RESUMO
OBJECTIVE: The present study evaluated the effect of endovascular administration of calcium chloride to the carotid artery of swines, to create a model of arterial calcification. METHODS: Fifteen Large White pigs were used for the study. Via endovascular treatment, carotid arteries were exposed during 9 min to either calcium chloride (experimental artery) or saline (control artery) with the use of the TAPAS catheter. Intravascular ultrasound (IVUS) imaging was obtained at baseline, postprocedure and at 30 days. Optical coherence tomography (OCT) imaging was obtained in vitro after carotids were harvested. Longitudinally cut parallel arterial segments were placed in a system of delicate clamps and underwent uniaxial strain test. All arteries underwent histopathological examination. RESULTS: Calcium chloride treated segments showed extensive circumferential parietal calcification evident on both IVUS and OCT. Reduction in minimal lumen area on IVUS was evident in experimental arteries both at 24 hr and 30 days postprocedure. Histopathologic assessment (Von Kossa stain) confirmed medial calcification with mild intimal thickening. Biomechanical testing showed treated segments to have smaller breaking strength and less elastic deformation than controls. CONCLUSION: We developed a nonexpensive, reproducible model of early carotid medial calcification in pigs. Our model has the potential to help the development of research to unravel mechanisms underlying arterial calcification, the use of current or new devices to treat calcified lesions as well as to serve as an option for training interventionalists on the use of such devices.
Assuntos
Cloreto de Cálcio , Doenças das Artérias Carótidas/induzido quimicamente , Artéria Carótida Primitiva/patologia , Calcificação Vascular/induzido quimicamente , Animais , Fenômenos Biomecânicos , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , Artéria Carótida Primitiva/diagnóstico por imagem , Modelos Animais de Doenças , Elasticidade , Masculino , Neointima , Sus scrofa , Fatores de Tempo , Tomografia de Coerência Óptica , Ultrassonografia de Intervenção , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/patologiaRESUMO
Objective- We hypothesized that ob/ob mice develop expansive vascular remodeling associated with calcification. Approach and Results- We quantified and investigated mechanisms of vascular remodeling and vascular calcification in ob/ob mice after vitamin D3(VD) stimulation or PBS (control), compared with C57BL/6 mice. Both ob/ob (OBVD [VD-treated ob/ob mice]) and C57BL/6 (C57VD [VD-treated C57BL/6 mice]) received 8×103 IU/day of intraperitoneal VD for 14 days. Control ob/ob (OBCT [PBS-treated ob/ob mice]) and C57BL/6 (C57CT [PBS-treated C57BL/6 mice]) received intraperitoneal PBS for 14 days. Hypervitaminosis D increased the external and internal elastic length in aortae from OBVD, resulting in increased total vascular area and lumen vascular area, respectively, which characterizes expansive vascular remodeling. OBVD decreased the aortic wall thickness, resulting in hypotrophic vascular remodeling. We demonstrated increased collagen deposition, elastolysis, and calcification in aortae from OBVD. Our results showed a positive correlation between expansive vascular remodeling and vascular calcification in OBVD. We demonstrated increased serum calcium levels, augmented Bmp (bone morphogenetic protein)-2 and osteochondrogenic proteins expression in OBVD aortae. Furthermore, aortae from OBVD increased oxidative stress, coincidently with augmented in situ MMP (matrix metalloproteinase) activity and exhibited no VDR (VD receptor) inhibition after VD. Conclusions- Our data provide evidence that obese and insulin-resistant mice (ob/ob) developed expansive hypotrophic vascular remodeling correlated directly with increased vascular calcification after chronic VD stimulation. Positive hypotrophic vascular remodeling and vascular calcification in this mouse model is possibly mediated by the convergence of absence VDR downregulation after VD stimulation, increased reactive oxygen species generation, and MMP activation.
Assuntos
Colecalciferol/farmacologia , Resistência à Insulina , Obesidade/complicações , Calcificação Vascular/induzido quimicamente , Remodelação Vascular/efeitos dos fármacos , Animais , Cálcio/sangue , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Receptores de Calcitriol/fisiologia , Remodelação Vascular/fisiologiaRESUMO
In vascular smooth muscle, calcium overload is linked to advancing age. The pharmacokinetics of Sulfanilamide (SA), a compound with antibacterial properties, was evaluated in a preclinical model of vascular calcification. SA was used since it is useful to study possible modifications in the renal and hepatic management of drugs. Vascular calcification was induced by administration of a single high dose of vitamin D3 to rats (treated group) 10 days before the experiments. A parallel control group was processed. The decrease of renal blood flow due to calcification of the renal arteries explains, at least in part, the decrease in the renal clearance of SA observed in treated rats. The liver metabolic function increased in treated rats as demonstrated by increases in plasma appearance rate of acetylated-Sulfanilamide (ASA), hepatic ASA content and hepatic N-acetyltransferase activity. The decrease in renal excretion of SA was not completely compensated by the hepatic metabolism increase, since the elimination rate of SA from the central compartment (K1-0 ) decreased in the treated group. In summary, in this experimental model with sustained arterial calcinosis induced by a single high dose of vitamin D3 10 days before the experiments, the pharmacokinetics of an aminobenzenesulfonamide is modified, at least in part, by the increase in the activity of hepatic N-acetyltransferase and the decrease in renal blood flow. This study emphasizes the importance of considering the presence of vascular calcification when a drug dose scheme is performed, in order to optimize pharmacotherapeutic results.
Assuntos
Antibacterianos/farmacocinética , Sulfanilamida/farmacocinética , Calcificação Vascular/metabolismo , Acetilação , Acetiltransferases/metabolismo , Animais , Antibacterianos/administração & dosagem , Biotransformação , Colecalciferol , Modelos Animais de Doenças , Fígado/enzimologia , Circulação Hepática , Masculino , Modelos Biológicos , Ratos Wistar , Circulação Renal , Eliminação Renal , Sulfanilamida/administração & dosagem , Calcificação Vascular/sangue , Calcificação Vascular/induzido quimicamenteRESUMO
Vascular calcification decreases compliance and increases morbidity. Mechanisms of this process are unclear. The role of oxidative stress and effects of antioxidants have been poorly explored. We investigated effects of the antioxidants lipoic acid (LA) and tempol in a model of atherosclerosis associated with elastocalcinosis. Male New Zealand white rabbits (2.5-3.0 kg) were fed regular chow (controls) or a 0.5% cholesterol (chol) diet+104 IU/day vitamin D2 (vitD) for 12 weeks, and assigned to treatment with water (vehicle, n=20), 0.12 mmol·kg-1·day-1 LA (n=11) or 0.1 mmol·kg-1·day-1 tempol (n=15). Chol+vitD-fed rabbits developed atherosclerotic plaques associated with expansive remodeling, elastic fiber disruption, medial calcification, and increased aortic stiffness. Histologically, LA prevented medial calcification by â¼60% and aortic stiffening by â¼60%. LA also preserved responsiveness to constrictor agents, while intima-media thickening was increased. In contrast to LA, tempol was associated with increased plaque collagen content, medial calcification and aortic stiffness, and produced differential changes in vasoactive responses in the chol+vitD group. Both LA and tempol prevented superoxide signals with chol+vitD. However, only LA prevented hydrogen peroxide-related signals with chol+vitD, while tempol enhanced them. These data suggest that LA, opposite to tempol, can minimize calcification and compliance loss in elastocalcionosis by inhibition of hydrogen peroxide generation.
Assuntos
Arteriosclerose/prevenção & controle , Óxidos N-Cíclicos/administração & dosagem , Ácido Tióctico/administração & dosagem , Calcificação Vascular/prevenção & controle , Animais , Aorta Torácica , Arteriosclerose/induzido quimicamente , Arteriosclerose/metabolismo , Complacência (Medida de Distensibilidade)/efeitos dos fármacos , Complacência (Medida de Distensibilidade)/fisiologia , Modelos Animais de Doenças , Masculino , Coelhos , Marcadores de Spin , Calcificação Vascular/induzido quimicamente , Resistência Vascular , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
Vascular calcification decreases compliance and increases morbidity. Mechanisms of this process are unclear. The role of oxidative stress and effects of antioxidants have been poorly explored. We investigated effects of the antioxidants lipoic acid (LA) and tempol in a model of atherosclerosis associated with elastocalcinosis. Male New Zealand white rabbits (2.5-3.0 kg) were fed regular chow (controls) or a 0.5% cholesterol (chol) diet+104 IU/day vitamin D2 (vitD) for 12 weeks, and assigned to treatment with water (vehicle, n=20), 0.12 mmol·kg-1·day-1 LA (n=11) or 0.1 mmol·kg-1·day-1 tempol (n=15). Chol+vitD-fed rabbits developed atherosclerotic plaques associated with expansive remodeling, elastic fiber disruption, medial calcification, and increased aortic stiffness. Histologically, LA prevented medial calcification by ∼60% and aortic stiffening by ∼60%. LA also preserved responsiveness to constrictor agents, while intima-media thickening was increased. In contrast to LA, tempol was associated with increased plaque collagen content, medial calcification and aortic stiffness, and produced differential changes in vasoactive responses in the chol+vitD group. Both LA and tempol prevented superoxide signals with chol+vitD. However, only LA prevented hydrogen peroxide-related signals with chol+vitD, while tempol enhanced them. These data suggest that LA, opposite to tempol, can minimize calcification and compliance loss in elastocalcionosis by inhibition of hydrogen peroxide generation.
Assuntos
Animais , Masculino , Coelhos , Arteriosclerose/prevenção & controle , Óxidos N-Cíclicos/administração & dosagem , Ácido Tióctico/administração & dosagem , Calcificação Vascular/prevenção & controle , Aorta Torácica , Arteriosclerose/induzido quimicamente , Arteriosclerose/metabolismo , Complacência (Medida de Distensibilidade)/efeitos dos fármacos , Complacência (Medida de Distensibilidade)/fisiologia , Modelos Animais de Doenças , Marcadores de Spin , Resistência Vascular , Calcificação Vascular/induzido quimicamente , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
BACKGROUND/AIMS: Calcium overload in vascular smooth muscle is a highly pathogenic event, which progresses with advancing age. Old patients are polymedicated, and several pharmacotherapeutic agents circulate in the plasma as organic anions. The organic anion transporters 1 and 3 (Oat1 and Oat3) are present in renal basolateral membranes, which transport organic anions of pharmacological and physiological interest. This study was designed to evaluate the renal expression and function of Oat1 and Oat3 in rats with vascular calcification. METHODS: Vascular calcification was induced by administration of a single dose of vitamin D(3) (300,000 UI/ kg b.w., i.m.) to male Wistar rats 10 days before the experiments. Oat1 and Oat3 expression was assessed by immunoblotting, immunohistochemistry and reverse-transcriptase polymerase chain reaction. The renal clearance of p-aminohippurate (PAH, a prototypical organic anion, substrate of Oat1 and Oat3) was measured by conventional clearance techniques. RESULTS: Oat1 and Oat3 protein levels showed an increase in plasma membranes of renal proximal tubules of treated animals, where both transporters are functional. This could explain the increase observed in the renal clearance of PAH in treated rats. CONCLUSIONS: These results suggest the relevance of considering the existence of vascular calcification, which is common in ageing, when organic anion drugs are prescribed.