Sustained Hypertension in Dahl Rats
Negative Correlation of Agonist Response to Blood Pressure
Abstract The perfused mesenteric vasculature of Dahl salt-sensitive rats on a high salt diet for 5 days (prehypertensive or early hypertensive) is selectively supersensitive to norepinephrine. The present goal was to determine whether that supersensitivity was maintained as hypertension developed. Littermates of salt-sensitive and salt-resistant rats (Dahl Brookhaven strain) were followed on low or high salt for up to 6 weeks. Systolic blood pressure was elevated in the salt-sensitive, high salt rats after 3 or 6 weeks but not after 5 days of the diet. The perfused mesenteric vascular beds from salt-sensitive rats were supersensitive to norepinephrine and nerve stimulation but not to potassium chloride when the rats had been maintained for 5 days or 3 weeks on the high salt diet. However, responses to norepinephrine declined after 6 weeks of the high salt diet. To determine whether sustained high blood pressure has a negative effect on mesenteric vascular responses, we conducted additional experiments with perfused mesenteric vascular beds from salt-sensitive Brookhaven (high salt, 5 weeks) and Rapp (high salt, 6 weeks) animals. Both groups exhibited significant negative correlations between in vivo systolic pressure and maximal responses of mesenteric vessels to norepinephrine and potassium chloride. We suggest that sustained hypertension in Dahl rats has a negative effect on the contractility of the mesenteric arterial system that, by 5 to 6 weeks, masks the initial supersensitivity to norepinephrine. No effects of any diet on the dilating responses of the mesenteric vessels to acetylcholine were observed in any group.
Among the problems encountered in attempts to relate vascular responsiveness to hypertension in animal models have been the frequent use of conduit rather than resistance vessels and the fact that hypertension per se alters vascular structure and responsiveness.1 In an attempt to avoid both of these problems, Kong et al2 investigated the responsiveness of the perfused mesenteric vascular bed of Dahl salt-sensitive rats on a high salt diet for only 5 days, ie, during a prehypertensive or early hypertensive period. Kong et al found a selective supersensitivity to norepinephrine in the salt-sensitive, high salt group. The sensitivity to potassium chloride, angiotensin II, and 5-hydroxytryptamine was no different in this group than in control groups.
We undertook the work presented here to determine whether that selective supersensitivity continued as hypertension developed with longer exposures to high salt. The discovery that the supersensitivity was no longer detected when the hypertension was well established (5 to 6 weeks of the high salt diet) led to an investigation of the relation of the response of the vascular preparation to the in vivo blood pressure of the animals from which the preparations were taken.
Male salt-sensitive and salt-resistant rats (either Brookhaven strain [DS and DR] or Rapp strain [SSJR and SRJR]) 3 to 4 weeks of age were purchased from Harlan Sprague Dawley (Indianapolis, Ind) and maintained for approximately 5 days before any treatment. After the acclimation period, systolic blood pressures were measured with tail-cuff plethysmography. All rats were initially fed a normal salt diet (0.45% NaCl, Teklad). One day after blood pressures were measured, salt-sensitive rats were randomly assigned to either normal salt (−) or high salt (+) groups. The normal salt group continued to receive normal rat chow, and the high salt rats were started on a diet in which NaCl was added to the regular lab chow to achieve a final content of 7% NaCl. The salt-resistant rats were given the high salt diet. Animals were maintained on the respective diets for 5 days to 6 weeks, and systolic blood pressure measurements were made by means of tail-cuff plethysmography weekly and 1 day before the rats were killed. Animal use was in accordance with institutional guidelines.
The isolated perfused mesenteric vasculature was prepared according to the method originally described by Castellucci et al3 with modifications previously established in our laboratory.2 4 This preparation involves the entire isolated mesenteric vascular bed with the intestinal tract intact. Preparations were obtained from three rats each day, one each from the salt-sensitive, normal salt; salt-resistant, high salt; and salt-sensitive, high salt groups. The rats were stunned and then killed by cervical dislocation followed by decapitation. Heparin (10 U/100 g IV) was administered approximately 5 minutes before the rats were killed to reduce clotting in the fine resistance vessels of the mesenteric vasculature.2 An incision was made in the abdomen, the inferior mesenteric and superior pancreaticoduodenal arteries were ligated, and the superior mesenteric artery was located. A PE-90 cannula was inserted into the superior mesenteric artery at its junction with the aorta and was tied in place. The entire mesenteric vascular bed and intestinal tract were removed from the animal, and the intestinal contents were flushed out with ice-cold Krebs’ solution. The cecum was identified, ligated, and removed. The preparation was then mounted on a holding apparatus containing platinum stimulating electrodes. One ring electrode encircled the proximal portion of the mesenteric artery. At a position 2.5 cm distal from the ring electrode, a hook electrode was embedded in the tissue fascia. The apparatus with the preparation attached was then placed into a 50-mL water-jacketed organ bath, and the preparation was perfused through the cannula with a modified Krebs-Henseleit solution of the following composition (mmol/L): NaCl 117, KCl 4.7, CaCl2 2.5, KH2PO4 1.2, MgSO4 1.2, NaHCO3 25, and glucose 11.5. The Krebs-Henseleit solution was continuously bubbled with a 95% O2/5% CO2 mixture, was maintained at 37°C, and was delivered to the tissues at a constant flow of 4 mL/min by means of a Gilson Minipuls 2 peristaltic pump (Rainin Instrument Co). A T-tube was inserted between the preparation and pump and was connected to a P23 AC pressure transducer (Statham Co), which was used to monitor perfusion pressure. Changes in perfusion pressure were recorded on a model 79D polygraph (Grass Instrument Co).
Noncumulative dose-response and frequency-response curves were determined in individual preparations. Agonists were injected (in bolus doses) intraluminally into the perfusion fluid near the cannula. Frequency-response curves were obtained using a Grass model S44 stimulator that produced square-wave pulses of 0.5-millisecond duration and supramaximal voltage from the platinum electrodes around the superior mesenteric artery. Preparations were stimulated for 20 seconds using increasing frequencies, with 2 minutes allowed after each return to baseline between successive stimulation periods. Cocaine (1 μmol/L) and deoxycorticosterone acetate (30 μmol/L) were added to the perfusion fluid 20 minutes before dose-response curves with norepinephrine or frequency-response curves with nerve stimulation were constructed to prevent any possible differences in neuronal or extraneuronal uptake from affecting responses between experimental groups. Responses of the preparations to nerve stimulation and norepinephrine remain unchanged for up to 5 hours after the perfusion procedure is begun.2 Multiple dose-response curves could be constructed on an individual preparation without significant alteration in responsiveness, permitting comparisons of dose-response data among different agonists. Depressor responses to acetylcholine were obtained in preparations in which vasoconstriction was maintained by an infusion of 20 μmol/L norepinephrine.
Body weight, systolic blood pressure, basal perfusion pressure, and changes in perfusion pressure were calculated as arithmetic mean values. The sensitivity of an individual preparation to a given stimulus was calculated by constructing full dose-response or frequency-response curves. From each norepinephrine dose-response curve, the dose increasing perfusion pressure 150 mm Hg (ED150mmHg) was calculated. From each stimulus-response curve, the stimulus frequency increasing perfusion pressure 150 mm Hg (EF150mmHg) was calculated. From each potassium chloride (KCl) dose-response curve, the dose increasing perfusion pressure 50 mm Hg (ED50mmHg) was calculated, recognizing that the maximal responses to KCl were much less than to norepinephrine or nerve stimulation. From these individual data, geometric mean equieffective doses or stimulus frequencies (the antilogs of the mean logs of the individual doses or frequencies) were calculated and statistically compared. For details and appropriateness of geometric means, see Fleming et al.5 Mean maximal responses were compared using arithmetic mean values of the maxima obtained for that agonist in that treatment group.
Statistical analysis was performed using ANOVA followed by the Newman-Keuls test for comparisons among multiple groups. In a few instances, as appropriate, Student’s t test for paired samples was used. A value of P≤.05 was considered to be significant. Correlation coefficients obtained from linear regression analysis were tested for statistical significance using Student’s t test.
Table 1⇓ presents the mean systolic blood pressures of all groups of animals in the study. The mean pressure of salt-sensitive rats on the high salt diet was significantly greater than that of either control group at all treatment periods except 5 days. The tendency for slightly higher pressure in the DS− versus DR+ rats was significant only at 3 weeks. There was a tendency of animals on the high salt diet to be smaller than those on a normal diet. However, this difference in body weight was significant only for the salt-sensitive animals on the high salt diet for 6 weeks. The mean basal perfusion pressures of the isolated mesenteric vascular preparations are presented in Table 2⇓. At any given time, basal perfusion pressure did not differ among experimental groups.
The first series of experiments examined the frequency-response or dose-response relations among treatment groups to nerve stimulation, norepinephrine, and KCl in perfused mesenteric vascular beds in matched Brookhaven littermates after 5 days, 3 weeks, or 6 weeks of a normal or high salt diet. The sensitivity of the perfused mesenteric vasculature was increased in response to norepinephrine (Fig 1A⇓, Table 3⇓; ED150mmHg for DS+, fourfold less than either DS− or DR+, P<.05) in the salt-sensitive group after 5 days of the high salt diet. Similarly, at that time the DS+ group demonstrated enhanced sensitivity to nerve stimulation (approximately twofold, Table 4⇓), although the difference reached the .05 level of significance only compared with the DS− group. After 5 days of the diets, sensitivity to the vasoconstrictor effects of KCl did not differ among the groups (Table 5⇓). These results are consistent with previous results2 obtained by our laboratory in Dahl rats on a 5-day diet of high or normal salt. Similar results were obtained with the same agonists after 3 weeks of the diets (Fig 1B⇓; Tables 3⇓, 4⇓, and 5⇓). The sensitivity to norepinephrine was fivefold greater in the DS+ group than in the DR+ group (Table 3⇓); the DS− group also was significantly more sensitive to norepinephrine (twofold) than the DR+ group. The DS+ group was statistically more sensitive to nerve stimulation than either the DS− or DR+ group. However, after 6 weeks of treatment, the supersensitivity to norepinephrine and nerve stimulation was no longer apparent (Fig 1C⇓; Tables 3⇓, 4⇓, and 5⇓). Consistent with the disappearance of supersensitivity, the maximal responses to norepinephrine were less in the DS+ group at 6 weeks (196±16 mm Hg) than in the DS+ group at 3 weeks (253±18 mm Hg) or 5 days (256±23 mm Hg) (P<.05). The maximal responses in the other treatment groups did not vary with the duration of diet. Dose-dependent depressor responses to acetylcholine were also measured in the 3- and 6-week groups. As shown in Fig 2⇓, the responses to acetylcholine did not differ among the groups at either time period.
An inspection of the maximal in vivo systolic pressures and maximal responses to agonists in the preparations from the 6-week DS+ animals did not suggest any relation between the two measures within the group. However, the number of preparations was small, and the blood pressures were relatively similar in all members of the DS+ group. Another shipment of Brookhaven rats received high or normal salt diets for 5 weeks. Group by group, their mean blood pressures were similar to those of the 6-week groups above (Table 1⇑). However, the individual blood pressures were more variable in the DS+ group. Dose-response curves for norepinephrine (Table 3⇑) indicated that mean ED150mmHg values among the experimental groups were similar to those in the 6-week group (Fig 1⇑), with the exception of a trend toward greater sensitivity (P=NS) to norepinephrine in the DS− group. There was no indication of increased responsiveness in the DS+ group. A plot of in vivo systolic pressure versus maximal response to norepinephrine of the isolated preparations from the same DS+ rats indicated a negative correlation between pressure and maximal responses to norepinephrine (Fig 3⇓, Table 6⇓), nerve stimulation (Table 6⇓), and KCl (Table 6⇓). However, there was no such correlation between in vivo pressure and the maximal depressor effect of acetylcholine (Table 6⇓). There was also no correlation between systolic pressure and maximal response to any agonist in the DS− or DR+ groups at any time. These groups, of course, were not hypertensive and exhibited little variability in systolic pressure.
To determine whether this surprising negative correlation between in vitro maximal pressor response and in vivo systolic pressure was limited to hypertensive animals of the Brookhaven strain, we carried out similar experiments with salt-sensitive and salt-resistant animals of the Rapp strain on high and low salt diets for 6 weeks. As can be seen in Table 1⇑, the subgroups of the Rapp strain on high or low salt diets had blood pressures similar to those of the same subgroups of the Brookhaven strain after 5 or 6 weeks of the diets. Just as in the Brookhaven DS rats on a high salt diet for 5 or 6 weeks, there was no indication of enhanced responses in the SSJR+ group to norepinephrine, nerve stimulation, or KCl (Tables 3⇑, 4⇑, and 5⇑). As is apparent from Fig 4⇓ and Table 6⇑, the same negative correlations existed between in vivo systolic pressure and maximal response of the isolated mesenteric vascular bed to pressor agonists. Again, as in the Brookhaven preparations, no correlation was detected between in vivo blood pressure and the maximal depressor effect of acetylcholine in the mesenteric vascular bed (Table 6⇑). There was also no correlation between in vivo systolic pressure and responses of the mesenteric vasculature in SSJR− or SRJR+ rats.
Differences in basal perfusion pressure did not contribute to differences in the responses detailed above. For example, basal perfusion pressure did not differ among the experimental groups at any time period (Table 2⇑). Furthermore, in the groups in which maximal response negatively correlated with in vivo systolic pressure (Figs 3⇑ and 4⇑, Table 6⇑), there was absolutely no correlation between in vivo systolic pressure and basal perfusion or between basal perfusion pressure and maximal response (Table 7⇓). Finally, basal perfusion pressure did not differ between the litter-matched rats in the 3- or 6-week groups, although the DS+ group demonstrated selectively enhanced responses to norepinephrine and nerve stimulation at 3 weeks but not at 6 weeks.
The isolated perfused mesenteric vascular preparation has proved to be very useful for studies of vascular responsiveness in models of hypertension. Since it represents a virtually complete arterial bed, changes in perfusion pressure represent the composite effect of a number of resistance vessels. Yet, as an isolated preparation, it is free of complications caused by reflexes or circulating vasoactive substances. Furthermore, it provides highly reproducible responses to a variety of agonists over a period of several hours.2
Using the perfused mesenteric vascular preparation, this laboratory has demonstrated that the arterial resistance vessels are selectively supersensitive to norepinephrine-mediated vasoconstriction in hypertensive rat models before or early in the appearance of hypertension (Dahl rats2 and spontaneously hypertensive rats [SHR]6 ). The responses to norepinephrine are limited to α1-adrenoceptors,2 7 and the supersensitivity is independent of endothelial relaxant factors, extraneuronal uptake, and neuronal uptake.2 6 Although there is evidence of altered neuronal uptake of norepinephrine in Dahl salt-sensitive, high salt animals2 and SHR,8 the selective supersensitivity in salt-sensitive, high salt rats is demonstrable even when uptake is blocked in all groups.2 Furthermore, the supersensitivity is not related to differences in the amount of released neurotransmitter.9 The early appearance of the supersensitivity of the smooth muscle to α1-adrenoceptor agonists suggests that the supersensitivity may contribute to the development of the hypertension.
The present results also indicate that there is a tendency for the mesenteric vasculature of the DS− group to be more sensitive to norepinephrine relative to the DR+ group at some time periods. This enhanced responsiveness is not as pronounced or consistent as it is in the DS+ group. This tendency in the DS− group may indicate that even the 0.45% NaCl diet represents a modest overload of salt for DS rats. Alternatively, it may represent a genetic difference that is marginally expressed even in the absence of salt load that is additionally expressed in the presence of a persistent high salt diet. DS− rats do tend to have somewhat elevated systolic blood pressure, as is found here and in other reports,2 10 11 when fed a “normal” diet of 0.45% NaCl. The DS− group, at least on the normal salt diet, appears to represent a borderline hypertensive group with characteristics intermediate between the DS+ and DR+ groups.
Responsiveness in blood vessels after hypertension has developed is more complex. Established hypertension can induce structural changes in blood vessel walls characterized by an increase in arterial wall thickness and/or the wall-to-lumen ratio. As reviewed by Heagerty et al,12 this relation has been demonstrated in hypertensive humans as well as several rat models, including SHR; coarctation of the aorta; deoxycorticosterone acetate–salt; chronic angiotensin infusion; one-kidney, one clip; and two-kidney, one clip. In an extensive morphometric analysis, Lee and Triggle10 documented medial thickening in the superior mesenteric artery as well as its large and small branches in DS rats on a high salt diet for 6 to 7 weeks. The altered geometry of the vascular wall is generally considered to result in enhanced nonspecific responsiveness from an increase in slope and maxima of concentration-response curves to unrelated pressor agonists without alterations in threshold or median effective concentration.1 13 Such an effect has been reported in the isolated mesenteric vascular bed of SHR.14 Indeed, in SHR, which have a genetic predisposition for an altered wall-to-lumen ratio, the increase in slope and maxima of agonist concentration-response curves is clearly demonstrable at an early age, when the development of hypertension is marginal.6
We undertook the present experiments to determine what happens to agonist dose-response curves in Dahl salt-sensitive rats on a high salt diet as the hypertensive state advances. The results confirmed the selectively enhanced responses to norepinephrine and to sympathetic nerve stimulation in young DS rats on a high salt diet for only 5 days,2 a time when the blood pressure, as measured by tail cuff, of the DS+ rats was not different from that of control groups. In contrast to the earlier study, the present results included an increased maximal response to norepinephrine. The selective supersensitivity to norepinephrine was maintained in the DS rats on the high salt diet for 3 weeks but was no longer apparent after 6 weeks of the diet. Indeed, at 5 or 6 weeks, neither the selective supersensitivity to norepinephrine, present after 5 days or 3 weeks of the high salt diet, nor the nonselective enhanced responses to agonists expected from structural changes of established hypertension was demonstrable. Therefore, one must conclude that although enhanced responsiveness to sympathetic nerve stimulation and circulating catecholamines may contribute to the development of hypertension in DS+ rats, they do not contribute to the maintenance of vasoconstriction in the mesenteric vascular bed in rats with chronic hypertension. If the mesenteric bed is typical of other resistance vessels in this model, the maintenance of hypertension must depend on other factors (such as increased sympathetic nerve activity, renin, or fluid volume).
Our findings of an enhanced response to nerve stimulation and greater neuronal uptake in the mesenteric vascular beds from prehypertensive or early hypertensive Dahl salt-sensitive rats fed a high salt diet for 5 days2 and the supersensitivity in early hypertension (3 weeks, present results) are consistent with existing evidence of altered adrenergic mechanisms in hypertensive Dahl rats.15 16 Takeshita and Mark15 determined that 50% of the elevated vasoconstriction in the perfused hindquarters of DS+ rats with established hypertension was neurogenically maintained. In a subsequent study from the same laboratory,16 it was found that destruction of the sympathetic nervous system with 6-hydroxydopamine prevented the development of hypertension in the animals and the development of elevated resistance in the perfused hindquarters. In addition, DS rats demonstrate a greater rate of adrenal synthesis of catecholamines compared with DR rats.17 Genain et al11 reported that salt loading fails to inhibit norepinephrine turnover in heart and brown fat of prehypertensive DS rats but not of DR rats. Thus, the overall picture is one of increased supply of norepinephrine combined with enhanced responsiveness to norepinephrine contributing to the development of hypertension in salt-sensitive rats.
The absence of enhanced responses in the mesenteric vasculature of DS animals after 6 weeks of a high salt diet is therefore surprising. However, the investigation of the relation between blood pressure and maximal response of the mesenteric vasculature to norepinephrine, nerve stimulation, and KCl in both DS and SSJR rats on 5 to 6 weeks of a high salt diet shows that higher pressures are associated with lesser responses to all three pressor procedures. These results suggest that, at least in the mesenteric arterial bed, prolonged high pressure leads to a nonspecific loss of responsiveness to vasoconstrictors that masks the earlier supersensitivity to norepinephrine in salt-sensitive rats on a high salt diet.
Existing evidence indicates that prolonged hypertension in Dahl salt-sensitive rats on a high salt diet induces vascular hypertrophy and/or luminal narrowing of mesenteric,10 renal,18 19 and retinal vessels,20 21 as observed in vessels of other models of hypertension. These structural changes are commonly associated with nonspecific increases in slopes and maxima of vasoconstrictor concentration-response curves. The absence of such changes in slope and maxima in the mesenteric vasculature may be due to the nonspecific loss of contractility in chronic hypertensive Dahl animals reported here. Since this loss of contractility is in contrast to what is observed in SHR (see, for example, Longhurst et al14 ), it seems that the loss of responsiveness is a consequence either of the genetics of the Dahl rat or of the prolonged effect of the high salt diet interacting with the elevated pressure.
A recent report has documented the fact that Dahl SSJR rats have been genetically contaminated such that some of them do not become hypertensive despite a high salt diet.22 This is likely to be the reason that some SSJR rats on the high salt diet for 6 weeks did not become hypertensive in the present study. However, this cannot explain the fact that in both Dahl Brookhaven and Rapp animals, those rats that did become hypertensive had clearly depressed responses to norepinephrine, nerve stimulation, and KCl.
There is evidence that DS+ rats with established hypertension experience endothelial damage in the mesenteric artery10 and that inhibitory responses to acetylcholine, which acts by the release of endothelium-dependent relaxing factor, are depressed in aortic preparations from Dahl animals with established hypertension.23 Aortic rings from hypertensive Dahl rats fed a high salt diet for 3 weeks demonstrated maximal relaxations to acetylcholine inversely related to in vivo pressures.24 In contrast, no such inverse relation was observed in the present experiments between depressor responses to acetylcholine in the mesenteric vasculature and in vivo systolic pressures in preparations from either Brookhaven or Rapp animals with established hypertension. Prior work2 had already established that 5 days of a high salt diet did not alter responses to acetylcholine. Thus, the depressed response to acetylcholine associated with high pressure in the mesenteric circulation is apparently limited to pressor substances. Although the mesenteric arterial system shows physical signs of endothelial damage,10 it is apparently less susceptible to the deleterious effects of sustained hypertension on endothelium-induced relaxation than the aorta.
The nonspecific nature of the depressed responses of the vessels of rats on a high salt diet with sustained hypertension to contractile agents suggests a defect in the contractile mechanism or in the regulation of intracellular free calcium rather than alterations in receptors or specific transduction processes. It has been reported25 that single-channel potassium current in aortic smooth muscle membranes of SHR with sustained hypertension is enhanced. However, in SHR responses to norepinephrine are enhanced8 14 because of the structural changes in the arteries1 despite the increased K+ conductance. Thus, even if enhanced K+ conductance were to be found in the mesenteric vascular smooth muscle of hypertensive Dahl rats, such a finding could not by itself explain why the responses to agonists are depressed in the presence of similar structural changes in the arterial wall. Clearly, the identification of the mechanism of the depressed responses unique to sustained hypertension in Dahl animals can only occur with further experiments at the cellular level.
This work was supported by grant 5 R01 GM29840 from the National Institutes of Health, Bethesda, Md.
Reprint requests to William W. Fleming, PhD, Department of Pharmacology and Toxicology, West Virginia University, Robert C. Byrd Health Sciences Center, PO Box 9223, Morgantown, WV 26506-9223.
- Received January 24, 1994.
- Revision received March 9, 1994.
- Accepted August 30, 1994.
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