RESUMEN
The aim of this study was to characterize a glucagon challenge test as a tool in diabetes research by assessing the inter- and intra-individual variability, and investigating the activity of the autonomic nervous system (ANS) during the challenge, as this might have an indirect impact on glucose homeostasis. The study was performed in 24 healthy volunteers separated in 2 groups. The first group of 12 volunteers underwent a 5-h glucagon challenge during a pancreatic clamp procedure with infusion of [6,6-2H2]-glucose infusion in combination with heart rate variability measurements. In the second group, 12 other healthy volunteers underwent two 6-h glucagon challenges separated by 6 weeks, and fat biopsies were taken for analysis of glucagon receptor expression. Serum glucose rose rapidly after glucagon infusion, and reached a plateau at 90 min. The time profiles suggested rapid development of tolerance for glucagon-induced hyperglycemia. During the glucagon challenge intra- and inter-individual variabilities for hepatic glucose production, the rate of disappearance of glucose, and plasma glucose were approximately 10-15% for all variables. Hyperglucagonemia did not affect heart rate variability. Human adipose tissue had a low, but variable, expression of glucagon receptor mRNA. This standardized glucagon challenge test has a good reproducibility with only limited variability over 6 weeks. It is a robust tool to explore in detail the contribution of glucagon in normal and altered glucose homeostasis and can also be used to evaluate the effects of drugs antagonizing glucagon action in humans without confounding changes in ANS tone.
Asunto(s)
Glucagón/farmacología , Farmacología Clínica/métodos , Farmacología Clínica/normas , Investigación , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Adolescente , Adulto , Glucemia/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glucagón/sangre , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Glucagón/genética , Receptores de Glucagón/metabolismo , Estándares de Referencia , Factores de Tiempo , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: Insulin action is purportedly modulated by Drosophila tribbles homologue 3 (TRIB3), which in vitro prevents thymoma viral proto-oncogene (AKT) and peroxisome proliferator-activated receptor-γ (PPAR-γ) activation. However, the physiological impact of TRIB3 action in vivo remains controversial. METHODS: We investigated the role of TRIB3 in rats treated with either a control or Trib3 antisense oligonucleotide (ASO). Tissue-specific insulin sensitivity was assessed in vivo using a euglycaemic-hyperinsulinaemic clamp. A separate group was treated with the PPAR-γ antagonist bisphenol-A-diglycidyl ether (BADGE) to assess the role of PPAR-γ in mediating the response to Trib3 ASO. RESULTS: Trib3 ASO treatment specifically reduced Trib3 expression by 70% to 80% in liver and white adipose tissue. Fasting plasma glucose, insulin concentrations and basal rate of endogenous glucose production were unchanged. However, Trib3 ASO increased insulin-stimulated whole-body glucose uptake by ~50% during the euglycaemic-hyperinsulinaemic clamp. This was attributable to improved skeletal muscle glucose uptake. Despite the reduction of Trib3 expression, AKT2 activity was not increased. Trib3 ASO increased white adipose tissue mass by 70% and expression of Ppar-γ and its key target genes, raising the possibility that Trib3 ASO improves insulin sensitivity primarily in a PPAR-γ-dependent manner. Co-treatment with BADGE blunted the expansion of white adipose tissue and abrogated the insulin-sensitising effects of Trib3 ASO. Finally, Trib3 ASO also increased plasma HDL-cholesterol, a change that persisted with BADGE co-treatment. CONCLUSIONS/INTERPRETATION: These data suggest that TRIB3 inhibition improves insulin sensitivity in vivo primarily in a PPAR-γ-dependent manner and without any change in AKT2 activity.
Asunto(s)
Resistencia a la Insulina/fisiología , PPAR gamma/metabolismo , Proteínas Quinasas/metabolismo , Animales , Compuestos de Bencidrilo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animales de Enfermedad , Compuestos Epoxi/farmacología , Técnica de Clampeo de la Glucosa , Immunoblotting , Resistencia a la Insulina/genética , Masculino , Oligonucleótidos Antisentido/genética , PPAR gamma/antagonistas & inhibidores , PPAR gamma/genética , Proteínas Quinasas/genética , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The PI-3 kinase signalling pathway is an important pathway in mediating the glucoregulatory effects of insulin and skeletal muscle (SKM) is the major tissue involved in glucose utilization. In diabetes this pathway is impaired, either due to lack of insulin as in Type I diabetes, or due to insulin resistance as in Type 2 diabetes. Bis(maltolato)-oxovanadium IV (BMOV), an insulin mimetic/enhancing agent, produces a marked glucose lowering effect in models of both types of diabetes. Some in vitro studies have shown that phosphatidylinositol 3 kinase (PI-3 kinase) activity is enhanced by vanadium. In the present study we looked at changes in PI-3 kinase expression and activity in SKM from STZ-diabetic and fa/fa Zucker rats treated with BMOV for 3 weeks. Although BMOV treatment completely normalized glucose levels in STZ-diabetic rats, no effect was observed on basal or insulin-stimulated PI-3 kinase activity. In fatty Zucker rats, activation of PI-3 kinase activity after insulin injection was impaired as compared to age matched lean controls, but BMOV again did not affect the activity. These results suggest that although PI-3 kinase is an important signalling factor in glucose utilization, vanadium treatment does not reduce hyperglycemia through activation of SKM PI-3 kinase in vivo.
Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Músculo Esquelético/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Pironas/farmacología , Vanadatos/farmacología , Animales , Peso Corporal , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Tipo 2/enzimología , Hipoglucemiantes/farmacología , Insulina/sangre , Insulina/farmacología , Masculino , Músculo Esquelético/enzimología , Músculo Esquelético/metabolismo , Pironas/administración & dosificación , Ratas , Ratas Wistar , Ratas Zucker , Transducción de Señal/fisiología , Vanadatos/administración & dosificaciónRESUMEN
In this study, the in vivo effects of insulin and chronic treatment with bis(maltolato)oxovanadium (IV) (BMOV) on protein kinase B (PKB) activity were examined in the liver and skeletal muscle from two animal models of diabetes, the STZ-diabetic Wistar rat and the fatty Zucker rat. Animals were treated with BMOV in the drinking water (0.75-1 mg/ml) for 3 (or 8) weeks and sacrificed with or without insulin injection. Insulin (5 U/kg, i.v.) increased PKBalpha activity more than 10-fold and PKBbeta activity more than 3-fold in both animal models. Despite the development of insulin resistance, insulin-induced activation of PKBalpha was not impaired in the STZ-diabetic rats up to 9 weeks of diabetes, excluding a role for PKBalpha in the development of insulin resistance in type 1 diabetes. Insulin-induced PKBalpha activity was markedly reduced in the skeletal muscle of fatty Zucker rats as compared to lean littermates (fatty: 7-fold vs. lean: 14-fold). In contrast, a significant increase in insulin-stimulated PKBalpha activity was observed in the liver of fatty Zucker rats (fatty: 15.7-fold vs. lean: 7.6-fold). Chronic treatment with BMOV normalized plasma glucose levels in STZ-diabetic rats and decreased plasma insulin levels in fatty Zucker rats but did not have any effect on basal or insulin-induced PKBalpha and PKBbeta activities. In conclusion (i) in STZ-diabetic rats PKB activity was normal up to 9 weeks of diabetes; (ii) in fatty Zucker rats insulin-induced activation of PKBalpha (but not PKBbeta) was markedly altered in both tissues; (iii) changes in PKBalpha activity were tissue specific; (iv) the glucoregulatory effects of BMOV were independent of PKB activity.
Asunto(s)
Diabetes Mellitus/enzimología , Insulina/farmacología , Hígado/enzimología , Músculo Esquelético/enzimología , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Pironas/farmacología , Vanadatos/farmacología , Animales , Glucemia/metabolismo , Peso Corporal , Diabetes Mellitus Experimental/enzimología , Diabetes Mellitus Tipo 2/enzimología , Prueba de Tolerancia a la Glucosa , Insulina/administración & dosificación , Insulina/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Proteínas Proto-Oncogénicas c-akt , Pironas/administración & dosificación , Distribución Aleatoria , Ratas , Ratas Wistar , Ratas Zucker , Extractos de Tejidos/química , Vanadatos/administración & dosificaciónRESUMEN
A vast array of fluoroquinolones having excellent broad-spectrum activity form an invaluable part of the present anti-infective armory of the clinicians. A number of these compounds are today's blockbusters of the antibacterial market due to their therapeutic efficacy having tolerable side effects and thus challenging the predominance of well established beta-lactam antibiotics which are becoming more prone to the resistant pathogenic bacteria. Since the discovery of nalidixic acid the development of fluoroquinolones has experienced an exponential growth and is being continued with more vigor to obtain better drugs having multifunctional action. This article attempts to review the current developments of the chemical and biological aspects of fluoroquinolones in a chronological manner touching upon their antibacterial properties based on the structure activity relationship while pointing out to their mode of action. It also provides an insight into a variety of approaches resulting in elegant manipulations of their basic skeleton and some breakthroughs in their synthetic strategies of a few widely used drugs, which had helped in accelerating their market growth as well as continuing research for newer fluoroquinolones. Since the mode of action of fluoroquinolones being different from beta-lactams and their transportation to the target site is slow several dual action quinolonyl-beta-lactams (Penicillins, Cephalosporins, Penems, Cephems, Carbapenams etc.) have come as a major breakthrough among the hybrid antibiotics. While focusing on the multifunctional activities of such compounds, this review briefly points out to the current trends in various techniques for de novo drug design and development of newer therapeutic molecules, which hold future promises in combating the fight against drug resistant bacteria as it still remains to be won.
Asunto(s)
Antiinfecciosos/farmacología , Antiinfecciosos/síntesis química , Antiinfecciosos/clasificación , Fluoroquinolonas , Relación Estructura-ActividadRESUMEN
The effects of tail-vein insulin injection (2 U/kg) on the regulation of protein-serine kinases in hindlimb skeletal muscle were investigated in hyperinsulinemic hypertensive fructose-fed (FF) animals that had been fasted overnight. Basal protein kinase B (PKB) activity was elevated about twofold in FF rats and was not further stimulated by insulin. Phosphatidylinositol 3-kinase (PI3K), which lies upstream of PKB, was increased approximately 3.5-fold within 2-5 min by insulin in control rats. Basal and insulin-activated PI3K activities were further enhanced up to 2-fold and 1.3-fold, respectively, in FF rats. The 70-kDa S6 kinase (S6K) was stimulated about twofold by insulin in control rats. Both basal and insulin-stimulated S6K activity was further enhanced up to 1.5-fold and 3.5-fold, respectively, in FF rats. In control rats, insulin caused a 40-50% reduction of the phosphotransferase activity of the beta-isoform of glycogen synthase kinase 3 (GSK-3beta), which is a PKB target in vitro. Basal GSK-3beta activity was decreased by approximately 40% in FF rats and remained unchanged after insulin treatment. In summary, 1) the PI3K --> PKB --> S6K pathway was upregulated under basal conditions, and 2) insulin stimulation of PI3K and S6K activities was enhanced, but both PKB and GSK-3 were refractory to the effects of insulin in FF rats.
Asunto(s)
Fructosa , Hipertensión/inducido químicamente , Hipertensión/enzimología , Insulina/fisiología , Músculo Esquelético/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Activación Enzimática/fisiología , Glucógeno Sintasa Quinasa 3 , Glucógeno Sintasa Quinasas , Hiperinsulinismo/enzimología , Hipertensión/metabolismo , Proteína Básica de Mielina/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfotransferasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas S6 Ribosómicas/metabolismoRESUMEN
The fructose-induced hypertensive rat is a widely used model to study the inter-relationship between hyperinsulinemia, insulin resistance and high blood pressure. Evidence suggests that hyperinsulinemia and insulin resistance may be pathogenic in the development of high blood pressure in this model. To determine the contribution of the sympathetic nervous system towards fructose-induced hypertension, the present study examined the effects of chemical sympathectomy (adrenal medullectomy, followed by weekly 6-hydroxydopamine injections) on plasma insulin levels and systolic blood pressure in control and fructose-induced hypertensive rats. Sympathectomy abrogated the development of both hyperinsulinemia and hypertension in fructose hypertensive rats without affecting these parameters in control rats. These data uncover, for the first time, the primacy of the sympathetic nervous system as a mediator of both elevated plasma insulin levels and high blood pressure in rats fed a high fructose diet.
Asunto(s)
Fructosa/farmacología , Hiperinsulinismo/prevención & control , Hipertensión/prevención & control , Simpatectomía , Animales , Presión Sanguínea/fisiología , Hiperinsulinismo/inducido químicamente , Hipertensión/inducido químicamente , Insulina/sangre , Masculino , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/fisiopatología , Sistema Nervioso Simpático/cirugíaRESUMEN
In the shark, C-type natriuretic peptide (CNP) is the only cardiac natriuretic hormone identified and is a potent activator of Cl- secretion in the rectal gland, an epithelial organ of this species that contains cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channels. We have cloned an ancestral CNP receptor (NPR-B) from the shark rectal gland that has an overall amino acid identity to the human homologue of 67%. The shark sequence maintains six extracellular Cys present in other NPR-B but lacks a glycosylation site and a Glu residue previously considered important for CNP binding. When shark NPR-B and human CFTR were coexpressed in Xenopus oocytes, CNP increased the cGMP content of oocytes (EC50 12 nM) and activated CFTR Cl- channels (EC50 8 nM). Oocyte cGMP increased 36-fold (from 0.11 +/- 0.03 to 4.03 +/- 0.45 pmol/oocyte) and Cl- current increased 37-fold (from -34 +/- 14 to -1,226 +/- 151 nA) in the presence of 50 nM CNP. These findings identify the specific natriuretic peptide receptor responsible for Cl- secretion in the shark rectal gland and provide the first evidence for activation of CFTR Cl- channels by a cloned NPR-B receptor.
Asunto(s)
Clonación Molecular , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Guanilato Ciclasa , Receptores del Factor Natriurético Atrial/genética , Receptores del Factor Natriurético Atrial/metabolismo , Glándula de Sal/metabolismo , Secuencia de Aminoácidos/genética , Animales , Cloruros/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/fisiología , Cazón , Electrofisiología , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Nucleótidos Cíclicos/metabolismo , Oocitos/metabolismo , ARN Mensajero/metabolismo , Receptores del Factor Natriurético Atrial/fisiología , XenopusRESUMEN
The in vivo effects of bis(maltolato)oxovanadium (IV) (BMOV) on the activity of protein serine kinases in skeletal muscle of STZ-diabetic Wistar rats were studied. BMOV was administered to STZ-diabetic rats at a concentration of 0.75 mg/ml for 8 weeks. Chronic BMOV treatment completely normalized plasma glucose levels in the diabetic animals after 8 weeks of treatment. Insulin-stimulated ERK-1 and ERK-2 activity was markedly increased in STZ-diabetic rats. Chronic BMOV treatment normalized the activity of ERK-2 in the diabetic treated animals, whereas the activity of ERK-1 was unaffected. In contrast to ERK-1 and ERK-2, the activity of the ribosomal S6 kinase p90rsk was decreased in STZ-diabetic rats. BMOV treatment restored the activity to normal levels. Basal p70 S6K activity was increased about 2.5-fold in the untreated diabetic group and no further increase in activity was observed after insulin stimulation. BMOV treatment did not correct the changes in p70 S6K activity in either the basal or insulin-stimulated states. In conclusion (i) the activity of ERK-1, ERK-2 and p90rsk were altered in skeletal muscle of STZ-diabetic rats; (ii) the glucoregulatory effects of BMOV were accompanied by concurrent improvement in the activities of ERK-2 and p90rsk; and (iii) there appears to be a dissociation between the activation of ERK-2 and p90rsk, suggesting that the regulation of p90rsk may be much more complex in vivo.
Asunto(s)
Diabetes Mellitus Experimental/enzimología , Hipoglucemiantes/farmacología , Músculo Esquelético/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Pironas/farmacología , Vanadatos/farmacología , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Experimental/sangre , Insulina/farmacología , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Ratas , Ratas WistarRESUMEN
Effects of pioglitazone on plasma insulin levels, systolic blood pressure and arterial reactivity were studied in spontaneously hypertensive (SH) rats. Chronic treatment of SH rats with pioglitazone decreased plasma insulin levels and blood pressure. Direct effects of pioglitazone on vascular reactivity were also studied in aortae and superior mesenteric arteries from SH rats. Pioglitazone markedly inhibited arginine vasopressin (AVP) and norepinephrine (NE) responses without affecting responses to potassium chloride (KCl). These data suggest that (a) antihypertensive effects of pioglitazone in SH rats may be mediated via a direct vasodepressor effect, and (b) vasodilation may be coupled to insulin sensitivity in SH rats.
Asunto(s)
Hiperinsulinismo/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Tiazoles/uso terapéutico , Tiazolidinedionas , Vasodilatadores/uso terapéutico , Animales , Arginina Vasopresina/farmacología , Evaluación Preclínica de Medicamentos , Insulina/sangre , Masculino , Norepinefrina/farmacología , Pioglitazona , Cloruro de Potasio/farmacología , Ratas , Ratas Endogámicas SHRRESUMEN
We previously demonstrated that mesenteric arteries from hyperinsulinemic, insulin resistant fructose hypertensive (FH) rats contain a higher absolute amount of ET-1 and exhibit defective endothelium-dependent vasodilation. Furthermore, chronic ET receptor blockade with bosentan completely prevented the rise in blood pressure in these rats. The present study was undertaken to examine 1) whether the reactivity of mesenteric arteries to ET-1 is altered in FH rats, and 2) whether chronic bosentan treatment has any effect on ET-1 responsiveness and endothelium-dependent vasodilation. Male Sprague Dawley rats were divided into four groups: control (C), control bosentan-treated (CB), fructose (F) and fructose bosentan-treated (FB). Chronic oral bosentan treatment (100 mg/kg/day) was initiated in the CB and FB groups 1 week prior to initiating the fructose diet. At week 16, the F group was hyperinsulinemic and hypertensive when compared to the C group (plasma insulin: 5.8 +/- 0.3 v C 3.2 +/- 0.5 ng/mL, P < .001; systolic BP: 157 +/- 5 v C 130 +/- 4 mm Hg, P < .001). Treatment of the F group with bosentan prevented the rise in BP (FB: 133 +/- 3 mm Hg; P < .001 v F). Analysis of the pressurized mesenteric resistance arterioles demonstrated that the wall thickness as expressed as percentage of internal diameter did not differ between arteries from C and F rats, when measured over a range of transmural pressures. Constrictor responses of resistance arterioles to NE were similar for C and F rats when studied at transmural pressures of either 120 mm Hg or 160 mm Hg, respectively. The maximum contractile response and the sensitivity of superior mesenteric arteries to NE did not differ between the groups, either with or without the endothelium. However, the maximum contractile response to ET-1 was depressed in the F group both with (+) and without (-) the endothelium [(+): 1.50 +/- 0.11 v C 1.88 +/- 0.1 g/mm3, P < .05, (-): 1.68 +/- 0.11 v C 2.05 +/- 0.1 g/mm3, P < .05.]. Furthermore, the endothelium intact F arteries exhibited a decreased sensitivity to ET-1 (pD2 values F 8.36 +/- 0.11 v C 8.83 +/- 0.07). Chronic bosentan treatment of the F group restored the maximum tension responses of arteries to ET-1 [(+) in the FB group: 1.88 +/- 0.12 g/mm3 v C, P > .05, (-): 1.95 +/- 0.05 g/mm3 v C, P > .05] but had no effect on the responses of the CB group. In arteries with intact endothelium, bosentan treatment restored the sensitivity of the F arteries to ET-1 (pD2 values FB 8.82 +/- 0.05 v C, P < .05). Endothelium-dependent relaxation responses were diminished in the F group, which were unaffected by bosentan treatment. These data suggest that mesenteric arteries from FH demonstrate a specific alteration towards the reactivity to ET-1, which is restored by long-term bosentan treatment.
Asunto(s)
Endotelina-1/farmacología , Fructosa , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Arterias Mesentéricas/efectos de los fármacos , Animales , Antihipertensivos/farmacología , Bosentán , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Masculino , Arterias Mesentéricas/fisiopatología , Norepinefrina/farmacología , Ratas , Ratas Sprague-Dawley , Sulfonamidas/farmacología , Resistencia Vascular , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
OBJECTIVES: To determine the effects of calcium antagonists on hyperinsulinemia, hypertriglyceridemia and hypertension, we examined the long-term effects of a new calcium channel blocker, mibefradil, on plasma insulin levels, plasma triglyceride levels and systolic blood pressure in insulin-resistant and hyperinsulinemic fructose-hypertensive (FH) rats. To this aim, both prevention and reversal protocols were employed. METHODS: Prevention study: Male Sprague-Dawley rats were procured at 6 weeks of age and were divided into: control (C, n = 6), control-treated (CT, n = 5), fructose (F, n = 7) and fructose-treated (FT, n = 6). Baseline measurements of plasma glucose, insulin and systolic blood pressure were conducted in all groups. At week 7, chronic mibefradil treatment (30 mg/kg/day, orally for 6 weeks) was initiated in the CT and FT groups. At week 8, the rats in the F and FT groups were started on a 66% fructose diet to induce hyperinsulinemia and hypertension. Weekly measurements of plasma insulin, plasma triglycerides and systolic blood pressure were conducted for the following 4 weeks. Reversal protocol: In a separate study, 8-week-treated FH rats and their age-matched controls were used to examine the effects of mibefradil on reversing fructose-induced hyperinsulinemia and hypertension. RESULTS: The F group exhibited hyperinsulinemia (3.2 +/- 0.1 vs. C 2.3 +/- 0.07 ng/ml, P < 0.05), hypertension (148 +/- 3 vs. C 121 +/- 1 mmHg, P < 0.002) and elevated triglyceride levels (5.4 +/- 0.8 vs. C 1.6 +/- 0.3 mM, P < 0.05). Chronic mibefradil treatment prevented the development of hyperinsulinemia (1.6 +/- 0.08 ng/ml, P < 0.004 vs. F) and hypertension (123 +/- 1 mmHg. P < 0.001 vs. F) and attenuated the development of hypertriglyceridemia. In the reversal study, mibefradil treatment reversed the development of hyperinsulinemia, hypertriglyceridemia and elevated BP in FH rats. Treatment did not affect the plasma glucose levels in any group (prevention or reversal). CONCLUSIONS: Long-term treatment with the calcium antagonist, mibefradil, both prevents and reverses the development of hyperinsulinemia, hypertriglyceridemia and hypertension in FH rats. These data indicate beneficial effects of mibefradil on carbohydrate and lipid metabolism in hyperinsulinemic and insulin-resistant states.
Asunto(s)
Bencimidazoles/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Hiperinsulinismo/prevención & control , Hipertensión/prevención & control , Resistencia a la Insulina , Tetrahidronaftalenos/uso terapéutico , Animales , Glucemia/análisis , Fructosa , Hiperinsulinismo/sangre , Hiperinsulinismo/tratamiento farmacológico , Hipertensión/sangre , Hipertensión/tratamiento farmacológico , Masculino , Mibefradil , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangreRESUMEN
Evidence suggests that insulin has direct, potent and physiologically relevant vasodilatory effects. This has led to the hypothesis that in states of insulin resistance, insulin's vasodilatory effects may be blunted leading to an increase in vascular tone and blood pressure. To examine this proposition we studied the direct effects of insulin on the reactivity of aortae from control and insulin-resistant fructose-hypertensive rats to angiotensin II. Insulin incubation caused marked vasodepressor effects in control aortae. Strikingly, this effect was absent in aortae from fructose-hypertensive rats. These data suggest the presence of vascular insulin resistance in fructose-hypertensive rats and provide a hemodynamic basis for hypertension in states of insulin resistance.
Asunto(s)
Fructosa/toxicidad , Hipertensión/inducido químicamente , Resistencia a la Insulina , Animales , Insulina/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Vasodilatación/fisiologíaRESUMEN
We have previously demonstrated that long-term metformin treatment prevents the development of hyperinsulinemia and hypertension in fructose-hypertensive (FH) rats; however, the exact nature of its antihypertensive effects remains elusive. Since hyperinsulinemia has been proposed to be a strong stimulus for norepinephrine (NE) release, the present study examined the effects of long-term metformin treatment (500 mg/kg/d for 10 weeks) on the reactivity of superior mesenteric arteries to NE in FH rats. Metformin treatment prevented the development of hyperinsulinemia and hypertension in FH rats. Mesenteric arteries from FH rats exhibited an increased cross-sectional area ([CSA] 0.45 +/- 0.07 mm2 v 0.32 +/- 0.05 in controls, P < .05), which was prevented by long-term metformin treatment (0.34 +/- 0.04 mm2, p > .05 v untreated FH). Interestingly, mesenteric arteries from metformin-treated fructose and control rats exhibited a reduction in maximum responsiveness to NE both with and without the endothelium. These data suggest that metformin directly reduces catecholamine constrictor responses in resistance arteries of rats, which may contribute to its antihypertensive effects in rats.
Asunto(s)
Antihipertensivos/uso terapéutico , Fructosa/efectos adversos , Hipertensión/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Arterias Mesentéricas/efectos de los fármacos , Metformina/uso terapéutico , Animales , Antihipertensivos/farmacología , Hiperinsulinismo/prevención & control , Hipertensión/fisiopatología , Hipertensión/prevención & control , Hipoglucemiantes/farmacología , Masculino , Arterias Mesentéricas/fisiopatología , Metformina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
The present study examined the endothelium-dependent and -independent responses of isolated mesenteric arteries to acetylcholine and the endothelium-independent vasodilator sodium nitroprusside in mesenteric arteries from fructose-induced hypertensive rats. Fructose feeding resulted in hyperinsulinemia and elevated blood pressure when compared to controls (plasma insulin, 5.9 +/- 0.4 v control 3.6 +/- 0.4 ng/mL, P < .05; systolic blood pressure, 154 +/- 5 v control 127 +/- 7 mm Hg, P < .05). The maximum contractile response of mesenteric arteries to norepinephrine did not differ between the control and fructose groups, either with or without the endothelium. In arteries with intact endothelia, precontracted with the approximate ED50 of norepinephrine, the percent maximum relaxation produced by acetylcholine in hypertensive rats was lower than the control arteries (62 +/- 7 v control 95 +/- 5, P < .05) without any change in sensitivity. In arteries precontracted with norepinephrine, the endothelium-independent vasodilator sodium nitroprusside produced a dose-dependent relaxation in arteries obtained from control and fructose groups, both with and without the endothelium. The maximum relaxation produced by sodium nitroprusside did not differ between control and fructose arteries, either with or without the endothelium; however, removal of the endothelium caused an increase in sensitivity of this agonist. These data suggest that in the insulin resistant and hyperinsulinemic fructose-hypertensive rats, there is a defective endothelium-dependent yet preserved endothelium-independent relaxation.
Asunto(s)
Fructosa/toxicidad , Hipertensión/inducido químicamente , Óxido Nítrico/metabolismo , Acetilcolina/farmacología , Animales , Hipertensión/metabolismo , Insulina/sangre , Resistencia a la Insulina , Masculino , Arterias Mesentéricas/efectos de los fármacos , Óxido Nítrico/fisiología , Nitroprusiato/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Evidence suggests that hyperinsulinemia may be causally related to the development of high blood pressure (BP) in fructose-hypertensive (FH) rats. Because plasma insulin has been shown to modulate endothelin (ET) release in vivo, we hypothesized that hyperinsulinemia may provide a continual stimulus for ET release, which could increase BP by altering plasma or blood vessel ET levels. To test this hypothesis, we studied the effect of chronic ET-receptor blockade (by using bosentan, a noncompetitive ET antagonist) on plasma insulin levels, plasma ET levels, blood vessel ET content, and BP in FH rats. Chronic oral bosentan treatment (100 mg.kg-1.day-1) was initiated in 6-wk-old Sprague-Dawley rats. One week after bosentan treatment was started, rats were fed either normal rat chow or a fructose-enriched diet. Plasma insulin, plasma glucose, and systolic BP were measured weekly. At termination (in 15-wk-old rats), plasma ET levels and total mesenteric ET content were determined. Bosentan treatment caused a sustained decrease in BP in the FH rats (treated 130 +/- 4 vs. untreated 149 +/- 2 mmHg, P < 0.001) but had no effect in the normotensive control group. FH rats had a higher total mesenteric ET content compared with the control group (21.5 +/- 3.2 vs. 14.1 +/- 2.1 fmol, P < 0.05). Bosentan treatment did not alter total mesenteric ET content (treated 18.8 +/- 5 fmol, P > 0.05 vs. untreated) nor did it affect plasma insulin or ET levels in any group. These data suggest that ET may be involved in the development of high BP in FH rats. Whether ET represents an intermediate, linking hyperinsulinemia to hypertension in rats, or is an independent hypertensinogenic mechanism remains to be determined.
Asunto(s)
Endotelinas/antagonistas & inhibidores , Hiperinsulinismo/fisiopatología , Hipertensión/fisiopatología , Animales , Glucemia/metabolismo , Bosentán , Fructosa , Hipertensión/inducido químicamente , Insulina/sangre , Masculino , Arterias Mesentéricas/metabolismo , Ratas , Ratas Sprague-Dawley , Sulfonamidas/farmacología , Factores de TiempoRESUMEN
Although considerable evidence lends credence to the association between insulin resistance, hyperinsulinemia and essential hypertension, the precise nature of this relationship remains unexplained. In the present investigation, we examined the proposition that these metabolic defects contribute causally to the development of high blood pressure. If these metabolic abnormalities were responsible for the development of hypertension, then drug interventions that improve these defects should also decrease high blood pressure. Since previous studies have demonstrated that vanadium compounds enhance insulin action and lower plasma insulin levels in nondiabetic rats, we examined the effects of these compounds on insulin sensitivity, plasma insulin concentration and blood pressure in two hyperinsulinemic models of experimental hypertension. The animal models studied were the genetically predisposed spontaneously hypertensive rat and the fructose-hypertensive rat, where hypertension is induced in normotensive rats by feeding them a high fructose diet. Vanadium compounds caused marked and sustained decreases in plasma insulin concentration and blood pressure in both the animal models studied. Furthermore, the effect of the drugs on blood pressure was reversed by restoring plasma insulin levels in the drug-treated rats to those observed in their untreated counterparts. These data suggest that either hyperinsulinemia contributes to the development of hypertension in both the spontaneously hypertensive and the fructose-hypertensive rats or that the underlying mechanism is closely related to the expression of both these disorders.
Asunto(s)
Hiperinsulinismo/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Compuestos de Vanadio/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Hiperinsulinismo/fisiopatología , Hipertensión/fisiopatología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
OBJECTIVES: To evaluate the safety, feasibility, and efficacy of transurethral ablative prostatectomy (TURAPY), a radiofrequency method of thermal tissue ablation of benign prostatic hyperplasia (BPH). METHODS: Twenty men, ages 55 to 81 years (mean, 67), with symptomatic BPH and with peak flow rate 12 mL/s or less, were treated with the TURAPY device (Direx Medical Systems). A 2 cm long heating element and 2 thermoprobes (for simultaneous prostatic temperature monitoring) are mounted on a Foley-like catheter and used for TURAPY treatment administration. This TURAPY catheter was modified by placing an extra set of thermoprobes in the sphincter region to allow sphincteric temperature monitoring. The treatment was administered at a maximum temperature of 70 degrees to 75 degrees C for 1 hour under local anesthesia as a day case. RESULTS: All 20 patients completed the treatment. The maximum recorded rectal temperature was 39.5 degrees C. The maximum sphincter temperature was not allowed to exceed 42 degrees C. The post-treatment morbidity included dysuria and minor urethral bleeding in 12 patients. Three patients developed urinary infection requiring antibiotic treatment. All 20 patients were followed up 3 months after treatment. The mean International Prostate Symptom Score (IPSS) improved from 19.4 to 6.2 (68%), the mean peak flow rate increased from 7.9 to 12.9 mL/s (63%), and the mean postvoid residue decreased from 222 to 81 mL (64%). Overall, 80% of patients exhibited at least a 50% improvement in either the IPSS or the peak flow rate. There was a mean reduction in prostatic volume measured by transrectal ultrasound of 14 mL (29% reduction). The subjective and objective improvements, in 8 patients followed up 6 months after treatment, have been maintained. There was extensive coagulative heat necrosis of periurethral tissue with sparing of subcapsular tissue in prostate biopsy specimens taken from 1 patient 5 days after treatment. There was endoscopic and sonographic evidence of canalization of the obstructed prostatic urethra 3 months after treatment. CONCLUSIONS: Treatment with the TURAPY device was found to be safe, feasible, and effective in improving both subjective and objective measurements of benign prostatic obstruction in this pilot study on 20 patients.