Effects of chronic taurine treatment on reactivity of the rat aorta

Summary. The effects of chronic taurine treatment on the reactivity of the aorta form male Wistar-Kyoto rats were investigated. Contractile responses to norepinephrine (NE) and potassium chloride (KCl) were attenuated in aortic rings from taurine-treated rats as compared to controls both in the absence and presence of endothelium. However, the degree of attenuation was greater in endothelium-intact tissues contracted with NE. Acetylcholine (Ach)-induced relaxation responses were augmented in endothelium-intact vessels from rats supplemented with taurine compared to the responses observed in control preparations. Relaxation responses of the aortae from control and taurine-treated rats to sodium nitroprusside (SNP) were not different from each other. Our results suggest that taurine treatment attenuates vascular contractility nonspecifically and this effect is partly mediated via the endothelium. Received December 20, 1999/Accepted January 9, 2000     

Effects of taurine on the reactivity of aortas from diabetic rats

The effects of the semi-essential amino acid-like nutrient, taurine, on alterations in the reactivities of aortas from male rats with chronic streptozotocin-induced diabetes were examined under in vitro conditions. In the absence of taurine, the contractile responsiveness of endothelium-denuded aortic rings from diabetic rats to norepinephrine, but not KCl, was enhanced compared to controls. This effect of norepinephrine on the diabetic rat aorta appeared to be associated with increased release of intracellular calcium, influx of extracellular calcium and protein kinase C-mediated responses. Incubation of endothelium-denuded aortic rings with 10 mM, but not 5 mM, taurine for 2 h reduced the augmented contractile responses of the tissues from diabetic rats to norepinephrine close to control levels, and this was associated with inhibition of responses linked to the release and influx of calcium, and protein kinase C activation. Endothelium-dependent relaxation of aortas from diabetic rats to acetylcholine was depressed relative to controls. This effect of diabetes was ameliorated close to control levels by incubating the tissues with 10 mM, but not 5 mM, taurine for 2 h. Incubation of nondiabetic rat aortic rings with 45 mM glucose for 3 h caused enhancement of contraction of the vascular smooth muscle to phenylephrine and impairment of endothelium-mediated vasorelaxation to acetylcholine, as compared to control responses. Co-incubation of the tissues with 5-10 mM taurine concentration-dependently reduced the alterations in both contractile and relaxant responses caused by high glucose. Overall, the data suggest that taurine ameliorates or prevents vascular reactivity alterations in diabetes. Such an observation provides preliminary evidence for taurine's potential as a therapeutic agent for the prevention or amelioration of vascular disorders in diabetes.     

Effect of heating on vascular reactivity in rat mesenteric arteries

Vasoconstrictionin the viscera is one of the primary cardiovascular adjustments toheating. Local temperature can influence vascular responsiveness tocatecholamines and sympathetic nerve activity. Therefore, wehypothesized that heating would alter vascular reactivity in ratmesenteric arteries. Concentration-response curves to norepinephrine,phenylephrine, potassium chloride (KCl), calcium, acetylcholine, andsodium nitroprusside were obtained in vascular ring segments from ratmesenteric arteries at 37 and 41°C. In some rings, basal tensionincreased slightly during heating. Heating to 41°C did not alterthe contractile responses to norepinephrine in endothelium-intact or-denuded rings but augmented the responses to KCl and calcium inendothelium-intact rings. The potentiating effect of heating on theresponses to KCl and calcium was eliminated after endothelium removal.In contrast, the relaxant responses to acetylcholine and sodiumnitroprusside were significantly attenuated at 41°C. Collectively,these results demonstrate that heating alters vascular reactivity inrat mesenteric arteries. Furthermore, these data imply that heatingreduces the ability of vascular smooth muscle to relax, possibly due toa decrease in sensitivity to nitric oxide.

     

Effect of cooling on vascular smooth muscle from the thirteen-lined ground squirrel

Peripheral vascular resistance in the ground squirrel (Spermophilus tridecemlineatus) increases when the animal enters hibernation. The goals of this study were to determine if a change in vascular reactivity contributes to this hemodynamic response, and to compare the effects of temperature on vascular responsiveness in a hibernator (ground squirrel) and a nonhibernating mammal (rat). Helically cut strips of aortae and femoral arteries were mounted in organ chambers (37 degrees C) and isometric contractions were recorded. The arteries were made to contract in response to exogenous norepinephrine (5.9 X 10(-7) M). Cooling the organ chamber (11 degrees C) potentiated contractions to norepinephrine (5-15% increase) in ground squirrel femoral arteries but depressed those (80-100% decrease) in ground squirrel aortae and rat aortae and femoral arteries. Contractions in response to depolarizing concentrations of potassium in ground squirrel femoral arteries were depressed by cooling (11 degrees C), suggesting that the augmented response to norepinephrine at low temperature is specific. Treatment with indomethacin, propanolol, and ouabain did not alter the potentiating effect of temperature on contractions to norepinephrine in ground squirrel femoral arteries. Apparently, the potentiation is not related to prostaglandins generated in the vascular wall, to blockade of beta-adrenergic receptors, nor to inhibition of the electrogenic sodium pump. The observations are consistent with the hypothesis that a change in vascular responsiveness contributes to the regional control of blood flow in hibernation. This adaptive response is specific in that it does not occur in the aorta of the ground squirrel and the response is not present in the vasculature of the rat, a nonhibernating mammal.     

Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells.

We investigated the mechanisms by which cytokines lead to a diminished responsiveness of vascular smooth muscle to vasoconstrictors. The attenuation of noradrenaline-induced contraction by 6 to 24 h incubations with the cytokines, tumor necrosis factor and interleukin-1, in endothelium-denuded rabbit aorta was associated with an increase in intracellular cyclic GMP level. This increase was abolished by the stereoselective inhibitor of nitric oxide-synthase, NG-nitro-L-arginine and by cycloheximide. Formation of nitric oxide was detected in the cytosol of cytokine-treated native and cultured smooth muscle cells by activation of purified soluble guanylate cyclase, and depended on tetrahydrobiopterin, but not on Ca2(+)-calmodulin. The results indicate that cytokines induce a nitric oxide-synthase of the macrophage-type in vascular smooth muscle.     

The influence of chronic experimental diabetes on contractile responses of rat isolated blood vessels

The influence of experimental diabetes induced by streptozotocin on responses of rat isolated aortae and portal veins to noradrenaline, 5-hydroxytryptamine, and KCl was examined 7, 100, 180, and 360 days after the onset of diabetes. No significant changes in reactivity were seen 7 days after the onset of diabetes. After 100 days aortae from diabetic rats were supersensitive (defined as a significant increase in the pD2 value) to noradrenaline. However, 180 days after the onset of diabetes, the sensitivity of diabetic aortae to noradrenaline was not significantly different from control, while the responsiveness (defined as the maximum developed tension divided by cross-sectional area of aorta) to 5-hydroxytryptamine was reduced. A generalized increase in both the sensitivity and responsiveness of diabetic aortae to all three agonists was observed after 360 days of diabetes. In contrast, no changes in either the sensitivity or the responsiveness of portal veins to noradrenaline, 5-hydroxytryptamine, or KCl could be detected at any time after the onset of diabetes. These results indicate that changes in vascular reactivity can be detected with increasing duration of experimental diabetes. However, these changes do not follow a consistent pattern and are not seen in all parts of the vasculature.     

Effects of docosahexaenoic acid on vascular pathology and reactivity in hypertension

Previous studies have shown that docosahexaenoic acid (DHA) has an antihypertensive effect in spontaneously hypertensive rats (SHR). To investigate possible mechanisms for this effect, vascular pathology and reactivity were determined in SHR treated with dietary DHA. SHR (7 weeks) were fed a purified diet with either a combination of corn/soybean oils or a DHA-enriched oil for 6 weeks. Histological evaluation of heart tissue, aorta, coronary, and renal arteries was performed. Vascular responses were determined in isolated aortic rings. Contractile responses to agonists, including norepinephrine (10(-9) to 10(-4) M), potassium chloride (5-55 mM), and angiotensin II (5 x 10(-7) M) were assessed. Vasorelaxant responses to acetylcholine (10(-9) to 10 (-4) M), sodium nitroprusside (10(-9) to 10(-6) M), papaverine (10(-5) to 10(-4) M), and methoxyverapamil (D600, 1-100 microM) were determined. DHA-fed SHR had significantly reduced blood pressure (P < 0.001) and vascular wall thicknesses in the coronary, thoracic, and abdominal aorta compared with controls (P < 0.05) Contractile responses to agonists mediated by receptor stimulation and potassium depolarization were not altered in DHA-fed SHR. Endothelial-dependent relaxations to acetylcholine were not altered which suggests endothelial-derived nitric oxide production/release is not affected by dietary DHA. Other mechanisms of vascular relaxation, including intracellular cyclic nucleotides, cGMP, and cAMP were not altered by dietary DHA because aortic relaxant responses to sodium nitroprusside and papaverine were similar in control and DHA-fed SHR. No significant differences were seen in relaxant responses to the calcium channel blocker, D600, or contractile responses to norepinephrine in the absence of extracellular calcium. These results suggest that dietary DHA does not affect mechanisms related to extracellular calcium channels or intracellular calcium mobilization. Moreover, the contractile and vasorelaxant responses are not differentially altered with dietary DHA in this in vivo SHR model. The findings demonstrate that dietary DHA reduces systolic blood pressure and vascular wall thickness in SHR. This may contribute to decrease arterial stiffness and pulse pressure, in addition to the antihypertensive properties of DHA. The antihypertensive properties of DHA are not related to alterations in vascular responses.     

Role of phospholamban in NO/EDRF-induced relaxation in rat aorta.

The role of endothelium-derived nitric oxide (NO) to cause smooth muscle phospholamban (PLB) phosphorylation was studied in the isolated perfused rat aorta precontracted with norepinephrine using a back-phosphorylation technique. NO-induced relaxation was associated with increased PLB-phosphorylation while norepinephrine as such was ineffective. Removal of endothelium significantly reduced PLB-phosphorylation in indomethacin treated vessels. Stimulation of NO-formation by ATP augmented PLB-phosphorylation in intact vessels but was ineffective in denuded aortas. The results indicate that PLB-phosphorylation of vascular smooth muscle plays an important role in mediating NO-dependent relaxation by enhancing Ca(++)-uptake into sarcoplasmic reticulum.     

Reactivity of the aorta and mesenteric resistance arteries from the obese spontaneously hypertensive rat: effects of glitazones

The obese spontaneously hypertensive rat (SHROB) is a model of metabolic syndrome in which, to our knowledge, vascular function has never been studied. The actions of insulin sensitizers (glitazones) on vascular function have not been analyzed either. Our purpose was to characterize microvascular and macrovascular responses of the SHROB and to study the effects of glitazones on these responses. The reactivity of mesenteric resistance arteries (MRAs) and the aorta from SHROBs and control rats to cumulative concentrations of phenylephrine, ACh, and sodium nitroprusside (SNP) was myographically analyzed. Some animals were orally treated with rosiglitazone (3 mg·kg(-1)·day(-1), 3 wk), and myography was performed. Phenylephrine, ACh, and SNP dose-response curves were impaired to different extents in arteries of SHROBs. Incubation with N-nitro-L-arginine methyl ester caused little effects on phenylephrine and ACh curves in MRAs but enhanced phenylephrine contractions and abolished ACh-induced relaxations of aortae. Incubation with indomethacin reduced phenylephrine reactivity and improved ACh-induced relaxations of all vessels studied. NS-398 and tempol increased relaxations to ACh of MRAs. Incubation with pioglitazone or rosiglitazone (both 10(-5) M) or oral treatment with rosiglitazone improved, to different extents, ACh and SNP curves in all vessels. Glitazone incubation diminished aortic ACh sensitivity. The release of thromboxane A(2) and PGI(2) metabolites (thromboxane B(2) and 6-keto-PGF(1α)) was analyzed. ACh increased the MRA release of thromboxane B(2) from SHROBs but not control rats, and the former was prevented by rosiglitazone coincubation. In contrast, in aortae, ACh failed to alter the release of metabolites, and rosiglitazone treatment increased that of 6-keto-PGF(1α). Thus, SHROBs displayed microvascular and macrovascular dysfunction. MRAs, but not aortae, of SHROBs revealed an impaired endothelial nitric oxide pathway, whereas both, but especially MRAs, displayed an impaired cyclooxygenase pathway. Glitazones elicited beneficial effects on macrovascular and, especially, microvascular function of SHROBs.     

Depressor effect of diabetes in spontaneously hypertensive rat: role of vascular reactivity and prolyl hydroxylase and lysyl oxidase activities

Streptozotocin (STZ)-induced diabetes (8 weeks) produced a marked depressor effect in the spontaneously hypertensive rat (SHR), confirming earlier studies, but had no effect on arterial pressure of normotensive controls (WKY). We investigated the phenomenon further by examining the effects of diabetes on the activities of aortic prolyl hydroxylase (PH) and lysyl oxidase (LO), marker enzymes for collagen biosynthesis, and on the reactivity of isolated mesenteric arteries to vasoactive agents. PH and LO activities of nondiabetic SHR were greater than those of the WKY controls. Diabetes markedly reduced PH and LO activities of SHR aortae, but had no significant effect on PH and LO activities of the WKY strain. The effects of diabetes on vascular collagen biosynthetic enzymes of SHR were not associated with reductions in mesenteric arterial responsiveness or sensitivity to norepinephrine, methoxamine, serotonin or KC1. These results suggest that the depressor effect of diabetes in SHR is associated with a reduction in vascular collagen biosynthesis but not a reduction in vascular reactivity.     

Oxygen concentration regulates NO-dependent relaxation of aortic smooth muscles

Nitric oxide (NO) functions as an endothelium-derived relaxation factor and regulates vascular resistance. Recent studies in this laboratory (Arch. Biochem. Biophys. 323, 27–32, 1995) revealed that the lifetime of NO significantly increased at physiologically low levels of oxygen concentrations and, hence, this gaseous radical strongly inhibited mitochondrial electron transport for a fairly long duration at low oxygen concentrations. The present work describes the effect of oxygen concentration on NO-induced relaxation and guanylate cyclase (GC) activity of endothelium-denuded aorta of the rat. Both NO and 2,2′-hydroxynitrosohydrazono)bis-ethanamine (NOC18), an NO donor, induced the relaxa-tion of endothelium-denuded helical segments of rat aorta which were contracted by norepinephrine. NO-dependent relaxation of arterial specimens was enhanced by lowering oxygen concentration in the medium with concomitant increase in their cGMP levels. Anoxia induced the relaxation of the aorta by some NO-enhanceable and methylene blue-insensitive mechanism. These results suggested that local concentrations of oxygen might play important roles in the regulation of NO-dependent GC activity and vascular tonus of resistance arteries.     

Oxygen concentration regulates NO-dependent relaxation of aortic smooth muscles

Nitric oxide (NO) functions as an endothelium-derived relaxation factor and regulates vascular resistance. Recent studies in this laboratory (Arch. Biochem. Biophys. 323, 27-32, 1995) revealed that the lifetime of NO significantly increased at physiologically low levels of oxygen concentrations and, hence, this gaseous radical strongly inhibited mitochondrial electron transport for a fairly long duration at low oxygen concentrations. The present work describes the effect of oxygen concentration on NO-induced relaxation and guanylate cyclase (GC) activity of endothelium-denuded aorta of the rat. Both NO and 2,2'-hydroxynitrosohydrazono)bis-ethanamine (NOC18), an NO donor, induced the relaxa-tion of endothelium-denuded helical segments of rat aorta which were contracted by norepinephrine. NO-dependent relaxation of arterial specimens was enhanced by lowering oxygen concentration in the medium with concomitant increase in their cGMP levels. Anoxia induced the relaxation of the aorta by some NO-enhanceable and methylene blue-insensitive mechanism. These results suggested that local concentrations of oxygen might play important roles in the regulation of NO-dependent GC activity and vascular tonus of resistance arteries.     

Interleukin-1 impairs both vascular contraction and relaxation in rabbit isolated aorta.

Incubation of rabbit aortic rings with interleukin-1 (100 U/ml) in vitro led to a depressed contractile response to norepinephrine, whether the endothelium was present or not. In both cases norepinephrine-induced contraction was restored in the presence of NG-methyl-L-arginine (300 microM), an inhibitor of nitric oxide synthesis. In interleukin-1-treated rings precontracted with norepinephrine (1 microM), the relaxing response to acetylcholine was totally suppressed independently on the presence of endothelium. High concentrations of acetylcholine (greater than 1 microM) induced a slight contraction which was of lower amplitude than that obtained in control endothelium-denuded rings and was increased in the presence of NG-methyl-L-arginine. These results show that interleukin-1 (i) affects not only vascular contraction but also relaxation and (ii) involves both endothelial and non-endothelial factors. These observations suggest an impairment of the whole vascular reactivity during septic shock.     

Effects of dexamethasone and L-canavanine on the intracellular calcium-contraction relation of the rat tail artery during septic shock

The intracellular mechanism by which sepsis lowers vascular reactivity and the subsequent reversal by dexamethasone or nitric oxide synthase (NOS) inhibitors remain unclear. We measured the sensitivity of contraction of the rat tail artery to intracellular Ca2+ in a model of polymicrobial septic shock. At 22 h after cecal ligation and puncture (CLP), rats were treated with an anti-inflammatory glucocorticoid (dexamethasone, 1 mg/kg ip), an inducible NOS inhibitor (L-canavanine, 100 mg/kg ip), or saline. At 24 h after CLP, endothelium-denuded, perfused segments of tail artery were loaded with the intracellular Ca2+-sensitive dye fura 2 in vitro. Intracellular Ca2+ concentration and perfusion pressure were measured simultaneously. The rightward shift of the perfusion pressure-intracellular Ca2+ mobilization curve after norepinephrine stimulation subsequent to CLP indicates decreased intracellular Ca2+ sensitivity of contraction. The relation was restored by dexamethasone (which also restored in vivo blood pressure and flow), but not by L-canavanine (which restored perfusion pressure by further mobilization of intracellular Ca2+). We conclude that CLP lowers vasomotion by lowering intracellular Ca2+ sensitivity, which can be restored with glucocorticoid treatment. The involvement of inducible NOS does not solely account for the sepsis-induced reduction in Ca2+ sensitivity of contraction.     

Evidence for regionally selective changes in response to potassium chloride but not vasopressin or methoxamine in vasculature from diabetic rats

In the present study we examined the contractile responses of aortae and mesenteric and femoral arteries taken from rats treated 3 weeks previously with streptozotocin (55 mg/kg, i.v.) or saline (1 mL/kg, i.v.) to vasopressin, potassium chloride, and methoxamine. The dose-response curves obtained with vasopressin and methoxamine were not significantly different between control and diabetic animals. However, both the diabetic mesenteric and femoral arteries showed a significantly (p less than 0.05) greater maximum response to potassium chloride as compared with their respective controls. The reactivity of the diabetic aortae to this agonist was not different. It is concluded that while the contractile responses of the diabetic tissues were normal when the agonist was vasopressin or methoxamine, there would appear to be regionally selective changes in responsiveness to potassium chloride.     

Vascular smooth muscle-derived relaxing factor (MDRF) and its close similarity to nitric oxide

The principal finding in this study is that vascular smooth muscle generates a labile relaxing factor that possesses pharmacological and chemical properties that are similar to those of authentic nitric oxide. MDRF was generated by perfusion of endothelium-denuded bovine pulmonary artery as assessed by bioassay. In addition, endothelium-denuded arterial rings that were incubated at 37 degrees C for 24 hr to lower endogenous L-arginine levels relaxed in response to L-arginine but not D-arginine. Freshly mounted, endothelium-denuded arterial rings were not relaxed by L-arginine but did relax in response to the dipeptide L-arginyl-L-alanine. Relaxant responses were accompanied by increases in smooth muscle levels of cyclic GMP and nitrite, and were inhibited by oxyhemoglobin, methylene blue, and NG-nitro-L-arginine. NG-Nitro-L-arginine also caused endothelium-independent contractile responses. Thus, a relaxing factor with the properties of nitric oxide can be generated from vascular smooth muscle.     

Reduced constrictor reactivity balances impaired vasodilation in the mesenteric circulation of the obese Zucker rat

Obesity causes whole body insulin resistance and impaired vasodilation to nitric oxide (NO). Because NO is a major contributor to the regulation of mesenteric blood flow, the mesenteric circulation of obese animals is faced with reduced capacity to increase flow and increased demand for flow associated with elevated consumption of food. This study hypothesized that insulin resistance impairs NO-mediated dilation but that constrictor reactivity would be reduced to compensate in obese animals. We further hypothesized that elevated superoxide levels caused impaired responses to NO in insulin resistance. Vasodilator reactivity and vasoconstrictor reactivity of mesenteric resistance arteries from lean (LZR) and obese (OZR) Zucker rats were examined in vitro using videomicroscopy. Insulin resistance independent of obesity was induced via fructose feeding in LZR (FF-LZR). Endothelium-dependent NO-mediated dilation was reduced in OZR and FF-LZR compared with LZR. Impairments in NO-mediated dilation were reversed with 1 mM tempol, a SOD mimetic. Constrictor reactivity to norepinephrine was reduced in OZR but not in FF-LZR relative to LZR. Basal mesenteric vascular resistance was similar in LZR and OZR despite impaired NO-dependent dilation in OZR. Mesenteric vascular resistance was increased in FF-LZR relative to LZR. These data indicate that there is reduced constrictor reactivity in OZR that may offset the impaired NO-mediated dilation and preserve mesenteric blood flow in hyperphagic, obese animals.     

Upregulation of neuronal nitric oxide synthase in skeletal muscle by swim training

Exercise enhances cardiac output and blood flow to working skeletal muscles but decreases visceral perfusion. The alterations in nitric oxide synthase (NOS) activity and/or expression of the cardiopulmonary, skeletal muscle, and visceral organs induced by swim training are unknown. In sedentary and swim-trained rats (60 min twice/day for 3-4 wk), we studied the alterations in NOS in different tissues along with hindquarter vasoreactivity in vivo during rest and mesenteric vascular bed reactivity in vitro. Hindquarter blood flow and conductance were reduced by norepinephrine in both groups to a similar degree, whereas N(G)-nitro-L-arginine methyl ester reduced both indexes to a greater extent in swim-trained rats. Vasodilator responses to ACh, but not bradykinin or S-nitroso-N-acetyl-penicillamine, were increased in swim-trained rats. Ca(2+)-dependent NOS activity was enhanced in the hindquarter skeletal muscle, lung, aorta, and atria of swim-trained rats together with increased expression of neuronal NOS in the hindquarter skeletal muscle and endothelial NOS in the cardiopulmonary organs. Mesenteric arterial bed vasoreactivity was unaltered by swim training. Physiological adaptations to swim training are characterized by enhanced hindquarter ACh-induced vasodilation with upregulation of neuronal NOS in skeletal muscle and endothelial NOS in the lung, atria, and aorta.     

Vascular hyporesponsiveness in simulated microgravity: role of nitric oxide-dependent mechanisms.

Simulated microgravity depresses the ability of arteries to constrict to norepinephrine (NE). In the present study the role of nitric oxide-dependent mechanisms on the vascular hyporesponsiveness to NE was investigated in peripheral arteries of the rat after 20 days of hindlimb unweighting (HU). Blood vessels from control rats and rats subjected to HU (HU rats) were cut into 3-mm rings and mounted in tissue baths for the measurement of isometric contraction. Mechanical removal of the endothelium from carotid artery rings, but not from aorta or femoral artery rings, of HU rats restored the contractile response to NE toward control. A 10-fold increase in sensitivity to ACh was observed in phenylephrine-precontracted carotid artery rings from HU rats. In the presence of the nitric oxide synthase (NOS) substrate L-arginine, the inducible NOS inhibitor aminoguanidine (AG) restored the contractile responses to NE to control levels in the femoral, but not carotid, artery rings from HU rats. In vivo blood pressure measurements revealed that the peak blood pressure increase to NE was significantly greater in the control than in the HU rats, but that to AG was less than one-half in control compared with HU rats. These results indicate that the endothelial vasodilator mechanisms may be upregulated in the carotid artery, whereas the inducible NOS expression/activity may be increased in the femoral artery from HU rats. These HU-mediated changes could produce a sustained elevation of vascular nitric oxide levels that, in turn, could contribute to the vascular hyporesponsiveness to NE.     

Role of ET(A) receptors in the regulation of vascular reactivity in rats with congestive heart failure

Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to regulate vascular tone. In congestive heart failure (CHF), the release and/or the activity of both factors is affected. We hypothesized that the increased ET-1 production associated with CHF may result in a reduced smooth muscle sensitivity to NO. The aim of this study was to evaluate the effects of a chronic treatment with the ET(A)-receptor (ET receptor A) antagonist LU-135252 (LU) on cerebrovascular reactivity to sodium nitroprusside (SNP) in the rat infarct model of CHF. Rats were subjected to coronary artery ligation and were treated for 4 wk with placebo (n = 24) or LU (50 mg. kg(-1). day(-1), n = 29). CHF was associated with a decreased (P < 0.05) efficacy of SNP to induce relaxation of isolated middle cerebral arteries. Furthermore, neither NO synthase inhibition with N(omega)-nitro-L-arginine (L-NNA) nor endothelial denudation affected the efficacy of SNP. Thus the endothelium no longer influences smooth muscle sensitivity to SNP. LU treatment, however, normalized (P < 0.05) smooth muscle sensitivity to SNP. Sensitivity of ET-1-induced contraction was increased in CHF only in the presence of L-NNA, whereas contraction induced by ET(B) receptor (receptor B) stimulation was increased (P < 0.05) in endothelium-denuded vessels. LU treatment restored these changes in reactivity and revealed a significant endothelium-dependent ET(B)-mediated relaxation after NO synthase inhibition. In conclusion, CHF decreases and uncouples cerebrovascular smooth muscle sensitivity to SNP from endothelial regulation. The observation that chronic ET(A) blockade restored most of the changes associated with CHF suggests that activation of the ET-1 system importantly contributes to the alteration in vascular reactivity observed in experimental CHF.