No abstract

Background & Aims:Nitrovasodilators have been proposed for the treatment of portal hypertension alone or in combination with ␤-blockers. In addition to their vasodilatory properties, nitric oxide (NO) donors may exert direct antifibrogenic properties. We evaluated the effect of nitroglycerin (NTG) and S-nitroso-N-acetyl penicillamine (SNAP) on the mitogenic and chemotactic properties of platelet-derived growth factor (PDGF)-BB and the modulation of the relative intracellular signaling pathways in fully activated human hepatic stellate cells (HSCs), a cell type that plays an active role in liver fibrogenesis and portal hypertension. Methods & Results: Both NTG and SNAP induced a dosedependent decrease in PDGF-induced DNA synthesis and cell migration, which was associated with a decrease in PDGF-induced intracellular Ca 2؉ increase and extracellular signal-regulated kinase (ERK) activity. These effects were not related to activation of the classic soluble guanylate cyclase (sGC)/guanosine 3 ,5 -cyclic monophosphate pathway; accordingly, Western blot analysis of HSC lysates revealed the absence of the ␣ 1 ␤ 1 ubiquitous subunits of sGC, whereas they were detectable in quiescent HSCs, freshly isolated from normal human liver. Conversely, both NTG and SNAP induced a more than 10 -20-fold increase in prostaglandin E 2 in cell supernatants within 1 minute, associated with an increase in intracellular adenosine 3 ,5 -cyclic monophosphate levels. Accordingly, the inhibitory effects of NO donors on PDGF action and signaling were eliminated after preincubation with ibuprofen. Conclusions: These results suggest that NO donors may exert a direct antifibrogenic action by inhibiting proliferation, motility, and contractility of HSCs in addition to a reduction of fibrillar extracellular matrix accumulation.

We investigated the effects of prostaglandin synthesis blockade on the changes in breathing pattern, mean blood pressure (MBP), and heart rate (HR) elicited by 3 min of static handgrip at 30% of the maximum voluntary contraction in 12 healthy volunteers. Before each handgrip trial, subjects were treated with intravenous administration of either saline placebo (control) or 1 mg/kg of ketoprofen. Muscle tension and integrated electromyographic activity of exercising muscles remained fairly constant during each trial. In agreement with our earlier findings, during control handgrip minute ventilation progressively increased (P < 0.01) due to a rise in tidal volume and, to a lesser extent, in respiratory frequency. Mean inspiratory flow, MBP, and HR also increased (P < 0.01). End-tidal PCO2 decreased (P < 0.05) during the late phases of control handgrip bouts. Ketoprofen administration reduced serum thromboxane B2 levels (from 57.5 +/- 7.0 to 1.6 +/- 0.4 pg/ml; P < 0.01) and significantly attenuated mean increases in minute ventilation (40.25 +/- 0.60%), tidal volume (37.78 +/- 7.48%), respiratory frequency (55.94 +/- 17.92%), inspiratory flow (42.66 +/- 5.11%), MBP (22.33 +/- 6.82%), and HR (11.04 +/- 2.75%) during the 3rd min of handgrip. End-tidal PCO2 remained close to normocapnic levels. In agreement with previous animal investigations, the present results show that arachidonic acid metabolites are involved in the regulation of the cardiovascular responses to static efforts in humans, possibly through a stimulatory action on muscle receptors. Furthermore, they provide the first experimental evidence that products of the cyclooxygenase metabolic pathway play a role in the mediation of the respiratory adjustments elicited by this form of exercise.

To investigate the effects of physiological increases in plasma brain natriuretic peptide concentration in humans, we studied six healthy volunteers who received incremental infusions (0.25 pmol/kg per minute in the first hour and 0.50 pmol/kg per minute in the second) of synthetic human brain natriuretic peptide-32 in a placebo-controlled, crossover study. Peptide plasma levels were 1.69 +/- 0.39 pmol/L at baseline and rose 1.5- and 3-fold with the lower and higher doses, respectively. These values were within the normal range and also comparable to those reported in patients with mild essential hypertension. The urinary excretion rate of cGMP also increased during brain natriuretic peptide infusion, indicating stimulation of natriuretic peptide receptors. Peptide administration induced a significant 1.7-fold increase in urinary sodium excretion without affecting renal plasma flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and urine flow rate. Fractional proximal sodium reabsorption (lithium clearance method) was unchanged, and fractional distal sodium reabsorption significantly decreased. Brain natriuretic peptide caused no changes in arterial pressure, heart rate, hematocrit, and serum proteins, but it exerted an inhibitory effect on the renin-aldosterone axis, as indicated by the significant 50% or more decrease of plasma renin activity and urinary excretion rate of aldosterone. These results suggest that brain natriuretic peptide may be involved in the overall regulation of body fluid and cardiovascular homeostasis in humans, mainly through its natriuretic and endocrine effects.