies in which the structural properties of resistance arteries from normotensive and hypertensive animals have been examined with the use of pressure myography.12 13 14 15 We have recently shown that hypertension induced by long-term inhibition of nitric oxide synthase does not produce alterations in the structure of pressurized mesenteric resistance arteries in vasopressin-deficient Brattleboro rats.12 16 In contrast, pressurized mesenteric resistance arteries from SHR have a reduced internal diameter and increased media-to-lumen ratio compared with vessels isolated from WKY.14 In the present study we have examined the structural properties of mesenteric resistance arteries isolated from a vasopressin-deficient rat model of genetic hypertension to determine whether our previous observations are limited to hypertension induced by long-term inhibition of nitric oxide synthase or are a common feature of hypertension in vasopressin-deficient rats. Genetically hypertensive, vasopressin-deficient (DI/H) rats were developed by crossbreeding Brattleboro rats with the New Zealand strain of genetically hypertensive rats.17 18 This model is somewhat advantageous over other models of genetic hypertension because the appropriate matched normotensive controls for the DI/H rats are available (DI/N rats). This is in contrast to SHR, for which there is some debate concerning the availability of matched controls.19 20
Our group has recently demonstrated that responses to endothelium-dependent vasodilators are not impaired in DI/H rats in vivo compared with DI/N rats.18 This is contrary to the widely held belief that endothelial function is impaired in hypertensive animals.21 However, it is difficult to compare directly in vivo vasodilator responses when the baseline hemodynamics are markedly different, as is the case between normotensive and hypertensive animals.18 Therefore, we have also examined responses to acetylcholine in arteries isolated from DI/H and DI/N rats. Furthermore, in view of the potential role for enhanced vascular smooth muscle sensitivity contributing to the hypertensive state,22 we have also examined responses to norepinephrine and AVP in arteries isolated from DI/N and DI/H rats.
All experiments were carried out on aged-matched (22 to 26 weeks old) male rats (350 to 500 g) bred in the Queen’s Medical School Biomedical Services Unit. The original homozygous breeding pairs of DI/N and DI/H rats were obtained from Dr R.J. Balment (University of Manchester, UK) and have been characterized by him as described by Ashton and Balment.17
At least 48 hours before the in vitro analysis of vascular structure, rats were anesthetized (sodium methohexital, 60 mg/kg IP) and had an intra-arterial catheter implanted in the distal abdominal aorta (via the ventral caudal artery) and a venous catheter placed in the jugular vein. Catheters were tunneled subcutaneously and exteriorized at the back of the neck, from where they were led through a flexible spring. This spring was connected to a harness that was fitted to the rat and counterbalanced by a lever system that allowed the rat free movement when it was returned to its home cage. On the morning of experimentation, when rats were fully conscious and unrestrained, recordings were made of MAP. Rats were subsequently anesthetized (sodium methohexital, 4 to 10 mg/kg IV) and killed.
Protocol for Artery Selection
Care was taken to ensure that comparable arteries were examined from normotensive and hypertensive rats. Therefore, the mesentery was removed from each rat, and the superior mesenteric artery was located and cleaned of connective tissue until the sixth branch leading to the gut wall was exposed. The first and second branches deriving from this branch were then used for study, as described previously.12
Analysis of Resistance Artery Structure
Mesenteric resistance arteries were prepared for measurement of vascular diameter with a Halpern pressure-perfusion myograph.3 In brief, vessel segments were secured between two cannulas using single strands (20-μm diameter) teased apart from a 1-cm length of surgical braided nylon suture. One cannula was closed and the other connected to a system containing PSS, which in turn was linked to a pressure-servo unit. The arteriograph was a 10-mL vessel chamber with an input and output channel to allow superfusion of PSS. The blood vessel was imaged with the use of a video camera and analyzed with an appropriate dimension analyzer (Living Systems Instrumentation) that was linked to a MACLAB data acquisition system in conjunction with a Macintosh computer (Leicester Computing Centre).
The arteriograph in which the vessel was secured was connected to a 200-mL reservoir of PSS that was bubbled with a 5% CO2/95% O2 gas mixture and circulated with the use of a Masterflex pump (Cole-Parmer) at a rate of approximately 10 mL/min. This ensured that the arteriograph volume was exchanged once every minute. Temperature was maintained at 37°C in the organ bath, and perfusate pH was continually monitored.
For assessment of vascular structure the intraluminal pressure in each arterial segment was set to the MAP of the rat from which the vessel had been isolated. On pressurization, mesenteric resistance arteries markedly elongate. Therefore, vessels were retracted with the use of a micrometer to a length whereby buckling of the artery was no longer apparent.12 Throughout, arterial segments were superfused with Ca2+-free PSS, which was subsequently exchanged with Ca2+-free PSS containing a 1.5% glutaraldehyde solution at 37°C for 30 minutes and was then allowed to cool to room temperature over a further 60-minute period to fix vessels. In preliminary experiments this procedure was shown to minimize shrinkage or contraction artifacts (vessel diameter for second-order vessels from DI/N rats was, by video dimension analysis, 314±17 μm; by histology, 304±20 [n=5]; for second-order vessels from DI/H rats by video dimension analysis, 247±14; by histology 253±9 [n=5]). The cannulas to which arterial segments were attached were broken and used to transport the vessel to a Petri dish, where the segment was washed three times with Ca2+-free PSS and then stored overnight at 4°C. The following day arteries were stained with 1% osmium tetroxide and dehydrated with acetone before being embedded in Araldite CY212 epoxy resin. Subsequently, 1-μm-thick sections were cut and placed on glass microscope slides. Structural analysis of these sections was carried out with the use of a morphometric grid, and luminal and medial cross-sectional areas were determined. Because of the spherical nature of the arterial cross section, values for internal lumen diameter and average media thickness could subsequently be calculated. This methodology has previously been shown to produce minimal processing artifacts.23
The hearts from some rats were also removed, dried on blotting paper, and weighed for comparison with animal body weight for assessment of any gross change in the ratio between heart weight and body weight in normotensive and hypertensive rats.
Analysis of Resistance Artery Function
For assessment of vascular function resistance arteries were again set up in the Halpern pressure-perfusion myograph. The intraluminal pressure in each arterial segment was set to either 75% (first order) or 65% (second order) of the MAP from normotensive or hypertensive rats, respectively, and left to equilibrate for 60 to 120 minutes. These pressures were chosen as a rough estimate of the pressures these vessels would be exposed to in vivo based on the observation that mesenteric arcade pressure is significantly smaller than (but proportional to) MAP in both SHR and WKY.1 In preliminary experiments it was found that vasoconstrictor function was impaired in vessels exposed to excessive pressure.
Vessels were subsequently exposed to the cumulative addition of norepinephrine (in the presence of 1 μmol/L propranolol and 50 μmol/L cocaine to inhibit β-adrenoceptor function and uptake1, respectively) until vascular diameter had been reduced by approximately 50%. After a maintained equilibrium response to norepinephrine had been achieved, the effects of acetylcholine were determined in a concentration-dependent manner. Tissues were then washed for at least 90 minutes. Vascular diameter was once more reduced by approximately 50% with norepinephrine, and a cumulative concentration-response curve to papaverine was obtained. All drugs were added to a recirculated volume of 200 mL, and the circulation rate (10 mL/min) ensured that the arteriograph volume was exchanged once every minute and equilibrium responses were achieved within 5 minutes. Arteries isolated from DI/H rats were more sensitive to norepinephrine than those from DI/N rats, and this effect was most apparent in second-order resistance arteries (see “Results”). Therefore, in a subsequent series of experiments a cumulative concentration-response curve to AVP was obtained in second-order arteries isolated from DI/N and DI/H rats.
At the end of each experiment passive diameter measurements were made in a Ca2+-free PSS solution containing 0.5 mmol/L EGTA.
Where appropriate, results are shown as mean±SEM (number of rats or vessels). Differences between means were considered significant at a value of P<.05 using Student’s paired or unpaired t test.
Drugs and Solutions
The following drugs and chemicals were used: osmium tetroxide (Johnson Matthey), Araldite CY212 epoxy resin (TAAB Laboratories), glutaraldehyde (TAAB Laboratories), (−)-norepinephrine bitartrate (Sigma Chemical Co), acetylcholine chloride (Sigma), papaverine HCl (Sigma), cocaine HCl, and propranolol HCl (Sigma). The composition of the PSS was (mmol/L) NaCl 119, NaHCO3 24, KCl 4.7, KH2PO4 1.17, MgSO4 · 7H2O 1.17, disodium EDTA 0.023, CaCl2 1.25, and glucose 5.5. Ca2+-free PSS was prepared by omitting Ca2+ and adding 0.5 mmol/L EGTA.
DI/N rats had a MAP of 121±2 mm Hg (n=15) compared with 176±3 mm Hg (n=12) in DI/H rats (P<.001).
Resistance Artery Structure
Table 1⇓ summarizes the structural characteristics of blood vessels isolated from DI/N and DI/H rats. The internal diameter of resistance arteries isolated from DI/H rats was significantly smaller than the diameter of arteries from DI/N controls. This reduction in vascular diameter was associated with an increased media-to-lumen ratio in both first- and second-order arteries but was not associated with an increase in the amount of vascular smooth muscle present in arteries from DI/H rats, because the media cross-sectional area did not differ from that in vessels isolated from DI/N rats. The same amount of material enclosed in a smaller area tended to increase the media thickness of resistance arteries from the DI/H rats, although this did not reach statistical significance.
Heart Weight–Body Weight Ratio
As shown in Table 2⇓, DI/N rats were heavier than age-matched DI/H rats, but gross heart weight was greater in DI/H rats. Hence, there was a significant difference between the heart weight–body weight ratios for DI/N and DI/H rats.
Resistance Artery Function: Responses to Vasoconstrictors
Fig 1⇓ illustrates the responses of pressurized mesenteric resistance arteries to norepinephrine. As shown, both first- and second-order mesenteric resistance arteries from DI/H rats displayed hyperresponsiveness to norepinephrine at low concentrations.
Fig 2⇓ illustrates the responses of pressurized second-order mesenteric resistance arteries to AVP. No significant difference was observed in responses to AVP in arteries isolated from DI/N and DI/H rats.
Resistance Artery Function: Responses to Vasodilators
Fig 3⇓ illustrates the response of resistance arteries to acetylcholine. In first-order vessels norepinephrine was used to reduce vascular diameter to 53.9±3.1% and 52.1±1.9% of the maximum possible diameter in arteries from DI/N and DI/H rats, respectively. Thereafter, acetylcholine completely relaxed vessels from DI/H and DI/N rats (Fig 3a⇓). However, acetylcholine-induced vasodilatation was more potent in arteries isolated from DI/H rats compared with DI/N rats (Fig 3a⇓). In second-order arteries vascular diameter was reduced to 49.7±3.7% and 54.1±2.0% by norepinephrine in arteries isolated from DI/N and DI/H rats, respectively. Acetylcholine completely reversed norepinephrine-induced tone; however, in contrast to first-order arteries there was no significant difference in the sensitivity to acetylcholine between vessels isolated from DI/N and DI/H rats (Fig 3b⇓).
Fig 4⇓ illustrates the response of mesenteric resistance arteries to papaverine. This agent abolished norepinephrine-induced tone in a concentration-dependent manner. No differences were found for the potency of papaverine in first- or second-order resistance arteries from either DI/N or DI/H rats (Fig 4⇓).
The aim of the present study was to examine the structural and functional properties of isolated, pressurized mesenteric resistance arteries from a vasopressin-deficient rat model of genetic hypertension.
Many studies in recent years have implicated an altered microvascular structure in the genesis and maintenance of hypertension.4 5 6 7 8 9 10 11 In the present study we have provided further evidence that resistance arteries from genetically hypertensive rats have a reduced internal diameter compared with arteries from their normotensive controls. In order to do this, we used a pressure myograph. This technique has the advantage that it allows arteries to assume the stereological conformation they would attain in vivo,12 13 in contrast to some other methodologies used for examining resistance artery structure, such as wire myography.13
The media-to-lumen ratio of resistance arteries from DI/H rats was increased compared with DI/N controls. Although this could be taken as evidence for vascular growth, there was no difference in media cross-sectional surface area in arteries from DI/N and DI/H rats. Our results suggest, therefore, that the architecture of the mesenteric vasculature in DI/H rats develops differently from that in DI/N rats, such that a similar amount of media material is arranged in a manner whereby the internal diameter is smaller. This remodeling hypothesis was first suggested by Baumbach and Heistad,24 who demonstrated that perfusion-fixed cerebral arterioles from stroke-prone SHR had a reduced external diameter compared with those from WKY. Although they also demonstrated that media cross-sectional area was greater in arteries from hypertensive rats, they calculated that the contribution of remodeling to the reduced vascular diameter was far greater (75%) than the contribution of vascular hypertrophy (25%). Using the remodeling index of Baumbach and Heistad we have calculated that the difference in structure in arteries isolated from DI/N and DI/H rats could be completely accounted for by remodeling (first-order remodeling index, 102%; second-order, 100%), without any evidence for vascular growth. It should be noted that our conclusion is based on the comparison of vessels from normotensive and hypertensive rats at only one intravascular pressure. Therefore, as an alternative it is possible that the reduction in the internal diameter of arteries from DI/H rats is in part due to a reduced distensibility of these vessels, as has been suggested for second-order cerebral resistance arteries isolated from stroke-prone SHR compared with vessels isolated from WKY.25 Reductions in resistance artery diameter without any increase in media cross-sectional area, whether a consequence of reduced artery distensibility or remodeling, have also been demonstrated for subcutaneous resistance arteries isolated from humans with essential hypertension26 and in mesenteric resistance arteries from hypertensive transgenic rats expressing the mouse Ren-2 gene.22 On reviewing the literature, Heagerty and colleagues10 concluded that remodeling was a fundamental process in genetic hypertension. They acknowledged that vascular growth contributed to the reduced internal diameter in some hypertensive models, particularly the SHR, and they also suggested that vascular growth was more important than vascular remodeling in altering resistance artery structure in experimentally induced hypertension. As they noted, however, most of these studies were carried out with the isometric wire myograph, and confirmation of the relative importance of remodeling versus growth for many of these models of hypertension awaits analysis of vascular structure under more physiological conditions, such as those used in the present study.
Only a limited number of other studies have reported on resistance artery structure with the use of the pressure myograph.12 13 14 15 27 28 Most of these studies have involved a comparison of arteries from SHR and WKY. In common with our observations in genetically hypertensive Brattleboro rats, they have indicated a reduced internal diameter and increased media-to-lumen ratio in mesenteric13 14 and cerebral27 resistance arteries from hypertensive rats. It has been reported, however, that there are no differences in the structure of skeletal muscle arterioles isolated from WKY and SHR, indicating potential regionally specific alterations in vascular structure in hypertension.28 It should be noted that in contrast to the present study, the aforementioned studies determined media thickness indirectly by measuring the shadow produced by transillumination of the pressurized artery. Differentiation between media and adventitia under this circumstance is not possible, thus preventing a detailed analysis of the relative importance of growth or remodeling in reducing vascular diameter.
Some investigators have examined the structure of resistance arteries from normotensive and hypertensive animals at the same transmural pressure.14 15 However, equivalent resistance arteries from normotensive and hypertensive animals may not experience equivalent pressures. For example, the pressure in arcade mesenteric vessels in conscious SHR is considerably higher than in their normotensive controls1 (although arcade pressure is proportional to MAP). Therefore, we compared arteries from normotensive and hypertensive rats pressurized to the MAP of the rat from which they had been isolated. Although this value is undoubtedly higher than the pressure these vessels experience in vivo, in the absence of data concerning the absolute pressure in each branching order of artery for each individual animal, MAP gives an accessible measurement to use as a standard for comparison. Furthermore, even though vessels from DI/H rats were fixed at a higher distending pressure than those from DI/N rats, this did not mask the smaller internal diameter of arteries isolated from DI/H rats compared with those isolated from DI/N rats.
The mechanism by which resistance artery structure is altered, whether by remodeling or reduced artery distensibility, in this vasopressin-deficient rat model of hypertension is unknown. However, it is likely that this process involves some growth factor or humoral agent (or lack thereof), because we have recently demonstrated that increased pressure per se (induced by nitric oxide synthase inhibition) is an insufficient stimulus for producing vascular remodeling in Brattleboro rats.12
Resistance Artery Function
Resistance artery contractility has been shown, with the use of isometric techniques, to be decreased, unchanged, or increased in hypertension.19 29 30 However, we have recently highlighted marked differences in the responsiveness of resistance arteries when examined under pressurized or isometric conditions, demonstrating that the pressure myograph offers a more physiological system with which to examine vasoconstrictor function.31 In the present study we have demonstrated that pressurized mesenteric resistance arteries from DI/H rats are more sensitive to norepinephrine than arteries from their DI/N controls. This enhanced vasoconstrictor response was specific for norepinephrine because responses to AVP were similar in arteries from DI/N and DI/H rats. The enhanced sensitivity of responses to norepinephrine was not related to an alteration in the function of β-adrenoceptors or in neuronal uptake because experiments were carried out in the presence of propranolol and cocaine. These results therefore suggest that the increased blood pressure in DI/H rats may be in part due to an enhanced number or function of α-adrenoceptors. Enhanced responses to norepinephrine have also been observed in pressurized-perfused mesenteric resistance arteries from SHR compared with WKY controls.14 In this latter study the difference in sensitivity to norepinephrine in arteries from hypertensive and normotensive rats was abolished after endothelium removal, suggesting it was a consequence of an impaired endothelial function in hypertensive vessels.
The potential role for impaired endothelial function in the pathogenesis of hypertension has received much attention in recent years. There are many reported examples of impaired responses to endothelium-dependent vasodilators in resistance arteries from different forms of hypertension, such as in the SHR and in human essential hypertension (for a limited selection see References 14, 15, and 3214 15 32 through 34). Since vasodilator responses have been reported to be normal (or enhanced) in young prehypertensive SHR,35 36 the attenuation of endothelium-dependent relaxations has been suggested to be a secondary consequence of the hypertension but subsequently contributing to the increased vascular resistance.37 However, the evidence is not entirely consistent, and a number of reports, in some cases from identical resistance arteries or vascular beds from the same species, have indicated that endothelium-dependent function remains intact during hypertension.38 39 40 41 Our results obtained in DI/H rats are consistent with the latter observations. We have recently shown in vivo that endothelium-dependent responses are not impaired in this model of genetic hypertension.18 Furthermore, in the present study we have demonstrated that responses to acetylcholine are not attenuated in isolated mesenteric resistance arteries from hypertensive rats compared with their normotensive controls. Indeed, there was an enhanced response to acetylcholine in first-order mesenteric arteries from DI/H rats compared with DI/N rats. These observations indicate that although an impaired endothelial function may occur in certain blood vessels or vascular beds in some models of hypertension, it is not a necessary consequence of the hypertension per se. The results also illustrate that an impaired endothelial function is not the cause of the hypertension observed in DI/H rats, nor is it responsible for the enhanced sensitivity of responses to norepinephrine observed in mesenteric resistance arteries isolated from hypertensive rats. The mechanism by which responses to acetylcholine are enhanced in arteries from DI/H rats is unknown, but it is not associated with a generalized greater ability of these arteries to vasodilate, as evidenced by the similarity of responses to papaverine in arteries from normotensive and hypertensive rats.
In summary, in DI/H Brattleboro rats the increased blood pressure is associated with an altered vascular structure of mesenteric resistance arteries and an increased sensitivity of these vessels to norepinephrine. Both of these factors may contribute to the hypertension. The increased blood pressure, however, is not associated with an impaired endothelium-dependent vasodilatation.
Selected Abbreviations and Acronyms
|MAP||=||mean arterial pressure|
|PSS||=||physiological salt solution|
|SHR||=||spontaneously hypertensive rat(s)|
Breeding colonies of DI/N and DI/H rats were supported by a grant from the Medical Research Council.
- Received March 28, 1995.
- Revision received April 27, 1995.
- Accepted June 1, 1995.
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