RESUMEN
In experimental and human diabetes mellitus, evidence for an impaired function of the vascular endothelium has been found and has been suggested to contribute to the development of vascular complications in this disease. The aim of the study was to evaluate possible regional hemodynamic in vivo differences between healthy and diabetic rats which would involve nitric oxide (NO). Central hemodynamics and regional blood flow (RBF) were studied using radioactive microspheres in early streptozotocin (STZ)-diabetic rats and compared to findings in healthy control animals. This method provides a possibility to study the total blood flow and vascular resistance (VR) in several different organs simultaneously. L-NAME iv induced widespread vasoconstriction to a similar extent in both groups. In the masseter muscle of both groups, acetylcholine 2 microg/kg per min, induced a RBF increase, which was abolished by pretreatment with L-NAME, suggesting NO as a mediator of vasodilation. In the heart muscle of both groups, acetylcholine alone was without effect while the combined infusion of acetylcholine and L-arginine induced an L-NAME-sensitive increase in RBF. The vasodilation induced by high-dose acetylcholine (10 microg/kg per min) in the kidney was more pronounced in the STZ-diabetic rats. The results indicate no reduction in basal vasodilating NO-tone in the circulation of early diabetic rats. The sensitivity to vasodilating effects of acetylcholine at the level of small resistance arterioles vary between tissues but was not impaired in the diabetic rats. In the heart muscle the availability of L-arginine was found to limit the vasodilatory effect of acetylcholine in both healthy and diabetic rats. In conclusion, the results indicate a normal action of NO in the investigated tissues of the early STZ-diabetic rat.
Asunto(s)
Circulación Cerebrovascular , Circulación Coronaria , Diabetes Mellitus Experimental/fisiopatología , Hemostasis , Músculo Masetero/irrigación sanguínea , Óxido Nítrico/metabolismo , Circulación Renal , Acetilcolina/farmacología , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Músculo Masetero/efectos de los fármacos , Músculo Masetero/fisiopatología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/agonistas , Óxido Nítrico/antagonistas & inhibidores , Especificidad de Órganos , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Estreptozocina , Resistencia Vascular/efectos de los fármacosRESUMEN
Using both in vitro and in vivo techniques, it has repeatedly been shown that endothelium-dependent vasodilation (EDV) is impaired in different forms of experimental hypertension (SHR, Dahl salt-sensitive rat, DOCA-salt rat and renovascular hypertension). EDV has also been found to be impaired in primary, as well as in secondary forms of human hypertension. Although impaired EDV is a general finding in hypertension, the pathophysiological mechanisms might differ between different forms of hypertension and between different types of vessels and vascular beds. Impaired activity of nitric oxide synthase, increased release of endothelin-1, increased production of a prostanoid-derived contracting factor, decreased generation of endothelium-derived hyperpolarizing factor/s and impairment caused by superoxide ions have all been shown to contribute to the impairment of EDV during different conditions. While most antihypertensive treatments improve EDV in experimental hypertension, no uniform picture has been seen in human hypertension, possibly because different antihypertensive drugs have different direct actions on EDV. This review shows that while impaired EDV has been found to be a general feature of hypertension, the mechanisms involved and the therapeutic opportunities have still to be established.
Asunto(s)
Endotelio Vascular/fisiopatología , Hipertensión/fisiopatología , Vasodilatación , Animales , Circulación Sanguínea , Endotelinas/fisiología , Humanos , Óxido Nítrico/fisiologíaRESUMEN
PURPOSE: In experimental and human diabetes mellitus evidence for an impaired function of the vascular endothelial cells has been found. The purpose of the present experiments was to measure uveal and retinal blood flow and vascular resistance at an early stage of experimental diabetes mellitus and to evaluate the effects of acetylcholine and L-arginine in control and L-NAME-pretreated animals. METHOD: The radioactively labelled microsphere method was applied to normal Sprague-Dawley rats and rats with STZ-induced diabetes of three weeks duration. RESULTS: In the present study, similar blood flow and vascular resistance were observed in the uvea of normal and STZ-diabetic rats. Evidence for a basal vasodilating NO-tone was found both in the uvea and in the retina of both groups. In the normal rats as well as in the diabetic animals, acetylcholine induced choroidal vasodilation. Local blood flow increased from 54 +/- 17 to 142 +/- 32 mg x min(-1) in normal rats and from 57 +/- 18 to 112 +/- 23 mg x min(-1) in diabetic rats (P < 0.05 respectively). No hemodynamic changes were observed in the anterior uvea, demonstrating a difference in reactivity between these vascular beds. In animals pretreated with the NO-synthase inhibitor L-NAME, acetylcholine did not significantly affect local blood flow in the choroid, suggesting NO as a mediator of the vasodilation. CONCLUSION: The results indicate a normal action of NO in the ocular vascular beds at this stage of experimental diabetes mellitus in the rat.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Óxido Nítrico/fisiología , Vasos Retinianos/fisiología , Úvea/irrigación sanguínea , Acetilcolina/farmacología , Animales , Arginina/farmacología , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Coroides/irrigación sanguínea , Inhibidores Enzimáticos/farmacología , NG-Nitroarginina Metil Éster/farmacología , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional , Úvea/fisiopatología , Resistencia Vascular , Vasodilatación/efectos de los fármacosRESUMEN
Effects of the endothelin receptor type A antagonist BQ 123 and the NO synthase inhibitor L-NMMA on cerebral blood flow were studied in vivo in anaesthetized hypertensive (SHR) and normotensive (WKY) rats. The effects of acetylcholine following pre-treatment with these drugs were also studied with the microsphere method for blood flow determination in the cortex, thalamus, caudatus, pons, medulla, cerebellum and hypophysis. BQ 123 (1 mg kg-1) induced only minor effects on cerebral blood flow in both strains (n = 8), whereas L-NMMA (N = 8; 20 mg kg-1) reduced regional cerebral blood flow significantly in most regions (21-54%) in the hypertensive, but not in the normotensive rat. In normotensive rats pre-treated with BQ 123 intravenous administration of acetylcholine (2 micrograms kg-1 min-1) induced a widespread significant increase (20-50%) in cerebral blood flow despite a reduction of the mean arterial blood pressure, while no significant effects were seen in hypertensive animals. Intravenous infusion of acetylcholine in animals pre-treated with L-NMMA did not affect cerebral blood flow in most regions in either of the two rat strains. In conclusion, a vasodilatory response to acetylcholine was found following endothelin receptor A antagonism in the WKY rat only, suggesting a role for endothelin in the control of cerebral blood flow in this strain. Furthermore, a higher basal vasodilating nitric oxide-tone seems to be present in the hypertensive rat compared with the normotensive rat.
Asunto(s)
Circulación Cerebrovascular/fisiología , Antagonistas de los Receptores de Endotelina , Endotelio Vascular/enzimología , Hipertensión/fisiopatología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Acetilcolina/farmacología , Animales , Velocidad del Flujo Sanguíneo , Presión Sanguínea , Química Encefálica/efectos de los fármacos , Química Encefálica/fisiología , Arterias Cerebrales/fisiología , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Masculino , Péptidos Cíclicos/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptor de Endotelina A , omega-N-Metilarginina/farmacologíaRESUMEN
1. In a previous report, we have shown that vasodilatation induced by acetylcholine is impaired in the kidney and the heart of the spontaneously hypertensive rat (SHR) in vivo. The present investigation was performed to study the influence of oral antihypertensive treatment with carvedilol for 6 to 10 weeks on acetylcholine-induced changes in regional haemodynamics in SHR in vivo. Cardiac output, regional blood flow and vascular resistance in organs of major importance in hypertensive disease, such as the kidney, heart, skeletal muscle, brain and eye, were measured with radioactively labelled microspheres in anaesthetized rats (aged 12-16 weeks).2. Mean arterial blood pressure was significantly lower in the carvedilol-treated SHR group (156+/-3 mmHg, n=17) than in an untreated SHR group (172+/-6 mmHg, n=13). Infusion of acetylcholine (2 microgram.min-1.kg-1) caused similar significant reductions in blood pressure in the two groups (-13+/-1% and -14+/-2%). However, acetylcholine induced a significant increase in total peripheral vascular resistance in the carvedilol group (29+/-10%, P<0.01), whereas no significant change was observed in the control group (0+/-11%).3. Acetylcholine significantly increased renal vascular resistance in the carvedilol group (+62+/-15%, P<0.01), but did not change vascular resistance in the control group (-6+/-6%). In the heart, acetylcholine did not affect vascular resistance in the carvedilol group, but reduced vascular resistance significantly in the control group (-17+/-8%, P<0.05). The circulatory changes induced by acetylcholine in the skeletal muscle, brain and ophthalmic circulation did not differ between the groups.4. In conclusion, the results demonstrate that long-term oral carvedilol treatment in the SHR did not enhance acetylcholine-induced vasodilatation, but instead pronounced renal vasoconstriction was induced by acetylcholine, which could partly be due to a decreased cardiac index.
Asunto(s)
Acetilcolina/farmacología , Antagonistas Adrenérgicos/farmacología , Carbazoles/farmacología , Hemodinámica/efectos de los fármacos , Propanolaminas/farmacología , Vasodilatadores/farmacología , Administración Oral , Animales , Presión Sanguínea/efectos de los fármacos , Carvedilol , Circulación Coronaria/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas SHR , Flujo Sanguíneo Regional/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
1. The objectives of the present study were to study regional differences in haemodynamics between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats induced by the nitric oxide synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) and the endothelin ETA receptor antagonist BQ 123 in vivo in tissues known to be important for blood pressure (BP) regulation (heart, kidney and skeletal muscle). Furthermore, the effect of acetylcholine (ACh) infusion (2 micrograms/kg per min) was examined after L-NMMA or BQ 123. The microsphere method was used for determinations of cardiac index (CI) and regional haemodynamics. 2. NG-Monomethyl-L-arginine (20 mg/kg) increased BP (26-48%; P < 0.01) and reduced CI in both rat strains. BQ 123 (1 mg/kg) reduced BP slightly (-4 to 11%; P < 0.05). 3. NG-Monomethyl-L-arginine significantly increased myocardial and skeletal muscle vascular resistance in SHR only; however, in the kidney, L-NMMA reduced blood flow and increased vascular resistance in both rat strains. 4. BQ 123 induced minor changes in regional haemodynamics that were not significantly different between the two strains. 5. Acetylcholine following BQ 123 induced an increase in myocardial blood flow in WKY rats, but decreased blood flow in SHR. Acetylcholine following L-NMMA reduced myocardial blood flow in both strains. 6. Acetylcholine following BQ 123 induced renal vasodilation in WKY rats but, following L-NMMA, ACh did not induce renal vasodilation in either rat strain. In contrast, L-NMMA did not abolish the vasodilation of acetylcholine in skeletal muscle in WKY rats. 7. In conclusion, the contribution of nitric oxide to basal vessel tone was not impaired in the heart, skeletal muscle and kidney in SHR. Antagonism of ETA receptors caused similar haemodynamic responses in both rat strains in these organs. Furthermore, NOS inhibition, but not ETA blockade, blunted the expected ACh-induced vasodilation in the heart and kidney in WKY rats, but not in skeletal muscle in both strains.
Asunto(s)
Antagonistas de los Receptores de Endotelina , Inhibidores Enzimáticos/farmacología , Hipertensión/fisiopatología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Acetilcolina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Vasos Coronarios/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Concentración de Iones de Hidrógeno , Hipertensión/tratamiento farmacológico , Masculino , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Péptidos Cíclicos/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Flujo Sanguíneo Regional/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Vasodilatadores/farmacología , omega-N-Metilarginina/farmacologíaRESUMEN
The objective of the present study was to compare systemic and regional haemodynamics in a large series of spontaneously hypertensive rats (SHR, n=32) with normotensive Wistar-Kyoto rats (WKY, n=26) at the age of 12-16 weeks. All rats were anaesthetized with thiobutabarbital and the radioactively labelled microsphere method was used to evaluate regional blood flow with special emphasis on different cerebral areas. The high blood pressure in the SHR was mainly due to elevated total peripheral resistance, which was 90% higher in the SHR compared to the WKY. Furthermore, heart rate was 25% (p<0.001) higher, but the cardiac index was lower by 20% (p<0.01) in the SHR. Blood flow was significantly lower and vascular resistance higher in several organs such as the kidneys, other visceral organs, skeletal muscle and skin of the SHR compared to the WKY. On the contrary, blood flow in the myocardium was augmented by 40% (p<0.01) in the SHR. Blood flow was 20-50% higher in the cerebral cortex, thalamus and caudatus (p<0.05-0.001), but attenuated in the hypophysis of the SHR. In the pons, medulla and cerebellum, blood flow was similar in the two strains. In this large microsphere study, the basal cardiac index was lower in the SHR already at this relatively early stage of established hypertension. Despite this, increased blood flow in the above mentioned cerebral regions was found in the SHR compared to the WKY.
Asunto(s)
Hemodinámica/fisiología , Hipertensión/fisiopatología , Ratas Endogámicas SHR/fisiología , Animales , Masculino , Microesferas , Ratas , Ratas Endogámicas WKY , Valores de Referencia , Flujo Sanguíneo Regional/fisiología , Resistencia Vascular/fisiologíaRESUMEN
This study was performed to investigate the in vivo effects of acetylcholine, a stimulator of endogenous NO production, and nitroprusside, an exogenous NO-donor, on hemodynamics in the normotensive (WKY) and the hypertensive (SHR) rat. Anesthetized rats were given microspheres for the measurement of cardiac index (CI), total vascular resistance (TPRI), regional blood flow and vascular resistance. Infusion of acetylcholine (2 microg/kg/min) caused a marked decrease in TPRI by (-35+/-5%, +/-SEM) in the WKY (n=8), whereas in the SHR (n=8) a less pronounced reduction was seen (-14+/-3%, p<0.01 between groups). CI increased by 27+/-9% in the WKY, but was unaltered in the SHR. Blood pressure decreased similarly (17-20%). Acetylcholine significantly increased blood flow by about 40% in the kidneys and the heart in the WKY, but had no significant effect in the SHR. Other tissues, such as skeletal muscle and cerebral tissues, showed no major changes. Infusion of nitroprusside (1 microg/kg/min) reduced blood pressure by 5 to 10% in the strains. The regional effects of nitroprusside did not differ between the strains. In conclusion, the acetylcholine-induced vasodilation in the kidney and the heart was attenuated in the SHR compared to the WKY. These findings might suggest a difference in the endothelial response between the SHR and the WKY in some, but not in all, tissues.
Asunto(s)
Acetilcolina/farmacología , Hemodinámica/efectos de los fármacos , Hipertensión/fisiopatología , Nitroprusiato/farmacología , Animales , Circulación Coronaria/efectos de los fármacos , Masculino , Microesferas , Óxido Nítrico/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Flujo Sanguíneo Regional/efectos de los fármacos , Resistencia Vascular/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
PURPOSE: The effects of endothelium-related substances such as acetylcholine, a stimulator of endogenous NO-production, the NO-synthesis inhibitor L-NMMA, the exogenous NO-donor sodium nitroprusside and the endothelin (ET)A-receptor antagonist BQ123, on uveal blood flow were investigated in normotensive and hypertensive SHR rats. METHOD: The radioactively-labelled microsphere method was applied for the measurement of regional blood flow in the uvea. RESULTS: Under resting conditions, local blood flow was lower in the hypertensive animals. The increase in choroidal blood flow (145 +/- 50%; P < 0.01) and reduction in vascular resistance (-58 +/- 7%; P < 0.01) observed in the WKY after i.v. infusion of acetylcholine, 2 micrograms x kg bw-1 x min-1, were significantly less pronounced in animals pretreated with L-NMMA, indicating local formation of NO as a vasodilator mechanism. In contrast, acetylcholine did not induce significant vasodilation in the choroid of SHR rats. In the anterior uvea of both strains, acetylcholine did not affect local blood flow. L-NMMA, 20 mg x kg bw-1, alone reduced blood flow in the entire uvea of both strains. Intravenous injection of BQ123, 1 mg x kg bw-1, did not affect regional blood flow in the uvea of WKY or SHR animals. Infusion of acetylcholine following ETA-receptor blockade induced vasodilation in both the choroid and anterior uvea in the WKY but not in the SHR. CONCLUSIONS: Acetylcholine-stimulated NO-mediated vasodilation, but not basal NO-formation, was impaired in the choroid of the SHR. Furthermore, an interaction between vasoconstricting ET and acetylcholine was found in the anterior uvea of normotensive but not hypertensive rats.
Asunto(s)
Endotelio Vascular/fisiología , Hipertensión/fisiopatología , Úvea/irrigación sanguínea , Vasodilatación/fisiología , Acetilcolina/farmacología , Animales , Antagonistas de los Receptores de Endotelina , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Masculino , Microesferas , Óxido Nítrico/fisiología , Nitroprusiato/farmacología , Péptidos Cíclicos/farmacología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Flujo Sanguíneo Regional/fisiología , Resistencia Vascular/fisiología , Vasodilatación/efectos de los fármacos , omega-N-Metilarginina/farmacologíaRESUMEN
The effects of short-time exposure to cigarette smoke on duodenal mucosal bicarbonate secretion were studied in anesthetized rabbits and rats. The bicarbonate secretion was measured by continuous titration of recirculating luminal perfusate. In artificially ventilated rabbits, intermittent exposure to cigarette smoke during two 10-min periods caused a marked (approximately 40%) decrease (p less than 0.01) in duodenal bicarbonate secretion. After the exposures, secretion gradually recovered and had returned to the pre-exposure rate after 50 min. The decrease in secretion was associated with decreases in heart rate (approximately 15%) and blood pressure (approximately 30%) that, however, were of shorter duration. Neither reduced amounts of smoke (1/6 or 1/3) nor nicotine (25-1,000 micrograms/kg, intravenously) had any major effect on the bicarbonate secretion. In the spontaneously breathing rat, smoke was administered for 1-2 breaths every 30 s during a 5-min period. This exposure resulted in a significant (p less than 0.05) decrease in bicarbonate secretion and some increase in the blood pressure. Exposure to smoke had no effect on the secretion in rats with both splanchnic nerves cut, suggesting neural sympathetic mediation of the smoke-induced inhibition.
Asunto(s)
Bicarbonatos/metabolismo , Duodeno/efectos de los fármacos , Mucosa Intestinal/metabolismo , Nicotiana , Nicotina/farmacología , Plantas Tóxicas , Humo/efectos adversos , Animales , Femenino , Mucosa Intestinal/efectos de los fármacos , Masculino , Conejos , Ratas , Ratas Endogámicas , Factores de TiempoRESUMEN
Duodenal HCO-3 secretion in anaesthetized rabbits was measured by continuous titration of the recirculating luminal perfusate at pH 7.4. The segment under study started 3-4 cm distal to the pylorus and was devoid of pancreatic and biliary HCO-3 secretion. On histological examination the submucosa was seen to contain Brunner's glands, mainly of a mucous type. Duodenum in rabbit secreted HCO3- at a considerably higher basal rate (100-125 mu equiv h-1 cm-1 of intestine) than has previously been found in the rat, cat or dog. The cyclo-oxygenase inhibitor indomethacin (20 mg kg-1) reduced the secretion by 30%, while prostaglandin E2 (5-80 microM, luminal) caused a dose-dependent increase. Prostaglandins thus seem to be important in regulation of duodenal HCO3- secretion in the rabbit and may play a role in duodenal protection against acid. Carbachol (1 and 10 micrograms kg-1) and atropine (0.5 and 1 mg kg-1) had no effects whereas hexamethonium (10 mg kg-1) caused a persistent decrease (25%) in secretion. Effects of electrical stimulation of the vagal nerves or injection of the alpha 2-adrenergic agonist clonidine markedly depended on the agent used for anaesthesia. In urethane-anaesthetized animals, clonidine (0.75-75 micrograms kg-1) tended to increase the secretion whereas with nembutal, clonidine (5-150 micrograms kg-1) decreased it significantly. Electrical stimulation of the cervical vagal nerves decreased the HCO3- secretion in urethane-anaesthetized animals but had no significant effect during nembutal anaesthesia. The responses in the nembutal-anaesthetized rabbit are similar to those previously observed in the cat, rat or dog.