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PubMed2004

Mechanism of the endothelium-dependent vasodilation and the antihypertensive effect of Brazilian red wine.

The mechanisms involved in the cardioprotector effect of red wine have not yet been completely elucidated but probably an endothelium-dependent vasodilator action may play a significant role in this effect. Experiments were undertaken to determine whether a Brazilian red wine (BRW) induces vasodilation in the mesenteric vascular bed (MVB) and an antihypertensive effect was also assessed in rats with NO-deficient hypertension. In MVB precontracted with norepinephrine, BRW (alcohol-free lyophilized) induces a long-lasting endothelium-dependent vasodilation that is not reduced by indomethacin. Inhibition of NO-synthase by NG-nitro-L-arginine methyl ester (L-NAME) and guanylyl cyclase by 1H-[1,2,3] oxadiazolo [4,4-a]quinoxalin-1-one (ODQ) reduces the vasodilator effect of BRW. In vessels precontracted with norepinephrine and depolarized with KCl (25 Mm) or treated with Ca-dependent K channel blockers charybdotoxin (ChTx) plus apamin, the effect of BRW was significantly reduced. However, this effect is not affected by ATP-dependent K (KATP) channel blocker (glibenclamide). The residual vasodilator effect of BRW observed in vessels pretreated with ChTx plus apamin is completely abolished by ChTx plus apamin plus L-NAME. Concentrations of atropine, pyrilamine, yohimbine, and HOE 140 that significantly reduced the vasodilator effect of acetylcholine, histamine, clonidine, and bradykinin, respectively did not change the vasodilator effect of BRW. Chronic oral administration of BRW induced a significant reduction in systolic, mean and diastolic arterial pressure in rats with L-NAME hypertension. The present results demonstrated that vasodilator effect of BRW is dependent on endothelium-derived hyperpolarizing factor (EDHF) in combination with nitric oxide (NO). The antihypertensive effect of red wine demonstrated in the present study may play a significant role on the cardioprotective action of chronic red wine consumption.

Acetylcholine↗
PubMed1986

Aspects on "traditional" vasodilators in the treatment of chronic heart failure.

Vasodilator therapy of heart failure has through the last 5-10 years become a well established treatment. Traditionally these drugs have been classified after their primary site of action on the vascular beds. Thus drugs primarily acting on the arteriolar bed are called afterload-reducing agents and are exemplified by hydralazine. Drugs primarily acting on the venous bed have been called preload-reducing reducing agents and the typical example is nitroglycerin. Other drugs, like prazosin, act on both the arteriolar and venous vascular beds. The classification is, however, not as sharp as originally believed since preload- and afterload-reducing activities mix with each other. Treatment with vasodilators for chronic heart failure has mainly been advocated in patients with valvular regurgitation, ischemic heart disease and various types of dilated cardiomyopathies. It seems appropriate today to put some questions concerning vasodilator therapy for heart failure. Among such questions are: When in the natural history of congestive heart failure should vasodilator therapy be commenced? How effective is long-term administration of vasodilating drugs? May vasodilator therapy decrease mortality in congestive heart failure? What about the efficacy of new vasodilating drugs compared to more traditional ones? In the review of vasodilating drugs besides ACE inhibitors, these questions will be addressed.

Cardiac Output↗
PubMed1993

Effects of chronic treatment with nitric oxide synthase inhibitors on regional haemodynamic responses to vasodilators in conscious Brattleboro rats.

1. The effects of acute inhibition of nitric oxide (NO) synthase on cardiovascular responses to vasodilator challenges have already been described. We now report the responses to vasodilators during and after chronic NO synthase inhibition. 2. In conscious Brattleboro rats, the regional haemodynamic effects of 3 min infusions of acetylcholine (4 micrograms min-1), sodium nitroprusside (15 micrograms min-1) or adrenaline (0.2 micrograms min-1) were assessed (from areas under or over curves (AUC, AOC)) under control conditions, 6 and 72 h after the addition of the NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA) to the drinking water (1 mg ml-1), and 6, 24 and 48 h after the withdrawal of L-NMMA. In a separate group of Brattleboro rats, responses to acetylcholine, sodium nitroprusside and adrenaline were assessed before and 6 h after the onset of oral ingestion of the more potent nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.05 mg ml-1). 3. Acetylcholine caused renal vasodilation (87 +/- 11 units) and mesenteric vasoconstriction (-31 +/- 5 units), sodium nitroprusside caused vasodilatation in renal (96 +/- 12 units), mesenteric (222 +/- 13 units) and hindquarters (49 +/- 15 units) vascular beds, whereas adrenaline caused hindquarters vasodilatation (92 +/- 8 units). Seventy two h after the onset of oral ingestion of L-NMMA, acetylcholine had a decreased renal vasodilator (59 +/- 9 units) effect, sodium nitroprusside had an increased renal vasodilator (142 +/- 23 units) action, while adrenaline had a decreased hindquarters vasodilator (55 +/- 6 units) influence. Twenty four h after withdrawal of L-NMMA, the renal vasodilator effect of acetylcholine was greater than the control response (106 +/- 14 units), but the regional haemodynamic effects of sodium nitroprusside and adrenaline were not different from those under control conditions. Hence, the increased renal vasodilator response to acetylcholine was probably due to changes in muscarinic receptor-mediated mechanisms rather than to any increase in guanylyl cyclase or its sensitivity to NO.

Acetylcholine↗
PubMed1993

Effects of heparin on the vasodilator action of protamine in the rabbit mesenteric artery.

1. The effects of protamine on the rabbit isolated small mesenteric artery were investigated both in the presence and in the absence of heparin, by the isometric tension-recording method. 2. The dissociation constant for the binding of heparin to protamine has never been previously reported, so in order to minimize the effects of protamine, known to have a vasodilator action, and to examine only the effects of a heparin-protamine complex, the experiments with heparin were performed in the presence of high concentrations of heparin (21-700 u ml-1), concentrations at which heparin itself does not affect the vascular tone. 3. Protamine (15-500 micrograms ml-1), in the absence of heparin, was found to inhibit (P < 0.05) noradrenaline (1 microM)-induced contractions both in endothelium-intact and in endothelium-denuded tissues. 4. Such vasodilator action of protamine in either endothelium-intact or -denuded tissues continued, even in the presence of excess heparin at a heparin/protamine (H/P) ratio of 1.4 u micrograms -1, but was almost completely blocked in the presence of a much greater excess of heparin (H/P ratio > or = 4.7 u micrograms -1): heparin was present both before and during the application of protamine. 5. The vasodilator action of protamine in the absence of heparin was prolonged both in the endothelium-intact and -denuded tissues after protamine had been washed out from the bath with Krebs solution. Although this washing out with a Krebs solution containing excess heparin (4.7 u ml-1) readily reversed such prolonged vasodilator action of protamine both in the endothelium-denuded strips and in the endothelium-intact strips which had been pretreated with inhibitors of the endothelium-derived relaxing factor (EDRF) pathway, it did not affect the prolonged vasodilator action of protamine in the endothelium-intact strips which received no pharmacological intervention.6. These results suggest that: (1) only protamine, not a heparin-protamine complex, exerts vasodilator action in vitro; (2) the vasodilator action of protamine presumably has an EDRF-mediated component;and (3) protamine probably exerts its direct vasodilator action without entering the smooth muscle cell.

Animals↗
PubMed2005

Impaired EDHF-mediated vasodilation and function of endothelial Ca-activated K channels in uremic rats.

BACKGROUND: Chronic renal failure (CRF) is associated with increased cardiovascular morbidity, abnormal arterial tone, and endothelial dysfunction. Ca(2+)-activated K(+)-channels (K(Ca)) are important regulators of endothelial function by controlling endothelial hyperpolarization and thus endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilations. Here we tested the hypothesis whether an altered function of endothelial K(Ca) and diminished EDHF-mediated vasodilation contribute to the endothelial dysfunction in the rat remnant kidney model of chronic renal failure. METHODS: Functional expression of endothelial K(Ca) currents and endothelium-dependent vasodilations in rat carotid arteries were assessed by using patch-clamp techniques, single-cell reverse transcription-polymerase chain reaction (RT-PCR), and a pressure myograph 8 weeks after either subtotal 5/6 nephrectomy in normotensive or hypertensive, or sham-operated rats. RESULTS: Acetylcholine (ACh)-induced EDHF-mediated vasodilations were present in sham-operated rats, but almost absent in both normotensive 5/6 nephrectomy rats and hypertensive 5/6 nephrectomy rats. In experiments without blocking nitric oxide/prostacyclin synthesis, endothelium-dependent vasodilation to ACh was significantly reduced in both normotensive 5/6 nephrectomy rats and hypertensive 5/6 nephrectomy rats. In sham-operated rats, 1-ethyl-2-benzimidazolinone (1-EBIO), a selective opener of endothelial small and intermediate K(Ca), induced a substantial EDHF-mediated vasodilation, which was greatly reduced in hypertensive 5/6 nephrectomy rats and in normotensive 5/6 nephrectomy rats. In patch-clamp experiments, mean K(Ca) currents were significantly reduced in endothelial cells from hypertensive 5/6 nephrectomy rats and normotensive 5/6 nephrectomy rats when compared to sham-operated rats. Concordantly, single-cell reverse-transcription-polymerase chain reaction (RT-PCR) analysis revealed a greatly reduced frequency of endothelial cells expressing the K(Ca) genes, SKCa3 and IKCa1 in 5/6 nephrectomy rats compared to sham-operated rats. CONCLUSION: Experimental CRF leads to a loss of EDHF-type vasodilation which was caused at least in part by an impaired functional expression of endothelial hyperpolarizing K(Ca). The loss of EDHF-type vasodilation may contribute to endothelial dysfunction and abnormal arterial tone in CRF.

Acetylcholine↗
PubMed2003

The nitric oxide- and prostaglandin-independent component of the renal vasodilator effect of thimerosal is mediated by epoxyeicosatrienoic acids.

Epoxyeicosatrienoic acids (EETs) are cytochrome P450-derived metabolites of arachidonic acid that elicit vasodilation via activation of K(+) channels. They have been implicated as endothelium-derived hyperpolarizing factors (EDHFs), mediating the effect of some endothelium-dependent vasodilator agents such as bradykinin in some vascular tissues. We reasoned that an agent that increases the availability of free arachidonic acid should also elicit cytochrome P450-dependent vasodilation that is associated with increased release of EETs and attenuated by agents that inhibit the synthesis or action of EETs. Thus, we used thimerosal as an inhibitor of reacylation of arachidonic acid and determined the contribution of prostaglandins, nitric oxide, and EETs to the vasodilator effect in the isolated, perfused, preconstricted kidney of the rat. Thimerosal elicited vasodilator responses that were unaffected by inhibition of cyclooxygenase with indomethacin but were reduced by the further inhibition of nitric oxide synthesis. The vasodilator activity that remained after inhibition of cyclooxygenase and nitric oxide synthase was reduced by inhibition of K(+) channels with tetraethylammonium and was associated with increased release of EETs measured by gas chromatography-mass spectroscopy following hydrolysis to the corresponding diols. Inhibition of cytochrome P450 with miconazole or epoxygenase with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexamide reduced the nitric oxide- and prostaglandin-independent vasodilator effect of thimerosal and attenuated the increase in the release of EETs. We conclude that thimerosal causes vasodilation of the isolated perfused kidney via nitric oxide-dependent and -independent mechanisms. The nitric oxide-independent component of the response involves activation of K(+) channels and is likely mediated by EETs, possibly acting as EDHFs.

8,11,14-Eicosatrienoic Acid↗
PubMed2003

Nucleotide coronary vasodilation in guinea pig hearts.

The role of P1 receptors and P2Y1 receptors in coronary vasodilator responses to adenine nucleotides was examined in the isolated guinea pig heart. Bolus arterial injections of nucleotides were made in hearts perfused at constant pressure. Peak increase in flow was measured before and after addition of purinoceptor antagonists. Both the P1 receptor antagonist 8-(p-sulfophenyl)theophylline and adenosine deaminase inhibited adenosine vasodilation. AMP-induced vasodilation was inhibited by P1 receptor blockade but not by adenosine deaminase or by the selective P2Y1 antagonist N6-methyl-2'-deoxyadenosine 3',5'-bisphosphate (MRS 2179). ADP-induced vasodilation was moderately inhibited by P1 receptor blockade and greatly inhibited by combined P1 and P2Y1 blockade. ATP-induced vasodilation was antagonized by P1 blockade but not by adenosine deaminase. Addition of P2Y1 blockade to P1 blockade shifted the ATP dose-response curve further rightward. It is concluded that in this preparation ATP-induced vasodilation results primarily from AMP stimulation of P1 receptors, with a smaller component from ATP or ADP acting on P2Y1 receptors. ADP-induced vasodilation is largely due to P2Y1 receptors, with a smaller contribution by AMP or adenosine acting via P1 receptors. AMP responses are mediated solely by P1 receptors. Adenosine contributes very little to vasodilation resulting from bolus intracoronary injections of ATP, ADP, or AMP.

Adenine Nucleotides↗
PubMed1992

Endotoxin impairs flow-induced vasodilation of porcine coronary arterioles.

The purpose of this study was to test the hypothesis that endotoxemia impairs endothelium-dependent (both receptor-mediated and flow-induced) vasodilation in porcine coronary arterioles. Coronary arterioles were isolated from three groups of 4- to 8-wk old (10.3 +/- 0.8 kg) pigs: endotoxemic (E; 250 micrograms/kg endotoxin iv), control (C; equal volume of saline), and untreated pigs (UT). Subepicardial arterioles (60-120 microns) were isolated and cannulated with two micropipettes that were connected to two independent reservoir systems. Intraluminal pressure was set at 60 cmH2O throughout the experiments. All C vessels developed spontaneous tone and exhibited flow-induced vasodilation from 65 to 95% maximal diameter. Spontaneous tone developed in only three of five arterioles from E pigs, and flow-induced vasodilation was not observed in any arteriole from E pigs. Spontaneous tone developed in all six arterioles isolated from UT pigs but disappeared in four of these vessels as a result of 1 h of in vitro incubation with endotoxin (2.5 micrograms/ml). Flow-induced vasodilation was also abolished in these vessels after 1 h of endotoxin exposure. Incubation with 3 mM L-arginine, in vitro, restored flow-induced vasodilation in E arterioles and endotoxin-treated UT arterioles. Vasoconstriction induced by acetylcholine (ACh) and vasodilation induced by nitroprusside (NP) and bradykinin (BK) were similar in arterioles from all groups. In contrast, endotoxin impairs flow-induced vasodilation of coronary arterioles. The mechanism responsible for the impairment of flow-induced vasodilation seems to reside in disruption of the L-arginine/nitric oxide pathway.

Acetylcholine↗
PubMed1995

EDRF and norepinephrine-induced vasodilation in the canine coronary circulation.

Experiments were performed to characterize the role of endothelium-derived relaxing factor (EDRF) in coronary vasodilation caused by norepinephrine. The circumflex or left anterior descending coronary artery was cannulated and pump perfused with constant pressure or constant flow in closed-chest anesthetized dogs. Prostaglandin synthesis was blocked with ibuprofen. During constant-pressure perfusion, EDRF inhibition with intracoronary N omega-nitro-L-arginine (L-NNA) did not affect the vasodilation due to nitroglycerin (an endothelium-independent process). However, L-NNA did significantly inhibit (P < 0.001) the vasodilation due to acetylcholine (an endothelium-dependent process). In response to bolus injections of norepinephrine, EDRF inhibition with L-NNA significantly reduced coronary vasodilation (P < 0.001). This inhibition was partially reversed with L-arginine infusion. To determine whether an increase in shear stress due to an increase in flow was the stimulus for EDRF release, experiments were performed during constant-flow conditions. Vasodilation caused by nitroglycerin was not inhibited by L-NNA, but EDRF inhibition did blunt acetylcholine-induced vasodilation significantly (P < 0.001) during constant-flow perfusion. During EDRF inhibition with L-NNA, vasodilation due to norepinephrine was not significantly altered when coronary flow was held constant (P = 0.19). In conclusion, EDRF plays a role in norepinephrine-induced coronary vasodilation that is largely flow dependent.

Acetylcholine↗
PubMed1996

Hypoxia-reoxygenation impairs NO-mediated vasodilation in rat lungs.

Isolated rat lungs subjected to hypoxia-reoxygenation (H/R) were used to study NO-mediated pulmonary vasodilation during oxidant-induced vascular injury. After ventilation with 3% O2, reoxygenation with 21% (H/R 21%) or 95% O2 (H/R 95%) caused lung edema and lipid peroxidation. Vasodilation to A23187 was attenuated after H/R 21% and abolished after H/R 95%. The vasodilator-response curve to NO was more shifted to the right after H/R 95% than after H/R 21%. Pretreatment with superoxide dismutase (SOD; 150 U/ml) and catalase (120 U/ml) prevented impairment of A23187- and NO-mediated vasodilation. SOD and catalase added after reoxygenation restored vasodilation to NO but not to A23187. In lungs obtained from chronically hypoxic rats but studied under conditions of normoxic ventilation, vasodilation to A23187 was abolished, but vasodilation to NO remained unchanged. The data suggest that generation of oxygen-derived reactive species after H/R produces impairment of NO formation as well as direct inactivation of NO. This does not explain the decreased endothelial NO-mediated pulmonary vasodilation in chronically hypoxic rats.

Animals↗
PubMed1993

Failure of vasodilator administration to increase blood flow to the fatiguing diaphragm.

Recent studies have suggested that coronary and limb muscle vessels do not maximally vasodilate under conditions in which cardiac and limb muscle contractile function is dependent on the level of blood flow but, rather, maintain a "vasodilator reserve." If a vasodilator reserve is also present in the fatiguing diaphragm, it may be possible to augment flow to this muscle with vasodilator administration, improving muscle function. The purpose of the present study was therefore to examine the effect of administration of a potent vasodilator, nitroprusside, on the blood flow and contractile function of the fatiguing diaphragm. Studies were performed using an in situ canine diaphragmatic strip preparation that permitted direct measurement of force and blood flow; cardiac output was monitored with a thermodilution catheter. The effects of nitroprusside were examined with the diaphragm rhythmically contracting in response to both subfatiguing and fatiguing stimulation paradigms. For both contraction paradigms, nitroprusside infusions elicited appreciable increases in cardiac output. Nitroprusside infusions also produced significant increases in diaphragmatic blood flow during subfatiguing diaphragmatic contractions but had no effect on flow during fatiguing contractions. Nitroprusside also had no effect on the rate of diaphragmatic fatigue. These data suggest that, under the conditions examined, the diaphragm exhausts its vasodilator reserve during the development of fatigue and vasodilator administration has no appreciable effect on diaphragm blood flow and function. Moreover, although vasodilator drugs with actions similar to nitroprusside are used clinically to augment flow to vital organs, our data would indicate that these drugs have no functionally significant effect on blood flow to the fatiguing diaphragm.

Animals↗
PubMed2001

Baroreceptor modulation of active cutaneous vasodilation during dynamic exercise in humans.

The hypothesis that baroreceptor unloading during dynamic limits cutaneous vasodilation by withdrawal of active vasodilator activity was tested in seven human subjects. Increases in forearm skin blood flow (laser-Doppler velocimetry) at skin sites with (control) and without alpha-adrenergic vasoconstrictor activity (vasodilator only) and in arterial blood pressure (noninvasive) were measured and used to calculate cutaneous vascular conductance (CVC). Subjects performed two similar dynamic exercise (119 +/- 8 W) protocols with and without baroreceptor unloading induced by application of -40 mmHg lower body negative pressure (LBNP). The LBNP condition was reversed (i.e., either removed or applied) after 15 min while exercise continued for an additional 15 min. During exercise without LBNP, the increase in body core temperature (esophageal temperature) required to elicit active cutaneous vasodilation averaged 0.25 +/- 0.08 and 0.31 +/- 0.10 degrees C (SE) at control and vasodilator-only skin sites, respectively, and increased to 0.44 +/- 0.10 and 0.50 +/- 0.10 degrees C (P < 0.05 compared with without LBNP) during exercise with LBNP. During exercise baroreceptor unloading delayed the onset of cutaneous vasodilation and limited peak CVC at vasodilator-only skin sites. These data support the hypothesis that during exercise baroreceptor unloading modulates active cutaneous vasodilation.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Current-induced vasodilation during water iontophoresis (5 min, 0.10 mA) is delayed from current onset and involves aspirin sensitive mechanisms.

Study of the microcirculation by iontophoresis is potentially confounded by any non-specific effects of current application. Laser Doppler flow (LDF, mean +/- SD; arbitrary units; AU) was recorded on the forearms of healthy volunteers during and 20 min following application of 0.10-mA current for 1, 3 and 5 min, using deionised water as a vehicle. Local heating to 44 degrees C was then applied for 24 min to assess maximal vasodilation. Cathodal current applications resulted in delayed and prolonged vasodilation (peak values: 78 +/- 29, 75 +/- 19, 80 +/- 37 AU) whereas anodal peak LDF was 13 +/- 6, 27 +/- 34 and 72 +/- 40 AU for 1-, 3- and 5-min periods of current applications, respectively. From current onset, inflexion points in the responses to 3- and 5-min anodal current applications occurred at 4.5 and 6.5 min, respectively, and at approximately 1.5 min for all cathodal current applications. For 5-min current applications: a preliminary tourniquet ischaemia neither changed the time course nor the amplitude of the response to current application. In this situation, local anaesthesia abolished the current-induced vasodilation. Chronic capsaicin pretreatment decreased the amplitude of the vasodilation. Pretreatment with 500 mg oral aspirin decreased the cathodal vasodilation and abolished the anodal vasodilation, even in the absence of preliminary ischaemia. We conclude that vasodilation to prolonged application of 0.10-mA continuous monopolar current after transient tourniquet ischaemia cannot be exclusively the result of an axon reflex initiated by current onset. This current-induced vasodilation is at least partly dependent on capsaicin-sensitive afferent fibres and relies on aspirin-sensitive mechanisms at both polarities.

Adult↗
PubMed2005

Involvement of NO and EDHF in flow-induced vasodilation in isolated hamster cremasteric arterioles.

Flow-induced vasodilation in hamster cremasteric arterioles was investigated with special reference to the roles of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). Arterioles (approximately 60 microm resting diameter) were cannulated, and suffused with MOPS solution at 37 degrees C (mean intraluminal pressure: 80 cm H(2)O). Step increases in the perfusate flow elicited a dose-dependent vasodilation, which was almost proportional to the increases in calculated wall shear stress (WSS). N(omega)-nitro L-arginine methyl ester (L-NAME, 100 microM) reduced the flow-induced vasodilation by approximately 50%, whereas indomethacin (10 microM) produced no significant effect. In the presence of L-NAME, the residual vasodilation was eliminated by treatment with the cytochrome P-450 monooxygenase inhibitor 17-octadecynoic acid (17-ODYA, 50 microM), sulfaphenazol (10 microM), tetraethylammonium (TEA, 3 mM; a nonselective Ca(2+)-activated K(+) channel inhibitor), or charybdotoxin (ChTX, 0.1 microM; intermediate or large conductance Ca(2+)-activated K(+) channel inhibitor). In the absence of L-NAME, the dilation was also reduced by approximately 50% by treatment with 17-ODYA, TEA, or ChTX. The residual vasodilation was eliminated by additional treatment with L-NAME. The inhibitor of ATP-sensitive K(+) channels (K(ATP)), glibenclamide, also caused a significant, but partial, reduction of the flow-induced vasodilation. The residual vasodilation was completely reduced by additional treatment with 17-ODYA, but not L-NAME. These findings suggest that in hamster cremaster, higher flow rate produces NO, K(ATP), and EDHF vasodilation of the arterioles under physiological conditions.

Abdominal Muscles↗
PubMed2003

L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemia and sickle cell disease.

BACKGROUND: Hypercholesterolemia and sickle cell disease (SCD) impair endothelium-dependent vasodilation by dissimilar mechanisms. Hypercholesterolemia impairs vasodilation by a low-density lipoprotein (LDL)-dependent mechanism. SCD has been characterized as a chronic state of inflammation in which xanthine oxidase (XO) from ischemic tissues increases vascular superoxide anion (O2*-) generation. Recent reports indicate that apolipoprotein (apo) A-1 mimetics inhibit atherosclerosis in LDL receptor-null (Ldlr-/-) mice fed Western diets. Here we hypothesize that L-4F, an apoA-1 mimetic, preserves vasodilation in hypercholesterolemia and SCD by decreasing mechanisms that increase O2*- generation. METHODS AND RESULTS: Arterioles were isolated from hypercholesterolemic Ldlr-/- mice and from SCD mice that were treated with either saline or L-4F (1 mg/kg per day). Vasodilation in response to acetylcholine was determined by videomicroscopy. Effects of L-4F on LDL-induced increases in endothelium-dependent O2*- generation were determined on arterial segments via the hydroethidine assay and on stimulated endothelial cell cultures via superoxide dismutase-inhibitable ferricytochrome c reduction. Effects of L-4F on XO bound to pulmonary arterioles and content in livers of SCD mice were determined by immunofluorescence. Hypercholesterolemia impaired vasodilation in Ldlr-/- mice, which L-4F dramatically improved. L-4F inhibited LDL-induced increases in O2*- in arterial segments and in stimulated cultures. SCD impaired vasodilation, increased XO bound to pulmonary endothelium, and decreased liver XO content. L-4F dramatically improved vasodilation, decreased XO bound to pulmonary endothelium, and increased liver XO content compared with levels in untreated SCD mice. CONCLUSIONS: These data show that L-4F protects endothelium-dependent vasodilation in hypercholesterolemia and SCD. Our findings suggest that L-4F restores vascular endothelial function in diverse models of disease and may be applicable to treating a variety of vascular diseases.

Anemia, Sickle Cell↗
PubMed1988

No reflow and extent of infarction during maximal vasodilation in the porcine heart.

To explore the relation between myocardial and vascular injury in the generation of the no-reflow phenomenon, the pressure-flow relation during maximal vasodilation after coronary artery reperfusion was studied in the open-chest porcine model. During both endogenous and maximal vasodilation with intracoronary adenosine, pressure-flow (P/Q) plots were constructed before and after 20-minute (n = 9) or 40-minute (n = 17) circumflex artery occlusions. Decreases in circumflex vascular bed conductance were represented by downward shifts in P/Q plot regression lines. No significant change occurred in P/Q line slope or pressure at zero flow 30 minutes after release of the 20-minute occlusion, and no infarction was found. After release of the 40-minute occlusion, a small but insignificant decrease in P/Q line slope occurred during endogenous vasodilation. However, during maximal vasodilation, a significant (p less than 0.01) decrease in P/Q line slope was present during reperfusion compared with preocclusion corresponding to a decrease in vasodilatory reserve (P/Q line slope = 1.52 +/- 0.14 ml/min/mm Hg preocclusion vs. 1.03 +/- 0.13 at 15 minutes reperfusion). Pretreatment with aspirin did not prevent this decrease in vascular conductance during maximal vasodilation. Total circumflex, as well as subendocardial, midmyocardial, and subepicardial blood flows, was measured with radioactive microspheres. There was a good correlation between the extent of infarction measured by triphenyltetrazolium chloride staining and the decrease in vascular conductance during maximal vasodilation for all three myocardial layers as well as for the total circumflex vascular bed. Hence, the degree of no-reflow correlates closely with the extent of infarction during maximal vasodilation (but not during endogenous vasodilation) and is not altered by aspirin therapy.

Animals↗
PubMed1994

Contribution of endothelium-derived nitric oxide to exercise-induced vasodilation.

BACKGROUND: Endothelium-derived nitric oxide is an important modulator of resting vascular tone in animals and humans. However, the contribution of nitric oxide to exercise-induced vasodilation is unknown. METHODS AND RESULTS: The effect of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, on exercise-induced vasodilation was studied in 18 healthy subjects (mean +/- SD, 40 +/- 10 years; 10 women). Acetylcholine was used to test the efficacy of L-NMMA in inhibiting stimulation of nitric oxide synthesis and sodium nitroprusside to test the specificity of L-NMMA in inhibiting endothelium-dependent vasodilation. Intermittent handgrip exercise and infusions of acetylcholine and sodium nitroprusside were performed during intra-arterial infusion of 5% dextrose (control) and L-NMMA (4 to 16 mumol/min). Forearm blood flow was determined by strain-gauge plethysmography. Forearm oxygen extraction was measured from arterial and venous oxygen saturations. In a separate study, 10 subjects performed exercise during infusions of 5% dextrose, L-arginine (the substrate for nitric oxide production), and D-arginine (the stereoisomer that is not a substrate for nitric oxide production). L-NMMA reduced exercise blood flow by 7 +/- 13% (P = .04), increased exercise resistance by 18 +/- 20% (P = .02), and increased exercise oxygen extraction by 16 +/- 17% (P < .001). The degree of inhibition of acetylcholine-induced vasodilation with L-NMMA correlated positively with the degree of reduction in exercise blood flow (r = .55, P = .02). The highest dose of L-NMMA (16 mumol/min) produced the greatest effect; exercise blood flow was reduced by 11 +/- 14% (P = .03), and vascular resistance increased by 26 +/- 23% (P = .005). L-NMMA did not affect the forearm vasodilation produced by sodium nitroprusside. Exercise blood flow, resistance, and oxygen extraction were not significantly modified by infusions of either L- or D-arginine. CONCLUSIONS: Inhibition of nitric oxide synthesis reduces exercise-induced vasodilation in the human forearm, indicating that nitric oxide plays a role in exercise-induced vasodilation. Increased availability of nitric oxide substrate does not enhance exercise-induced vasodilation in healthy subjects. These findings have important implications for disease states in which endothelium-derived nitric oxide production is impaired.

Acetylcholine↗
PubMed1997

Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia.

BACKGROUND: Endothelium-dependent vasodilation is impaired in humans with hypercholesterolemia. Oxidative degradation of endothelium-derived nitric oxide plays a major role in endothelial dysfunction in animal models of hypercholesterolemia. To assess whether this mechanism is relevant to humans, we studied the effect of vitamin C, an antioxidant, on vasodilator function in forearm resistance vessels of patients with hypercholesterolemia. METHODS AND RESULTS: We studied 11 hypercholesterolemic and 12 healthy control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intra-arterial infusion of methacholine (0.3 to 10 micrograms/min). Endothelium-independent vasodilation was measured by intra-arterial infusion of nitroprusside (0.3 to 10 micrograms/min) and verapamil (10 to 300 micrograms/min). Forearm blood flow dose-response curves were determined for each drug before and during coadministration of vitamin C (24 mg/min). In hypercholesterolemic subjects, endothelium-dependent vasodilation to methacholine was augmented by coinfusion of vitamin C (P = .001); in contrast, endothelium-independent vasodilation to nitroprusside and verapamil were not affected by coinfusion of vitamin C (P = .8 and P = .3, respectively). In control subjects, vitamin C administration did not alter endothelium-dependent vasodilation (P = .2). CONCLUSIONS: We conclude that vitamin C improves endothelium-dependent vasodilation in the forearm resistance vessels of patients with hypercholesterolemia. These findings suggest that nitric oxide degradation by oxygen-derived free radicals contributes to abnormal vascular reactivity in hypercholesterolemic humans.

Adult↗