9 research outputs found
7-Nitro indazole, an inhibitor of neuronal nitric oxide synthase, attenuates pilocarpine-induced seizures
7-Nitro indazole (25–100 mg/kg i.p.), an inhibitor of neuronal nitric oxide (NO) synthase, attenuated the severity of pilocarpine (300 mg/kg i.p.)-induced seizures in mice. This indicates that the decreased neuroexcitability of the central nervous system (CNS) following administration of 7-nitro indazole may be due to inhibition of neuronal NO synthase, implying that NO acts as an excitatory and proconvulsant factor in the CNS
Bradykinin potentiation by angiotensin-(1-7) and ACE inhibitors correlates with ACE C- and N-domain blockade
ACE inhibitors block B(2) receptor desensitization, thereby potentiating
bradykinin beyond blocking its hydrolysis. Angiotensin (Ang)-(1-7) also
acts as an ACE inhibitor and, in addition, may stimulate bradykinin
release via angiotensin II type 2 receptors. In this study we compared the
bradykinin-potentiating effects of Ang-(1-7), quinaprilat, and captopril.
Porcine coronary arteries, obtained from 32 pigs, were mounted in organ
baths, preconstricted with prostaglandin F(2alpha), and exposed to
quinaprilat, captopril, Ang-(1-7), and/or bradykinin. Bradykinin induced
complete relaxation (pEC(50)=8.11+/-0.07, mean+/-SEM), whereas
quinaprilat, captopril, and Ang-(1-7) alone were without effect.
Quinaprilat shifted the bradykinin curve to the left in a biphasic manner:
a 5-fold shift at concentrations that specifically block the C-domain (0.1
to 1 nmol/L) and a 10-fold shift at concentrations that block both
domains. Captopril and Ang-(1-7) monophasically shifted the bradykinin
curve to the left, by a factor of 10 and 5, respectively. A 5-fold shift
was also observed when Ang-(1-7) was combined with 0.1 nmol/L quinaprilat.
Repeated exposure of porcine coronary arteries to 0.1 micromol/L
bradykinin induced B(2) receptor desensitization. The addition of 10
micromol/L quinaprilat or Ang-(1-7) to the bath, at a time when bradykinin
alone was no longer able to induce relaxation, fully restored the relaxant
effects of bradykinin. Angiotensin II type 1 or 2 receptor blockade did
not affect any of the observed effects of Ang-(1-7). In conclusion,
Ang-(1-7), like quinaprilat and captopril, po
AT(2) receptor-mediated vasodilation in the heart: effect of myocardial infarction
To investigate the functional consequences of postinfarct cardiac
angiotensin (ANG) type 2 (AT(2)) receptor upregulation, rats underwent
coronary artery ligation or sham operation and were infused with ANG II
3-4 wk later, when scar formation is complete. ANG II increased mean
arterial pressure (MAP) more modestly in infarcted animals than in sham
animals. The AT(1) receptor antagonist ir
HLA class II associations with Type 1 diabetes mellitus: A multivariate approach
The association of HLA class II phenotype with the development of insulin-dependent (Type 1) diabetes mellitus (IDDM) is well established but the contribution of the various HLA-DR and -DQ alleles and haplotypes to disease predisposition is not fully understood. We have determined haplo-type and genotype odds ratios, and further employed multivariate tree analysis to explore the contribution of individual HLA-DRDQ haplotypes to the genetic risk for developing IDDM in the Dutch population. Next to haplotype and genotype odds ratios, multivariate tree analysis techniques provide overall risk calculations for each modeled parameter, and offer insight in the interaction of the model parameters via tree-shaped reports, in which subsequent stratifications on the data can easily be followed. We compared 206 Dutch IDDM patients with 840 serologically typed random healthy unrelated Dutch Caucasoid controls. The multivariate tree analysis showed that the HLA-DR7DQ9 and DR15DQ6 haplotype were strongly associated with disease protection (OR=0.04, P=0.0003, and OR=0.07, P= <0.0001, respectively). The highest ORs were found for the DR4DQ8/ DR8DQ4 genotype (OR=21.04, P=0.001), followed by DR4DQ8/DR17DQ2 (OR= 12.45, P< 0.0001) and DR9DQ9/DR17DQ2 (OR= 10.87, P=0.02). DR4DQ8 homozygous and DR17DQ2 homozygous individuals have a disease OR of 9.0 and 3.0 (P=0.01 and 0.03), respectively. In conclusion, the results from haplotype, genotype, and tree analyses provide insight into the disease associations for combinations of HLA-DRDQ haplotypes. We confirm that the DR9DQ9/DR17DQ2 genotype is associated with susceptibility in the Dutch population, which has previously been noticed as a HLA risk genotypes in Asian populations only
Analysis of the vascular responses in a murine model of polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of the reproductive age, but the exact pathophysiological mechanisms involved remain unclear. Cardiovascular disease risk is increased in PCOS patients and endothelial damage has been observed. We recently developed a mouse model of PCOS with reproductive and metabolic characteristics resembling those observed in women with PCOS. In this model we studied vascular function with particular emphasis on markers of vascular endothelial function. Animals were treated for 90 days with dihydrotestosterone (DHT; 27.5 μg/day) or placebo using subcutaneous continuous-release pellets. Aortas were isolated for isometric force recordings in organ baths to investigate endothelial and vascular smooth muscle characteristics. Lungs were used to analyze endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Asymmetric dimethylarginine (ADMA) levels were investigated in serum to assess endothelial damage. Expression of androgen receptor (Ar) mRNA was studied in aortas. DHT treatment (compared with placebo) induced i) a significantdecrease in acetylcholine-induced aortic relaxations, with no change in calcitonin generelated peptide- or sodium nitroprusside-induced relaxations, as well as 5-hydroxytryptamine-induced contractions; ii) no change in eNOS expression/phosphorylation in lungs or in plasma ADMA levels; and iii) a twofold increase in aortic AR expression. Our results suggest that, in DHT-exposed mice, hyperandrogenemia specifically decreases endotheliumdependent vasorelaxation without deterioration of smooth muscle function. This study may initiate further investigations to elucidate underlying mechanism for the phenotype that is present in these animals, as well as in PCOS patients
Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries
The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant (MK-0974) [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2- trifluoroethyl) azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-1- yl)piperidine-1-carboxamide] on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration- dependent relaxation responses to human αCGRP were greater in distal coronary arteries (i.d. 600-1000 μm; Emax= 83 ± 7%) than proximal coronary arteries (i.d. 2-3 mm; Emax= 23 ± 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; Emax= 11 ± 3%), and coronary arterioles (i.d. 200-300 μm; Emax= 15 ± 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 μM) antagonized αCGRP-induced relaxation competitively in distal coronary arteries (pA2= 8.43 ± 0.24) and proximal coronary arteries and coronary arterioles (1 μM telcagepant, giving pKB= 7.89 ± 0.13 and 7.78 ± 0.16, respectively). αCGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardi