Objectives: The aim of this study was to test the effect of high-dose simvastatin therapy on vascular permeability, a key variable in the atherogenic process, and endothelial-mediated vasodilator responses in patients...
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Objectives: The aim of this study was to test the effect of high-dose simvastatin therapy on vascular permeability, a key variable in the atherogenic process, and endothelial-mediated vasodilator responses in patients with hypercholesterolemic atherosclerosis. Methods: The transcapillary albumin escape rate (TERalb, the 1-hour decline rate of intravenous I-125-albumin, a measure of macromolecular permeability of capillary endothelium) and forearm vasodilatation (venous plethysmography) to intraarterial acetylcholine and sodium nitroprusside (7.5, 15, 30 mug/min and 0.8, 1.6, and 3.2 mug/min respectively, 5 minutes at each rate) to account for endothelium-dependent and independent mechanisms, were measured at baseline and after 1-month simvastatin (40 mg once daily) in 16 hypercholesterolemic (low-density lipoprotein cholesterol >130 mg/dL), atherosclerotic men. Thirteen healthy, untreated subjects were the controls. Results: Baseline TERalb was higher and responsiveness to both acetylcholine and sodium nitroprusside was depressed in patients compared with controls. One-month high-dose simvastatin reduced low-density lipoprotein cholesterol by 39%, normalized TERalb, and improved local vasomotor responses to acetylcholine, without modifying those to sodium nitroprusside. Changes in TERalb and acetylcholine-mediated vasodilatation were dissociated and unrelated to lipid modifications. Conclusions: Low-density lipoprotein cholesterol reduction through 1 month of high-dose simvastatin normalized the exaggerated transvascular albumin leakage of patients with hypercholesterolemic atherosclerosis, perhaps by restoring an exaggerated endothelial permeability, apparently through mechanisms independent of circulating lipids. Improvements in acetylcholine-mediated vasomotion were also evident, but were dissociated from TERalb, demonstrating a heterogeneous behavior of the 2 indices of endothelial function in response to high-dose statin treatment.
In addition to nitric oxide (NO) and prostacyclin (PGl(2)) the endothelium generates the endothelium-derived hyperpolarizing factor (EDHF). We set out to determine whether an EDHF-like response can be detected in wild...
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In addition to nitric oxide (NO) and prostacyclin (PGl(2)) the endothelium generates the endothelium-derived hyperpolarizing factor (EDHF). We set out to determine whether an EDHF-like response can be detected in wild-type (WT) and endothelial NO synthase knockout mice (eNOS -/-) mice. Vasodilator responses to endothelium-dependent agonists were determined in vivo and in vitro. In vivo, bradykinin induced a pronounced, dose-dependent decrease in mean arterial pressure (MAP) which did not differ between WT and eNOS -/- mice and was unaffected by treatment with N-omega-nitro-L-arginine methyl ester and diclofenac. In the saline-perfuse hindlimb of WT and eNOS -/- mice, marked N-omega-nitro-L-arginine (L-NA, 300 mu mol/liter)- and diclofenac-insensitive vasodilations in response to both bradykinin and acetylcholine (ACh) were observed, which were more pronounced than the agonistinduced vasodilation in the hindlimb of WT in the absence of L-NA. This endothelium-dependent, NO/PGl(2)-independent vasodilatation was sensitive to KCl (40 mM) and to the combination of apamin and charybdotoxin. Cap junction inhibitors (18 alpha-glycyrrhetinic acid, octanol, heptanol) and CB-1 cannabinoid-receptor agonists (Delta 9-tetrahydrocannabinol, HU210) impaired EDHF-mediated vasodilation, whereas inhibition of cytochrome P450 enzymes, soluble guanylyl cyclase, or adenosine receptors had no effect on EDHF-mediated responses. These results demonstrate that in murine resistance vessels the predominant agonist-induced endothelium-dependent vasodilation in vivo and in vitro is not mediated by NO, PGl(2), or a cytochrome P450 metabolite, but by an EDHF-like principle that requires functional gap junctions.
Adrenomedullin, a potent hypotensive peptide, was originally isolated from human phaeochromocytoma. Adrenomedullin immunoreactivity and gene expression are found not only in peripheral organs but also in the central n...
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Adrenomedullin, a potent hypotensive peptide, was originally isolated from human phaeochromocytoma. Adrenomedullin immunoreactivity and gene expression are found not only in peripheral organs but also in the central nervous system. Adrenomedullin labelled cells were localised in the hypothalamus, including in the paraventricular and supraoptic nuclei, in rats. Abundant adrenomedullin-immunoreactive fibres and varicosities were found in the hypothalamo-neurohypophysial tract and the internal zone of the median eminence in colchicine-treated and hypophysectomized rats, whereas in control rats few adrenomedullin-labelled fibres were observed. We examined the effects of intracerebroventricular administration of adrenomedullin on neurosecretory cells in the paraventricular and supraoptic nuclei of rats, using immunohistochemistry for Pos protein and in situ hybridisation histochemistry for c-fos mRNA. Intracerebroventricular administration of adrenomedullin caused a marked induction of Fos-like immunoreactivity in the paraventricular nucleus and the dorsal part of the supraoptic nucleus. In the paraventricular and supraoptic nuclei, nuclear Fos-like immunoreactivity was predominantly in oxytocin-immunoreactive cells rather than vasopressin-immunoreactive cells. The induction of c-fos mRNA in the paraventricular and supraoptic nuclei was increased in a dose-related manner 30 min after intracerebroventricular administration of adrenomedullin. This induction was reduced by pre-treatment with the adrenomedullin receptor antagonist, human adrenomedullin-(22-52)-NH2. Intracerebroventricular administration of adrenomedullin also caused a marked increase in the plasma concentration of oxytocin. Extracellular recordings from magnocellular neurosecretory cells in the paraventricular nucleus revealed that putative oxytocin-secreting cells were activated by intracerebroventricular administration of adrenomedullin. These results suggest that central adrenomedullin preferentially stim
The flavoprotein inhibitor, diphenyleneiodonium (DPI), inhibits the action of glyceryl trinitrate (GTN) and the D-enantiomer of isoidide dinitrate (IIDN), but not the L-enantiomer (L-IIDN), in isolated rat aorta via i...
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The flavoprotein inhibitor, diphenyleneiodonium (DPI), inhibits the action of glyceryl trinitrate (GTN) and the D-enantiomer of isoidide dinitrate (IIDN), but not the L-enantiomer (L-IIDN), in isolated rat aorta via inhibition of the bioactivation of these prodrugs. Paradoxically, a vascular NAD(P)H oxidase, which also is inhibited by DPI, has been proposed to generate superoxide that quenches nitric oxide (NO) produced during GTN biotransformation, and increased oxidase levels are proposed to contribute to the phenomenon of organic nitrate tolerance. We examined the effect of DPI on isolated rat aorta using an in vivo model of organic nitrate tolerance. The EC50 values for GTN-, D-IIDN-, and L-IIDN-induced relaxation of aorta from GTN- tolerant rats were increased 4.5- to 7.5-fold. Treatment of blood vessels with DPI (0.3 mu M) increased the EC50 values for GTN and D-IIDN by the same magnitude in control and tolerant aortae, a result that would not be predicted if DPI and GTN tolerance affected common targets. The expression of NADPH-cytochrome P450 reductase (CPR) during in vivo tolerance was assessed by NADPH-dependent cytochrome c reductase activity of aortic microsomes, immunoblotting, and Northern analysis. By all three determinants, CPR expression was unchanged in aorta from GTN- tolerant rats. Superoxide dismutase-inhibitable NADPH-dependent cytochrome c reductase activity (a measure of superoxide generation) of tolerant rat aortic microsomes was not different from that of controls. Superoxide dismutase-inhibitable NADH-dependent cytochrome c reductase activity was detected only in microsomes from tolerant animals. DPI caused a modest increase in the sensitivity for relaxation by the NO donor DEA NONOate to an equal extent in tolerant and nontolerant tissues, whereas the superoxide scavenger, 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), had no effect on the sensitivity for relaxation by GTN. These results would not be expected if tolerance-induced incr
Thr endogenous ligand for the orphan NOR receptor (earlier named ORL1) was recently discovered. This ligand, nociceptin/orphanin FQ is involved in a number of pharmacological actions in the CNS, including modulation o...
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Thr endogenous ligand for the orphan NOR receptor (earlier named ORL1) was recently discovered. This ligand, nociceptin/orphanin FQ is involved in a number of pharmacological actions in the CNS, including modulation of pain and cognition. However, its specific physiological role remains to be determined. Two major pathways of metabolism have been identified;the action of aminopeptidase(s) that prominently occurs in plasma, and endopeptidase activity that successively generates the N-terminal 1-13 and 1-9 fragments. Both pathways result in fragments that are inactive at the NOR receptor. However, short N-terminal fragments appear to be active in blocking the release of substance P from primary afferent C-fiber terminals in the dorsal spinal cord. The same endopeptidase(s) may also be involved in the fragmentation of dynorphin A since the inhibitor profile is similar. Enzyme activity is upregulated by morphine using either peptide as substrate that may lead to pharmacological interactions. (C) 2000 Elsevier Science Inc. All rights reserved.
Prognosis in Takayasu's arteritis is limited owing to renovascular hypertension. The authors report a patient with Takayasu's arteritis,who had been unilaterally nephrectomized and presented with malignant hyp...
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Prognosis in Takayasu's arteritis is limited owing to renovascular hypertension. The authors report a patient with Takayasu's arteritis,who had been unilaterally nephrectomized and presented with malignant hypertension due to renal artery stenosis. Hypertension was refractory to conventional antihypertensive treatment, and stenosis was not accessible by interventional angioplasty. Initiation of enalapril and losartan therapy was successful in improving blood pressure without deterioration of renal function due to ischemic failure. Antihypertensive treatment resulted in dramatically stimulated endogenous nitric oxide (NO) synthesis, while elevated plasma endothelin-l levels were unchanged. Renovascular hypertension in Takayasu's arteritis is associated with an imbalance of vasoconstrictor peptide endothelin-l and vasodilator peptide NO. Successful treatment of hypertension by enalapril or losartan results in improved endogenous NO synthesis, which putatively counterbalances excessive vasoconstrictor actions and may retard the progression of renal failure.
PURPOSE: To explore the possible involvement of ade renomedullin in the pathophysiology of intraocular and orbital tumors. METHODS: Competitive reverse transcription-polymerase chain reaction was used to determine adr...
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PURPOSE: To explore the possible involvement of ade renomedullin in the pathophysiology of intraocular and orbital tumors. METHODS: Competitive reverse transcription-polymerase chain reaction was used to determine adrenomedullin mRNA levels in the tissues from 40 consecutive patients (40 eyes) undergoing vitrectomy, orbital tissue biopsy, or enucleation for various ocular diseases, including intraocular (n = 4) and orbital (n = 3) tumors, proliferative vitreoretinopathy (n = 8), proliferative diabetic retinopathy (n = 8), age related macular degeneration (n = 4), preretinal macular fibrosis (n = 9), and acute retinal necrosis (n = 4). RESULTS: Adrenomedullin mRNA levels in the tissues obtained from patients with intraocular or orbital tumors were significantly higher than those of patients with proliferative vitreoretinopathy (P < .05), proliferative diabetic retinopathy (P < .05), preretinal macular fibrosis (P < .005), and acute retinal necrosis (P < .01). CONCLUSION: Adrenomedullin may play a role in the pathophysiology of intraocular and orbital tumors. (Am J Ophthalmol 2000;129:555-556. (C) 2000 by Elsevier Science Inc. All rights reserved.).
Objective: In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A4 and 2C19. This study was designed to evaluate the effect of concomitant administration of omeprazole (...
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Objective: In vitro results suggest that cilostazol is metabolised by cytochrome P450 (CYP) isoforms 1A2, 2D6, 3A4 and 2C19. This study was designed to evaluate the effect of concomitant administration of omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of a single 100mg oral dose of cilostazol. Design: This study was conducted as a single-centre, open-label, nonrandomised, 2-period, crossover pharmacokinetic trial. A single 100mg dose of cilostazol was administered orally on days 0 and 14. Oral omeprazole (40mg every day) was administered on days 7 to 18. Study Participants: 20 healthy nonsmoking male and female volunteers. Main Outcome Measures: Serial blood samples were collected before and after cilostazol administration to characterise the pharmacokinetics of cilostazol and its metabolites. Results: Following omeprazole coadministration, the increases in cilostazol maximum plasma concentration (C-max) and area under the plasma concentration-time curve at time t (AUC(t)) were 18% (p = 0.062) and 26% (p < 0.001), respectively. For the 2 major circulating metabolites, OPC-13015 and OPC-13213, the OPC-13015 C-max and AUC(t) increased by 29 and 69%, respectively (p < 0.001). However, for OPC-13213, the Cmax and AUC(t) decreased by 22 and 31%, respectively (p < 0.001). The plasma protein binding of cilostazol was unaffected by coadministration of omeprazole. Conclusions: Coadministration of cilostazol with omeprazole resulted in an increase in the systemic exposure of cilostazol and its active metabolite, OPC-13015, by 26 and 69%, respectively. For the other active metabolite, OPC-13213, systemic exposure decreased by 31% because of inhibition of cilostazol metabolism to this metabolite. These changes in systemic exposure were well tolerated. A dose of 50mg cilostazol twice a day should be considered during coadministration of inhibitors of CYP2C19, such as omeprazole.
Objectives: The objectives of this research were to (1) assess the relative bioavailability following administration of a 100mg cilostazol suspension versus 100mg tablet;(2) assess dosage form equivalency (2 x 50mg co...
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Objectives: The objectives of this research were to (1) assess the relative bioavailability following administration of a 100mg cilostazol suspension versus 100mg tablet;(2) assess dosage form equivalency (2 x 50mg compared with 1 x 100mg);(3) compare the relative bioavailability following a single 50mg dose of cilostazol administered as an ethanolic solution versus a 50mg tablet;and (4) determine the effects of high fat diet on the pharmacokinetics of cilostazol following a single dose of 100mg cilostazol in the fed or fasted state. Results were compiled from 3 separate studies to address these objectives. Design: All studies involved healthy adult males receiving single oral doses of cilostazol in the fed or fasted state. The fed state consisted of administering cilostazol after ingestion of a high fat meal. One study compared the relative bioavailability of 100mg suspension and 2 x 50mg tablet versus 100mg tablet in a randomised crossover design. The study involving administration of a 50mg cilostazol ethanolic solution was a single treatment study. The effects of food on the pharmacokinetics of cilostazol after administration of 100mg cilostazol in the fed or fasted state as well as the pharmacokinetic profile following administration of a single 50mg oral dose of cilostazol were assessed in a randomised crossover design. Study Participants: All participants were healthy nonsmoking males aged between 19 and 48 years whose bodyweight was within 15% of ideal bodyweight. Main Outcome Measures: Noncompartmental pharmacokinetic parameters: were determined for each study participant. Results: The area under the plasma concentration-time curve (AUC) parameters were within the 80 to 125% criterion for bioequivalence for the cilostazol and its primary metabolite, OPC-13015. The maximum observed plasma concentrations (C-max) for these formulations were not equivalent and indicated that the absorption of cilostazol from a suspension is more rapid than from a tablet. The ap
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