Patients with coronary artery disease were randomly assigned to either methotrexate (15 to 20 mg weekly) or placebo. At a median of 2.3 years, there was no difference between the two groups in the ...rate of myocardial infarction, stroke, or cardiovascular death.
Pulmonary hypertension (PH) is a life-threatening disease with unclear vascular mechanisms. We tested whether PH involves abnormal pulmonary vasoconstriction and impaired vasodilation. Male ...Sprague-Dawley rats were exposed to hypoxia (9% O(2)) for 2 weeks or injected with single dose of monocrotaline (MCT, 60 mg/kg s.c.). Control rats were normoxic or injected with saline. After the hemodynamic measurements were performed, pulmonary and mesenteric arteries were isolated for measurement of vascular function. Hematocrit was elevated in hypoxic rats. Right ventricular systolic pressure and Fulton's Index right/(left + septum) ventricular weight were greater in hypoxic and MCT-treated rats than in normoxic rats. Pulmonary artery contraction by phenylephrine and 96 mM KCl was less in hypoxic and MCT-treated rats than in normoxic rats. Acetylcholine-induced relaxation was less in the pulmonary arteries of hypoxic and MCT-treated rats than of normoxic rats, suggesting reduced effects of endothelium-derived vasodilators. The nitric oxide synthase inhibitor, N(omega)-nitro-l-arginine methyl ester, and the guanylate cyclase inhibitor, 1H-1,2,4oxadiazolo4,3-aquinoxalin-1-one, inhibited acetylcholine relaxation, suggesting that it was mediated by nitric oxide (NO)-cGMP. The NO donor sodium nitroprusside caused less relaxation in the pulmonary arteries of hypoxic and MCT-treated than of normoxic rats, suggesting decreased responsiveness of vascular smooth muscle cells (VSMCs) to vasodilators. Phenylephrine and KCl contraction and acetylcholine and sodium nitroprusside relaxation were not different in the mesenteric arteries from all groups. In lung tissue sections, the wall thickness of pulmonary arterioles was greater in hypoxic and MCT-treated rats than in normoxic rats. The specific reductions in pulmonary, but not systemic, arterial vasoconstriction and vasodilation in hypoxia- and MCT-induced PH are consistent with the possibility of de-differentiation of pulmonary VSMCs to a more proliferative/synthetic and less contractile phenotype in PH.
Background Varicose veins (VarVs) are a common disorder of venous dilation and tortuosity with unclear mechanism. The functional integrity and the ability of various regions of the VarVs to constrict ...is unclear. This study tested the hypothesis that the different degrees of venodilation in different VarV regions reflect segmental differences in the responsiveness to receptor-dependent vasoconstrictive stimuli and/or in the postreceptor signaling mechanisms of vasoconstriction. Methods Varix segments and adjacent proximal and distal segments were obtained from patients undergoing VarV stripping. Control great saphenous vein specimens were obtained from patients undergoing lower extremity arterial bypass and coronary artery bypass grafting. Circular vein segments were equilibrated under 2 g of tension in a tissue bath, and changes in isometric constriction in response to angiotensin II (AngII, 10–11 -10–7 M), phenylephrine (PHE, 10–9 -10–4 M), and KCl (96 mM) were recorded. The amount of angiotensin type 1 receptor (AT1 R) was measured in vein tissue homogenate. Results AngII caused concentration-dependent constriction in control vein (max 35.3 ± 9.6 mg/mg tissue, pED50 8.48 ± 0.34). AngII caused less contraction and was less potent in proximal (max 7.9 ± 2.5, pED50 6.85 ± 0.61), distal (max 5.7 ± 1.2, pED50 6.74 ± 0.68), and varix segments of VarV (max 7.2 ± 2.0, pED50 7.11 ± 0.50), suggesting reduced AT1 R-mediated contractile mechanisms. VarVs and control veins had similar amounts of AT1 R. α-adrenergic receptor stimulation with PHE caused concentration-dependent constriction in control veins (max 73.0 ± 13.9 mg/mg tissue, pED50 5.48 ± 0.12) exceeding that of AngII. PHE produced similar constriction and was equally potent in varix and distal segments but produced less constriction and was less potent in proximal segments of VarVs (max 32.1 ± 6.4 mg/mg tissue, pED50 4.89 ± 0.13) vs control veins. Membrane depolarization by 96 mM KCl, a receptor-independent Ca2+ -dependent response, produced significant constriction in control veins and similar contractile response in proximal, distal, and varix VarV segments, indicating tissue viability and intact Ca2+ -dependent contraction mechanisms. Conclusions Compared with control veins, different regions of VarV display reduced AngII-mediated venoconstriction, which may be involved in the progressive dilation in VarVs. Postreceptor Ca2+ -dependent contraction mechanisms remain functional in VarVs. The maintained α-adrenergic responses in distal and varix segments, and the reduced constriction in the upstream proximal segments, may represent a compensatory adaptation of human venous smooth muscle to facilitate venous return from the dilated varix segments of VarV.
The article presents information on the treatment of inflammation related to atherothrombosis with canakinumab through neutralization of interleukin-1, resulting in the decreasing rates of ...cardiovascular diseases. It discusses the outcomes of the randomized controlled trials of low-dosage methotrexate, possibility of myocardial infarction, and the elevation of liver-enzyme levels with reduced leukocyte count.
Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of ...pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O(2)) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH(4)Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH(4)Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH.
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