Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia.
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Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli. (+info)
Anoxia-induced release of prostaglandins in rabbit isolated hearts.
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We investigated the relationship between prostaglandin release and the coronary vasodilation evoked by anoxia. Isolated rabbit hearts were perfused via the aorta with Krebs-Ringer's solution. The coronary effluent was bioassayed continuously in terms of prostaglandin E2 for prostaglandinlike substance which was present (at less than 1 ng/ml) in 60 of 66 hearts. This basal release was abolished by the prostaglandin synthetase inhibitor, indomethacin (1-2 mug/ml), a result which adds further to the identity of the prostaglandinlike substance as a prostaglandin. Anoxia increased coronary flow sometimes by 100% and evoked prostaglandin release shortly thereafter. Ablolition of prostaglandin synthesis by indomethacin pretreatment did not affect nor did infusion of exogenous prostaglandin mimic the anoxia-induced flow increment; thus, we conclude that prostaglandin release cannot account for the anoxia-induced vasodilator response. Furthermore, the failure of indomethacin to alter resting coronary blood flow suggests that a local prostaglandin release is not responsible for either the maintenance or the modulation of coronary flow in this preparation. (+info)
Collateral and collateral-adjacent hyperemic vascular resistance changes and the ipsilateral coronary flow reserve. Documentation of a mechanism causing coronary steal in patients with coronary artery disease.
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OBJECTIVES: The goal of this clinical study was to assess the influence of hyperemic ipsilateral, collateral and contralateral vascular resistance changes on the coronary flow velocity reserve (CFVR) of the collateral-receiving (i.e. ipsilateral) artery, and to test the validity of a model describing the development of collateral steal. METHODS: In 20 patients with one- to two-vessel coronary artery disease (CAD) undergoing angioplasty of one stenotic lesion, adenosine induced intracoronary (i.c.) CFVR during vessel patency was measured using a Doppler guidewire. During stenosis occlusion, simultaneous i.c. distal ipsilateral flow velocity and pressure (P(occl), using a pressure guidewire) as well as contralateral flow velocity measurements via a third i.c. wire were performed before and during intravenous adenosine. From those measurements and simultaneous mean aortic pressure (P(ao)), a collateral flow index (CFI), and the ipsilateral, collateral, and contralateral vascular resistance index (R(ipsi), R(coll), R(contra)) were calculated. The study population was subdivided into groups with CFI<0.15 and with CFI> or =0.15. RESULTS: The percentage-diameter coronary artery stenosis (%-S) to be dilated was similar in the two groups: 78+/-10% versus 82+/-12% (NS). CFVR was not associated with %-S. In the group with CFI> or =0.15 but not with CFI<0.15, CFVR was directly and inversely associated with R(coll) and R(contra), respectively. CONCLUSIONS: A hemodynamic interaction between adjacent vascular territories can be documented in patients with CAD and well developed collaterals among those regions. The CFVR of a collateralized region may, thus, be more dependent on hyperemic vascular resistance changes of the collateral and collateral-supplying area than on the ipsilateral stenosis severity, and may even fall below 1. (+info)
On the hypothesis that coronary sinus occlusion (CSO) may reduce myocardial ischemia, we examined the effects of CSO on coronary collateral blood flow and on the distribution of regional myocardial blood flow (RMBF) in dogs. Thirty-eight anesthetized dogs underwent occlusion of the left anterior descending coronary artery with or without CSO and intact vasomotor tone. We measured RMBF and intramyocardial pressure (IMP) in the subendocardium (Endo) and subepicardium (Epi) separately. With intact vasomotor tone, CSO during ischemia significantly increased RMBF in the ischemic region (IR), particularly in Endo from 0.17 +/- 0.03 to 0.33 +/- 0.05 ml x min(-1) x g(-1) (P < 0.05), and increased the Endo/Epi from 0.59 +/- 0.10 to 1.15 +/- 0.15 (P < 0.01). These effects of CSO were partially abolished by adenosine. However, the Endo/Epi was still increased from 0.90 +/- 0.13 to 2.09 +/- 0.30 (P < 0.01). The changes in RMBF in IR were significantly correlated with the peak CS pressure during CSO. The Endo/Epi of IMP in IR was significantly decreased during CSO. In conclusion, CSO potentially enhances coronary collateral flow, and preserves the ischemic myocardium, especially in Endo. (+info)
Exercise-induced hyperaemia and leg oxygen uptake are not altered during effective inhibition of nitric oxide synthase with N(G)-nitro-L-arginine methyl ester in humans.
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1. In the present study the highly potent nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was intravenously infused and examined for its efficacy in inhibiting NOS activity and in altering blood flow and oxygen uptake in human skeletal muscle. 2. The plasma concentrations of L-NAME and its active metabolite NG-nitro-L-arginine (L-NA), and the activity of NOS in skeletal muscle were measured in healthy male subjects (n = 6) before (control) and after 60 min of intravenous infusion of L-NAME (4 mg kg(-1)). In another group of healthy males (n = 8), the physiological effects of L-NAME were studied at rest, and during submaximal and exhaustive knee extensor exercise before (control) and 30 min after L-NAME infusion (4 mg kg(-1)). 3. The plasma concentrations of L-NAME and L-NA were highest (8.4 +/- 1.6 and 8.3 +/- 0.8 micromol l(-1)) after 60 min of L-NAME infusion. Ninety minutes later mainly L-NA remained in plasma (5.1 +/- 0.4 micromol l(-1)). Thirty minutes after L-NAME infusion, the muscle L-NA content was 38 +/- 4 micromol (kg dry wt)-1 and muscle NOS activity was reduced by 67 +/- 8 % (P < 0.05). 4. Leg blood flow and leg oxygen uptake during submaximal and exhaustive exercise were similar (P > 0.05) following L-NAME infusion and in control. Blood flow during recovery was lower in the L-NAME condition (P < 0.05). 5. In conclusion, the present study shows for the first time that systemic infusion of L-NAME in humans causes a marked reduction in skeletal muscle NOS activity. Despite this attenuated NOS activity, exercise-induced hyperaemia and oxygen uptake were unaltered. Thus, the data strongly suggest that NO is not essential for the regulation of blood flow or oxygen uptake in contracting human skeletal muscle. (+info)
Estradiol rapidly inhibits soluble guanylyl cyclase expression in rat uterus.
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Previous reports that investigated the regulation of the NO/soluble guanylyl cyclase (sGC)/cGMP pathway by estrogenic compounds have focused primarily on the levels of NO, NO-producing enzymes, and cGMP in various tissues. In this study, we demonstrate that 17beta-estradiol (E2) regulates the alpha(1) and beta(1) subunits of the NO receptor, sGC, at the mRNA and protein levels in rat uterus. Using real-time quantitative PCR, we found that within 1 h of in vivo E2 administration to rats, sGC mRNA levels begin to diminish. After 3 h, there is a maximal diminution of sGC mRNA expression (sGC alpha(1) 10% and sGC beta(1) 33% of untreated). This effect was blocked by the estrogen receptor antagonist, ICI 182,780, indicating that estrogen receptor is required. The effect of E2 also was observed in vitro with incubations of uterine tissue, indicating that the response does not depend on the secondary release of other hormones or factors from other tissues. Puromycin did not block the effect, suggesting the effects occur because of preexisting factors in uterine tissues and do not require new protein synthesis. Using immunoblot analysis, we found that sGC protein levels also were reduced by E2 over a similar time course as the sGC mRNA. We conclude that sGC plays a vital role in the NO/sGC/cGMP regulatory pathway during conditions of elevated estrogen levels in the rat uterus as a result of the reduction of sGC expression. (+info)
Effect of estrogen replacement therapy on endothelial function in peripheral resistance arteries in normotensive and hypertensive postmenopausal women.
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Both menopause and hypertension are associated with endothelial dysfunction and are risk factors for coronary heart disease. We evaluated forearm resistance artery endothelial function in hypertensive postmenopausal women (HPW, n=57) and compared it with endothelial function in normotensive postmenopausal women (NPW, n=67). In addition, we evaluated the effects of long-term estrogen replacement therapy (ERT, conjugated equine estrogen at a dose of 0.625 mg daily for 12 weeks) on endothelial function in HPW (n=10) and NPW (n=35). Forearm blood flow (FBF) was measured by strain-gauge plethysmography during reactive hyperemia to assess endothelium-dependent vasodilation and after sublingual nitroglycerin (NTG) administration to assess endothelium-independent vasodilation. Basal FBF was similar in the NPW and HPW groups. The FBF in the HPW group during reactive hyperemia was significantly lower than that in the NPW group. Increases in FBF after NTG were similar in the 2 groups. ERT decreased the LDL cholesterol concentration and circulating ACE activity and increased estradiol and HDL cholesterol in both groups. Basal blood pressures, heart rate, FBF, and body weight did not change with ERT. After 12 weeks of ERT, the maximal FBF response during reactive hyperemia increased significantly in both groups. The improvement in reactive hyperemia after ERT was significantly greater in the HPW group than in the NPW group (49+/-8 versus 17+/-5%, P<0.05). Changes in FBF after sublingual NTG administration were similar before and after 12 weeks of ERT. These findings suggest that continued ERT improves forearm resistance artery endothelial function in postmenopausal women and that this beneficial effect is greater in patients that are hypertensive. (+info)
Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats.
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It has been previously shown that spreading neuronal activation can generate a cortical spreading ischaemia (CSI) in rats. The purpose of the present study was to investigate whether vasodilators cause CSI to revert to a normal cortical spreading depression (CSD).A KCl-induced CSD travelled from an open cranial window to a closed window where the cortex was superfused with physiological artificial cerebrospinal fluid (ACSF). At the closed window, recordings revealed a short-lasting negative slow potential shift accompanied by a variable, small and short initial hypoperfusion followed by hyperaemia and then oligaemia. In contrast, spreading neuronal activation locally induced CSI at the closed window when ACSF contained a NO. synthase (NOS) inhibitor, N(G)-nitro-L-arginine, and an increased K+ concentration ([K+]ACSF). CSI was characterised by a sharp and prolonged initial cerebral blood flow decrease to 29 +/- 11 % of the baseline and a prolonged negative potential shift. Co-application of a NOa donor, S-nitroso-N-acetylpenicillamine, and NOS inhibitor with high [K+]ACSF re-established a short-lasting negative potential shift and spreading hyperaemia typical of CSD. Similarly, the NO.-independent vasodilator papaverine caused CSI to revert to a pattern characteristic of CSD. In acute rat brain slices, NOS inhibition and high [K+]ACSF did not prolong the negative slow potential shift compared to that induced by high [K+]ACSF alone. The data indicate that the delayed recovery of the slow potential was caused by vasoconstriction during application of high [K+]ACSF and a NOS inhibitor in vivo. This supports the possibility of a vicious circle: spreading neuronal activation induces vasoconstriction, and vasoconstriction prevents repolarisation during CSI. Speculatively, this pathogenetic process could be involved in migraine-induced stroke. (+info)