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PubMed1995

Muscarinic agonists and antagonists cause vasodilation in isolated rat lung.

The present study investigated the ability of atropine and different muscarinic receptor subtypes to affect acetylcholine (ACh)-induced bronchoconstriction and vasodilation in the isolated rat lung model. ACh (10(-7) M) given after U-46619 decreased total (RT), precapillary, and postcapillary vascular resistances and increased peak airway pressure. Atropine (20 microM) decreased RT and precapillary and postcapillary vascular resistances and blocked ACh-induced increases in peak airway pressure. The M1-selective agonist McN-A-343 (1.3 x 10(-5) M) decreased RT from 40.27 +/- 2.98 to 29.20 +/- 2.81 cmH2O.l-1.min-100 g lung wt (P = 0.01), and ACh caused no further dilation. The M1-selective antagonist pirenzepine (1.6 x 10(-6) M) blocked ACh-induced vasodilation. The M2-selective antagonist gallamine (7.5 x 10(-7) M) decreased RT from 45.50 +/- 3.19 to 34.86 +/- 1.25 cmH2O.l-1.min.100 g lung wt (P < 0.05), and after gallamine, ACh further decreased RT to 28.59 +/- 1.75 cmH2O.l-1.min.100 g lung wt (P < 0.01). Neither the selective muscarinic agonists nor antagonists affected peak airway pressures. We conclude that ACh-induced vasodilation in isolated rat lungs preconstricted with U-46619 is mediated by M1 receptors. Atropine-induced vasodilation in this model is mediated through the inhibition of the M2 receptor. We postulate that this represents either a blockade of postganglionic receptors, permitting release of vasodilator substances from local nerve terminals, or a direct vasodilatory effect on the vascular smooth muscle.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Bronchial vasodilator pathways in the vagus nerve of dogs.

Bronchial vasodilation in dogs is mediated largely by vagal pathways. To examine the relative contribution of cholinergic and noncholinergic parasympathetic pathways and of sensory axon reflexes to vagal bronchial vasodilation, we electrically stimulated the peripheral vagus nerve in 10 chloralose-anesthetized dogs and measured bronchial artery flow. Moderate-intensity electrical stimulation (which did not activate C-fiber axons) caused a rapid voltage- and frequency-dependent vasodilation. After atropine, vasodilation was slower in onset and reduced at all voltages and frequencies: bronchial vascular conductance increased by 9.0 +/- 1.5 (SE) ml. min-1. 100 mmHg-1 during stimulation before atropine and 5. 5 +/- 1.4 ml. min-1. 100 mmHg-1 after (P < 0.02). High-intensity stimulation (sufficient to recruit C fibers) was not studied before atropine because of the resulting cardiac arrest. After atropine, high-intensity stimulation increased conductance by 12.0 +/- 2.5 ml. min-1. 100 mmHg-1. Subsequent blockade of ganglionic transmission, with arterial blood pressure maintained by a pressure reservoir, abolished the response to moderate-intensity stimulation and reduced the increase to high-intensity stimulation by 82 +/- 5% (P < 0.01). In 13 other dogs, we measured vasoactive intestinal peptide-like immunoreactivity in venous blood draining from the bronchial veins. High-intensity vagal stimulation increased vasoactive intestinal peptide concentration from 5.7 +/- 1.8 to 18.4 +/- 4.1 fmol/ml (P = 0.001). The results suggest that in dogs cholinergic and noncholinergic parasympathetic pathways play the major role in vagal bronchial vasodilation.

Animals↗
PubMed2003

Attenuated thermoregulatory sweating and cutaneous vasodilation after 14-day bed rest in humans.

We investigated the effect of head-down bed rest (HDBR) for 14 days on thermoregulatory sweating and cutaneous vasodilation in humans. Fluid intake was ad libitum during HDBR. We induced whole body heating by increasing skin temperature for 1 h with a water-perfused blanket through which hot water (42 degrees C) was circulated. The experimental room was air-conditioned (27 degrees C, 30-40% relative humidity). We measured skin blood flow (chest and forearm), skin temperatures (chest, upper arm, forearm, thigh, and calf), and tympanic temperature. We also measured sweat rate by the ventilated capsule method in which the skin area for measurement was drained by dry air conditioned at 27 degrees C under similar skin temperatures in both trials. We calculated cutaneous vascular conductance (CVC) from the ratio of skin blood flow to mean blood pressure. From tympanic temperature-sweat rate and -CVC relationships, we assessed the threshold temperature and sensitivity as the slope response of variables to a given change in tympanic temperature. HDBR increased the threshold temperature for sweating by 0.31 degrees C at the chest and 0.32 degrees C at the forearm, whereas it reduced sensitivity by 40% at the chest and 31% at the forearm. HDBR increased the threshold temperature for cutaneous vasodilation, whereas it decreased sensitivity. HDBR reduced plasma volume by 11%, whereas it did not change plasma osmolarity. The increase in the threshold temperature for sweating correlated with that for cutaneous vasodilation. In conclusion, HDBR attenuated thermoregulatory sweating and cutaneous vasodilation by increasing the threshold temperature and decreasing sensitivity. HDBR increased the threshold temperature for sweating and cutaneous vasodilation by similar magnitudes, whereas it decreased their sensitivity by different magnitudes.

Adolescent↗
PubMed2004

Connexin expression and conducted vasodilation along arteriolar endothelium in mouse skeletal muscle.

Functional hyperemia requires the coordination of smooth muscle cell relaxation along and between branches of the arteriolar network. Vasodilation is conducted from cell to cell along the arteriolar wall through gap junction channels composed of connexin protein subunits. Within skeletal muscle, it is unclear whether arteriolar endothelium, smooth muscle, or both cell layers provide the cellular pathway for conduction. Furthermore, the constitutive profile of connexin expression within the microcirculation is unknown. We tested the hypothesis that conducted vasodilation and connexin expression are intrinsic to the endothelium of arterioles (17 +/- 1 microm diameter) that supply the skeletal muscle fibers in the cremaster of anesthetized C57BL/6 mice. ACh delivered to an arteriole (500 ms, 1-microA pulse; 1-microm micropipette) produced local dilation of 17 +/- 1 microm; conducted vasodilation observed 1 mm upstream was 9 +/- 1 microm (n = 5). After light-dye treatment to selectively disrupt endothelium (250-microm segment centered 500 microm upstream, confirmed by loss of local response to ACh while constriction to phenylephrine and dilation to sodium nitroprusside remained intact), we found that conducted vasodilation was nearly abolished (2 +/- 1 microm; P < 0.05). Whole-mount immunohistochemistry for connexins revealed punctate labeling at borders of arteriolar endothelial cells, with connexin40 and connexin37 in all branches and connexin43 only in the largest branches. Immunoreactivity for connexins was not apparent in smooth muscle or in capillary or venular endothelium, despite robust immunolabeling for alpha-actin and platelet endothelial cell adhesion molecule-1, respectively. We conclude that vasodilation is conducted along the endothelium of mouse skeletal muscle arterioles and that connexin40 and connexin37 are the primary connexins forming gap junction channels between arteriolar endothelial cells.

Acetylcholine↗
PubMed2002

Delayed distribution of active vasodilation and altered vascular conductance in aged skin.

Reflex vasodilation is attenuated in aged skin during hyperthermia. We used laser-Doppler imaging (LDI) to test the hypothesis that the magnitude of conductance and the spatial distribution of vasodilation are altered with aging. LDI of forearm skin was compared in 12 young (19- to 29-yr-old) and 12 older (64- to 75-yr-old) men during supine passive heating. Additionally, iontophoresis of bretylium tosylate was performed in a subset of subjects to explore the involvement of sympathetic vasoconstriction in limiting skin blood flow. Passive heating with water-perfused suits clamped mean skin temperature at 41.0 +/- 0.5 degrees C, causing a ramp increase in esophageal temperature (T(es)) to </=38.5 degrees C. LDI scans were performed at baseline and at every 0.2 degrees C increase in T(es). LDI at bretylium and control sites was identical, suggesting no influence of noradrenergic vasoconstriction. Forearm vascular conductance (venous occlusion plethysmography) was reduced in the older men (P </= 0.001) at every elevated T(es). Mean cutaneous vascular conductance (CVC) of the scanned area was reduced in the older men at 0.2 degrees C </= DeltaT(es) </= 0.8 degrees C. Early in heating (0.2 degrees C </= DeltaT(es) </= 0.6 degrees C), older men also responded with a reduced vasodilated area (P </= 0.05), implying a slower recruitment or filling of skin microvessels. The results indicate that the area of vasodilation and CVC within the vasodilated area are reduced in aged skin during early passive heating, but only CVC is reduced at DeltaT(es) = 0.8 degrees C.

Adult↗
PubMed2005

Differences in finger skin contact cooling response between an arterial occlusion and a vasodilated condition.

To assess the presence and magnitude of the effect of skin blood flow on finger skin cooling on contact with cold objects against the background of circulatory disorder risks in occupational exposures, this study investigates the effect of zero vs. close-to-maximal hand blood flow on short-term (< or =180 s) skin contact cooling response at a contact pressure that allows capillary perfusion of the distal pulp of the fingertip. Six male volunteers touched a block of aluminium with a finger contact force of 0.5 N at a temperature of -2 degrees C under a vasodilated and an occluded condition. Before both conditions, participants were required to exercise in a hot room for > or = 30 min for cutaneous vasodilation to occur (increase in rectal temperature of 1 degrees C). Under the vasodilated condition, forearm blood flow rate rose as high as 16.8 ml.100 ml(-1).min(-1). Under the occluded condition, the arm was exsanguinated, after which a blood pressure cuff was secured on the wrist inducing arterial occlusion. Contact temperature of the finger pad during the subsequent cold contact exposure was measured. No significant difference was found between the starting skin temperatures for the two blood flow conditions, but a distinct difference in shape of the contact cooling curve was apparent between the two blood flow conditions, with Newtonian cooling observed under the occluded condition, whereas a rewarming of the finger skin toward the end of the exposure occurred for the vasodilated condition. Blood flow was found to significantly increase contact temperature from 40 s onward (P < 0.01). It is concluded that, at a finger contact force compatible with capillary perfusion of the finger pad ( approximately 0.5 N), circulating blood provides a heat input source that significantly affects finger skin contact cooling during a vasodilated state.

Adult↗
PubMed1976

Vasodilator effect of thrombins prepared from normal or deficient human or canine plasmas.

Thrombins prepared from plasmas deficient in various clotting factors are capable of inducing vasodilator response to the hindlimb of the dog and this response proved to be similar to that produced by thrombins prepared from normal plasmas. Thus the vascular effect of thrombin is not mediated by any other clotting factor which might be present in small amounts in the thrombin preparations. Thrombin prepared from canine normal plasma exerted a more potent vasodilator response, indicating a species specificity for the vascular response to thrombin. Since the vasodilating effect of thrombin is not mediated by (i) a nervous mechanism, (ii) any known vasodilating substance or (iii) any other clotting factor, it is concluded that the thrombin moiety possesses vasodilating properties.

Animals↗
PubMed2001

Inhaled nitric oxide versus aerosolized iloprost in secondary pulmonary hypertension in children with congenital heart disease: vasodilator capacity and cellular mechanisms.

BACKGROUND: Inhaled nitric oxide (iNO) has been used to assess the vasodilator capacity of the pulmonary vascular bed in children with congenital heart disease and elevated pulmonary vascular resistance. Inhaled iloprost is a pulmonary vasodilator for the long-term treatment of pulmonary hypertension (PHT). Because these 2 vasodilators act through different pathways (release of cGMP or cAMP, respectively), we compared the pulmonary vasodilator capacity of each. METHODS AND RESULTS: A total of 15 children with congenital heart disease and PHT who had elevated pulmonary vascular resistance (preoperative, n=10; immediately postoperative, n=5) were first given 20 ppm of iNO for 10 minutes; then, after baseline values were reached again, they were given aerosolized iloprost at 25 ng. kg(-1). min(-1) for another 10 minutes. Finally, iNO and iloprost were given simultaneously for 10 minutes. With iNO, the pulmonary vascular resistance and systemic vascular resistance ratio decreased from 0.48+/-0.38 to 0.27+/-0.16 (P:<0.001). Similarly, iloprost decreased the ratio from 0.49+/-0.38 to 0.26+/-0.11 (P:<0.05). The combination had no additional effect on the resistance ratio. Plasma cGMP increased from 17.6+/-11.9 to 34.7+/-21.4 nmol/L during iNO (P:<0.01), and plasma cAMP increased from 55.7+/-22.9 to 65.1+/-21.2 nmol/L during iloprost inhalation (P:<0.05). CONCLUSIONS: In children with PHT and congenital heart disease, both iNO and aerosolized iloprost are equally effective in selectively lowering pulmonary vascular resistance through an increase in cGMP or cAMP, respectively. However, the combination of both vasodilators failed to prove more potent than either substance alone. Aerosolized iloprost might be an alternative to iNO for early testing of vascular reactivity and for the postoperative treatment of acute PHT.

Administration, Inhalation↗
PubMed1981

Long-term vasodilator therapy for heart failure: clinical response and its relationship to hemodynamic measurements.

To assess the clinical efficacy of chronic vasodilator therapy for refractory congestive heart failure, the long-term follow-up (mean 13 months, range 3-30 months) was evaluated in 56 patients treated with hydralazine, usually in combination with nitrates. In the first 6 months, 73% improved subjectively and 59% improved by one or two New York Heart Association classifications; early improvement was usually sustained. Mortality was high, 22% at 6 months and 37% at 12 months, but was significantly lower in patients who had a clinical response to vasodilators (21% in responders vs 55% in nonresponders at 1 year). The only clinical indicator that differentiated responders from nonresponders was the presence or absence of symptomatic progression before initiation of vasodilator therapy. Pulmonary artery pressure, pulmonary capillary wedge (PCW) pressure and stroke work index (SWI) before and during vasodilator therapy correlated with clinical response and survival. Fifteen of 20 patients with PCW < 20 mm Hg and SWI greater than or equal to 30 g-m/m2 improved and survived, compared with two of 19 with PCS greater than or equal to 20 mm Hg and SWI < 30 g-m/m2. Patients who did not have acute hemodynamic improvement generally did not improve clinically, but neither the percentage change nor the absolute change in any hemodynamic variable predicted outcome in the remaining patients. The findings of this study indicate that vasodilators produce clinical improvement in many patients with refractory heart failure and that hemodynamic measurements are helpful in predicting the outcome of therapy.

Blood Pressure↗
PubMed1987

The vasodilator potency of atrial natriuretic peptide in man.

The vasodilating potency of alpha-human atrial natriuretic peptide (alpha-hANP) was investigated in the forearms of 16 normotensive subjects, 22 to 48 (mean 28) years old, with the use of venous occlusion plethysmography. alpha-hANP, 0.005 to 1.5 micrograms/min/100 ml forearm volume (FAV), infused in nine dose steps into the brachial artery increased forearm blood flow (FAF; ml/min/100 ml FAV) from 2.8 +/- 0.4 (SEM) to a maximum of 9.6 +/- 1.1. Forearm vascular resistance (mean arterial pressure/FAF) decreased by 72%. The alpha-hANP dose that produced a 50% vasodilator response was 0.093 +/- 0.016 microgram/min/100 ml FAV (n = 11) and it resulted in a venous plasma concentration of ANP (pANP) of 115 +/- 7 pmol/liter (normal 2 to 80; radioreceptor assay). Intraindividually, the maximum dose of alpha-hANP induced an increase in FAF that was 60% of the maximum response to sodium nitroprusside (14.1 +/- 1.8). Combined infusions (n = 9) of maximum forearm vasodilator doses of alpha-hANP and nitroprusside increased FAF to 22.7 +/- 3.4; this additive vasodilator effect of alpha-hANP and nitroprusside is consistent with their different actions on the guanylate cyclase system. In man, the direct vasorelaxant effect of alpha-hANP occurs at concentrations within the upper normal range of pANP, suggesting a physiologic vasodilator role for alpha-hANP.

Adult↗
PubMed1988

Coronary vasodilator reserve after human orthotopic cardiac transplantation.

Cardiac transplantation is frequently associated with accelerated coronary atherosclerosis and immune-mediated microvascular injury. To determine if orthotopic cardiac transplantation impairs the capacity of the coronary vasculature to vasodilate and conduct hyperemic blood flow, maximal coronary vasodilator reserve was measured in 25 cardiac allograft recipients with no evidence of rejection 6-57 months after transplantation and in 20 normal subjects. Left ventricular wall thickness was assessed echocardiographically, and epicardial coronary anatomy was evaluated by quantitative coronary angiography. Coronary vasodilator reserve (CVDR) was measured in all patients with a coronary Doppler catheter and a maximally vasodilating dose of intracoronary papaverine. CVDR measured in the transplant recipients with normal coronary arteries, left ventricular function, and wall thickness (5.0 +/- 0.3 [mean +/- SEM] peak/resting velocity; range, 3.8-7.3; n = 16) was not different from that of normal subjects (4.8 +/- 0.2; range, 3.7-8.3). CVDR in the five cardiac allograft recipients with diffuse coronary atherosclerosis producing 30 +/- 5% narrowing (range, 25-38%) of epicardial vessel diameter also was normal (5.1 +/- 0.3; range, 4.3-6.2; n = 5). The CVDR was reduced, however, in two of the four cardiac allograft recipients with left ventricular hypertrophy. In the only transplant recipient in whom a regional wall motion abnormality was present, CVDR was abnormal in the vascular distribution of the hypokinetic wall segment (1.8) but was normal in the artery that supplied normally functioning myocardium (4.0). These findings demonstrate that in the absence of allograft rejection, acquired left ventricular hypertrophy, and regional wall motion abnormalities, coronary vasodilator reserve is normal after orthotopic human cardiac transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1994

Enhanced cholinergic cutaneous vasodilation in Raynaud's phenomenon.

BACKGROUND: Vasodilator function was determined in patients with Raynaud's phenomenon during intra-arterial infusions of the endothelium-dependent and -independent vasodilators, methacholine and sodium nitroprusside, respectively. Reactive hyperemia, induced by 5 minutes of arterial occlusion with exercise, was also measured. METHODS AND RESULTS: Total blood flow was measured in the fingertip and forearm by venous occlusion plethysmography, and blood flow in the forearm skin was determined with laser Doppler flowmetry. Basal fingertip blood flow was not significantly different between control subjects and patients with Raynaud's phenomenon. Infusions of methacholine had no significant effect on fingertip blood flow in control subjects, whereas patients with Raynaud's phenomenon showed a significant increase in fingertip blood flow. Basal total forearm blood flow was significantly lower in patients with Raynaud's phenomenon than in control subjects. Infusions of methacholine and sodium nitroprusside produced dose-related increases in total forearm blood flow that were of similar magnitudes in the two groups, as were the reactive hyperemic responses. Laser Doppler measurements of forearm skin blood flow, however, showed a significantly greater vasodilator response to methacholine in patients with Raynaud's phenomenon than in control subjects. Infusions of sodium nitroprusside produced a relatively small vasodilator response in the skin of the forearm that was smaller than that to methacholine and not significantly different between the two groups. CONCLUSIONS: In Raynaud's phenomenon, a greater vasodilator response to infusions of methacholine in the fingertip, where changes in blood flow mainly reflect those of skin, and in the skin of the forearm may reflect increased responsiveness of cutaneous blood vessels to stimulation of the endothelium. The mechanism involved is unclear but may result from a general abnormality of blood vessels in the skin, which is related to the pathophysiology of cutaneous vasospasm.

Adult↗
PubMed1998

EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension.

BACKGROUND: Nitric oxide (NO) and endothelin (ET) have been implicated in the pathogenesis of pulmonary hypertension (PH). Chronic ETA antagonist therapy reduces PH in monocrotaline (MCT)-treated rats. Interactions between the L-arginine-NO pathway and the ET system have been described. We therefore studied the effect of long-term treatment with an oral ETA antagonist (LU 135252) on NO-related vasodilation in isolated lungs from control rats and rats with MCT-induced PH. METHODS AND RESULTS: Three weeks after MCT injection, PH was associated with an increase in right ventricular pressure (from 27.4 +/- 0.9 to 66.6 +/- 4.1 mm Hg) and a decrease in endothelium-independent vasodilation in response to sodium nitroprusside (10(-10) to 10(-5) mol/L; delta Emax, from 11.1 +/- 0.9 to 2.7 +/- 0.3 mm Hg). Endothelium-dependent vasodilation in response to acetylcholine (10(-9) to 10(-4) mol/L) and the calcium ionophore A23187 (10(-9) to 10(-7) mol/L) remained unaffected. Treatment with LU 135252 did not significantly affect the endothelium-dependent and -independent vasodilations in control rats. However, in MCT-treated rats, LU 135252 therapy significantly reduced right ventricular pressure (39.7 +/- 2.1 mm Hg), potentiated acetylcholine-induced vasodilatation (delta Emax, from 1.6 +/- 0.2 to 3.7 +/- 0.4 mm Hg), and improved the responses to sodium nitroprusside (delta Emax, from 2.7 +/- 0.3 to 5.6 +/- 0.6 mm Hg). LU 135252 did not significantly alter the non-receptor-mediated endothelium-dependent vasodilation to A23187 or pulmonary constitutive NO synthase activity. CONCLUSIONS: MCT PH is associated with a reduced smooth muscle responsiveness to NO but a maintained endothelium-dependent vasodilatory potency. Long-term ETA antagonist therapy not only restores smooth muscle responsiveness to NO but also increases endothelium-dependent dilation in response to acetylcholine. This mechanism may contribute to the therapeutic benefit of ETA antagonists in PH.

Animals↗
PubMed2002

Endogenous endothelin-1 limits exercise-induced vasodilation in hypertensive humans.

Essential hypertension is a common disorder, associated with increased endothelin-1-mediated vasoconstrictor tone at rest. We hypothesized that increased vasoconstrictor activity of endothelin-1 might explain why the normal decrease in peripheral vascular resistance in response to exercise is attenuated in hypertensive patients. Therefore, we investigated the effect of endothelin A (ET(A)) receptor blockade on the vasodilator response to handgrip exercise. Forearm blood flow responses to handgrip exercise (15%, 30%, and 45% of maximum voluntary contraction) were assessed in hypertensive patients and matched normotensive subjects, before and after intra-arterial infusions of the ET(A) receptor antagonist BQ-123; a control dilator, hydralazine; and placebo (saline). Preinfusion (baseline) vasodilation in response to exercise was significantly attenuated at each workload in hypertensive patients compared with normotensive subjects. Intra-arterial infusions of hydralazine and saline did not increase the vasodilator response to exercise in either hypertensives or normotensives at any workload. The vasodilator response to exercise was markedly enhanced after BQ-123 at the 2 higher workloads in hypertensives (157+/-48%, P<0.01; 203+/-58%, P<0.01) but not in normotensives. This suggests that the impaired vasodilator response to exercise in hypertensive patients is, at least in part, a functional limitation caused by endogenous ET(A) receptor-mediated vasoconstriction. Treatment with endothelin receptor antagonists may, therefore, increase exercise capacity in essential hypertension.

Adult↗
PubMed1995

Effect of copper-zinc superoxide dismutase on endothelium-dependent vasodilation in patients with essential hypertension.

Patients with essential hypertension have abnormal endothelium-dependent vasodilation related to decreased nitric oxide activity. The specific mechanism responsible for this abnormality is unknown. Recent studies in hypertensive animals have suggested an augmented destruction of nitric oxide by superoxide anions. Therefore, in the present study we aimed to investigate whether this mechanism is responsible for the abnormal vasodilator function of hypertensive patients. To this end, we studied the vascular responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct smooth muscle dilator) before and after combined administration of copper-zinc superoxide dismutase (a scavenger of superoxide anions with poor intracellular penetrance; 6000 U/min) in 20 healthy control subjects (11 men and 9 women; aged 50 +/- 6 years) and 20 hypertensive patients (13 men and 7 women; aged 51 +/- 9 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by plethysmography. The vasodilator response to acetylcholine was significantly blunted in hypertensive patients compared with control subjects (maximal flow: 8.2 +/- 4 versus 12.7 +/- 3 mL/min per 100 mL; P < .02); however, no difference was observed in the response to sodium nitroprusside (8.1 +/- 4 versus 9.5 +/- 3 mL/min per 100 mL). In healthy control subjects superoxide dismutase infusion did not modify the vasodilator response to acetylcholine (maximal flow: 12.7 +/- 3 before versus 12.1 +/- 3 after superoxide dismutase). Similarly, in hypertensive patients superoxide dismutase infusion did not alter the response to acetylcholine (maximal flow: 8.2 +/- 4 versus 7.7 +/- 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1998

Vasodilator response to systemic but not to local hyperinsulinemia in the human forearm.

Insulin-mediated vasodilation has been proposed as an important determinant of whole-body insulin-stimulated glucose disposal. However, it is not clear whether the vasodilator effect of insulin results from a direct action of the hormone or whether alternative mechanisms are involved. To better characterize the mechanism of insulin-mediated vasorelaxation, we compared forearm blood flow (FBF) responses to local (intra-arterial) and systemic (intravenous, euglycemic clamp) hyperinsulinemia in 10 healthy lean subjects using venous occlusion plethysmography. In addition, we assessed the effect of nitric oxide (NO) synthase inhibition by NG-monomethyl-L-arginine (L-NMMA) on the vasodilator and metabolic responses to hyperinsulinemia. Similar forearm concentrations of insulin were achieved during local and systemic infusion (231+/-39 versus 265+/-22 microU/mL; P=0.54). Of note, FBF did not change significantly in response to local hyperinsulinemia (from 2.6+/-0.3 to 2.4+/-0.3 mL . min-1 . dL-1; P=0.50). In contrast, systemic hyperinsulinemia caused a 52% increase in FBF (from 2.5+/-0.2 to 3. 8+/-0.5 mL . min-1 . dL-1; P<0.004), which was reversed by L-NMMA (FBF decreased from 3.8+/-0.5 to 2.3+/-0.2 mL . min-1 . dL-1; P=0. 004). We conclude that systemic, but not local, hyperinsulinemia induces vasodilation in the forearm. Our findings suggest that insulin-mediated vasodilation is not due solely to a direct stimulatory effect of insulin but involves additional mechanisms activated only during systemic hyperinsulinemia.

Female↗
PubMed2005

Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet.

Previously we showed L-4F, a novel apolipoprotein A-I (apoA-I) mimetic, improved vasodilation in 2 dissimilar models of vascular disease: hypercholesterolemic LDL receptor-null (Ldlr(-/-)) mice and transgenic sickle cell disease mice. Here we determine the mechanisms by which D-4F improves vasodilation and arterial wall thickness in hypercholesterolemic Ldlr(-/-) mice and Ldlr(-/-)/apoA-I null (apoA-I(-/-)), double-knockout mice. Ldlr(-/-) and Ldlr(-/-)/apoA-I(-/-) mice were fed Western diet (WD) with and without D-4F. Oral D-4F restored endothelium- and endothelial NO synthase (eNOS)-dependent vasodilation in direct relationship to duration of treatments and reduced wall thickness in as little as 2 weeks in vessels with preexisting disease in Ldlr(-/-) mice. D-4F had no effect on total or HDL cholesterol concentrations but reduced proinflammatory HDL levels. D-4F had no effect on plasma myeloperoxidase concentrations but reduced myeloperoxidase association with apoA-I as well as 3-nitrotyrosine in apoA-I. D-4F increased endothelium- and eNOS-dependent vasodilation in Ldlr(-/-)/apoA-I(-/-) mice but did not reduce wall thickness as it had in Ldlr(-/-) mice. Vascular endothelial cells were treated with 22(R)-hydroxycholesterol with and without L-4F. 22(R)-Hydroxycholesterol decreased NO (*NO) and increased superoxide anion (O2*-) production and increased ATP-binding cassette transporter-1 and collagen expression. L-4F restored *NO and O2*- balance, had little effect on ATP-binding cassette transporter-1 expression, but reduced collagen expression. These data demonstrate that although D-4F restores vascular endothelial cell and eNOS function to increase vasodilation, HDL containing apoA-I, or at least some critical concentration of the antiatherogenic lipoprotein, is required for D-4F to decrease vessel wall thickness.

ATP Binding Cassette Transporter 1↗
PubMed1980

Role of medullary hemodynamics in the natriuresis of drug-induced renal vasodilation in the rat.

In contrast to most renal vasodilators, such as acetylcholine (ACh), secretin increases renal blood flow in the dog without a marked effect on sodium excretion (UNaV). To investigate this observation, we studied the relationship between renal vasodilation, UNaV, and papillary plasma flow (PPF) in rats, infused either with ACh or secretin into the aorta at the level of both renal arteries. ACh significantly increased GFR, PAH clearance, and UNaV (delta + 0.35 ml/min, + 2.11 ml/min and + 1.77 muEq/min, respectively; P < 0.05). PPF rose from 50 +/- 2.6 ml/min 100 g (mean +/- SE) in control rats to 91 +/- 4.7 ml/min 100 g after ACh (p < 0.001). Despite a similar increase in PAH clearance after secretin (+ 2.21 ml/min; P < 0.01), UNaV remained unchanged and PPF was only slightly, although significantly, increased (from 50 +/- 2.6 ml/min 100 g to 65 +/- 2.75 ml/min 100 g; P < 0.05). Both total kidney and papillary vasodilation, and the increase in UNaV after ACh were blocked by previous administration of meclofenamate (M), a prostaglandin inhibitor. No effect of M in secretin-infused rats was observed. In conclusion, the relationship between a total renal vasodilation and natriuresis was dissociated with secretin, but not with ACh. However, a relationship between the natriuresis and influence on papillary hemodynamics was observed with both vasodilators. Finally, the renal hemodynamic and natriuretic effects of ACh are probably mediated by prostaglandin release.

Acetylcholine↗