Effect of experimentally-induced hypertension on angiotensin converting enzyme activity in the aortic endothelium and smooth muscle cum adventitia of the Sprague Dawley rat.

The effect of experimentally-induced hypertension on the angiotensin converting enzyme (ACE) activity in the endothelium and smooth muscle cum adventitia of the Sprague Dawley rats was investigated. The ACE activity in both tissues of the 1-clip 2-kidney renovascular hypertensive rats and the deoxycorticosterone acetate/salt hypertensive rats were significantly higher than those of the normotensive control. These findings (i) support the suggestion that the 1-clip 2-kidney renovascular hypertensive rat represents a model of renin- and angiotensin-dependent hypertension and that the increased vascular ACE activity could play a role in the maintenance of hypertension (ii) provide new information regarding the association of increased vascular ACE activity and hypertension in the mineralocorticoid/salt treated hypertensive rats which may account for the finding by others that captopril is effective in preventing the development of hypertension in this low renin model of hypertension. On the other hand, the data also bring forth the possibility that the observed increase in vascular ACE activity could be the result of hypertension.     

Alterations of vascular prostacyclin and thromboxane A2 in Dahl genetical strain susceptible to salt-induced hypertension

To assess the implications of vascular eicosanoids system in the hypertension of Dahl salt-sensitive (Dahl S) strain, we investigated the production of vascular vasodepressor and vasoconstrictor eicosanoids in Dahl S rats. 14-week-old Dahl S rats on a 0.11% NaCl diet (normotension) or a 0.3% NaCl diet (borderline hypertension) had a significantly lowered generation of vascular prostacyclin (PGI2), compared with Dahl salt-resistant (Dahl R) rats. The impairment of vascular PGI2 in Dahl S rats was restored to the normal level of Dahl R rats with the elevation of blood pressure induced by a high salt diet (4% NaCl). The production of vascular PGI2 was closely related to the height of blood pressure. The deterioration of vascular PGI2 was also found in 4-week-old Dahl S rats with normotension. Conversely, vascular thromboxane A2 (TXA2) was significantly enhanced in 14-week-old Dahl S rats in all of the feeding groups. Thus, it seems possible that the proved alterations of the vasodepressor and vasoconstrictor eicosanoids partially contribute to the genesis of salt hypertension. Although the exact mechanisms remain obscure, the adaptation of vascular PGI2 on a high salt diet may be suitable to compete with the high blood pressure and to protect against the vascular damage.     

Endogenous angiotensin II enhances atherogenesis in apoprotein E-deficient mice with renovascular hypertension through activation of vascular smooth muscle cells

Renovascular hypertension is one of the most important risk factors in the development of atherosclerosis. However, very little is known about the role of angiotensin II (AII), a key regulator of blood pressure homeostasis, on renovascular hypertension-associated atherogenesis. To study a possible role of AII on atherogenesis, we generated apoE-deficient hypertensive mice with either normal or increased AII production by applying 1-kidney, 1-clip (1K1C) or 2-kidney, 1-clip (2K1C) operation, respectively. Hypertension was successfully achieved in both mice groups, and was persistent for 8 weeks. Atherosclerosis quantification showed a marked increase in lesion area in aortic sinus of 2K1C mice as compared with 1K1C mice, suggesting a potential role of endogenous AII on atherogenesis. In the immunohistochemical analysis, induction of renovascular hypertension with 2K1C for 8 weeks led to an enhanced accumulation of macrophages in the aortic sinus, which was accompanied by a parallel increase in scavenger receptor A (SRA) expression on the macrophages. In in vitro experiments, although treatment of cells with increasing concentrations of AII (0.1 to 10 microM) affects neither SRA expression nor oxLDL uptake by macrophages, conditioned media (CM) derived from AII-stimulated vascular smooth muscle cells (VSMC) increased macrophage uptake of oxLDL in association with an enhanced expression of SRA on the macrophages. These findings suggest that the increased generation of AII in renovascular hypertension may initiate and promote atherosclerosis by activation of VSMC.     

Alterations of vascular prostacyclin and thromboxane A2 in Dahl genetical strain susceptible to salt-induced hypertension

To assess the implications of vascular eicosanoids system in the hypertension of Dahl salt-sensitive (Dahl S) strain, we investigated the production of vascular vasodepressor and vasoconstrictor eicosanoids in Dahl S rats. 14-week-old Dahl S rats on a 0.11% NaCl diet (normotension) or a 0.3% NaCl diet (borderline hypertension) had a significantly lowered generation of vascular prostacyclin (PGI₂), compared with Dahl salt-resistant (Dahl R) rats. The impairment of vascular PGI₂ in Dahl S rats was restored to the normal level of Dahl R rats with the elevation of blood pressure induced by a high salt diet (4% NaCl). The production of vascular PGI₂ was closely related to the height of blood pressure. The deterioration of vascular PGI₂ was also found in 4-week-old Dahl S rats with normotension. Conversely, vascular thromboxane A₂ (TXA₂) was significantly enhanced in 14-week-old Dahl S rats in all of the feeding groups. Thus, it seems possible that the proved alterations of the vasodepressor and vasoconstrictor eicosanoids partially contribute to the genesis of salt hypertension. Although the exact mechanisms remain obscure, the adaptation of vascular PGI₂ on a high salt diet may be suitable to compete with the high blood pressure and to protect against the vascular damage.     

Prostacyclin synthase and phospholipases in the vascular wall of experimental hypertensive rats

To reveal the role of enzymes involved in PGI2 synthesis for vascular PGI2 generation in experimental hypertensive models, we defined PGI2 synthase and phospholipases activities in the aortic wall of two different experimental hypertensive rats, e.g. spontaneously hypertensive rats (SHR) and desoxycorticosterone acetate (DOCA)-salt hypertensive rats. In the stage of established hypertension both of the hypertensive models had a significantly large capacity of the vascular wall to produce PGI2, as compared to respective control rats. PGI2 synthase activities in the vascular wall were significantly increased by 27% for SHR and by 80% for DOCA-salt hypertensive rats. Moreover, the enzymatic activities were closely related to the blood pressure values for both of the models. On the other hand, phospholipase C or phospholipase A2 activities were increased or unchanged in SHR, respectively, whereas both of the phospholipases were significantly decreased in DOCA-salt hypertensive rats. Thus, it is indicated that PGI2 synthase is partly responsible for the increased PGI2 generation in the vascular wall of SHR and DOCA-salt hypertensive rats, and that vascular phospholipase C is playing a more important role in providing arachidonate for PGI2 synthesis in SHR.     

Vascular receptors for atrial natriuretic peptide in hypertension

Atrial natriuretic peptide (ANP) is secreted by the heart in response mainly to atrial distension and circulates in plasma in picomolar concentrations. It binds to receptors in blood vessels which it relaxes, renal glomeruli where it induces increased glomerular filtration rate, renal papilla to produce natriuresis, adrenal glomerulosa celts to inhibit aldosterone secretion, and median eminence and pituitary where it may inhibit vasopressin secretion. In experimental models of hypertension plasma levels of ANP are uniformly elevated, except in spontaneously hypertensive rats, in which plasma ANP may only rise transiently. The action of ANP on smooth muscle cells of the blood vessel wall results in production of cyclic GMP, which appears to be the second messenger producing relaxation of pre-contracted blood vessels. Mechanisms other than cGMP generation have been proposed but remain unproven as mediators of ANP action. Receptors for ANP in blood vessels are of two subtypes: B-receptors (or R₁-receptors), which contain guanylate cyclase in their structure, and C-receptors (or R₂-receptors), which have not been shown to the present to be biologically active. Our studies on vascular ANP receptors are reviewed. In several experimental models of hypertension such as saralasin-insensitive 2-kidney, 1-clip and 1-kidney, 1-clip Goldblatt hypertensive rats and in DOCA-salt hypertensive rats, we have found elevated plasma ANP, as well as decreased binding and ANP-induced vascular relaxation and blood pressure-lowering effects of ANP. Both the B and C ANP receptors appear decreased in density, even after acid washing of membranes to remove any retained circulating ANP. In SHR we have found that plasma ANP was higher than in control WKY rats only transiently at 8 weeks. Binding was significantly lower in 4 and 8 week-old SHR, but cGMP generation and relaxation produced by ANP were increased in the 4 week-old SHR but normal at 8, 12 or 16 weeks. Expression of B-receptors was exaggerated in 4 week-old SHR relative to C receptors in comparison to age-matched WKY and Wistar rats. These results may underly the normalization of blood pressure found in SHR when a small dose of ANP is infused intravenously, in contrast to other models of experimental hypertension which appear to be more resistant to ANP-induced blood pressure lowering effects. In humans with essential hypertension, plasma ANP was increased in patients with moderate to severe uncontrolled high blood pressure, associated with echocardiographic evidence of left ventricular hypertrophy. In these patients, platelet ANP binding was significantly reduced. If these sites resemble vascular ANP sites in their behavior, severely hypertensive patients may be less sensitive to ANP, which may contribute to blood pressure elevation.     

Influence of ovariectomy on cardiac oxidative stress in a renovascular hypertension model

The aim of this study was to evaluate the potential influence of endogenous ovarian hormones on cardiac oxidative stress in renovascular hypertension. Female Wistar rats (N = 10 per group) were divided among 4 groups: (i) normotensive control; (ii) hypertensive control; (iii) normotensive ovariectomized; and (iv) hypertensive ovariectomized rats. To induce hypertension, 2-kidney 1-clip (2K1C) Goldblatt's method was followed. Blood pressure (BP) was enhanced (25%) in 2K1C and it was not further altered in hypertensive ovariectomized animals. Lipid peroxidation (measured by thiobarbituric acid reactive substances; TBARS) increased in heart homogenates after ovariectomy (253%) and was additionally augmented when associated with hypertension (by 28%). Superoxide dismutase and catalase activities were similar in both hypertensive groups. Hypertension enhanced glutathione peroxidase activity (75%), but the association with ovariectomy prevented this change. Total radical trapping antioxidant potential (TRAP) decreased in hypertensive rats (34%) and was recovered when associated with ovariectomy. However, this adaptation seems not to be sufficient to avoid the increased oxidative damage in ovariectomized hypertensive animals. These results suggest a protective role for physiological ovarian hormones in the cardiac oxidative stress induced by 2K1C hypertension.     

No rarefaction of cerebral arterioles in hypertensive rats

A reduction in the density of small arterioles (rarefaction) has been reported in several vascular beds of the spontaneously hypertensive rat (SHR). There have been conflicting reports on the existence of rarefaction in the pial vasculature of SHR. In this study, we determined whether there was rarefaction of pial arterioles in several models of hypertension. We studied SHR; two-kidney, one-clip Goldblatt hypertensive rats; deoxycorticosterone-salt hypertensive rats; and Dahl salt-sensitive rats fed high salt diet. The two groups of normotensive controls were Wistar--Kyoto rats and Dahl salt-sensitive rats fed low salt diet. The duration of hypertension was about 2 months. Density of first-, second-, third-, and fourth-order arterioles was determined by counting the number of vessels from enlarge photographs. We also measured the lengths of segments of the arterioles. We did not observe any evidence of rarefaction of arterioles in the pial vasculature in any of the hypertensive groups of rats. We conclude that (i) rarefaction of arterioles does not occur in the pial microvasculature after approximately 2 months of hypertension and (ii) rarefaction of pial arterioles does not account for abnormalities in the cerebral circulation of hypertensive rats such as protection of the blood-brain barrier or changes in autoregulation of cerebral blood flow.     

A novel vascular clip design for the reliable induction of 2-kidney, 1-clip hypertension in the rat

The 2-kidney, 1-clip (2K1C) model has provided many insights into the pathogenesis of renovascular hypertension. However, studies using the 2K1C model often report low success rates of hypertension, with typical success rates of just 40-60%. We hypothesized that these low success rates are due to fundamental design flaws in the clips traditionally used in 2K1C models. Specifically, the gap widths of traditional silver clips may not be maintained during investigator handling and these clips may also be easily dislodged from the renal artery following placement. Therefore, we designed and tested a novel vascular clip possessing design features to maintain both gap width and position around the renal artery. In this initial study, application of these new clips to the left renal artery produced reliable and consistent levels of hypertension in rats. Nine-day application of clips with gap widths of 0.27, 0.25, and 0.23 mm elicited higher mean arterial blood pressures of 112 ± 4, 121 ± 6, and 135 ± 7 mmHg, respectively (n = 8 for each group), than those of sham-operated controls (95 ± 2 mmHg, n = 8). Moreover, 8 out of 8 rats in each of the 0.23 and 0.25 mm 2K1C groups were hypertensive, whereas 7 out of 8 rats in the 0.27 mm 2K1C group were hypertensive. Plasma renin concentrations were also increased in all 2K1C groups compared with sham-operated controls. In summary, this novel clip design may help eliminate the large degree of unreliability commonly encountered with the 2K1C model.     

Inhibitory effects of beta adrenoceptor antagonist, atenolol, on the thromboxane system in the kidney of spontaneously hypertensive rats

We attempted to investigate the alterations in the vasoconstrictor thromboxane (TXA2) system in the kidney when spontaneously hypertensive rats (SHR) were treated subchronically with atenolol, a beta 1-adrenoceptor antagonist. Atenolol treatment (30 mg/kg body weight per day for 2 weeks) reduced systolic blood pressure by 11%, being accompanied by a decrease in heart rate. This treatment strikingly decreased thromboxane content in the renal cortex by 48% (p less than 0.05), whereas the tissue content was unaltered for prostaglandin E2 (PGE2) or slightly decreased for prostacyclin (PGI2). These alterations in the eicosanoid system led to an increase in the ratio of PGE2/TXA2 and of PGI2/TXA2. Similarly, thromboxane content in the renal papilla was lowered significantly with atenolol treatment, which raised the ratio of PGE2 to TXA2. Thromboxane reduction was not observed in the aortic walls and heart. However, in the vascular walls, PGI2 synthesis was markedly stimulated with atenolol treatment, resulting in an increase in the ratio of PGI2 to TXA2. Thus, these data indicate that subchronic atenolol-treatment inhibits the thromboxane system in the kidney, thereby shifting the eicosanoid system towards a vasodilator state. These alterations contribute, in part, to the anti-hypertensive properties of atenolol in genetic hypertension.     

Effects of high salt intake on brain AT1 receptor densities in Dahl rats

To assess effects of dietary salt on brain AT1 receptor densities, 4-wk-old Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats were fed a regular (101 mumol Na/g) or high (1,370 mumol Na/g)-salt diet for 1, 2, or 4 wk. AT1 receptors were assessed by quantitative in vitro autoradiography. AT1 receptor densities did not differ significantly between strains on the regular salt diet. The high-salt diet for 1 or 2 wk increased AT1 receptor binding by 21-64% in the Dahl S rats in the subfornical organ, median preoptic nucleus, paraventricular nucleus, and suprachiasmatic nucleus. No changes were noted in the Dahl R rats. After 4 wk on a high-salt diet, increases in AT1 receptor binding persisted in Dahl S rats but were now also noted in the paraventricular nucleus, median preoptic nucleus, and suprachiasmatic nucleus of Dahl R rats. At 4 wk on the diet, intracerebroventricular captopril caused clear decreases in blood pressure only in the Dahl S on the high-salt diet but caused largely similar relative increases in brain AT1 receptor densities in Dahl S and R on the high-salt diet versus regular salt diet. These data demonstrate that high salt intake rapidly (within 1 wk) increases AT1 receptor densities in specific brain nuclei in Dahl S and later (by 4 wk) also in Dahl R rats. Because the brain renin-angiotensin system only contributes to salt-induced hypertension in Dahl S rats, further studies are needed to determine which of the salt-induced increases in brain AT1 receptor densities contribute to the hypertension and which to other aspects of body homeostasis.     

Flavonoid-induced reduction of ENaC expression in the kidney of Dahl salt-sensitive hypertensive rat

Flavonoid, a plant extract, exhibits various biological actions. Dietary flavonoid intake is reported to reduce an elevated blood pressure, however the mechanism is unknown. The epithelial Na+ channel (ENaC) in the kidney plays a key role in the regulation of blood pressure by contributing to the Na+ reabsorption in renal tubules. Thus, we investigated the effect of quercetin, a flavonoid, on ENaC mRNA expression in the kidney of hypertensive Dahl salt-sensitive rats. Dahl salt-sensitive rats of 8 weeks were acclimated for 1 week in a metabolic cage and were subsequently kept for 4 weeks under four different conditions: (1) normal salt diet (0.3% NaCl), (2) normal salt diet with quercetin (10 mg/kg/day), (3) high-salt diet (8% NaCl), and (4) high-salt diet with quercetin. Quercetin diminished the alphaENaC mRNA expression in the kidney associated with reduction of the systolic blood pressure elevated by high-salt diet, suggesting that one of the mechanisms of the flavonoid's antihypertensive effect on salt-sensitive hypertension would be mediated through downregulation of ENaC expression in the kidney.     

Swimming training promotes cardiac remodeling and alters the expression of mRNA and protein levels involved in calcium handling in hypertensive rats

Aim

The aim of this study was to identify the effects of swimming training on the mRNA expression and protein levels of the calcium handling proteins in the hearts of renovascular hypertensive rats submitted to swimming protocol during 6 weeks.

Main methods

Fischer rats with renovascular hypertension 2-kidney 1-clip (2K1C) and SHAM groups were divided among sedentary and exercised groups. The exercise protocol lasted for 6 weeks (1 h/day, 5×/week), and the mean arterial pressure, cardiomyocytes hypertrophy parameters, mRNA expression and protein levels of some calcium handling proteins in the left ventricle were evaluated.

Key findings

Swimming training was able to reduce the levels of mean arterial pressure in the hypertensive group compared to 2K1C SED, and to promote cardiac hypertrophy in SHAM EX and 2K1C EX groups in comparison to the respective control groups. The mRNA levels of B-type natriuretic peptide were reduced in the 2K1C EX when compared to 2K1C SED. The mRNA and protein levels of the sarcoplasmic reticulum Ca^2 +-ATPase increased after the swimming training in SHAM and 2K1C groups. The mRNA and protein levels of phospholamban, displayed an increase in their levels in the exercised SHAM and in hypertensive rats in comparison to their respective controls; while mRNA levels of Na⁺/Ca^2 + exchanger was reduced in the left ventricle comparing to the sedentary hypertensive rats.

Significance

Taken altogether, we provide evidence that the aerobic training may lead to cardiac remodeling, and modulate the calcium handling proteins expression in the heart of hypertensive rats.     

Progesterone is not responsible for the blood pressure fall in late-pregnant New Zealand genetically hypertensive rats

In various models of experimental and genetic hypertension in rats, blood pressure is markedly reduced during late pregnancy. The period during which the blood pressure reduction occurs is also the period when plasma progesterone is maximally elevated, and administration of progesterone to renal hypertensive rats has been reported to reduce blood pressure (J. Armstrong, 1959, Proc. Soc. Exp. Biol. Med. 102:452-455). To test the possibility that elevated plasma progesterone is responsible for the blood pressure reduction in late pregnancy, on Day 14 of pregnancy a group of New Zealand genetically hypertensive (NZGH) rats was ovariectomized and implanted with progesterone-filled capsules, to maintain plasma progesterone at low levels just sufficient to maintain pregnancy, and compared with intact, pregnant NZGH. Ovariectomy did not alter the characteristic course of blood pressure reduction seen in late-pregnant intact NZGH rats. In addition, daily administration of progesterone (15 mg/kg, sc) for 14 days did not alter blood pressure of either nonpregnant NZGH rats or New Zealand normotensive rats with chronic 1-kidney, 1-clip hypertension. It is concluded that blood pressure of NZGH rats is reduced to near normotensive levels in late pregnancy, as reported for other models of rat hypertension, but that elevated plasma progesterone levels are not requisite for that reduction and do not reduce blood pressure of renal hypertensive rats.     

In vivo and in vitro magnesium effects on aortic prostacyclin generation in DOCA-salt hypertensive rats.

To investigate the blood pressure lowering effect of magnesium (Mg2+) in the hypertensive rat, we measured the prostacyclin release (PGI2, as immunoreactive 6-keto-PGF1 alpha) by isolated aortae from normotensive and deoxycorticosterone acetate (DOCA)-salt hypertensive rats fed a control or Mg(2+)-enriched diet. We also studied the in vitro effect of Mg2+ on aortic PGI2 release. The Mg(2+)-enriched diet significantly decreased by 10% blood pressure in DOCA-salt hypertensive rats but not in normotensive rats. The Mg(2+)-enriched diet significantly increased by 122% aortic PGI2 release in DOCA-salt hypertensive rats, but not in normotensive rats. Mg2+ supplementation in the incubation medium (4.8 mM) significantly increased aortic PGI2 release by 94% in DOCA-salt hypertensive rats, but not in normotensive rats. These data suggest that the Mg(2+)-induced attenuation of blood pressure in DOCA-salt hypertensive rats could be linked with the enhanced vascular PGI2 release.     

Thromboxane blockade reduces blood pressure and progression of renal failure independent of endothelin-1 in uremic rats

This study was designed to investigate the role of eicosanoids, thromboxane A2 (TXA2) and prostacyclin (PGI2) as well as their relationship with endothelin-1 (ET-1) in the pathogenesis of renal parenchymal hypertension. Uremic rats were prepared by renal mass ablation and compared with sham-operated controls. The stable metabolites of TXA2 (TXB2) and PGI2 (6-keto-PGF1alpha) and immunoreactive ET-1 concentrations were measured by specific RIAs in biological fluids and in vascular and renal tissues. To investigate the functional role of TXA2 in the progression of hypertension and renal failure, a group of uremic rats were treated with ridogrel (25 mg/kg/day), a TXA2 synthase inhibitor and receptor antagonist. Renal preproET-1 expression was assessed by Northern blot analysis. Systolic blood pressure (SBP), serum creatinine and proteinuria were found to be higher in uremic rats as compared to sham-operated controls (P < 0.01). TXB2 and ET-1 concentrations were increased in blood vessels, the renal cortex and in urine (P < 0.05). 6-keto-PGF1alpha concentrations were also increased in blood vessels and the renal cortex but decreased in urine (P < 0.05). Ridogrel significantly lowered SBP and proteinuria (P < 0.05) and blunted the increase of serum creatinine. Treatment with ridogrel resulted in a marked fall in vascular, renal and urine TXA2 concentrations, while ET-1 and 6-keto-PGF1alpha concentrations remained unchanged. The preproET-1 expression was higher in uremic rats than in the controls and was unaffected by ridogrel. These results suggest that TXA2 is involved in the pathogenesis of hypertension and renal failure progression in rats with subtotal 5/6 nephrectomy and that this effect is independent of the ET-1 system.     

Regional blood flows and cardiac hemodynamics in renovascular and mineralocorticoid hypertensive rats

Regional blood flows and cardiac hemodynamics were studied in 3 models of hypertensive rats: one-kidney DOC-saline, one-kidney, one-clip and two-kidney, one-clip hypertension and in normotensive control rats. All hypertensive models were characterized by increased peripheral vascular resistance and normal cardiac output. Coronary and cerebral blood flows varied among the hypertensive models but did not significantly differ from the normotensive rats. However, coronary blood flow of one-kidney, one-clip rats (8.4 +/- 1.3 ml X min-1 X g-1) was significantly higher than that of the two-kidney one-clip rats (6.5 +/- 1.2 ml X min.-1 X g-1, P less than 0.05). Cerebral blood flow of DOC-saline rats was lower than that of two-kidney one-clip or one-kidney one-clip renovascular rats. Renal blood flows of the unclipped kidney of two-kidney renovascular rats (3.77 +/- 0.85 ml X min-1 X g-1) and DOC-saline rats (2.95 +/- 0.83 ml X min-1 X g-1) were significantly lower than those of normotensive rats (5.92 +/- 1.16 ml X min-1 X g-1, P less than 0.05). In conclusion, although vascular resistance becomes elevated in all models of experimental hypertension, regional vascular resistance and blood flow distribution may differ depending on the vasoconstrictor mechanisms that participate in each model.     

Cyclooxygenase inhibition with acetylsalicylic acid unmasks a role for prostacyclin in erythropoietin-induced hypertension in uremic rats

We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosano?ds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.     

Role of the adenosine(2A) receptor-epoxyeicosatrienoic acid pathway in the development of salt-sensitive hypertension

Activation of rat adenosine(2A) receptors (A(2A) R) dilates preglomerular microvessels, an effect mediated by epoxyeicosatrienoic acids (EETs). High salt (HS) intake increases epoxygenase activity and adenosine levels. A greater vasodilator response to a stable adenosine analog, 2-chloroadenosine (2-CA), was seen in kidneys obtained from HS-fed rats which was mediated by increased EET release. Because this pathway is antipressor, we examined the role of the A(2A) R-EET pathway in a genetic model of salt-sensitive hypertension, the Dahl salt-sensitive (SS) rats. Dahl salt resistant (SR) rats fed a HS diet demonstrated a greater renal vasodilator response to 2-CA. In contrast, Dahl SS rats did not exhibit a difference in the vasodilator response to 2-CA whether fed normal salt (NS) or HS diet. In Dahl SR but not Dahl SS rats, HS intake significantly increased purine flux, augmented the protein expression of A(2A) R and cytochrome P450 2C23 and 2C11 epoxygenases, and elevated the renal efflux of EETs. Thus the Dahl SR rat is able to respond to HS intake by recruiting EET formation, whereas the Dahl SS rat appears to have exhausted its ability to increase EET synthesis above the levels observed on NS intake. In vivo inhibition of the A(2A) R-EET pathway in Dahl SR rats fed a HS diet results in reduced renal EETs levels, diminished natriuretic capacity and hypertension, thus supporting a role for the A(2A) R-EET pathway in the adaptive natriuretic response to modulate blood pressure during salt loading. An inability of Dahl SS rats to upregulate the A(2A) R-EET pathway in response to salt loading may contribute to the development of salt-sensitive hypertension.     

Neurogenic pulmonary edema induced by spinal cord injury in spontaneously hypertensive and Dahl salt hypertensive rats

Neurogenic pulmonary edema (NPE), which is induced by acute spinal cord compression (SCC) under the mild (1.5 %) isoflurane anesthesia, is highly dependent on baroreflex-mediated bradycardia because a deeper (3 %) isoflurane anesthesia or atropine pretreatment completely abolished bradycardia occurrence and NPE development in rats subjected to SCC. The aim of the present study was to evaluate whether hypertension-associated impairment of baroreflex sensitivity might exert some protection against NPE development in hypertensive animals. We therefore studied SCC-induced NPE development in two forms of experimental hypertension - spontaneously hypertensive rats (SHR) and salt hypertensive Dahl rats, which were reported to have reduced baroreflex sensitivity. SCC elicited NPE in both hypertensive models irrespective of their baroreflex sensitivity. It is evident that a moderate impairment of baroreflex sensitivity, which was demonstrated in salt hypertensive Dahl rats, does not exert sufficient protective effects against NPE development.