The role of corticosterone in corticotrophin (ACTH)-induced hypertension in the rat

OBJECTIVE: Corticotrophin (ACTH)-induced hypertension in the rat is prevented by L- but not D-arginine. We examined the effects of exogenous corticosterone in the male Sprague Dawley (SD) rat to determine whether ACTH-induced hypertension is mediated by corticosterone. METHODS: Exogenous corticosterone (10, 20 or 40 mg/kg per day) or sham (polyethylene glycol (PEG) 1 ml/kg per day) was injected subcutaneously in divided doses (s/c b.d.) over 15 treatment days to 40 SD rats (n = 10 each group). Subsequently, the effects of L-arginine, D-arginine or L-arginine + N-nitro-L-arginine (NOLA) on corticosterone-induced hypertension (corticosterone 20 mg/kg per day) were examined. Systolic blood pressure (SBP) and metabolic parameters were measured every two days. RESULTS: Twenty and 40 mg/kg per day of corticosterone increased SBP compared with sham (P< 0.01, P< 0.05 respectively, sham versus respective group). Forty mg/kg per day of corticosterone raised serum corticosterone concentration compared with sham (502 +/- 20 versus 364 +/- 25 ng/ml, P < 0.001). L-arginine prevented the rise in SBP produced by corticosterone (131 +/- 3 to 131 +/- 2 mmHg, control versus day 10) but D-arginine did not (129 +/- 3 to 142 +/- 4 mmHg on day 8, P < 0.01). NOLA blocked the effect of L-arginine and amplified the rise in blood pressure produced by corticosterone (130 +/- 3 to 171 +/- 6 mmHg on day 10, P < 0.001). CONCLUSIONS: The haemodynamic features of ACTH-induced hypertension were reproduced by corticosterone excess, at concentrations of corticosterone similar to those in studies of exogenous ACTH administration. It is likely that ACTH-stimulated adrenal production of corticosterone accounts for the features of ACTH-induced hypertension in the 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.     

Apocynin but not allopurinol prevents and reverses adrenocorticotropic hormone-induced hypertension in the rat

BACKGROUND: Adrenocorticotropic hormone (ACTH)-induced hypertension in the rat is accompanied by increased oxidative stress. This study examines the enzymatic source of reactive oxygen species in ACTH-hypertension. METHODS: Male Sprague-Dawley rats were divided into 10 groups of 10-20 rats per group. The NAD(P)H oxidase inhibitor apocynin (1.5 mmol/L in drinking water) or the xanthine oxidase inhibitor allopurinol (200 mg/kg/day via food) were administered daily. After 4 days, rats were co-administered ACTH (0.2 mg/kg/day) or saline by subcutaneous injection daily for 11 days (prevention study). In a reversal study, ACTH/saline was administered for 13 days and from day 8, apocynin or allopurinol was added for 5 days. Systolic blood pressure (SBP) was measured by the tail-cuff method and oxidative stress using plasma F2-isoprostane concentrations. Results were expressed as mean+/-SEM. RESULTS: ACTH increased SBP (P<.001) but apocynin or allopurinol alone had no effect. Apocynin (but not allopurinol) co-treatment prevented (142+/-3 ACTH, 120+/-4 mm Hg apocynin+ACTH, P'<0.001) and reversed ACTH-induced hypertension (133+/-4 to 118+/-5 mm Hg, P<.05). Plasma F2-isoprostane concentrations were increased in ACTH-treated rats compared with saline (11.9+/-1.0 vs 8.2+/-0.8 nmol/L, P<.01), and apocynin attenuated the ACTH-induced rise in plasma F2-isoprostane concentrations. Serum urate concentrations were undetectable in 75% of rats treated with allopurinol and were not affected by ACTH. CONCLUSIONS: Apocynin but not allopurinol prevented and reversed ACTH-induced hypertension in the rat. These results suggest superoxide production through NAD(P)H oxidase plays a role in ACTH-induced hypertension.     

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.     

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.     

Effect of local delivery of L-arginine on in-stent restenosis in humans

To determine whether intramural administration of L-arginine reduces intimal thickening after optimal Palmaz-Schatz stent deployment in humans, 50 patients with native coronary artery disease who received a single Palmaz-Schatz stent were enrolled in this pilot study. Patients were randomized into 2 treatment groups: an L-arginine group (n = 25) and a saline group (n = 25). After stent deployment, L-arginine (600 mg/6 ml) or saline (6 ml) was locally delivered via the Dispatch catheter (Scimed) over 15 minutes. Serial angiography and intravascular ultrasound examinations (motorized pull-back at 0.5 mm/s) were performed before and after the procedure, and at 6-month follow-up. Measurements of stent area, lumen area, and neointimal area were computed within the stents at 1-mm intervals, by technicians who were blinded to the treatment assignment. Using Simpson's rule, stent, plaque, and lumen volumes, neointimal volume within the stent, and percent neointimal volume were measured before and after the procedure, and at 6-month follow-up. The 6-month volume data in quantitative coronary ultrasound showed that neointimal volume in the L-arginine group was significantly less than in the saline group (25 vs 39 mm(3); p = 0.049). Similarly, percent neointimal volume was significantly less in the L-arginine group at 6-month follow-up (17 +/- 13% vs 27 +/- 21%; p = 0.048). Thus, these results showed that local delivery of L-arginine reduces in-stent neointimal hyperplasia in humans, indicating that this approach may be a novel strategy to prevent in-stent restenosis.     

Circadian blood pressure variability in adrenocorticotrophin-induced hypertension in the rat

OBJECTIVES: Secondary hypertension is often characterized by loss of diurnal blood pressure variability. This study examined circadian (24 h) blood pressure variability in adrenocorticotrophin (ACTH)-induced hypertension in the Sprague-Dawley rat. METHODS: Male Sprague-Dawley rats were randomly allocated to sham (0.9% saline, s.c.), n = (9), ACTH (0.5 microg/kg per day, s.c., n = 8) or ACTH (100 microg/kg per day, s.c., n = 7) in a room with a 12 h light/dark cycle (0600 h to 1800 h). A radio telemetry transducer was used to measure blood pressure in unrestrained animals over 3 control days (C1-C3) and 10 treatment days (T1-T10). Heart rate, systolic (SBP), mean arterial (MAP) and diastolic (DBP) blood pressure were continuously recorded. Body weight was measured daily and serum corticosterone concentration ([B]) prior to death. RESULTS: Sham treatment had no effect on any parameters. ACTH 100 microg/kg per day increased SBP from 124+/-2 pooled control (PC) to 134+/-2 mmHg (T10), MAP from 105+/-2 to 115+/-2 mmHg and DBP from 87+/-1 to 99+/-2 mmHg and decreased heart rate from 305+/-6 to 249+/-5 beats/min and body weight from 299+/-6 (C3) to 280+/-8 g (T10) (all P' < 0.0036). Serum [B] was higher in ACTH- (881+/-44 ng/ml) than sham-treated rats (384+/-17 ng/ml, P < 0.001). There were no differences between sham treatment and ACTH 0.5 microg/kg per day. SBP, MAP, DBP and heart rate were consistently higher for ACTH 100 microg/kg per day and sham-treated animals during the dark cycle (1800 h to 0600 h) than the light cycle (0600 h to 1800 h). CONCLUSIONS: ACTH 100 microg/kg per day raises blood pressure in conscious unrestrained Sprague-Dawley rats without any change in normal diurnal rhythm.     

L-arginine reverses severe nephrosclerosis in aged spontaneously hypertensive rats

OBJECTIVE: Acute and prolonged effects of L-arginine on systemic and renal hemodynamics and on renal pathological changes were examined in 85-week-old spontaneously hypertensive rats (SHR). RESULTS: After 3 weeks of L-arginine administration (n = 9; 2 g/l in drinking water), mean arterial pressure remained unchanged, although the cardiac index increased (187 +/- 26 versus 263 +/- 15 ml/min per kg; P < 0.05) and total peripheral resistance decreased (1.15 +/- 0.18 versus 0.67 +/- 0.06 AU; P < 0.05); the glomerular filtration rate increased (0.41 +/- 0.07 versus 0.79 +/- 0.07 ml/min; P < 0.01). Control untreated, aged SHR (n = 10) demonstrated severe nephrosclerosis histologically, but those treated with L-arginine demonstrated a markedly reduced glomerular injury score (164 +/- 22 versus 83 +/- 9; P < 0.005), and their urinary protein excretion (39 +/- 5 versus 19 +/- 5 mg/100 g body weight per day; P < 0.05) and serum creatinine concentration (1.4 +/- 0.1 versus 0.9 +/- 0.1 mg/dl; P < 0.05) diminished. Intravenous L-arginine (300 mg/kg body weight) given to untreated SHR reduced mean arterial pressure, increased the cardiac index (+98 versus +1%; P < 0.05) and decreased total peripheral resistance (+56 versus +13%, P < 0.005); however, these variables remained unchanged after 3 weeks of L-arginine treatment. CONCLUSIONS: Three weeks of treatment with L-arginine improved systemic hemodynamics, renal function and renal histologic changes in aged SHR with naturally occurring nephrosclerosis. These data provide an important insight into the pathophysiology of nephrosclerosis in hypertension and with aging, which is seen clinically.     

AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin II-dependent hypertension

Angiotensin (Ang) II-infused hypertensive rats exhibit increases in renal angiotensinogen mRNA and protein, as well as urinary angiotensinogen excretion in association with increased intrarenal Ang II content. The present study was performed to determine if the augmentation of intrarenal angiotensinogen requires activation of Ang II type 1 (AT1) receptors. Male Sprague-Dawley rats (200 to 220 g) were divided into 3 groups: sham surgery (n=10), subcutaneous infusion of Ang II (80 ng/min, n=11), and Ang II infusion plus AT1 blocker (ARB), olmesartan (5 mg/d, n=12). Ang II infusion progressively increased systolic blood pressure (SBP) compared with sham (178+/-8 mm Hg versus 119+/-4 at day 11). ARB treatment prevented hypertension (113+/-6 at day 11). Twenty-four-hour urine collections were taken at day 12, and plasma and tissue samples were harvested at day 13. The Ang II+ARB group had a significant increase in plasma Ang II compared with Ang II and sham groups (365+/-46 fmol/mL versus 76+/-9 and 45+/-14, respectively). Nevertheless, ARB treatment markedly limited the enhancement of kidney Ang II by Ang II infusion (65+/-17 fmol/g in sham, 606+/-147 in Ang II group, and 288+/-28 in Ang II+ARB group). Ang II infusion significantly increased kidney angiotensinogen compared with sham (1.69+/-0.21 densitometric units versus 1.00+/-0.17). This change was reflected by increased angiotensinogen immunostaining in proximal tubules. ARB treatment prevented this increase (1.14+/-0.12). Urinary angiotensinogen excretion rates were enhanced 4.7x in Ang II group (4.67+/-0.41 densitometric units versus 1.00+/-0.21) but ARB treatment prevented the augmentation of urinary angiotensinogen (0.96+/-0.23). These data demonstrate that augmentation of intrarenal angiotensinogen in Ang II-infused rats is AT1-dependent and provide further evidence that urinary angiotensinogen is closely linked to intrarenal Ang II in Ang II-dependent hypertension.     

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.     

Effects of L-arginine on forearm vessels and responses to acetylcholine.

This study was designed to investigate the effects of L-arginine (the substrate of endothelium-derived nitric oxide) in human forearm vessels. We examined whether intra-arterial infusion of L-arginine dilated forearm vessels and augmented vasodilatory responses to acetylcholine in young, healthy humans. The left brachial artery was cannulated for drug infusions and direct measurement of arterial pressure. Forearm blood flow was measured by a strain gauge plethysmograph. Intra-arterial infusions of L-arginine at 10, 20, 40, and 60 mg/min increased forearm blood flow from 4.7 +/- 0.6 to 4.9 +/- 0.5, 5.7 +/- 0.5, 7.2 +/- 0.8, and 8.2 +/- 0.9 ml.min-1.100 ml-1, respectively (n = 8, p less than 0.01), whereas D-arginine at the same doses did not alter forearm blood flow (n = 7). Intra-arterial infusions of acetylcholine (n = 7) (4, 8, 16, and 24 micrograms/min) and sodium nitroprusside (n = 5) (0.2, 0.4, 0.8, and 1.2 micrograms/min) increased forearm blood flow dose dependently (p less than 0.01 for both). Arterial pressure was not altered with infusions of these drugs. Responses to acetylcholine were augmented with simultaneous intra-arterial infusion of L-arginine at 10 mg/ml (p less than 0.01) but not with D-arginine. Responses to sodium nitroprusside were not altered by L-arginine. These results in human forearm resistance vessels support the notion that vasodilation induced by acetylcholine is a result of the conversion from L-arginine to endothelium-derived nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adrenocorticotrophin-induced hypertension: effects of mineralocorticoid and glucocorticoid receptor antagonism

OBJECTIVE: To examine whether the increase of blood pressure in adrenocorticotrophin-treated rats is mediated through mineralocorticoid or glucocorticoid receptors or corticosterone 6 beta-hydroxylation inhibition. DESIGN: Rats were randomly allocated to 14 treatment groups for 10 days. The treatments included sham injection (n = 35), adrenocorticotrophin (5, 100, 500 micrograms/kg per day, subcutaneously, n = 5, 15 and 15, respectively), spironolactone (100 mg/kg per day, subcutaneously, n = 15), standard-dose or high-dose RU 486 (70 mg/kg every 3 days or 70 mg/kg per day, subcutaneously, n = 5 and 10, respectively), spironolactone + adrenocorticotrophin (100 micrograms/kg per day, n = 5, or 500 micrograms/kg per day, n = 10), standard-dose RU 486 + adrenocorticotrophin (500 micrograms/kg per day, n = 5), high-dose RU 486 + adrenocorticotrophin (100 micrograms/kg per day, n = 10), troleandomycin (40 mg/kg per day, subcutaneously, n = 5) and troleandomycin + adrenocorticotrophin (5 micrograms/kg per day, n = 5). Systolic blood pressure and metabolic parameters were measured every second day. RESULTS: Adrenocorticotrophin treatment increased systolic blood pressure dose-dependently (5 micrograms/kg per day: +14 +/- 2 mmHg; 100 micrograms/kg per day: +20 +/- 2 mmHg; 500 micrograms/kg per day: +28 +/- 2 mmHg, all P < 0.001). Adrenocorticotrophin at 100 and 500 micrograms/kg per day increased plasma sodium and decreased plasma potassium concentrations. Spironolactone did not block adrenocorticotrophin-induced systolic blood pressure changes but did block changes in plasma sodium and potassium levels. Standard-dose RU 486 did not modify the adrenocorticotrophin-induced (500 micrograms/kg per day) systolic blood pressure rise but blocked the effect of adrenocorticotrophin on body weight. High-dose RU 486 partially blocked the adrenocorticotrophin-induced (100 micrograms/kg per day) systolic blood pressure increase (adrenocorticotrophin at 100 micrograms/kg per day: 143 +/- 3 mmHg; high-dose RU 486 + adrenocorticotrophin at 100 micrograms/kg per day: 128 +/- 5 mmHg, P < 0.001) and body-weight loss. Troleandomycin did not alter the development of adrenocorticotrophin-induced hypertension. CONCLUSIONS: Spironolactone and standard-dose RU 486 did not modify adrenocorticotrophin-induced hypertension despite demonstrable antimineralocorticoid and antiglucocorticoid actions. High-dose RU 486 partially blocked adrenocorticotrophin-induced (100 micrograms/kg per day) hypertension, suggesting either a permissive effect of glucocorticoid on blood pressure or other antihypertensive actions of RU 486. Inhibition of glucocorticoid 6 beta-hydroxylation by troleandomycin did not modify adrenocorticotrophin-induced hypertension, suggesting that effects of corticosterone 6 beta-hydroxylation in adrenocorticotrophin-induced hypertension are negligible.     

Olmesartan, but not amlodipine, improves endothelium-dependent coronary dilation in hypertensive patients.

OBJECTIVES: We aimed to compare the effects of the angiotensin II receptor blocker (ARB) olmesartan versus the calcium channel blocker (CCB) amlodipine on coronary endothelial dysfunction in patients with hypertension. BACKGROUND: Angiotensin II receptor blockers are thought to have greater beneficial effects than CCBs on coronary vasomotion by directly blocking action of angiotensin II. METHODS: Twenty-six patients with untreated essential hypertension were prospectively assigned to treatment with either olmesartan (27.7 +/- 12.4 mg/day, n = 13) or amlodipine (5.6 +/- 1.5 mg/day, n = 13) for 12 weeks. Changes of corrected myocardial blood flow (DeltaMBF) and coronary vascular resistance (DeltaCVR) from rest to cold pressor were measured by using 15O-water and positron emission tomography before and after treatment. Blood biomarkers including lipids, glucose, insulin, high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor-alpha, and superoxide dismutase (SOD) were also measured. RESULTS: Olmesartan and amlodipine reduced blood pressure (BP) to the same extent (-28.7 +/- 16.2 mm Hg vs. -26.7 +/- 10.8 mm Hg). In the olmesartan group, DeltaMBF tended to be greater (-0.15 +/- 0.19 ml/g/min vs. 0.03 +/- 0.17 ml/g/min, p = 0.09 by 2-way analysis of variance), and DeltaCVR was significantly decreased (7.9 +/- 23.5 mm Hg/[ml/g/min] vs. -16.6 +/- 18.0 mm Hg/[ml/g/min], p < 0.05) after treatment, whereas these parameters did not change in the amlodipine group (DeltaMBF: -0.15 +/- 0.12 ml/g/min vs. -0.12 +/- 0.20 ml/g/min; DeltaCVR: 6.5 +/- 18.2 mm Hg/[ml/g/min] vs. 4.8 +/- 23.4 mm Hg/[ml/g/min]). Serum SOD activity tended to increase (4.74 +/- 4.77 U/ml vs. 5.57 +/- 4.74 U/ml, p = 0.07 by 2-way analysis of variance) only in the olmesartan group. CONCLUSIONS: Olmesartan, but not amlodipine, improved endothelium-dependent coronary dilation in hypertensive patients independent of BP reduction. These beneficial effects on coronary vasomotion might be via an antioxidant property of ARBs.     

Effects of lipo-prostaglandin E1 on pulmonary hemodynamics and clinical outcomes in patients with pulmonary arterial hypertension

OBJECTIVE: To determine whether lipid microspheres containing prostaglandin E1 (lipo-PGE1) improve pulmonary hemodynamics and clinical outcomes in patients with pulmonary arterial hypertension (PAH). METHODS: Forty-nine patients with PAH (8 patients with primary pulmonary hypertension, 21 patients with collagen vascular disease, 20 patients with congenital systemic-to-pulmonary shunts) were randomly classified into a conventional therapy group (n = 22) or a group receiving lipo-PGE1 plus conventional drugs (lipo-PGE1 group; n = 27). Echocardiographic pulmonary parameters, New York Heart Association (NYHA) functional class, and Bruce treadmill test results for exercise capacity were recorded before and after treatment. RESULTS: After 2 weeks of treatment with lipo-PGE1 (10 microg bid for 14 days), there were significant improvements in the values (+/- SD) for systolic pulmonary arterial pressure (SPAP) [76.9 +/- 27.9 mm Hg vs 66.5 +/- 22.8 mm Hg, p < 0.001]; total pulmonary resistance (27.2 +/- 13.3 dyne.s.cm(-5) vs 20.2 +/- 10.7 dyne.s.cm(-5), p < 0.001); left ventricular ejection fraction (58.7 +/- 9.6% vs 64.4 +/- 6.8%, p < 0.001); and cardiac output (3.1 +/- 0.8 L/min vs 3.7 +/- 1.1 L/min, p < 0.01). The NYHA functional class decreased from 3.0 +/- 0.6 to 2.5 +/- 0.6 (p < 0.001), and the exercise capacity increased from 2.8 +/- 1.0 to 4.3 +/- 1.3 metabolic equivalents (MET) [p < 0.001]. Compared with the conventional therapy group, the lipo-PGE(1) group achieved significant reduction of SPAP (10.4 +/- 10.3 mm Hg vs 2.2 +/- 5.6 mm Hg, p = 0.002) and a significant elevation of exercise capacity (1.5 +/- 0.9 MET vs 0.6 +/- 1.1 MET, p = 0.018). CONCLUSION: Lipo-PGE1 can decrease pulmonary artery pressure and increase exercise capacity in patients with PAH.     

Simvastatin and L-arginine preserve renal function after ischemia/reperfusion injury

BACKGROUND: HMG-CoA reductase inhibitors have been shown to have beneficial renal hemodynamic effects by increasing renal blood flow, independent of their lipid-lowering properties. Currently in organ transplantation, the calcineurin inhibitor cyclosporine A (CyA) is the immunosuppressant of choice. However, its use is limited by its nephrotoxic effects, namely its renal vasoconstrictor properties. The purpose of this study was to determine the effect of an HMG-CoA reductase inhibitor, simvastatin (Zocor), on renal function in rats and on urinary nitrite/nitrate production following ischemia/reperfusion injury (I/R) with concomitant cyclosporine treatment. In addition, L-NAME (N(G)-nitro-L-arginine methyl ester) and L-arginine were administered with CyA to the rats to test the hypothesis that simvastatin's beneficial effects were due to nitric oxide. METHODS: Male Wistar rats (250 g) were anesthetized and the supra-aorta clamped for 40 minutes. The right kidney was removed. After recovery, the rats were divided into five groups: 1) controls, no ischemia, no treatment (CTRL, n = 8); 2) ischemia (ISCH) plus cyclosporine A only (CyA, 5 mg/kg/day i.p., n = 8); 3) ischemia plus CyA and simvastatin (SIM, 10 mg/kg/day, gavage, n = 8); 4) ischemia plus simvastatin plus L-NAME plus CyA (10 mg/kg/day, gavage, n = 8), and 5) ischemia plus simvastatin plus L-arginine (2% in drinking water, n = 7) plus CyA. Five to 7 days after I/R injury, the glomerular filtration rate (GFR) was determined using urinary iohexol clearance. Urinary nitrite/nitrate production was determined using nitrate reductase and the Greiss reaction. Data are expressed as mean +/- SEM, and intergroup comparisons were made using one-way analysis of variance. RESULTS: The GFR values (mL/min) for all five groups are as follows: 1) CTRL = 1.25 +/- 0.10; 2) ISCH plus CyA only = 0.45 +/- 0.06 (P < 0.05 versus CTRL, ISCH only and simvastatin and cyclosporine and simvastatin plus L-arginine and cyclosporine); 3) CyA and SIM = 0.78 +/- 0.09, CyA and L-NAME = 0.62 +/- 0.12, and CyA and L-arginine and SIM = 1.57 +/- 0.12. Results in the control were significantly different from results in the ischemic only and the L-NAME groups (P < 0.05). The L-arginine plus cyclosporine and simvastatin group was significantly higher than the ischemic only group, ischemic plus simvastatin and cyclosporine and the L-NAME plus cyclosporine group (P < 0.05). No significant differences could be detected in the urinary nitric oxide concentrations. CONCLUSIONS:: After I/R injury and cyclosporine treatment, simvastatin and L-arginine preserved renal function, compared with cyclosporine treatment alone, because simvastatin and L-arginine may not have a direct vasoconstrictor effect on the renal microcirculation. They may be suppressing endothelin or increasing other vasodilator mediators such as the vasodilator prostaglandins and/or nitric oxide.     

Asymmetric dimethylarginine determines the improvement of endothelium-dependent vasodilation by simvastatin: Effect of combination with oral L-arginine.

OBJECTIVES: We hypothesized that the level of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide (NO) synthase (eNOS), might determine the endothelial effects of statins. BACKGROUND: Endothelial NO synthase is up-regulated by statins. However, statins failed to improve endothelial function in some studies. Asymmetric dimethylarginine inhibits eNOS by a mechanism that is reversible by L-arginine. METHODS: Ninety-eight clinically asymptomatic elderly subjects had their plasma ADMA levels screened. Those in the highest (high ADMA, n = 15) and lowest quartiles of the ADMA distribution (low ADMA, n = 13) were eligible to receive, in a randomized order, simvastatin (40 mg/day), L-arginine (3 g/day), or a combination of both, each for 3 weeks. Endothelium-dependent vasodilation (EDD) was assessed by brachial artery ultrasound. RESULTS: Simvastatin had no effect on EDD in subjects with high ADMA (6.2 +/- 1.2% vs. 6.1 +/- 0.9%), whereas simvastatin plus L-arginine significantly improved EDD (9.8 +/- 1.5% vs. 5.3 +/- 0.8%; p < 0.01). In subjects with low ADMA, simvastatin improved endothelial function when given alone (9.5 +/- 3.2% vs. 6.1 +/- 3.8%; p < 0.001) or in combination with L-arginine (9.0 +/- 3.1% vs. 6.3 +/- 3.3%; p = 0.001). L-arginine alone improved endothelial function in both groups. Endothelium-independent vasodilation was not affected. CONCLUSIONS: Simvastatin does not enhance endothelial function in subjects with elevated ADMA, whereas it does so in patients with low ADMA. Combination of simvastatin with oral L-arginine improves endothelial function in subjects with high ADMA, but has no additional effect in subjects with low ADMA. As NO-mediated effects may play a major role in the therapeutic effects of statins, ADMA concentration is an important factor that influences the "pleiotropic" effects of simvastatin.     

Propranolol enhances the effect of ACTH on plasma cortisol, but not on aldosterone in man

An accidental observation led to the suspicion that propranolol (P) enhances the effect of exogenous ACTH on plasma cortisol. To examine this matter further, large-dose ACTH tests (25 IU im) were performed in 10 normal young males: i) without treatment (n =10); ii) after 11/2 days of P treatment (n = 10); iii) after 11/2 days of metoprolol treatment (n = 6). Six other subjects received infusions of 0.2 IU of ACTH/hour for 12 h: i) without pretreatment; ii) after 11/2 days of P treatment. P pretreatment (80 mg t.i.d.) led to a small but significant decrease in plasma cortisol (9.4 +/- 0.8 micrograms/100 mg; mean +/- SE, vs. 11.3 +/- 0.7 micrograms/100 ml in controls). The maximum percentage increase of plasma cortisol after ACTH injection was 383% +/- 35% (mean +/- SE) after P and 253% +/- 22% in controls (p less than 0.05). The enhancement of the absolute and relative increase of plasma cortisol after ACTH injection seems to be mainly due to lowering of basal cortisol levels, since the effect of ACTH on plasma cortisol in normal subjects in inversely related to basal cortisol. The effect of metoprolol on basal cortisol and the cortisol response to ACTH was less pronounced than that of P. In the long-term-infusion study the effect of P was less apparent than in the acute study. P had no significant effect on basal plasma aldosterone or on the aldosterone response to ACTH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary angiotensinogen as an indicator of intrarenal Angiotensin status in hypertension

Angiotensin II (AngII) infusions augment renal angiotensinogen mRNA and protein and urinary angiotensinogen excretion (U(AGT)). Further experiments were performed in 4 groups of rats: normal salt diet with sham operation, NS+Sham, n=6; NS with AngII infusion at 40 ng/min via osmotic minipump, NS+AngII(40), n=9; NS with AngII infusion at 80 ng/min, NS+AngII(80), n=9; high-salt diet with deoxycorticosterone acetate salt pellet (100 mg), HS+DOCA, n=4. These experiments sought to determine whether enhanced U(AGT) is specifically associated with increased kidney AngII levels or is a nonspecific consequence of the hypertension. Systolic BP (SBP) was significantly increased to 131+/-2 and 162+/-2 mm Hg at day 11 in NS+AngII(40) and NS+AngII(80), respectively, compared with NS+Sham (110+/-1). Regression analysis demonstrated a positive relationship (R=0.49) between SBP and U(AGT) for NS+Sham (1.1+/-0.3 nmol AngI/d), NS+AngII(40) (2.5+/-0.9), and NS+AngII(80) (5.5+/-1.5). U(AGT) was also highly correlated (R=0.70) with kidney AngII content for NS+Sham (49+/-6 fmol/g), NS+AngII(40) (215+/-49), and NS+AngII(80) (347+/-47); but not with plasma AngII (R=0.12). HS+DOCA rats also exhibited increased SBP to 134+/-1 mm Hg, but U(AGT) (1.4+/-0.4 nmol AngI/d) and intrarenal AngII content (13+/-2 fmol/g) were not increased despite the hypertension. Infused human angiotensinogen could not be detected in urine of sham-operated or AngII-infused rats (n=4 each). These data demonstrate that U(AGT) increases in AngII-dependent hypertension in a dose- and time-dependent manner, but not in hypertension elicited by HS+DOCA. The results support the hypothesis that AngII-dependent hypertension results in elevated intrarenal AngII and angiotensinogen levels, reflected by increased U(AGT), which does not occur in an AngII-independent hypertensive model.     

Growth hormone improves bioenergetics and decreases catecholamines in postinfarct rat hearts

The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n = 7), MI rats treated with GH (MI + GH; n = 11; 3 mg/kg x day), and sham-operated rats (sham; n = 8). All rats were investigated with 31P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI = 1.69 +/- 0.09 vs. MI + GH = 2.42 +/- 0.05, P < 0.001; sham = 2.34 +/- 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P < 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham = 124.1 +/- 8.4; MI = 203.9 +/- 34.7; MI + GH = 118.3 +/- 8.4 ng/ml; P < 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling.     

Dystrophin-deficient myocardium is vulnerable to pressure overload in vivo

OBJECTIVE: Dystrophin provides mechanical reinforcement to the membranes of myocytes. Dystrophin abnormalities are known to cause cardiomyopathy and skeletal muscle disorders; however, the pathogenesis of these abnormalities remains unclear. Dystrophin-deficient skeletal muscle is vulnerable to stresses such as stretch and hypo-osmotic shock. We investigated whether the myocardium of dystrophin-deficient (mdx) mice shows increased vulnerability to acute pressure overload in vivo. METHODS AND RESULTS: Abdominal aortic banding was performed in 12-week-old mdx and control mice. The aortic pressure was measured by cannulation of the right carotid artery at the time of sacrifice. Systolic pressures in mdx mice at 0, 1, 2, 7 and 14 days after aortic banding were 100 +/- 11, 119 +/- 7, 123 +/- 4, 134 +/- 11 and 130 +/- 10 mmHg, respectively. Microscopic analysis revealed focal lesions in the left ventricular wall in banded mdx mice. These lesions consisted of damaged myocytes and inflammatory cells, and also of fibrosis at a late stage. Similar lesions were not observed in non-banded or banded control mice. The proportion of areas of lesions to total left ventricular area increased over time: 1.0 +/- 0.6% in mdx mice without aortic banding (sham, n = 6), and 1.7+/-1.4% 1 day (n = 6, vs. sham, NS), 2.6 +/- 1.9% 2 days (n = 7, vs. sham, P < 0.05), 6.3+ /- 6.5% 7 days (n = 13, vs. sham, P < 0.05) and 9.9 +/- 8.3% 14 days after aortic banding (n=15, vs. sham, P < 0.01). Furthermore, linear regression analysis revealed a significant correlation between percentage of lesion area and systolic pressure in mdx mice (P < 0.05). CONCLUSION: Dystrophin-deficient myocardium is more vulnerable than normal myocardium to pressure overload in vivo. This result has two clinical implications: (1) the patients with dystrophynopathy, such as the Duchenne and the Becker types of muscular dystrophy and X-linked type of dilated cardiomyopathy, who develop arterial hypertension should be treated aggressively, and (2) they should avoid stresses that elevate blood pressure.