General Pharmacology-the Vascular System最新文献

Few studies using human subcutaneous resistance arteries acknowledge the possibility of functional heterogeneity in these vessels. Large (∼500 μm) and small (≥200 μm) resistance arteries (n=11) and veins (n=5) were identified using physical, structural and functional criteria in 14 biopsies of human gluteal fat. Endothelium-dependent relaxation was not evident in veins, while, unlike small resistance arteries (E_max 95.74±1.86%; −log IC₅₀ 7.28±0.09), large resistance arteries with an intact endothelium failed to respond to acetylcholine. These results suggest that large resistance arteries may lack muscarinic receptors on the endothelium and emphasise the importance of careful vessel selection and characterisation in studies using human resistance arteries.

Our earlier observations suggest that M₃ muscarinic acetylcholine (ACh) receptors (mAChRs) are involved in Ca²⁺ signaling and regulation of c-fos gene expression in T lymphocytes. Here, we describe the effects of YM905, a novel M₃ antagonist, on evoked Ca²⁺ signaling and c-fos gene expression in CEM human leukemic T cells. YM905 significantly inhibited increases in intracellular free Ca²⁺ evoked by 10 μM oxotremorine-M, an M₁/M₃ agonist (IC₅₀=100 nM), and also inhibited 10 μM oxotremorine-M-induced upregulation of c-fos gene expression at 1 μM. These findings demonstrate that YM905 antagonizes the intracellular responses in T cells induced via mAChRs, possibly M₃ receptors.

An important factor in the development of vascular wall alterations is degradation of the elastic fiber major protein–elastin. Elastin peptides derived from this degradation are present in the circulating blood and they are a stimulus for increased production of anti-elastin antibodies (AEAb). The aim of the present study was to examine the possible association between serum elastin AEAb and the development of diabetic vascular complications. Levels of AEAb (IgG, IgM and IgA) were determined by ELISA in sera of 28 children with Type 1 (insulin-dependent) diabetes mellitus (mean age 11.6±2.8 years, diabetes duration 5.1±2.5 years). None of the children had clinical or laboratory evidence of vascular complications. The children were followed over a period of 7 years, and 24 healthy children of similar age and sex served as a control group. During the study, four diabetics developed retinopathy, six microalbuminuria and two both retinopathy and microalbuminuria. Anti-elastin IgG showed correlation with diabetes duration (r=.48, P=.0007), HbA1c (r=.28, P=.05), triglycerides (r=.28, P=.05) and antibodies to advanced glycation endproducts (AGE) (r=.41, P=.005). Anti-elastin IgM correlated with HbA1c (r=.26, P=.038) and IgA with retinopathy (r=.32, P=.017). Our results suggest an association between the level of anti-elastin IgA antibodies and the development of diabetic retinopathy.

In this work, we report for first time that: (1) low doses of ketanserin (0.2 mg/kg) produce a transient hypotensive response in anaesthetized rats, which is basically due to the blockade of 5-hydroxytryptamine _2A (5-HT)_2A receptors, whereas high doses (1 mg/kg) of ketanserin cause a sustained hypotension also mediated by the blockage of α₁-adrenergic receptors; (2) the in vitro vasorelaxant action of high concentrations of ketanserin (>10 μM) involves Ca²⁺ antagonism, which may also be responsible, at least in part, for the inhibition of high-K⁺-induced ⁴⁵Ca²⁺ uptake, the inhibition of Ca²⁺-induced contractions in initially Ca²⁺-free high-K⁺ medium, and the negative chronotropic effects on isolated atria. This Ca²⁺ antagonistic activity does not seem to contribute to the in vivo cardiovascular effects of ketanserin at therapeutic doses.

(1) To verify the proposed role of reactive oxygen species (ROS) in ulcerative colitis, the effect of an antioxidant N-acetylcysteine (NAC) was studied in acetic acid (AA)-induced colonic inflammation. (2) Depending on the dose used, NAC administered intracolonically was found to reduce the extent of colonic damage, along with a decrease in myeloperoxidase (MPO) activity, colonic wet weight and wet/dry weight ratio. (3) NAC attenuated the enhanced vascular permeability and prevented the depletion of colonic reduced glutathione (GSH) caused by AA administration. (4) The findings indicate that NAC may prove beneficial in the treatment of colitis.

Levels of elastin-derived peptides (EDP) were determined by enzyme-linked immunosorbent assay (ELISA) in sera of 28 children with Type 1 (insulin-dependent) diabetes mellitus (mean age 11.6±2.8 years, diabetes duration 5.1±2.5 years). None of the children had clinical or laboratory evidence of vascular complications. The children were followed over a period of 6 years, and 24 healthy children of similar age and sex served as a control group. During the investigative period, 10 diabetic patients had increased EDP levels, with 9 having been diabetic for more than 5 years and 1 patient less than 5 years. Seven of these patients developed diabetic microvascular complications. In this group, EDP were independently associated with age (r=.39, P=.047), retinopathy (r=.48, P=.034), and antibodies to advanced glycation endproducts (AGE) (r=.52, P=.018). The data of this pilot study are not strong enough to appear that EDP are a useful predictor of subsequent development of microvascular complications. This may be due to the small number of subjects, short duration of the study, manner in which EDP or the endpoints were measured, or frequency of which EDP measurements were made. Further prospective and longer studies of larger populations are needed to identify the role of EDP as an early marker for the development of diabetic microvascular complications.

The present study explores the hypothesis that age-related variations in cerebrovascular responses to vasodilators reflect corresponding age-dependent differences in the mechanisms coupling changes in cytosolic cGMP to vasorelaxation. The experiments focused on cGMP's ability to decrease either [Ca²⁺]_i or myofilament Ca²⁺ sensitivity, because both effects can contribute to cGMP-induced vasodilation. Use of the cGMP analog 8-pCPT-cGMP minimized problems associated with limited cell permeation or cGMP hydrolysis. In fetal basilars contracted with 10 μM serotonin, the EC₃₀ for 8-pCPT-cGMP-induced relaxation was 6 μM. In fura-2 loaded fetal basilars, pretreatment with 6 μM 8-pCPT-cGMP significantly depressed the sensitivity of [Ca²⁺]_i to 5HT, and also myofilament sensitivity to calcium, but only in fetal arteries. In fetal basilar arteries contracted with 120 mM potassium, the EC₃₀ for 8-pCPT-cGMP-induced relaxation was 25 μM. In fura-2 loaded ovine arteries, pretreatment with 25 μM 8-pCPT-cGMP had no effect on the ability of graded concentrations of potassium to elevate [Ca²⁺]_i but reduced potassium's ability to induce contraction and attenuated myofilament calcium sensitivity; these latter effects were significant only in fetal arteries. In α-toxin permeabilized preparations, 25 μM 8-pCPT-cGMP significantly depressed both basal- and agonist-stimulated myofilament calcium sensitivity, only in fetal but not in adult basilars. Together, these results demonstrate that: (1) sensitivity to cGMP is greater in fetal than adult sheep arteries independent of method of contraction; (2) cGMP can reduce [Ca²⁺]_i but only in agonist-contracted and not in potassium-contracted arteries; (3) and cGMP attenuates myofilament calcium sensitivity regardless of method of contraction. Overall, the data demonstrate that variations in the ability of cGMP to produce vasodilatation reflect age-, artery-, and agonist-dependent differences in the combination of mechanisms mediating responses to cGMP.

The aim of the present study was to investigate if the function of 5-hydroxytryptamine-1B/1D (5-HT_1B/1D) receptors in human radial artery (RA) and internal thoracic artery (ITA) can be modified by thromboxane A₂ (TXA₂) released from the vessel wall in these two arteries that are commonly used in coronary artery bypass grafts. The 5-HT_1B/1D agonist sumatriptan contracted the RA with a maximum response of 23.5±6.8 mN and a pD₂ value of 6.6±0.1. The effect of sumatriptan was significantly reduced in the ITA with a maximum of 5.8±2.7 mN (P<.05) and a pD₂ value of 6.4±0.2. The TXA₂ receptor antagonist SQ30741 inhibited contractions to sumatriptan in the RA but not in the ITA. It is concluded that the effect mediated by 5-HT_1B/1D is augmented by endogenous TXA₂ in the RA.

The aim of the present study was to compare the effects of propofol on cardiac contractile force in normal and hypercholesterolemic isolated rabbit hearts. While one group was fed with standard chow pellets (150 g/day), the other group received cholesterol (1% w/w) in addition to the same amount of rabbit chow pellets during 1 month. Hearts from standard-fed rabbits were given intralipid solvent or 25, 50 and 100 μM propofol by infusion. Hypercholesterolemic rabbit hearts were administered 25, 50 and 100 μM propofol by infusion. All concentrations of propofol did not result in any significant change of the heart rates (HR) in two groups. Propofol (25, 50 and 100 μM) infusion induced a concentration- and time-dependent inhibition in left ventricular pressure (LVP) in standard chow diet group (P<.05, .05 and .05, respectively). In hypercholesterolemic rabbit hearts, 25 and 50 μM propofol infusion developed a significant inhibition in LVP when compared with the standard chow diet group (P<.05 and .05, respectively). Propofol (100 μM) infusion developed a significant increase in LVP after 20 min in hypercholesterolemic rabbit hearts when compared with normal rabbit hearts (P<.05). Supratherapeutic concentration of propofol might have cardioprotective effect on hypercholesterolemic rabbit hearts.

The present study was designed to determine whether nitric oxide (NO)-induced reduction of [Ca²⁺]_i is associated with Ca²⁺-induced Ca²⁺ release (CICR) in coronary arterial smooth muscle cells (CASMCs). Caffeine was used as a CICR activator to induce Ca²⁺ release in these cells. The effects of NO donor, sodium nitroprusside (SNP), on caffeine-induced Ca²⁺ release were examined in freshly dissociated bovine CASMCs using single cell fluorescence microscopic spectrometry. The effects of NO donor on caffeine-induced coronary vasoconstriction were examined by isometric tension recordings. Caffeine, a CICR or ryanodine receptor (RYR) activator, produced a rapid Ca²⁺ release with a 330 nM increase in [Ca²⁺]_i. Pretreatment of the CASMCs with SNP, CICR inhibitor tetracaine or RYR blocker ryanodine markedly decreased caffeine-induced Ca²⁺ release. Addition of caffeine to the Ca²⁺-free bath solution produced a transient coronary vasoconstriction. SNP, tetracaine and ryanodine, but not guanylyl cyclase inhibitor, ODQ, significantly attenuated caffeine-induced vasoconstriction. These results suggest that CICR is functioning in CASMCs and participates in the vasoconstriction in response to caffeine-induced Ca²⁺ release and that inhibition of CICR is of importance in mediating the vasodilator response of coronary arteries to NO.