Biomedical subjects

Ralph Theo Schermuly

Publications and source records attributed to Ralph Theo Schermuly.

At least 19 recordsLinked to original sources

PubMed2006

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange.

Regional alveolar hypoxia causes local vasoconstriction in the lung, shifting blood flow from hypoxic to normoxic areas, thereby maintaining gas exchange. This mechanism is known as hypoxic pulmonary vasoconstriction (HPV). Disturbances in HPV can cause life-threatening hypoxemia whereas chronic hypoxia triggers lung vascular remodeling and pulmonary hypertension. The signaling cascade of this vitally important mechanism is still unresolved. Using transient receptor potential channel 6 (TRPC6)-deficient mice, we show that this channel is a key regulator of acute HPV as this regulatory mechanism was absent in TRPC6(-/-) mice whereas the pulmonary vasoconstrictor response to the thromboxane mimetic U46619 was unchanged. Accordingly, induction of regional hypoventilation resulted in severe arterial hypoxemia in TRPC6(-/-) but not in WT mice. This effect was mirrored by a lack of hypoxia-induced cation influx and currents in smooth-muscle cells from precapillary pulmonary arteries (PASMC) of TRPC6(-/-) mice. In both WT and TRPC6(-/-) PASMC hypoxia caused diacylglycerol (DAG) accumulation. DAG seems to exert its action via TRPC6, as DAG kinase inhibition provoked a cation influx only in WT but not in TRPC6(-/-) PASMC. Notably, chronic hypoxia-induced pulmonary hypertension was independent of TRPC6 activity. We conclude that TRPC6 plays a unique and indispensable role in acute hypoxic pulmonary vasoconstriction. Manipulation of TRPC6 function may thus offer a therapeutic strategy for the control of pulmonary hemodynamics and gas exchange.

Acute Disease↗

PubMed2006

Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies.

OBJECTIVES: This study sought to investigate the effects of inhaled treprostinil on pulmonary hemodynamics and gas exchange in severe pulmonary hypertension. BACKGROUND: Inhaled iloprost therapy has a proven clinical efficacy in pulmonary arterial hypertension, but this therapy necessitates 6 to 9 inhalation sessions per day. Treprostinil has a longer plasma half-life and might provide favorable properties when applied by inhalation. METHODS: Three different studies were conducted on a total of 123 patients by means of right heart catheterization: 1) a randomized crossover-design study (44 patients), 2) a dose escalation study (31 patients), and 3) a study of reduction of inhalation time while keeping the dose fixed (48 patients). The primary end point was the change in pulmonary vascular resistance (PVR). RESULTS: The mean pulmonary arterial pressure of the enrolled patients was approximately 50 mm Hg in all studies. In study 1, both treprostinil and iloprost at an inhaled dose of 7.5 mug displayed a comparable PVR decrease, with a significantly different time course (p < 0.001), treprostinil showing a more sustained effect on PVR (p < 0.0001) and fewer systemic side effects. In study 2, effects of inhalation were observed for 3 h. A near-maximal acute PVR decrease was observed at 30 mug treprostinil. In study 3, treprostinil was inhaled at increasing concentrations with a pulsed ultrasonic nebulizer, mimicking a metered dose inhaler. A dose of 15 mug treprostinil was inhaled with 18, 9, 3, 2 pulses, or 1 pulse, each mode achieving comparable, sustained pulmonary vasodilation without significant side effects. CONCLUSIONS: Inhaled treprostinil exerts sustained pulmonary vasodilation with excellent tolerability at relatively low doses and may be inhaled in a few breaths.

Administration, Inhalation↗

PubMed2006

Oxygen sensors in hypoxic pulmonary vasoconstriction.

Hypoxic pulmonary vasoconstriction (HPV) is an essential mechanism adapting lung perfusion to regional ventilation. Perturbations to HPV, such as those occurring in pneumonia, acute respiratory distress syndrome and liver failure, can result in arterial hypoxemia. Under conditions of general hypoxia, HPV increases pulmonary vascular resistance and thus causes acute pulmonary hypertension. Despite intensive research, the underlying mechanisms of HPV have not been fully elucidated. Deciphering signalling pathways that result in HPV could suggest novel approaches to address a failure of HPV, as well as for the treatment of pulmonary hypertension associated with HPV. Within this context, this review focuses on current concepts in the oxygen sensing mechanisms that underlie HPV.

Adenosine Triphosphate↗

PubMed2006

Activation of soluble guanylate cyclase reverses experimental pulmonary hypertension and vascular remodeling.

BACKGROUND: Severe pulmonary hypertension is a disabling disease with high mortality, characterized by pulmonary vascular remodeling and right heart hypertrophy. Using wild-type and homozygous endothelial nitric oxide synthase (NOS3(-/-)) knockout mice with pulmonary hypertension induced by chronic hypoxia and rats with monocrotaline-induced pulmonary hypertension, we examined whether the soluble guanylate cyclase (sGC) stimulator Bay41-2272 or the sGC activator Bay58-2667 could reverse pulmonary vascular remodeling. METHODS AND RESULTS: Both Bay41-2272 and Bay58-2667 dose-dependently inhibited the pressor response of acute hypoxia in the isolated perfused lung system. When wild-type (NOS3(+/+)) or NOS3(-/-) mice were housed under 10% oxygen conditions for 21 or 35 days, both strains developed pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling, demonstrated by an increase in fully muscularized peripheral pulmonary arteries. Treatment of wild-type mice with the activator of sGC, Bay58-2667 (10 mg/kg per day), or the stimulator of sGC, Bay41-2272 (10 mg/kg per day), after full establishment of pulmonary hypertension from day 21 to day 35 significantly reduced pulmonary hypertension, right ventricular hypertrophy, and structural remodeling of the lung vasculature. In contrast, only minor efficacy of chronic sGC activator therapies was noted in NOS3(-/-) mice. In monocrotaline-injected rats with established severe pulmonary hypertension, both compounds significantly reversed hemodynamic and structural changes. CONCLUSIONS: Activation of sGC reverses hemodynamic and structural changes associated with monocrotaline- and chronic hypoxia-induced experimental pulmonary hypertension. This effect is partially dependent on endogenous nitric oxide generated by NOS3.

Animals↗

PubMed2006

Comparison of pharmacokinetics and vasodilatory effect of nebulized and infused iloprost in experimental pulmonary hypertension: rapid tolerance development.

Aerosolized iloprost has been suggested for selective pulmonary vasodilatation in severe pulmonary hypertension, but its pharmacokinetic profile is largely unknown. In perfused rabbit lungs, continuous infusion of the thromboxane mimetic U46619 was employed for establishing stable pulmonary hypertension. Delivery of a total amount of 75, 300, and 900 ng of iloprost to the bronchoalveolar space by a 10 min-aerosolization maneuver caused a dose-dependent pulmonary vasodilatation. Similarly, dose-dependent appearance of iloprost in the recirculating perfusate was noted, with maximum intravascular concentrations of iloprost ranging at 140, 510, and 1163 pg/mL at the same time period. Comparing pharmacokinetics and pharmacodynamics in a more detailed fashion, the following aspects were of interest. (i) The bioavailability (i.e., the percentage of aerosolized iloprost appearing intravascularly) decreased from 76% at the lowest to 33% at the highest iloprost dosage. (ii) The pulmonary vasodilatory response commenced already during the nebulization maneuver and preceded the perfusate entry of iloprost. (iii) After 3-3.5 h, the pulmonary vasodilatory response to aerosolized iloprost had virtually completely leveled off, whereas approximately two-thirds of the maximum iloprost perfusate levels were still detectable. A corresponding loss of vasodilatory response was also noted in experiments with continuous iloprost perfusion for clamping of the intravascular concentration of this prostanoid. We conclude that aerosolized iloprost causes dose-dependent vasodilatation and iloprost entry into the vascular space in a pulmonary hypertension model. Limited bioavailability in the higher dose range may suggest active prostanoid transport processes, and the early pulmonary vasodilatory response appears to be independent of prostanoid entry into the vessel lumen. Surprisingly, rapid tolerance development to the vasodilatory effect of iloprost is noted, occurring even with fully maintained perfusate levels of this agent.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2006

Effect of nitric oxide synthase (NOS) inhibition on macro- and microcirculation in a model of rat endotoxic shock.

Treatment of hemodynamic instability in septic shock often demands the administration of vasopressor agents, although these may have deleterious effects on microcirculatory homeostasis. Inhibition of nitric oxide synthase (NOS) has been suggested as an alternative therapeutic approach, as NO formation may be excessively increased in sepsis. To compare the effects of epinephrine titration, non-selective NOS inhibition by L-NMMA and selective inhibition of inducible NOS (iNOS) by 1400W on hemodynamics and on the regulation of microcirculation in a rat model of endotoxic shock, we intravenously injected endotoxin (LPS) or saline to male Wistar rats and after 2 hours randomized LPS treated rats into four different groups that received either saline, norepinephrine, L-NMMA or 1400W (n = 6 per group). Three hours after LPS administration, rats presented with severe systemic arterial hypotension (64 +/- 3 vs. 115 +/- 4 mmHg, p < 0.001), unresponsiveness to volume treatment, lactate acidosis and a marked increase in plasmatic nitrite and nitrate levels (15 +/- 8 vs. 263 +/- 47 microM, p < 0.001). Measurement of the tissue oxygenation in the ileum mucosal layer by the Erlangen micro-lightguide spectrophotometer (EMPHO) technique demonstrated marked heterogeneity of hemoglobin saturation, with appearance of low oxygenated areas. Norepinephrine, usually stabilizing blood pressure (99 +/- 7 vs. 67 +/- 4 mmHg 60 min after infusion, p < 0.01), increased lactate formation (7.9 +/- 0.2 vs. 3.7 +/- 0.5 mM, p < 0.001) and drastically increased low oxygenated regions in the ileum mucosal layer. L-NMMA similarly increased blood pressure (92 +/- 6 vs. 67 +/- 4 mmHg 60 min after infusion, p < 0.05), but did not enhance lactate acidosis. However, some further deterioration of mucosa oxygenation was again noted. 1400W forwarded stabilization of blood pressure (88 +/- 5 vs. 67 +/- 4 mmHg 60 min after injection, p < 0.05), reduced plasmatic nitrite and nitrate levels similar to L-NMMA, without an aggravation of lactate acidosis. In addition, mucosal oxygenation did not deteriorate in response to this agent. Thereby, we conclude that in a rat model of endotoxic shock selective iNOS inhibitors are superior to non-specific NOS inhibitors and in particular to norepinephrine for the treatment of macro- and microcirculatory abnormalities in experimental septic shock.

Amidines↗

PubMed2005

In vivo characterization of the novel imidazopyridine BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine], a potent and highly selective inhibitor of inducible nitric-oxide synthase.

Excessive release of nitric oxide from inducible nitric-oxide synthase (iNOS) has been postulated to contribute to pathology in a number of inflammatory diseases. We recently identified imidazopyridine derivatives as a novel class of potent nitricoxide synthase inhibitors with high selectivity for the inducible isoform. In the present study, we tested the in vivo potency of BYK191023 [2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo-[4,5-b]pyridine], a selected member of this inhibitor class, in three different rat models of lipopolysaccharide-induced systemic inflammation. Delayed administration of BYK191023 dose-dependently suppressed the lipopolysaccharide-induced increase in plasma nitrate/nitrite (NO(x)) levels with an ED(50) of 14.9 micromol/kg/h. In a model of systemic hypotension following high-dose lipopolysaccharide challenge, curative administration of BYK191023 at a dose that inhibited 83% of the NO(x) increase completely prevented the gradual decrease in mean arterial blood pressure observed in vehicle-treated control animals. The vasopressor effect was specific for endotoxemic animals since BYK191023 did not affect blood pressure in saline-challenged controls. In addition, in a model of lipopolysaccharide-induced vascular hyporesponsiveness, BYK191023 infusion partially restored normal blood pressure responses to norepinephrine and sodium nitroprusside via an l-arginine competitive mechanism. Taken together, BYK191023 is a member of a novel class of highly isoform-selective iNOS inhibitors with promising in vivo activity suitable for mechanistic studies on the role of selective iNOS inhibition as well as clinical development.

Animals↗

PubMed2005

Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration.

BACKGROUND: The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. METHODS: CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. RESULTS: Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 +/- 4.0 to 68.9 +/- 3.2 after 4 weeks and 74.9 +/- 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response. CONCLUSION: In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics.

Administration, Inhalation↗

PubMed2005

Lung vasodilatory response to inhaled iloprost in experimental pulmonary hypertension: amplification by different type phosphodiesterase inhibitors.

Inhaled prostanoids and phosphodiesterase (PDE) inhibitors have been suggested for treatment of severe pulmonary hypertension. In catheterized rabbits with acute pulmonary hypertension induced by continuous infusion of the stable thromboxane analogue U46619, we asked whether sildenafil (PDE1/5/6 inhibitor), motapizone (PDE3 inhibitor) or 8-Methoxymethyl-IBMX (PDE1 inhibitor) synergize with inhaled iloprost. Inhalation of iloprost caused a transient pulmonary artery pressure decline, levelling off within <20 min, without significant changes in blood gases or systemic hemodynamics. Infusion of 8-Methoxymethyl-IBMX, motapizone and sildenafil caused each a dose-dependent decrease in pulmonary artery pressure, with sildenafil possessing the highest efficacy and at the same time selectivity for the pulmonary circulation. When combining a per se ineffective dose of each PDE inhibitor (200 microg/kg x min 8-Methoxymethyl-IBMX, 1 microg/kg x min sildenafil, 5 microg/kg x min motapizone) with subsequent iloprost nebulization, marked amplification of the prostanoid induced pulmonary vasodilatory response was noted and the area under the curve of PPA reduction was nearly threefold increased with all approaches, as compared to sole iloprost administration. Further amplification was achieved with the combination of inhaled iloprost with sildenafil plus motapizone, but not with sildenafil plus 8MM-IBMX. Systemic hemodynamics and gas exchange were not altered for all combinations. We conclude that co-administration of minute systemic doses of selective PDE inhibitors with inhaled iloprost markedly enhances and prolongs the pulmonary vasodilatory response to inhaled iloprost, with maintenance of pulmonary selectivity and ventilation perfusion matching. The prominent effect of sildenafil may be operative via both PDE1 and PDE5, and is further enhanced by co-application of a PDE3 inhibitor.

Administration, Inhalation↗

PubMed2005

Inhaled iloprost reverses vascular remodeling in chronic experimental pulmonary hypertension.

RATIONALE: Inhaled iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled iloprost on changes to pulmonary vascular structure that occur in PAH. OBJECTIVES: The present study was designed to investigate chronic antiremodeling effects of inhaled iloprost in monocrotaline (MCT)-induced PAH in rats. METHODS: Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with iloprost at a dose of 6 microg . kg(-1) . day(-1), or underwent sham nebulization with saline. RESULTS: After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to iloprost. Furthermore, the MCT-induced increase in matrix metalloproteinase-2 and -9 activities and tenascin-C expression was suppressed. CONCLUSIONS: We conclude that the inhalation of iloprost reverses PAH and vascular structural remodeling in MCT-treated rats. This regimen suggests the possibility of an antiremodeling therapy in PAH.

Administration, Inhalation↗

PubMed2005

Increased levels and reduced catabolism of asymmetric and symmetric dimethylarginines in pulmonary hypertension.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) and has been implicated in endothelial dysfunction. ADMA is metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), with DDAH2 representing the predominant endothelial DDAH isoform. Symmetric dimethylarginine (SDMA), also originating from arginine methylation by protein arginine methyltransferases, is an inhibitor of intracellular arginine uptake. In both chronic pulmonary hypertensive rats and patients suffering from idiopathic pulmonary arterial hypertension (IPAH; NYHA class III and IV), a marked increase in plasma ADMA and SDMA levels, as well as tissue levels of asymmetric and symmetric dimethylated proteins, was observed. Moreover, when comparing lung tissue from pulmonary hypertensive rats and IPAH patients to corresponding normal lung tissue, expression of DDAH2 was found to be reduced at both the mRNA and the protein level with no significant changes in DDAH1 expression. These findings were further supported by demonstrating a decrease in DDAH2 function in the experimental pulmonary hypertension model. Immunohistochemistry in human and rat control tissue demonstrated both isoforms of DDAH in the endothelial layer and in the alveolar epithelium. In contrast, in pulmonary hypertensive tissue, the immunoreactivity of DDAH2 in pulmonary endothelium was significantly decreased compared with DDAH1. Therefore, altogether we can conclude that enhanced dimethylarginine levels may contribute to vascular abnormalities in pulmonary arterial hypertension. Suppression of endothelial DDAH2 expression and function represents an important underlying mechanism.

Amidohydrolases↗

PubMed2005

Prostanoids and phosphodiesterase inhibitors in experimental pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis, characterized by intimal lesions, medial hypertrophy, and adventitial thickening of precapillary pulmonary arteries. Several approved therapies are currently available for the treatment of PAH, of which intravenous epoprostenol is the best explored over the past decade. Newly available oral endothelin receptor antagonists, although clinically efficacious, bear the risk of liver toxicity in a significant portion of patients. Substances that stimulate the formation of the second messengers cyclic adenosine monophosphate (cAMP) or guanosine monophosphate (cGMP) have proved useful in the treatment of various forms of pre-capillary pulmonary hypertension. These second messengers of the endogenous vasodilator mediators that include prostacyclin and nitric oxide (NO) are hydrolyzed by cyclic nucleotide phosphodiesterases (PDEs), a class of enzymes from which 11 isoforms have been characterized. This chapter highlights developments in the treatment of experimental pulmonary hypertension with special attention to prostanoids and PDE inhibitors. We summarize findings for the acute vasodilatory as well as chronic effects of prostanoids, PDE inhibitors, or combinations of both, in animal models of pulmonary hypertension.

Animals↗

PubMed2005

Reversal of experimental pulmonary hypertension by PDGF inhibition.

Progression of pulmonary hypertension is associated with increased proliferation and migration of pulmonary vascular smooth muscle cells. PDGF is a potent mitogen and involved in this process. We now report that the PDGF receptor antagonist STI571 (imatinib) reversed advanced pulmonary vascular disease in 2 animal models of pulmonary hypertension. In rats with monocrotaline-induced pulmonary hypertension, therapy with daily administration of STI571 was started 28 days after induction of the disease. A 2-week treatment resulted in 100% survival, compared with only 50% in sham-treated rats. The changes in RV pressure, measured continuously by telemetry, and right heart hypertrophy were reversed to near-normal levels. STI571 prevented phosphorylation of the PDGF receptor and suppressed activation of downstream signaling pathways. Similar results were obtained in chronically hypoxic mice, which were treated with STI571 after full establishment of pulmonary hypertension. Moreover, expression of the PDGF receptor was found to be significantly increased in lung tissue from pulmonary arterial hypertension patients compared with healthy donor lung tissue. We conclude that STI571 reverses vascular remodeling and cor pulmonale in severe experimental pulmonary hypertension regardless of the initiating stimulus. This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension.

Animals↗

PubMed2005

HIF-1alpha attenuates tumor growth in spite of augmented vascularization in an A549 adenocarcinoma mouse model.

The hypoxia-inducible transcription factor, HIF-1, adapts cells to low oxygen tension. In addition to the activation of angiogenesis by induction of VEGF, HIF-1 may trigger hypoxia-induced growth arrest and apoptosis. The aim of this study was to analyze the overall effect of HIF-1 on tumor growth in a mouse model, employing human lung adenocarcinoma A549 cells. The A549 cells were transfected to overexpress HIF-1alpha. These cells displayed decreased proliferation, cell-cycle entry, colony formation in soft agar and elevated levels of apoptosis, when compared to control cells transfected with empty vector. The cells were employed in a tumor model by subcutaneous injection into CD-1 nude mice. Persistent overexpression of HIF1alpha and VEGF was demonstrated in these tumors. The HIF-1alpha-overexpressing tumors displayed less tumor growth when compared to tumors formed by control cells. Tumors derived from HIF-1alpha-overexpressing cells revealed an increase in apoptosis when compared to control tumors, in spite of a marked increase in vascular density. We conclude that in lung A549 cells, overexpression of HIF-1alpha negatively affects tumor growth due to decreased proliferation and increased apoptosis, despite augmented angiogenesis.

Adenocarcinoma↗

PubMed2004

Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension.

Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2004

Basic features of hypoxic pulmonary vasoconstriction in mice.

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation which tends to optimize pulmonary gas exchange. Investigations using genetically engineered mice represent a promising approach to understand the underlying mechanisms. Our goal was to characterize basic features of HPV in the isolated buffer-perfused and ventilated mouse lung system. HPV was reproducible for several hours when ventilating the lungs with 1% O2 (10 min) alternated with normoxic ventilation periods (21% O2, 15 min). HPV was well elicitable and most constant using Krebs-Henseleit buffer with the addition of hydroxyethylamylopectin as an oncotic agent. Inhibition of both lung NO and prostanoid formation amplified HPV in an over-additive fashion. HPV was higher in BALB/c mive as compared to C57BL/6 mice, and was approximately threefold enhanced under positive pressure ventilation as compared to negative pressure ventilation. A three hour hypoxic ventilation period resulted in a biphasic vasoconstrictor response with loss of posthypoxic vasodilatation. In summary, we have characterised HPV and established an experimental set-up optimized for investigation of the basic mechanisms of HPV in mice.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2003

Subthreshold doses of nebulized prostacyclin and rolipram synergistaically protect against lung ischemia-reperfusion.

BACKGROUND: Pulmonary edema caused by increased microvascular permeability is an important feature of lung ischemia-reperfusion (I/R) injury. METHODS: We investigated the impact of co-aerosolized prostaglandin (PG)I(2) and the 3',5-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase inhibitor rolipram on microvascular leakage following I/R injury. Buffer-perfused rabbit lungs were exposed to 270 minutes of warm ischemia while anoxic ventilation and a positive intravascular pressure were maintained. RESULTS: On reperfusion, a massive increase of the capillary filtration coefficient and severe edema formation were noted, whereas microvascular pressures displayed only minor changes. Short-time aerosolization of subthreshold doses of either rolipram (33 microg) or PGI(2) (2.6 microg) at the beginning of ischemia did not attenuate the leakage response, whereas the co-aerosolization of both agents largely blocked any permeability increase and edema formation, independent of hemodynamic effects. The same was true when the co-aerosolization was undertaken before onset of ischemia. Similarly, the intravascular administration of rolipram and PGI(2) showed a synergistic reduction of I/R-induced vascular leak but demanded 10-fold higher doses. Intravascular release of cAMP was markedly enhanced on combined PGI(2)-rolipram administration but depended on the mode of delivery of these agents. CONCLUSIONS: Low doses of aerosolized prostacyclin and rolipram synergistically protect against severe lung I/R injury and can be used independently of lung perfusion. This strategy may be suitable for an improvement of organ preservation in lung transplantation including early management of non-heart-beating donors.

Animals↗

PubMed2002

Downregulation of hypoxic vasoconstriction by chronic hypoxia in rabbits: effects of nitric oxide.

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion to ventilation for optimizing pulmonary gas exchange. Chronic alveolar hypoxia results in vascular remodeling and pulmonary hypertension. Previous studies have reported conflicting results of the effect of chronic alveolar hypoxia on pulmonary vasoreactivity and the contribution of nitric oxide (NO), which may be related to species and strain differences as well as to the duration of chronic hypoxia. Therefore, we investigated the impact of chronic hypoxia on HPV in rabbits, with a focus on lung NO synthesis. After exposure of the animals to normobaric hypoxia (10% O(2)) for 1 day to 10 wk, vascular reactivity was investigated in ex vivo perfused normoxic ventilated lungs. Chronic hypoxia induced right heart hypertrophy and increased normoxic vascular tone within weeks. The vasoconstrictor response to an acute hypoxic challenge was strongly downregulated within 5 days, whereas the vasoconstrictor response to the thromboxane mimetic U-46619 was maintained. The rapid downregulation of HPV was apparently not linked to changes in the lung vascular NO system, detectable in the exhaled gas and by pharmacological blockage of NO synthesis. Treatment of the animals with long-term inhaled NO reduced right heart hypertrophy and partially maintained the reactivity to acute hypoxia, without any impact on the endogenous NO system being noted. We conclude that chronic hypoxia causes rapid downregulation of acute HPV as a specific event, preceding the development of major pulmonary hypertension and being independent of the lung vascular NO system. Long-term NO inhalation partially maintains the strength of the hypoxic vasoconstrictor response.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗