Apocynin but not L-arginine prevents and reverses dexamethasone-induced hypertension in the rat

BACKGROUND: Dexamethasone (Dex)-hypertension in rats is associated with increased oxidative stress. We investigated effects of the NAD(P)H oxidase inhibitor apocynin and the nitric oxide (NO) precursor L-arginine on Dex-hypertension to determine the relative roles of NAD(P)H oxidase and uncoupling in the reactive oxygen species (ROS) generation and hypertension. METHODS: Male Sprague-Dawley rats (n = 10/group) received Dex (20 microg/kg/day subcutaneously) or saline (vehicle) for 14 days. In a prevention study, rats received 4 days of apocynin treatement (1.5 mmol/L in drinking water) followed by Dex/saline for 12 days. In reversal studies, apocynin or L-arginine was given from day 8 to 14. Systolic blood pressure (SBP) was measured by tail cuff, and thymus weight was used as a marker of glucocorticoid activity. RESULTS: Administration of Dex increased SBP (104 +/- 3 to 122 +/- 3 mm Hg, P < .01, mean +/- SEM) and decreased thymus and body weight (P' < .05). Apocynin alone had no effect on SBP, BW, or thymus weight. Apocynin prevented (122 +/- 4 Dex, 111 +/- 3 mm Hg Apocynin+Dex, P' < .05) and reversed Dex-hypertension (130 +/- 4 to 116 +/- 4 mm Hg, P < .01). L-arginine did not reverse Dex-hypertension. CONCLUSIONS: In male SD rats, apocynin but not l-arginine prevented and reversed Dex-hypertension, suggesting that NAD(P)H oxidase-mediated superoxide production but not endothelial nitric oxide synthase uncoupling is important in Dex-hypertension.     

Aspirin prevents and partially reverses adrenocorticotropic hormone-induced hypertension in the rat

BACKGROUND: Glucocorticoid-induced hypertension is associated with increased oxidative stress. The aim of the present study was to investigate the effects of aspirin, a potent antioxidant, on adrenocorticotropic hormone (ACTH) and dexamethasone (Dex)-induced hypertension. METHODS: Male Sprague-Dawley (SD) rats were treated with saline, ACTH (0.2 mg/kg/d subcutaneously) or Dex (10 mug/rat/d subcutaneously). Aspirin (100 mg/kg/d in drinking water) was given 4 days before and during glucocorticoid-treatment (prevention studies). In reversal studies, saline, ACTH, or Dex was administered for 13 days and at day 8 (T8), rats were co-administered aspirin for 5 days. Systolic blood pressure (BP) was measured by the tail-cuff method. Thymus wet weight was measured as a marker of glucocorticoid activity and lucigenin-enhanced chemiluminescence as a marker of aortic superoxide production. RESULTS: Saline or aspirin alone did not change systolic BP. Systolic BP was increased by ACTH (mean +/- SEM; from 99 +/- 2 to 133 +/- 4 mm Hg, n = 10, P < .001) and Dex (from 102 +/- 3 to 125 +/- 5 mm Hg, n = 10, P < .001). Aspirin prevented the development of hypertension caused by ACTH (P' < .01) and tended to prevent Dex-induced hypertension (P' = .07). ACTH- but not Dex-induced hypertension was partially reversed by aspirin. Both ACTH and Dex decreased thymus weight. Aspirin had no effect on thymus weight. ACTH tended to increase lucigenin-enhanced chemiluminescence (P' = .07). Aspirin had no effect on this marker of tissue superoxide production. CONCLUSIONS: Aspirin prevented and partially reversed ACTH-induced hypertension in the SD rats.     

The anti-oxidant Tempol reverses and partially prevents adrenocorticotrophic hormone-induced hypertension in the rat

OBJECTIVE: To investigate the effects of the antioxidant Tempol on prevention and reversal of adrenocorticotrophic hormone (ACTH)-induced hypertension in the rat, a model of hypertension characterized by nitric oxide deficiency. METHODS: Male Sprague-Dawley rats (n = 10 in each group) were treated with either saline or ACTH (0.2 mg/kg per day, s.c.) for 12 days. Tempol (1 mmol/l in drinking water) treatment was started on either day 8 (T8) of ACTH or saline treatment (reversal study), or 4 days prior to ACTH or saline treatment (prevention study). Systolic blood pressure (SBP) was measured using tail-cuff sphygmomanometry. Plasma F2-isoprostanes, a marker of oxidative stress, were measured by gas chromatography-mass spectrometry. RESULTS: ACTH increased SBP (mean +/- SEM: 119 +/- 5 to 147 +/- 7 mmHg, P < 0.0005) and plasma F2-isoprostane concentration (8.4 +/- 1.2 saline versus 12.9 +/- 1.6 nmol/l ACTH, P < 0.05). Tempol alone did not alter SBP, but administration of Tempol on T8 reversed ACTH-induced hypertension (from 134 +/- 4 T8 to 118 +/- 3 mmHg, P < 0.005). Tempol pre-treatment partially prevented ACTH-induced hypertension (123 +/- 2 mmHg, P' < 0.05). However, Tempol had no effect on F2-isoprostane concentrations at the dose used in this study. CONCLUSIONS: ACTH-induced hypertension in the rat is associated with increased oxidative stress. Tempol treatment reversed, and pretreatment partially prevented ACTH-induced hypertension, independent of improvement in systemic oxidative stress.     

Role of tetrahydrobiopterin in adrenocorticotropic hormone-induced hypertension in the rat

Adrenocorticotropic hormone (ACTH)-induced hypertension in the rat is characterized by nitric oxide deficiency. Tetrahydrobiopterin (BH4) is an essential cofactor for the enzyme nitric oxide synthase and glucocorticoids have been reported to reduce cytokine-induced BH4 production. Accordingly we hypothesized that ACTH-induced hypertension would be reversed by BH4 supplementation. Male Sprague-Dawley rats (n = 33) were treated with BH4 in vehicle (10 mg/kg/day i.p.) or vehicle alone (5 mg/kg/day i.p. of ascorbic acid in 4 mM HCl) for 10 days. ACTH (0.2 mg/kg s.c.) or saline daily injection was started 2 days after BH4 or vehicle treatment and continued for 8 days. Systolic blood pressure (SBP) was measured on alternate days using the tail cuff method. Treatment with HCl, ascorbic acid or BH4 alone had no effect on SBP. In saline treated rats, neither BH4 nor its vehicle modified SBP. In ACTH treated rats, SBP was increased in both BH4 (from 128 +/- 6 to 142 +/- 4 mmHg, T0 to T10, P < 0.0005, one way ANOVA) and vehicle groups (from 127 +/- 3 to 158 +/- 7 mmHg, T0 to T10, P < 0.001, one way ANOVA). There was no significant difference in SBP between BH4 + ACTH treated and vehicle + ACTH treated rats. Thus, daily injection of BH4 (10 mg/kg i.p.) failed to prevent the development of ACTH-induced hypertension in rat.     

Lipopolysaccharide reverses adrenocorticotrophic hormone-induced hypertension in the rat.

Lipopolysaccharide (LPS) was used to stimulate nitric oxide (NO) release and investigate the effect of endogenous NO on adrenocorticotrophic hormone (ACTH)-induced hypertension in rats. After preliminary studies to determine the appropriate dose of LPS, 40 male Sprague-Dawley rats were treated with ACTH (200 microg/kg/day, s.c.) or saline (sham) for 8 days and then given a single dose of LPS (10 mg/kg, i.p.) or saline. ACTH treatment was continued for a further 5 days. Systolic blood pressure (SBP) was measured daily using the tail cuff method. Results were expressed as the mean +/- SEM. ACTH treatment significantly increased SBP (from 105 +/- 3 to 129 +/- 4 mmHg; p<0.05), whereas saline had no effect on SBP. The ACTH-induced increase in SBP was reversed by LPS injection (from 125 +/- 6 to 102 +/- 7 mmHg; p<0.05). SBP was also decreased in sham + LPS-treated rats compared with that of sham + saline-treated rats (p<0.05), but the SBP change in response to LPS was greater in ACTH-treated than in sham-treated rats (-23 vs. -8 mmHg; p<0.05). These data are compatible with the notion that reduced NO availability plays a role in ACTH-induced hypertension.     

Folic acid prevents and partially reverses glucocorticoid-induced hypertension in the rat

BACKGROUND: To investigate the effect of folic acid on the increased pressure in rats treated with either adrenocorticotropic hormone (ACTH) or dexamethasone (Dex), and to further investigate the role of tetrahydrobiopterin (BH(4)) in any effect of folic acid by comparing the effect of BH(4) with that of folic acid in Dex hypertension. METHODS: Male Sprague-Dawley (SD) rats were treated with saline, subcutaneous ACTH (0.2 mg/kg/d) or Dex (10 microg/rat/d). Folic acid (0.04 g/L drinking) or BH(4) (10 mg/kg/d intraperitoneally) was started before (prevention) and during (reversal) glucocorticoid treatment. RESULTS: Saline, BH(4), vehicle for BH(4), or folic acid alone did not change systolic blood pressure (BP). Systolic BP was increased by ACTH and Dex. Folic acid, but not BH(4), prevented the development of hypertension caused by ACTH and Dex treatment. The ACTH and Dex hypertension were partially reversed by folic acid. The BH(4) increased plasma total biopterin concentrations. The Dex decreased plasma NOx concentrations but had no effect on plasma biopterin concentrations. The ACTH and Dex increased plasma F(2)-isoprostane concentrations and decreased serum homocysteine concentrations compared with control but had no effect on serum folate concentrations. Folic acid increased serum folate concentrations compared with control but had no effect on homocysteine concentrations. CONCLUSIONS: Folic acid prevented and partially reversed both ACTH and Dex hypertension in rats without modifying the increase in plasma F(2)-isoprostane concentrations. Given that BH(4) failed to prevent ACTH or Dex hypertension, folic acid is unlikely to be acting through increased BH(4) production. The precise mechanism for the BP-lowering effect of folic acid in this model of hypertension remains to be determined.     

The antioxidant tempol prevents and partially reverses dexamethasone-induced hypertension in the rat

BACKGROUND: Many forms of hypertension are associated with increased oxidative stress. This study investigated the effects of Tempol, a superoxide scavenger, on prevention and reversal of hypertension induced by the synthetic glucocorticoid dexamethasone (Dex) in the rat. METHODS: Male Sprague-Dawley rats (n = 10 in each group) were treated with saline or Dex (10 microg/kg/day subcutaneously) for 13 days. Tempol (1 mmol/L) was given in drinking water from 4 days before treatment (prevention) or from treatment day 8 (T8) (reversal). Systolic blood pressure (SBP) was measured by the tail-cuff method. Plasma F(2)-isoprostane concentrations were measured as a highly specific marker of oxidative stress. Thymus weight was measured as a marker of glucocorticoid activity. RESULTS: Dex treatment increased SBP (122 +/- 5 to 136 +/- 3 mm Hg, P <.05) and plasma F(2)-isoprostane concentrations (P =.005). Tempol alone did not alter SBP, but Tempol pretreatment prevented Dex-induced hypertension compared with that in rats treated with Dex alone (128 +/- 4 and 144 +/- 7 mm Hg respectively, P' <.05). Tempol partially reversed Dex-induced hypertension (122 +/- 5 and 136 +/- 3 mm Hg, respectively, P' =.057). Thymus weight was decreased in Dex-treated rats compared with saline treated rats (157 +/- 10 saline and 105 +/- 6 mg/100 g body weight Dex, P <.0005). Tempol affect neither thymus weight nor F(2)-isoprostane concentrations. CONCLUSIONS: Chronic Dex treatment increased SBP and tended to increase oxidative stress shown as increased plasma F(2)-isoprostane concentrations. Tempol prevented and partially reversed Dex-induced hypertension, independent of improvement in systemic oxidative stress measured by F(2)-isoprostane concentrations.     

Dehydroepiandrosterone (DHEA) prevents and reverses chronic hypoxic pulmonary hypertension

Pulmonary artery (PA) hypertension was studied in a chronic hypoxic-pulmonary hypertension model (7-21 days) in the rat. Increase in PA pressure (measured by catheterism), cardiac right ventricle hypertrophy (determined by echocardiography), and PA remodeling (evaluated by histology) were almost entirely prevented after oral dehydroepiandrosterone (DHEA) administration (30 mg/kg every alternate day). Furthermore, in hypertensive rats, oral administration, or intravascular injection (into the jugular vein) of DHEA rapidly decreased PA hypertension. In PA smooth muscle cells, DHEA reduced the level of intracellular calcium (measured by microspectrofluorimetry). The effect of DHEA appears to involve a large conductance Ca2+-activated potassium channel (BKCa)-dependent stimulatory mechanism, at both function and expression levels (isometric contraction and Western blot), via a redox-dependent pathway. Voltage-gated potassium (Kv) channels also may be involved because the antagonist 4-amino-pyridine blocked part of the DHEA effect. The possible pathophysiological and therapeutic significance of the results is discussed.     

N-acetylcysteine antagonizes the development but does not reverse ACTH-induced hypertension in the rat

We investigated the effect of antioxidant N-acetylcysteine (NAC) on adrenocorticotropic hormone (ACTH)-hypertension. Male Sprague-Dawley rats received NAC (10 mg/L) or water 4 days before ACTH/saline treatment for 13 days (prevention study). In a reversal study, NAC commenced on day 8 of ACTH/saline treatment and continued for 5 days. ACTH increased systolic blood pressure (SBP) in water drinking rats (111 +/- 1 to 131 +/- 3 mmHg, p < 0.001). In the prevention study, NAC + ACTH increased SBP (108 +/- 2 to 120 +/- 2 mmHg, p < 0.001) but less than ACTH alone (p' < 0.05). In the reversal study, NAC had no significant effect (132 +/- 4 to 124 +/- 3 mmHg, ns). Thus, NAC partially prevented but did not reverse ACTH-induced hypertension.     

Apocynin is not an inhibitor of vascular NADPH oxidases but an antioxidant

A large body of literature suggest that vascular reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species. Many studies, however, relied on data obtained with the inhibitor apocynin (4'-hydroxy-3'methoxyacetophenone). Because the mode of action of apocynin, however, is elusive, we determined its mechanism of inhibition on vascular NADPH oxidases. In HEK293 cells overexpressing NADPH oxidase isoforms (Nox1, Nox2, or Nox4), apocynin failed to inhibit superoxide anion generation detected by lucigenin chemiluminescence. In contrast, apocynin interfered with the detection of reactive oxygen species in assay systems selective for hydrogen peroxide or hydroxyl radicals. Importantly, apocynin interfered directly with the detection of peroxides but not superoxide, if generated by xanthine/xanthine oxidase or nonenzymatic systems. In leukocytes, apocynin is a prodrug that is activated by myeloperoxidase, a process that results in the formation of apocynin dimers. Endothelial cells and smooth muscle cells failed to form these dimers and, therefore, are not able to activate apocynin. Dimer formation was, however, observed in Nox-overexpressing HEK293 cells when myeloperoxidase was supplemented. As a consequence, apocynin should only inhibit NADPH oxidase in leukocytes, whereas in vascular cells, the compound could act as an antioxidant. Indeed, in vascular smooth muscle cells, the activation of the redox-sensitive kinases p38-mitogen-activate protein kinase, Akt, and extracellular signal-regulated kinase 1/2 by hydrogen peroxide and by the intracellular radical generator menadione was prevented in the presence of apocynin. These observations indicate that apocynin predominantly acts as an antioxidant in endothelial cells and vascular smooth muscle cells and should not be used as an NADPH oxidase inhibitor in vascular systems.     

Heart rate reduction with ivabradine prevents thyroid hormone-induced cardiac remodeling in rat

Ivabradine slows the heart rate (HR) by selectively inhibiting the I(f) current in the sinus node without a negative inotropic effect. We aimed to investigate the effects of ivabradine on thyroid hormone-induced left ventricular (LV) remodeling and ion channel activity in rats. Thirty Sprague–Dawley rats were randomly selected into the groups of control, injection of l-thyroxine (T₄, 100 μg/kg/day), and injection of l-thyroxine with ivabradine (T₄-Iva, T₄ + 10 mg/kg/day). Circumferential (S _circ), radial (S _rad), and longitudinal (S _long) strains were assessed by speckle tracking echocardiography (STE). Myocardial width and fibrosis were assessed from histological LV cross sections, and electrophysiological analysis was done by patch clamp method. In comparison with the control group, the T₄ group showed significantly increased HR and LV end-systolic diameter (LVESD), reduced S _circ (?16.04 ± 3.95 vs. ?7.84 ± 2.98 %, p < 0.001), S _rad (20.94 ± 3.81 vs. 40.57 ± 6.70 %, p < 0.001), and S _long (?15.26 ± 5.15 vs. ?23.83 ± 5.19 %, p < 0.001), despite the 59.5 % increase of average I _Ca,L density at 0 mV (13.4 ± 1.2 pA/pF) compared to control group (8.4 ± 0.8 pA/pF). Treatment with ivabradine significantly reduced HR and LVESD, improved SR_circ, S _long and SR_long in the T₄ group, and the average I _Ca,L density at 0 mV in T₄-Iva groups (9.9 ± 1.6 pA/pF) was restored to the control level. Morphologically, the T₄ group showed significantly increased cardiomyocyte width (25.3 ± 1.89 vs. 18.90 ± 1.14 μm in control, p < 0.001) and fibrosis, which were not significantly changed by ivabradine. In conclusion, selective HR reduction by ivabradine attenuates thyroid hormone-induced reduction of myocardial deformation and altered intracellular Ca²⁺ handling without modification of the myocyte hypertrophy with fibrosis in rats.     

Cryoblockade of the ventromedial frontal cortex reverses hypertension in the rat

The anteroventral part of the hypothalamus adjacent to the third ventricle (AV3V) has been implicated in electrolytic lesion studies as a site crucial to the development and maintenance of hypertension. Cryoblockade is known to alter synaptic and axonal transmission differently at different temperatures. In this study, cooling of the hypothalamus, including the AV3V area, to the temperature known to block only synaptic function did not alter blood pressure in two different models of experimental hypertension in the rat. Cooling sufficient to block both synaptic and axonal transmission, however, reduced blood pressure elevations to near normotensive levels. Synaptic cryoblockade in the ventromedial portion of the frontal cortex lowered experimental hypertension by 21 +/- 3 mm Hg (p less than 0.05). In normotensive controls, blood pressure was not altered by cryoblockade in either the frontal cortex or hypothalamus. Anatomical evidence provided by others shows that cells in the ventromedial frontal cortex project, in part, through the AV3V region to the brainstem cardioregulatory structures. These results indicate that neural activity arising in frontal cortex is axonally projected through the hypothalamus to maintain elevated blood pressure in experimental hypertension.     

Filipin prevents and reverses insulin stimulation of rat adipocyte phosphodiesterase.

A membrane fraction prepared from isolated rat adipocytes contained an insulin-sensitive cyclic nucleotide phosphodiesterase (EC 3.1.4.17) which catalyzed the hydrolysis of both adenosine 3',5'-monophosphate (cAMP) and guanosine 3',5'-monophosphate (cGMP). The rate of hydrolysis of cGMP was about one-third that of cAMP. The hydrolysis of the two nucleotides appeared to be assoicated with one catalytic site: one nucleotide interfered with the hydrolysis of the other, in a manner predictable from the kinetic constants in that the Km of one nucleotide as a substrate was comparable to its Ki as an inhibitor of the hydrolysis of the other nucleotide. Incubation of the adipocytes with insulin increased the Vmax of phosphodiesterase without affecting the Km values for either substrate. After adipocytes had been treated with filipin, a membrane perturbant, at a concentration that did not cause cell lysis, the response of phosphodiesterase to insulin was obliterated. Further, the insulin-stimulated phosphodiesterase activity was reversed when hormone-treated cells were subsequently incubated with this agent. These results suggest that the response of membrane phosphodiesterase to insulin is impaired once adipocytes have been exposed to filipin, either preceding or following the incubation with insulin.     

L-arginine partially reverses established adrenocorticotrophin-induced hypertension and nitric oxide deficiency in the rat

BACKGROUND: L-arginine treatment prevents adrenocorticotrophin (ACTH) induced hypertension in the rat. This study examined whether L-arginine treatment could reverse established ACTH hypertension and its effects on markers of decreased NO activity. METHODS: Sixty-four male Sprague-Dawley rats were randomly divided into 6 groups given 12 days of treatment: (1) sham (0.9% NaCl, 0.5 ml/kg, subcutaneously, sc, n = 16); (2) ACTH (0.5 mg/kg/day, sc, n = 16); (3) sham + L-arginine (0.6% in food, from treatment day 8 onwards, n = 10); (4) ACTH + L-arginine (n = 10); (5) sham + D-arginine (0.6% in food, from T 8 onwards) (n = 6); and (6) ACTH + D-arginine (n = 6). Systolic blood pressure, water intake, urine volume, and body weight were measured every second day. At the end of the experiments, plasma and urinary nitrate/nitrite (NOx), plasma amino acid concentrations (in groups 1-4), and urinary cyclic guanosine monophosphate (cGMP) concentrations were measured. RESULTS: Sham, sham + L-arginine, and sham + D-arginine treatments did not affect blood pressure. ACTH increased systolic blood pressure (from 121 +/- 1 to 147 +/- 2 mmHg, p < 0.001, pooled control vs treatment day 12, mean +/- sem), and this was partially reversed by L-arginine (group 4: from 141 +/- 2 on day 8 to 133 +/- 1 mmHg on day 12, n = 10, p < 0.001). In contrast, D-arginine did not affect blood pressure in ACTH-treated rats (group 6). ACTH increased water intake and urine volume and decreased body weight, and L-arginine administration did not alter these parameters. ACTH decreased plasma citrulline (group 1 vs 2: 115 +/- 7 vs 67 +/- 6 micro M/L, n = 16, p < 0.001) and NOx concentrations (group 1 vs 2: 8.3 +/- 0.8 vs 4.5 +/- 0.6 microM/L, n= 10, p < 0.001) and these decreases were reversed by L-arginine treatment (group 4: citrulline 98 +/- 9 micro M/L, NOx 9.1 +/- 1.6 micro M/L, group 2 vs 4, both p < 0.05). ACTH produced marked increases in urinary cGMP excretion (group 1 vs 2: 0.5 +/- 0.1 vs 1.9 +/- 0.4 nmol/24 h, p < 0.01). CONCLUSION: Supplementation with L-arginine partly reversed established ACTH-induced hypertension and restored plasma NOx and citrulline concentrations to levels seen in sham-treated rats. These data are consistent with previous studies suggesting that functional NO deficiency has a role in ACTH-induced hypertension in rats.     

Alteration in relaxation of atypical beta-adrenergic but not beta-3 receptors in arterial hypertension in the rat

The aim of this study was to investigate the involvement of beta 3-adrenoceptors (beta 3-AR) in hypertension. Aortic rings were isolated from 12 weeks old WKY (Wistar-Kyoto) and SHR (spontaneously hypertensive rat) rats. Rings were placed in organ baths and constricted with phenylephrine. Then, cumulative concentration-relaxation curves to the beta 3-AR agonists were constructed. In both strains, SR58611, a preferential beta 3-agonist, produced similar concentration-dependent relaxation. CGP 12177 (CGP), (a partial beta 3-AR and atypical beta-AR agonist with beta 1-/beta 2-AR antagonistic properties) produced similar relaxation in WKY (pD2 = 5.10 +/- 0.06; Emax = 54 +/- 2%; n = 6) and in SHR (pD2 = 4.98 +/- 0.02; Emax = 58 +/- 4%; n = 6). In WKY, relaxant response to CGP was not modified by nadolol (10 microM) or L-748.337 (3 microM) suggesting an atypical beta-AR activation. By contrast, in SHR, the effect of CGP was strongly decreased by 3 microM L-748.337 (Emax = 27.8 +/- 5.4%; n = 7; p < 0.05 vs CGP alone), suggesting a possible participation of beta 3-AR in CGP-induced relaxation. In order to investigate the role of endothelium in CGP-induced relaxation, experiments were performed in denuded aortic rings. In WKY, CGP-induced relaxation was not modified by endothelium removal, by contrast, this was greatly inhibited in SHR (Emax = 18.3 +/- 1.9%; n = 9; p < 0.05 vs CGP in intact aortic rings). Endothelium-independent relaxation to CGP was resistant to nadolol or L-748.337 treatment which seems to rule out the involvement of beta 1, beta 2 and beta 3-AR. Endothelium-independent relaxation to CGP was significantly reduced by SQ 22536 or MDL 12330A, non-selective adenylyl cyclase inhibitors, indicating a role of cAMP-dependent pathway in CGP response. By contrast, the relaxant effect to CGP was not modified by SQ 22536 in SHR. In conclusion, these results show that [1] functional response to beta 3-AR stimulation was not altered in hypertension [2]. CGP activated an atypical beta-AR distinct from beta 1, beta 2 and beta 3-AR, partly through cAMP-dependent pathway. Impaired atypical beta-AR relaxation to CGP in SHR could contribute to the pathogenesis of the hypertension.     

Leptin antagonist reverses hypertension caused by leptin overexpression, but fails to normalize obesity-related hypertension

OBJECTIVE: The present study employed a rat leptin antagonist to evaluate the role of elevated leptin in obesity-associated hypertension. METHODS: First, leptin was overexpressed in the hypothalamus of lean rats for 155 days through the administration of a recombinant adeno-associated viral-mediated central vector-encoding leptin. Then a leptin antagonist was infused intracerebroventricularly for 14 days. In a second experiment, rats were fed with a high-fat diet or chow for 5 months, then the leptin antagonist was infused intracerebroventricularly for 14 days. RESULTS: Hypothalamic overexpression of leptin elevated blood pressure by 18 mmHg, but 14-day central infusion of the leptin antagonist reversed leptin-induced hypertension. High-fat feeding increased blood pressure (by approximately 8-9 mmHg) and tyrosine hydroxylase activity (by 76%) in superior cervical ganglia compared with chow feeding. Leptin antagonist infusion accelerated weight gain, food intake, and adiposity in high-fat-fed rats compared with chow-fed rats, and tyrosine hydroxylase activity was also reversed in the superior cervical ganglia. Elevated mean arterial pressure was not affected, although there was a small decrease in heart rate in both chow and high-fat-fed groups. CONCLUSION: Central overexpression of leptin leads to hypertension that can be reversed by a leptin antagonist. In contrast, this leptin antagonist does not reverse the high-fat feeding-induced elevation of blood pressure, even though there is apparent blockade of other leptin-mediated metabolic and sympatho-excitatory responses.     

Misoprostol but not antacid prevents endotoxin-induced gastric mucosal injury

Many of the complications of septic shock are believed to be a consequence of elevated circulating levels of tumor necrosis factor (TNF), which is an important mediator of tissue injury. Prostaglandins (PGs) of the E series have recently been reported to inhibit TNF production in vitro. We investigated the in vivo effect of misoprostol, a PGE1 analog, on endotoxin-induced gastric mucosal injury and TNF production. For the gastric mucosal injury studies, groups of animals were pretreated with intragastric misoprostol (100 and 200 micrograms/kg) or with antacid (2 ml/animal of Maalox Plus) 30 min prior to a challenge with intravenous E. coli lipopolysaccharide (LPS) at 5.0 mg/kg. Stomachs were examined 3 hr after LPS. Systemic endotoxin alone induced microscopic edema, vascular congestion, and polymorphonuclear (PMN) infiltration of the gastric mucosa. Pretreatment with misoprostol, but not with antacid, significantly and dose-dependently reduced the gastric mucosal injury. For the TNF studies, groups of rats were given either misoprostol (100 or 200 micrograms/kg, intragastric), or saline 1 hr prior to LPS challenge. Serum samples were obtained 1.5 hr after LPS challenge. Misoprostol dose-dependently and significantly (P less than 0.01) inhibited TNF activity. We conclude that misoprostol is a potent inhibitor of TNF systemic production and inhibits the gastric mucosal injury induced by endotoxemia. These studies suggest a potentially important therapeutic role for misoprostol in inflammatory diseases in which TNF exerts a contributory role.     

Genistein, a soy phytoestrogen, reverses severe pulmonary hypertension and prevents right heart failure in rats

Pretreatment with a phytoestrogen genistein has been shown to attenuate the development of pulmonary hypertension (PH). Because PH is not always diagnosed early, we examined whether genistein could also reverse preexisting established PH and prevent associated right heart failure (RHF). PH was induced in male rats by 60 mg/kg of monocrotaline. After 21 days, when PH was well established, rats received daily injection of genistein (1 mg/kg per day) for 10 days or were left untreated to develop RHF by day 30. Effects of genistein on human pulmonary artery smooth muscle cell and endothelial cell proliferation and neonatal rat ventricular myocyte hypertrophy were assessed in vitro. Severe PH was evident 21 days after monocrotaline, as peak systolic right ventricular pressure increased to 66.35±1.03 mm Hg and right ventricular ejection fraction reduced to 41.99±1.27%. PH progressed to RHF by day 30 (right ventricular pressure, 72.41±1.87 mm Hg; RV ejection fraction, 29.25±0.88%), and mortality was ≈75% in RHF rats. Genistein therapy resulted in significant improvement in lung and heart function as right ventricular pressure was significantly reduced to 43.34±4.08 mm Hg and right ventricular ejection fraction was fully restored to 65.67±1.08% similar to control. Genistein reversed PH-induced pulmonary vascular remodeling in vivo and inhibited human pulmonary artery smooth muscle cell proliferation by ≈50% in vitro likely through estrogen receptor-β. Genistein also reversed right ventricular hypertrophy (right ventricular hypertrophy index, 0.35±0.029 versus 0.70±0.080 in RHF), inhibited neonatal rat ventricular myocyte hypertrophy, and restored PH-induced loss of capillaries in the right ventricle. These improvements in cardiopulmonary function and structure resulted in 100% survival by day 30. Genistein restored PH-induced downregulation of estrogen receptor-β expression in the right ventricle and lung. In conclusion, genistein therapy not only rescues preexisting severe PH but also prevents the progression of severe PH to RHF.