(Hypertension. 2000;35:403.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Elevated Sympathetic Activity Contributes to Hypertension and Salt Sensitivity in Diabetic Obese Zucker Rats
From the Vascular Biology and Hypertension Program of the Department of Medicine and Department of Cell Biology, University of Alabama at Birmingham.
Correspondence to Scott H. Carlson, PhD, Department of Cell Biology, 1670 University Blvd, Birmingham, AL 35294-0019. E-mail scarlson{at}uab.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Zucker rats are a useful model in which to define the mechanisms that link obesity to diabetes and associated cardiovascular disease. The present study tests the hypothesis that diabetic obese (compared with nondiabetic lean) Zucker rats are hypertensive and display a further increase in arterial pressure when fed a high salt diet. Male, nondiabetic lean and diabetic obese Zucker rats were chronically instrumented with telemetry probes and fed a basal salt diet for 3 weeks followed by exposure to a high salt diet for 11 days. On the basal diet, obese (vs lean) rats had significantly higher arterial pressures (
13 mm Hg), and the high salt diet significantly elevated mean arterial pressure (MAP) in obese (but not lean) Zucker rats (12 mm Hg). Blockade of the sympathetic nervous system with hexamethonium caused a significantly larger decrease in MAP in obese (vs lean) Zucker rats fed the basal diet (51 vs 33 mm Hg), but the high salt diet did not increase the hexamethonium-induced reduction in arterial pressure in obese rats. Acute blockade of angiotensin receptors with losartan resulted in similar decreases in MAP in both groups on either diet. Acetylcholine-induced vasodilatory capacity of the carotid artery was significantly less in the obese (vs lean) Zucker rats. Together these data indicate that increased sympathetic nervous system activity and decreased vascular reactivity may contribute to elevated arterial pressure in type 2 diabetic, obese Zucker rats, but the sympathetic nervous system does not appear to contribute to the dietary salt-sensitive hypertension in this model.
Key Words: carotid artery • diabetes mellitus • angiotensin II • circadian rhythm
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Approximately 25 million individuals in the United States have diabetes mellitus,1 which results in numerous pathological changes, including nephropathy, retinopathy, neuropathy, and cardiovascular disease. Of these factors, cardiovascular disease is the single largest cause of death in diabetes mellitus, accounting for an estimated 80% of deaths in diabetic individuals.2 The risk of cardiovascular disease in diabetic individuals is increased by concomitant hypertension, which occurs in an estimated 70% of type 2 diabetic patients.3 Results from the Framingham4 and MRFIT5 trials indicate that the coexistence of the 2 diseases triples the risk of cardiovascular disease. Moreover, the presence of hypertension probably accelerates diabetic nephropathy, which in turn exacerbates the hypertension, creating a vicious feed-forward cycle that contributes to the extremely high occurrence of end-stage kidney failure in type 2 diabetic patients.6
The mechanisms underlying type 2 diabetes and its associated pathologies have begun to be elucidated through the use of several animal models, including obese Zucker rats, in which a mutation of the leptin receptor–encoding gene impairs the ability of leptin to suppress food intake. Thus Zucker rats are obese, dyslipidemic, and hyperinsulinemic; however, it is unclear whether they are hypertensive. Several reports indicate that obese (compared with lean) Zucker rats are hypertensive,7 8 9 10 11 12 13 but other studies suggest that they are not.14 15 16 17 18 These differing findings may relate to the common use of hyperinsulinemic obese Zucker rats that display normal (or only slightly elevated) plasma glucose concentrations.11 14 18 19 20 21 Only a few studies have used the Zucker rat as a model that were hyperglycemic,9 22 23 24 a more appropriate model for type 2 diabetes.
Telemetric monitoring has proved to be a powerful technique for analyzing arterial pressure, heart rate, and activity in animals.25 26 Rats remain unrestrained and untethered throughout the experiment, thereby removing potential stress associated with other methods. The present study used telemetric recording to test the hypothesis that hyperglycemic, diabetic obese (compared with normoglycemic, nondiabetic lean) Zucker rats have elevated arterial pressure and that a high salt diet further elevates arterial pressure in obese (but not lean) Zucker rats. The present study also tested the hypotheses that the sympathetic nervous system,17 22 the renin-angiotensin system,7 11 and changes in vascular reactivity8 20 21 27 28 29 30 contribute to the elevated arterial pressure observed in Zucker rats.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Nine-week-old male obese Zucker rats that have a genetically induced form of type 2 diabetes with severe hyperglycemia and nondiabetic and nonobese lean Zucker rats were used (Genetic Models Inc). All rats were housed in individual cages in a sound-attenuated room at constant humidity (60±5%), temperature (24±1°C), and light cycle (6 AM to 6 PM) and were allowed ad libitum access to either basal (0.6%; diet No. 8746, Teklad) or high salt (8%; diet No. 5008, Teklad) diet and water. All protocols for the use of animals were approved by the University of Alabama at Birmingham’s Institutional Animal Care and Use Committee in accordance with the NIH guide on The Humane Treatment of Experimental Animals.
Surgical Procedures
Rats were chronically instrumented with telemetry probes (TA11-PA40; Data Sciences International) for continuous monitoring of mean arterial pressure (MAP) and heart rate (HR), as described previously.25 Briefly, rats were anesthetized with isoflurane (inhalant); by a midline abdominal incision, the descending aorta was exposed, and the flexible tip of the telemetry probe was inserted into the aorta just below the renal arteries. The transmitter was surgically sutured into the abdominal wall, the incision was closed, and the rat was returned to its home cage and allowed a 7-day recovery period.
At the conclusion of the telemetry experiments, rats were anesthetized (isoflurane) and chronically instrumented with an indwelling Silastic femoral venous catheter, as described previously.31 On recovery from anesthesia, rats were returned to their home cage and recovered for 3 days before initiation of further experiments. The catheters were flushed daily with 100 µL of heparinized saline (50 U/mL).
Experimental Protocol
MAP and HR were monitored while rats were on a basal salt diet for 3 weeks and a high salt diet for 11 days. Thereafter they were returned to the basal salt diet for 2 weeks, and changes in MAP were measured in response to angiotensin (AT1) receptor blockade with losartan (10 mg/kg body wt IV) and (24 hours later) in response to ganglionic blockade with hexamethonium (10 mg/kg body wt IV). Rats were then fed a high salt diet for 1 week, and the blockade experiments were repeated.
At the conclusion of the study, rats were deeply anesthetized with sodium pentobarbital (100 mg/kg body wt), and the thoracic cavity was opened. A blood sample (2 mL) was quickly taken in a chilled, heparinized syringe through cardiac puncture, and portions of the right common carotid artery were excised, cut into individual ring segments (2 to 3 mm in width), and suspended from a force-displacement transducer (Radnotti) in a tissue bath containing a bicarbonate-buffered Krebs-Henseleit solution. Vascular reactivity was then determined with capacitative force transducers, as described previously.32 Briefly, changes in isometric tension were measured changes in response to graded concentrations of phenylephrine (10-8 to 10-7 mol/L), acetylcholine (10-9 to 10-6 mol/L) or sodium nitroprusside (1 nmol/L to 30 µmol/L).
Data Acquisition and Analysis
For the telemetry experiments, data were collected and analyzed as described previously.25 Circadian rhythm analysis of the individual hourly MAP and HR data were performed with the nonlinear, least-squares fitting program PHARMFIT33 and the subprogram SYNOPS,26 as described previously.25 All analyses were based on data for 4 consecutive days, and the MESOR (24-hour average), amplitude, and acrophase (clock time of peak amplitude) of the 24-hour adjusted rhythm were determined. Daily peak and nadir values (highest and lowest arterial pressure for each rat) for MAP and HR were calculated from the curve-fit data.
For analysis of ganglionic and AT1 receptor blockade, MAP and HR were sampled continuously every 2 seconds for a 10-minute control period, at which time the drug was administered, and MAP and HR were recorded until they returned to control levels. For measurement of vascular reactivity, real-time data were acquired and digitized with the use of a PC computer and stored for later analysis using Workbench for Windows (Strawberry Tree, Inc). Dose-response profiles for different experimental conditions were analyzed and tested to determine differences in contraction and relaxation responses.
Analysis of Blood Samples
Blood samples were centrifuged at 4°C, and the plasma was saved for subsequent analysis. Plasma glucose levels were measured colorimetrically with the use of a commercially available kit (Sigma). Obese Zucker rats were included in the present study only if their plasma glucose levels exceeded 200 mg/dL. Two rats were excluded on the basis of this criteria. The serum lipid profile was measured by the Outreach Pathology Laboratory at the University of Alabama Hospital.
Statistical Analysis
All data were evaluated by ANOVA (significance criteria of P<0.05) with appropriate post hoc tests (Newman-Keuls) to determine the source of main effects and interactions.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Obese (compared with lean) Zucker rats were significantly heavier throughout the study (initial body weights 326±6.7 vs 266.5±4.7 g; final body weights 437.8±12.8 vs 373.7±7.2 g). Obese rats also displayed significantly higher plasma glucose, cholesterol, triglyceride, and very-low-density lipoprotein concentrations (Table).
|
Baseline MAP was significantly elevated in obese (compared with lean) rats maintained on the basal salt diet (Figure 1 and Table), and obese rats also had significantly higher nighttime peak and daytime nadir arterial pressures (Figure 1 and Table). Both obese and lean Zucker rats displayed a significant 24-hour circadian MAP rhythm with similar amplitude, although the acrophase of the rhythm occurred earlier in the lean animals (Figure 1 and Table).
|
Exposure to the high salt diet significantly elevated MAP in the obese (but not lean) Zucker rats (Figure 1 and Table). Peak arterial pressures were significantly elevated in both obese and lean Zucker rats (Figure 1 and Table), whereas nadir arterial pressures did not significantly change in either group (Figure 1 and Table). Both peak and nadir pressures in obese rats were significantly higher than in the lean rats. The high salt diet increased the amplitude of arterial pressure in lean rats and shifted its acrophase in both groups (Figure 1 and Table).
Baseline blood pressure was significantly higher in obese (vs lean) rats for both the ganglionic blockade (106.4 vs 91.9 mm Hg) and losartan (108.4 vs 97.4 mm Hg) studies. Ganglionic blockade with hexamethonium led to a significantly greater decrease in MAP in the obese (compared with lean) rats fed the basal salt diet, but AT1-receptor blockade with losartan produced similar decreases in MAP in both groups (Figure 2). After exposure to the high salt diet, arterial pressure was significantly higher in obese (vs lean) rats for both the ganglionic blockade (125.9 vs 88.0 mm Hg) and losartan (120.5 vs 97.2 mm Hg) studies. Hexamethonium produced a significantly greater decrease in MAP in the obese (compared with lean) rats (Figure 2), but the absolute reduction in MAP was not significantly different from the reduction in obese rats fed the basal diet. The high salt diet did not significantly affect the reductions in MAP after losartan infusion in either group of rats (Figure 2).
|
Throughout the study, HR was significantly lower in obese rats (Figure 1 and Table). Exposure to the high salt diet led to a significant reduction in heart rate in lean animals, whereas HR remained unchanged in the obese group (Figure 1 and Table).
There was no significant difference between obese and lean rats in the contractile response (ie, the maximum force generating capacity and the ED50) of carotid ring segments to phenylephrine (data not shown). Similarly, vasodilatory responses to the endothelium-independent dilator sodium nitroprusside were not significantly different in lean compared with obese Zucker rats (data not shown). In contrast, ring segments from obese (compared with lean) Zucker rats displayed a diminished response to cumulative addition of acetylcholine (Figure 3).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
These data demonstrate that diabetic obese (vs nondiabetic lean) Zucker rats have increased arterial pressure and suggest that the sympathetic nervous system and changes in vascular reactivity contribute to this elevation. Conversely, increased vascular sensitivity to circulating angiotensin does not appear to contribute to the elevation in arterial pressure. Furthermore, the results demonstrate that diets high in salt raise arterial pressure in diabetic Zucker obese (but not lean) rats. This salt -sensitive response is not dependent on the sympathetic nervous system but may relate to impaired vascular reactivity.
Previous studies of the arterial pressure control in Zucker obese rats have yielded contradictory results, describing Zucker obese rats as both hypertensive7 8 9 10 11 12 13 19 21 and normotensive.14 15 16 17 18 The design of the present experiments shed light on this dispute. This study is the first to use telemetry to chronically compare arterial pressure in diabetic obese and nondiabetic lean Zucker rats. This method facilitates an accurate assessment of arterial pressure that is not confounded by the stress of tethering or a limited number of sampling times. The only previous study that chronically monitored arterial pressure (tethered system for a 5-day average) in lean and obese Zucker rats found that MAP was significantly higher (14 mm Hg) in the latter rats.11 The present study confirms these observations and demonstrates that both the daytime (normal sleep phase) and the nighttime (normal awake phase) arterial pressures are elevated in the obese rats. Second, this study focused on Zucker rats that were severely hyperglycemic, therefore more closely approximating the physiological conditions observed in type 2 diabetes.1
Both hyperinsulinemia and increased blood glucose levels probably contribute to hypertension in type 2 diabetes,34 and elevated arterial pressure has been observed in all previous studies in which obese Zucker rats had either mild11 or moderate hyperglycemia.9 22 23 24 In contrast, the majority of studies using normoglycemic, hyperinsulinemic obese Zucker rats have found no increase in arterial pressure.14 18 These results support the hypothesis that hyperglycemia contributes to hypertension in obese Zucker rats. It should be noted that most studies examining arterial pressure control in obese Zucker rats have not reported blood glucose concentrations,7 8 10 12 13 15 16 17 thus precluding an estimation of the contribution of glycemic levels to elevated arterial pressure.
The present results demonstrate that ganglionic blockade leads to a significantly greater reduction in MAP in the obese Zucker rats, whereas blockade of AT1 receptors with losartan produced similar decreases in MAP in both groups. These observations confirm previous reports suggesting that obese Zucker rats have elevated sympathetic nervous system activity17 22 and that the vasculature is not more sensitive to circulating angiotensin II.35 However, other studies indicate that obese Zucker rats display increased vascular responsiveness to circulating angiotensin II. Similar to the present report, Zemel et al7 have demonstrated that obese Zucker rats have higher arterial pressure, but their results indicate that the sympathetic nervous system does not contribute to this differential. In contrast, they report that responsiveness to angiotensin II is enhanced in the obese Zucker rats, but they also saw a similar increase in sensitivity to norepinephrine, suggesting a general impairment in vascular reactivity.7 Likewise, Alonso-Galicia et al11 have reported that chronic losartan treatment leads to a greater reduction in MAP in obese Zucker rats, but their data demonstrated no differential response after 
1- and ß-adrenergic blockade. Furthermore, obese Zucker rats had an exaggerated pressor response to a bolus injection of angiotensin II. The differences between these latter findings and those of the present study may reflect the fact that the rats in the present study had circulating glucose levels that were nearly triple those of the other 2 studies. Alternatively, the continuous sodium infusion used by Alonso-Galicia et al11 to normalize sodium ingestion may have disrupted the 24-hour plasma sodium, renin-angiotensin, and MAP rhythms. Additionally, the present experiments have measured MAP responses to hexamethonium and losartan at 1 time point during the daytime, whereas Alonso-Galicia et al11 analyzed these variables over a 24-hour period. It should be noted that the present study did not assess differences in food intake in the lean and obese rats. Thus a greater intake of dietary salt in the obese (compared with lean) Zucker rats may result in a higher plasma sodium concentration, which could in turn activate central osmoreceptors and thereby reflexly increase sympathetic nervous system activity.
Impaired endothelial cell function also may contribute to hypertension in obese Zucker rats in the present study. These results demonstrate for the first time that vasodilatory responses to acetylcholine are impaired in carotid arteries of obese Zucker rats. These data also indicate that isolated carotid arteries of obese Zucker rats do not have an enhanced sensitivity to phenylephrine or nitric oxide. Together this suggests that endothelially mediated vasodilation is impaired in diabetic obese Zucker rats. Isolated blood vessels from both type 1 and 2 diabetic patients36 37 and hyperglycemic animal models38 exhibit increases in vessel tone. Thus a reduction in nitric oxide signaling from endothelial cells to vascular smooth muscle may contribute to the elevation in MAP in obese Zucker rats and in diabetic patients.
When the Zucker rats are placed on a high salt diet, MAP significantly increases in the obese but not the lean rats. This confirms previous reports that obese Zucker rats are salt sensitive.16 It is unclear what mechanisms account for this mild salt sensitivity in the obese rats, although the reduction in vasodilatory capacity probably contributes to it. First, the present ganglionic blockade results indicate that the sympathetic nervous system does not contribute to the differential response. Second, HR in response to the high salt diet is significantly decreased in lean (but not obese) Zucker rats, thus perhaps limiting any rise in MAP. Interestingly, HR appears to already be suppressed in obese rats fed the basal salt diet, potentially limiting the ability for further decrease after exposure to the high salt diet. Third, impaired baroreflex responses15 and increased plasma volume also may contribute to the dietary salt-induced rise in arterial pressure in obese Zucker rats.39 40 Thus the nervous system mechanisms that contribute to the elevated arterial pressure in obese (compared with lean) Zucker rats on a basal salt diet are distinct from the mechanisms that underlie the dietary salt-induced elevation of arterial pressure in these rats.
In summary, the present results demonstrate that diabetic obese (compared with nondiabetic lean) Zucker rats display elevated arterial pressure that appears to be due, at least in part, to sympathetic nervous system overactivity and impaired vasodilatory capacity. Furthermore, arterial pressure in obese Zucker rats is sensitive to dietary salt excess, but the salt-induced increase in arterial pressure appears to be independent of enhanced sympathetic nervous system activity. Finally, these results suggest the usefulness of hyperglycemic obese Zucker rats as a model in which to study the interaction of mechanisms that contribute to type 2 diabetes.
|
Acknowledgments |
|---|
This work was supported by the National Institutes of Health grant HL-37722 (J.M.W.) and the American Diabetes Association (C.R.W.). The authors wish to express their appreciation to Xinhua Feng for technical assistance.
Received September 15, 1999; first decision October 11, 1999; accepted October 19, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. El-Mas MM, Abdel-Rahman AA. Estrogen enhances baroreflex control of heart rate in conscious ovariectomized rats. Can J Physiol Pharmacol. 1998;76:381–386.[Medline] [Order article via Infotrieve]
2. O’Keefe JHJ, Miles JM, Harris WH, Moe RM, McCallister BD. Improving the adverse cardiovascular prognosis of type 2 diabetes. Mayo Clin Proc. 1999;74:171–180.[Abstract]
3. Williams, B. The unique vulnerability of diabetic subjects to hypertensive injury. J Hum Hypertens. 1999;13(suppl 2):S3–S8.
4.
Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation. 1979;59:8–13.
5. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16, 434–444.
6. Bakris GL, Weir MR, Sowers JR. Therapeutic challenges in the obese diabetic patient with hypertension. Am J Med. 1996;101:33S–46S.
7.
Zemel MB, Peuler JD, Sowers JR, Simpson L. Hypertension in insulin-resistant Zucker obese rats is independent of sympathetic neural support. Am J Physiol. 1992;262:E368–E371.
8. Turner NC, Gudgeon C, Toseland N. Effects of genetic hyperinsulinaemia on vascular reactivity, blood pressure, and renal structure in the Zucker rat. J Cardiovasc Pharmacol. 1995;26:714–720.[Medline] [Order article via Infotrieve]
9. Maher MA, Banz WJ, Zemel MB. Variations of blood pressures in lean Zucker rats fed low or high fat diets. J Nutr. 1995;125:2618–2622.
10. Ambrozy SL, Shehin SE, Chiou CY, Sowers JR, Zemel MB. Effects of dietary calcium on blood pressure, vascular reactivity and vascular smooth muscle calcium efflux rate in Zucker rats. Am J Hypertens. 1991;4:592–596.[Medline] [Order article via Infotrieve]
11.
Alonso-Galicia M, Brands MW, Zappe DH, Hall JE. Hypertension in obese Zucker rats: role of angiotensin II and adrenergic activity. Hypertension. 1996;28:1047–1054.
12.
Kurtz TW, Morris RC, Pershadsingh HA. The Zucker fatty rat as a genetic model of obesity and hypertension. Hypertension. 1989;13:896–901.
13. Kim JH, Snider T, Abel M, Zemel MB. Hypertension in young, healthy Zucker obese rats is not responsive to reduced NaCl intake. J Nutr. 1994;124:713–716.
14. Pamidimukkala J, Jandhyala BS. Evaluation of hemodynamics, vascular reactivity and baroreceptor compensation in the insulin resistant Zucker obese rats. Clin Exp Hypertens. 1996;18:1089–1104.
15. Bunag RD, Barringer DL. Obese Zucker rats, though still normotensive, already have impaired chronotropic baroreflexes. Clin Exp Hypertens [A]. 1988;10(suppl 1):257–262.
16.
Reddy SR, Kotchen TA. Dietary sodium chloride increases blood pressure in obese Zucker rats. Hypertension. 1992;20:389–393.
17.
Morgan DA, Anderson EA, Mark AL. Renal sympathetic nerve activity is increased in obese Zucker rats. Hypertension. 1995;25:834–838.
18. Pawloski CM, Kanagy NL, Mortensen LH, Fink GD. Obese Zucker rats are normotensive on normal and increased sodium intake. Hypertension. 1992;19:I-90–I-95.
19.
Fujiwara K, Hayashi K, Matsuda H, Kubota E, Honda M, Ozawa Y, Saruta T. Altered pressure-natriuresis in obese Zucker rats. Hypertension. 1999;33:1470–1475.
20. Walker AB, Dores J, Buckingham RE, Savage MW, Williams G. Impaired insulin-induced attenuation of noradrenaline-mediated vasoconstriction in insulin-resistant obese Zucker rats. Clin Sci. 1997;93:235–241.[Medline] [Order article via Infotrieve]
21. Zanchi A, Delacretaz E, Taleb V, Gaillard R, Jeanrenaud B, Brunner HR, Waeber B. Endothelial function of the mesenteric arteriole and mechanical behaviour of the carotid artery in rats with insulin resistance and hypercholesterolaemia. J Hypertens. 1995;13:1463–1470.[Medline] [Order article via Infotrieve]
22. Yakubu-Madus FE, Johnson WT, Zimmerman KM, Dananberg J, Steinberg MI. Metabolic and hemodynamic effects of moxonidine in the Zucker diabetic fatty rat model of type 2 diabetes. Diabetes. 1999;48:1093–1100.[Abstract]
23. van Zwieten PA. Diabetes and hypertension: experimental models for pharmacological studies. Clin Exp Hypertens. 1999;21:1–16.
24. van Zwieten PA, Kam KL, Pijl AJ, Hendriks MG, Beenen OH, Pfaffendorf M. Hypertensive diabetic rats in pharmacological studies. Pharmacol Res. 1996;33:95–105.[Medline] [Order article via Infotrieve]
25.
Carlson SH, Osborn JW, Wyss JM. Hepatic denervation chronically elevates arterial pressure in Wistar-Kyoto rats. Hypertension. 1998;32:46–51.
26.
Calhoun DA, Zhu S, Wyss JM, Oparil S. Diurnal blood pressure variation and dietary salt in spontaneously hypertensive rats. Hypertension. 1994;24:1–7.
27. Hopfner RL, McNeill JR, Gopalakrishnan V. Vanadate treatment normalizes exaggerated vascular smooth muscle responses in the obese Zucker rat. Eur J Pharmacol. 1998;357:61–65.[Medline] [Order article via Infotrieve]
28. Ouchi Y, Han SZ, Kim S, Akishita M, Kozaki K, Toba K, Orimo H. Augmented contractile function and abnormal Ca2+ handling in the aorta of Zucker obese rats with insulin resistance. Diabetes. 1996;45(suppl 3):S55–S58.
29. Duarte J, Martinez A, Bermejo A, Vera B, Gamez MJ, Cabo P, Zarzuelo A. Cardiovascular effects of captopril and enalapril in obese Zucker rats. Eur J Pharmacol. 1999;365:225–232.[Medline] [Order article via Infotrieve]
30. Wu X, Makynen H, Kahonen M, Arvola P, Porsti I. Mesenteric arterial function in vitro in three models of experimental hypertension. J Hypertens. 1996;14:365–372.[Medline] [Order article via Infotrieve]
31. Carlson SH, Wyss JM. Hepatic denervation does not affect plasma vasopressin response to intragastric hypertonic saline in conscious rats. Am J Physiol. 1999;277:E161–E167.
32.
White CR, Shelton J, Chen SJ, Darley-Usmar V, Sanders PW, Chen YF, Oparil S. Estrogen restores endothelial cell function in an experimental model of vascular injury. Circulation. 1997;96:1624–1630.
33. Mattes A, Witte K, Hohman W, Lemmer B. PHARMFIT: a non-linear fitting program for pharmacology. Chronobiol Int. 1991;8:460–476.[Medline] [Order article via Infotrieve]
34. Sowers JR, Khoury S, Standley P, Zemel P, Zemel M. Mechanisms of hypertension in diabetes. Am J Hypertens. 1991;4:177–182.[Medline] [Order article via Infotrieve]
35. Harker CT, O’Donnell MP, Kasiske BL, Keane WF, Katz SA. The renin-angiotensin system in the type II diabetic obese Zucker rat. J Am Soc Nephrol. 1993;4:1354–1361.[Abstract]
36. Giugliano D, Ceriello A, Paolisso G. Diabetes mellitus, hypertension, and cardiovascular disease: which role for oxidative stress? Metab Clin Exp. 1995;44:363–368.
37. Giugliano D, Acampora R, D’Onofrio F. Medical hypothesis: cardiovascular complications of diabetes mellitus-from glucose to insulin and back. Diabete Metabolisme. 1994;20:445–453.[Medline] [Order article via Infotrieve]
38. Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med. 1994;16:383–391.[Medline] [Order article via Infotrieve]
39.
Greene AS, Yu ZY, Roman RJ, Cowley AWJ. Role of blood volume expansion in Dahl rat model of hypertension. Am J Physiol(Heart Circ Physiol). 1990;258:H508–H514.
40.
Krieger JE, Cowley AWJ. Prevention of salt angiotensin II hypertension by servo control of body water. Am J Physiol(Heart Circ Physiol). 1990;258:H994–H1003.
This article has been cited by other articles:
 |
|
 |
|
  R. D. Rudic and D. J. Fulton Pressed for time: the circadian clock and hypertension J Appl Physiol, October 1, 2009; 107(4): 1328 - 1338. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nagae, M. Fujita, H. Kawarazaki, H. Matsui, K. Ando, and T. Fujita Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Obesity-Induced Hypertension Circulation, February 24, 2009; 119(7): 978 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. da Costa Goncalves, J. Tank, A. Diedrich, A. Hilzendeger, R. Plehm, M. Bader, F. C. Luft, J. Jordan, and V. Gross Diabetic Hypertensive Leptin Receptor-Deficient db/db Mice Develop Cardioregulatory Autonomic Dysfunction Hypertension, February 1, 2009; 53(2): 387 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Doczi, A. D. Morielli, and D. H. Damon Kv1.3 channels in postganglionic sympathetic neurons: expression, function, and modulation Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2008; 295(3): R733 - R740. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. C. Kopp, M. Z. Cicha, and M. A. Yorek Impaired responsiveness of renal sensory nerves in streptozotocin-treated rats and obese Zucker diabetic fatty rats: role of angiotensin Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R858 - R866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Cho, N. Peng, J. T. Clark, L. Novak, S. Roysommuti, J. Prasain, and J. M. Wyss Genistein Attenuates the Hypertensive Effects of Dietary NaCl in Hypertensive Male Rats Endocrinology, November 1, 2007; 148(11): 5396 - 5402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. W. Stepp, E. I. Boesen, J. C. Sullivan, J. D. Mintz, C. D. Hair, and D. M. Pollock Obesity augments vasoconstrictor reactivity to angiotensin II in the renal circulation of the Zucker rat Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2537 - H2542. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Schreihofer, D. A. Mandel, S. C. Mobley, and D. W. Stepp Impairment of sympathetic baroreceptor reflexes in obese Zucker rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2543 - H2549. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D'Angelo, J. D. Mintz, J. E. Tidwell, A. M. Schreihofer, D. M. Pollock, and D. W. Stepp Exaggerated Cardiovascular Stress Responses and Impaired {beta}-Adrenergic-Mediated Pressor Recovery in Obese Zucker Rats Hypertension, December 1, 2006; 48(6): 1109 - 1115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ruggeri, A. Brunori, C. E. Cogo, D. Storace, F. Di Nardo, and R. Burattini Enhanced sympathetic reactivity associates with insulin resistance in the young Zucker rat Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R376 - R382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Frisbee Impaired hemorrhage tolerance in the obese Zucker rat model of metabolic syndrome J Appl Physiol, February 1, 2006; 100(2): 465 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. P. Romanko and D. W. Stepp Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2097 - H2102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D'Angelo, A. A. Elmarakby, D. M. Pollock, and D. W. Stepp Fructose Feeding Increases Insulin Resistance but Not Blood Pressure in Sprague-Dawley Rats Hypertension, October 1, 2005; 46(4): 806 - 811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Tallam, D. E. Stec, M. A. Willis, A. A. da Silva, and J. E. Hall Melanocortin-4 Receptor-Deficient Mice Are Not Hypertensive or Salt-Sensitive Despite Obesity, Hyperinsulinemia, and Hyperleptinemia Hypertension, August 1, 2005; 46(2): 326 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Schreihofer, C. D. Hair, and D. W. Stepp Reduced plasma volume and mesenteric vascular reactivity in obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R253 - R261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Cheng, X. S. Cheng, K.-H. Kuo, and C. C.Y. Pang Inhibition of iNOS augments cardiovascular action of noradrenaline in streptozotocin-induced diabetes Cardiovasc Res, November 1, 2004; 64(2): 298 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Frisbee Enhanced arteriolar {alpha}-adrenergic constriction impairs dilator responses and skeletal muscle perfusion in obese Zucker rats J Appl Physiol, August 1, 2004; 97(2): 764 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Banday, T. Hussain, and M. F. Lokhandwala Renal dopamine D1 receptor dysfunction is acquired and not inherited in obese Zucker rats Am J Physiol Renal Physiol, July 1, 2004; 287(1): F109 - F116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Sharma Is There a Rationale for Angiotensin Blockade in the Management of Obesity Hypertension? Hypertension, July 1, 2004; 44(1): 12 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Stepp, D. M. Pollock, and J. C. Frisbee Low-flow vascular remodeling in the metabolic syndrome X Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H964 - H970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Grisk and R. Rettig Interactions between the sympathetic nervous system and the kidneys in arterial hypertension Cardiovasc Res, February 1, 2004; 61(2): 238 - 246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Frisbee Impaired skeletal muscle perfusion in obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1124 - R1134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Dobrian, S. D. Schriver, T. Lynch, and R. L. Prewitt Effect of salt on hypertension and oxidative stress in a rat model of diet-induced obesity Am J Physiol Renal Physiol, October 1, 2003; 285(4): F619 - F628. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Frisbee Remodeling of the skeletal muscle microcirculation increases resistance to perfusion in obese Zucker rats Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H104 - H111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Y.H. Chan, L.-L. Wang, Y.-M. Chao, and S. H.H. Chan Downregulation of Basal iNOS at the Rostral Ventrolateral Medulla Is Innate in SHR Hypertension, March 1, 2003; 41(3): 563 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. Carlson, S. Oparil, Y.-F. Chen, and J. M. Wyss Blood Pressure and NaCl-Sensitive Hypertension Are Influenced by Angiotensin-Converting Enzyme Gene Expression in Transgenic Mice Hypertension, February 1, 2002; 39(2): 214 - 218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Fang, S. H. Carlson, Y. F. Chen, S. Oparil, and J. M. Wyss Estrogen depletion induces NaCl-sensitive hypertension in female spontaneously hypertensive rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R1934 - R1939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Stojiljkovic, D. Zhang, H. F. Lopes, C. G. Lee, T. L. Goodfriend, and B. M. Egan Hemodynamic effects of lipids in humans Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2001; 280(6): R1674 - R1679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Overton, T. D. Williams, J. B. Chambers, and M. E. Rashotte Cardiovascular and metabolic responses to fasting and thermoneutrality are conserved in obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2001; 280(4): R1007 - R1015. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M Sharma and S. Engeli The renin-angiotensin system in obesity hypertension Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S114 - S119. [PDF]
|
|
|
|
|
|
D. W. Stepp and J. C. Frisbee Augmented adrenergic vasoconstriction in hypertensive diabetic obese Zucker rats Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H816 - H820. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||