RESUMO
The vascular effects of tamoxifen (Tam) and its metabolites are poorly known. We compared the vasorelaxation induced by Tam and its metabolites (N-desmethyl-Tam, 4-hydroxy-Tam, and endoxifen) in aortic rings from rats using standardized organ bath procedures, and we investigated the mechanisms involved in this effect. Tam and its metabolite-induced vasorelaxation in a concentration-dependent manner. Although 4-hydroxy-Tam and Tam had similar potency (pD2 = 8.5 ± 0.1 vs. 8.8 ± 0.1, respectively) and maximum effect (Emax = 88.5% ± 1.3% vs. 92.6% ± 1.3%, respectively), N-desmethyl-Tam and endoxifen were more potent and showed higher Emax than Tam did (pD2 = 9.0 ± 0.1 and 8.9 ± 0.1; Emax = 101.1% ± 1.8% and 101.0% ± 1.8% for N-desmethyl-Tam and endoxifen, respectively). Although preincubation of aortic rings with the estrogen receptor antagonist ICI 182780 or with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride induced no changes in the vasorelaxation induced by Tam or 4-hydroxy-Tam, both drugs significantly reduced Emax in response to N-desmethyl-Tam or to endoxifen. Inhibition of cyclooxygenase with indomethacin or the incubation with the prostaglandin D2 and E2 receptor antagonist AH6809 reduced the vasorelaxation-induced Tam and its metabolites by approximately 50%. Preincubation with Nω-nitro-L-arginine methyl ester hydrochloride combined with indomethacin abolished the vasorelaxation-induced Tam and its metabolites. These results show that Tam and its metabolites cause acute vasorelaxation by inducing vasodilator prostanoids synthesis.
Assuntos
Antineoplásicos Hormonais/farmacologia , Aorta Torácica/efeitos dos fármacos , Tamoxifeno/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Antineoplásicos Hormonais/metabolismo , Aorta Torácica/metabolismo , Estradiol/análogos & derivados , Estradiol/farmacologia , Fulvestranto , Indometacina/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Prostaglandinas/biossíntese , Ratos , Ratos Wistar , Tamoxifeno/análogos & derivados , Tamoxifeno/metabolismoRESUMO
Tamoxifen has been suggested to produce beneficial cardiovascular effects, although the mechanisms for these effects are not fully known. Moreover, although tamoxifen metabolites may exhibit 30-100 times higher potency than the parent drug, no previous study has compared the effects produced by tamoxifen and its metabolites on vascular function. Here, we assessed the vascular responses to acetylcholine and sodium nitroprusside on perfused hindquarter vascular bed of rats treated with tamoxifen or its main metabolites (N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen, and endoxifen) for 2 weeks. Plasma and whole-blood thiobarbituric acid reactive substances (TBARS) concentrations were determined using a fluorometric method. Plasma nitrite and NOx (nitrite + nitrate) concentrations were determined using an ozone-based chemiluminescence assay and Griess reaction, respectively. Treatment with tamoxifen reduced the responses to acetylcholine (pD(2) = 2.2 +/- 0.06 and 1.9 +/- 0.05 after vehicle and tamoxifen, respectively; P < 0.05), while its metabolites improved these responses (pD(2) = 2.5 +/- 0.04 after N-desmethyl-tamoxifen, 2.5 +/- 0.03 after 4-hydroxy-tamoxifen, and 2.6 +/- 0.08 after endoxifen; P < 0.01). Tamoxifen and its metabolites showed no effect on endothelial-independent responses to sodium nitroprusside (P > 0.05). While tamoxifen treatment resulted in significantly higher plasma and whole blood lipid peroxide levels (37% and 62%, respectively; both P < 0.05), its metabolites significantly decreased lipid peroxide levels (by approximately 50%; P < 0.05). While treatment with tamoxifen decreased the concentrations of markers of nitric oxide formation by approximately 50% (P < 0.05), tamoxifen metabolites had no effect on these parameters (P > 0.05). These results suggest that while tamoxifen produces detrimental effects, its metabolites produce counteracting beneficial effects on the vascular system and on nitric oxide/reactive oxygen species formation.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Tamoxifeno/análogos & derivados , Resistência Vascular/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotélio Vascular/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Masculino , Óxido Nítrico/sangue , Estresse Oxidativo/efeitos dos fármacos , Perfusão , Ratos , Ratos Wistar , Tamoxifeno/metabolismo , Tamoxifeno/farmacologia , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
OBJECTIVES: Most hypertensive patients require two or more drugs to control arterial blood pressure effectively. Although endothelial nitric oxide synthase (eNOS) haplotypes have been associated with hypertension, it is unknown whether eNOS genotypes/haplotypes are associated with resistance to antihypertensive therapy. METHODS: We studied the distribution of three eNOS genetic polymorphisms: single nucleotide polymorphisms in the promoter region (T(-786)C), and in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (b/a). Genotypes were determined for 111 normotensive controls (NT), 116 hypertensive individuals who were well controlled (HT), and 100 hypertensive individuals who were resistant to conventional antihypertensive therapy (RHT). We also compared the distribution of eNOS haplotypes in the three groups of subjects. RESULTS: No differences were found in genotype or allele distribution among the three groups (all P > 0.05). Conversely, the 'C Glu b' haplotype was more commonly found in the NT than in the HT or RHT groups (21 versus 8 and 7%, respectively; both P < 0.00625). In addition, the 'C Asp b' haplotype was more commonly found in the HT or RHT groups than in the NT group (22 and 20%, respectively, versus 8%; both P < 0.00625). The distribution of eNOS haplotypes was not significantly different in the HT and RHT groups (P > 0.05). CONCLUSIONS: Whereas our findings suggest a protective effect for the 'C Glu b' haplotype against hypertension and that the 'C Asp b' haplotype increases the susceptibility to hypertension, our results suggest that eNOS haplotypes are not associated with resistance to antihypertensive therapy.
Assuntos
Resistência a Medicamentos/genética , Haplótipos , Hipertensão/genética , Óxido Nítrico Sintase Tipo III/genética , Resistência a Medicamentos/fisiologia , Feminino , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/enzimologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVES: Controversy exists regarding the effects of polymorphisms in the endothelial nitric oxide synthase (eNOS) gene on nitrites/nitrates (NOx) plasma concentrations. In this study we compared the distribution of haplotypes involving three relevant eNOS polymorphisms (T-786C in the promoter region; b/a in intron 4, and Glu298Asp in exon 7) in healthy subjects with low and high circulating NOx levels. METHODS: We studied 154 healthy subjects (fasting, white males, who were non-smokers, 18-60 years of age, and not taking any medication). Genomic DNA was isolated from blood samples and genotypes were determined by PCR and restriction fragment length digestion. Circulating NOx was determined by chemiluminescence. RESULTS: Haplotype frequencies were compared in two groups of subjects: those with the 30 lowest NOx levels (group L) and those with the 30 highest NOx levels (group H). NOx levels in group L and H were 24.2+/-4.5 microM and 80.9+/-8.9 microM, respectively. Genotype frequencies for the three polymorphisms were not different when the two groups were compared (all P>0.05, chi-squared test). However, the haplotype including the alleles C (promoter), 4b (intron 4), and Glu (exon 7) was significantly more common in group L (16%) than in group H (4%) (P=0.0047). The frequencies of the remaining haplotypes were not different among group L and H. CONCLUSIONS: While eNOS genotypes are not significantly associated with changes in the circulating NOx concentrations, the specific eNOS haplotype that includes the 'C', '4b', and 'Glu' alleles is associated with lower circulating NOx concentrations.