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At least 595 records · Page 33Linked to original sources
PubMed2000

High K(+)-induced membrane depolarization attenuates endothelium-dependent pulmonary vasodilation.

Impairment of endothelium-dependent pulmonary vasodilation has been implicated in the development of pulmonary hypertension. Pulmonary vascular smooth muscle cells and endothelial cells communicate electrically through gap junctions; thus, membrane depolarization in smooth muscle cells would depolarize endothelial cells. In this study, we examined the effect of prolonged membrane depolarization induced by high K(+) on the endothelium-dependent pulmonary vasodilation. Isometric tension was measured in isolated pulmonary arteries (PA) from Sprague-Dawley rats, and membrane potential was measured in single PA smooth muscle cells. Increase in extracellular K(+) concentration from 4.7 to 25 mM significantly depolarized PA smooth muscle cells. The 25 mM K(+)-mediated depolarization was characterized by an initial transient depolarization (5-15 s) followed by a sustained depolarization that could last for up to 3 h. In endothelium-intact PA rings, ACh (2 microM), levcromakalim (10 microM), and nitroprusside (10 microM) reversibly inhibited the 25 mM K(+)-mediated contraction. Functional removal of endothelium abolished the ACh-mediated relaxation but had no effect on the levcromakalim- or the nitroprusside-mediated pulmonary vasodilation. Prolonged ( approximately 3 h) membrane depolarization by 25 mM K(+) significantly inhibited the ACh-mediated PA relaxation (-55 +/- 4 vs. -29 +/- 2%, P < 0.001), negligibly affected the levcromakalim-mediated pulmonary vasodilation (-92 +/- 4 vs. -95 +/- 5%), and slightly but significantly increased the nitroprusside-mediated PA relaxation (-80 +/- 2 vs. 90 +/- 3%, P < 0. 05). These data indicate that membrane depolarization by prolonged exposure to high K(+) concentration selectively inhibited endothelium-dependent pulmonary vasodilation, suggesting that membrane depolarization plays a role in the impairment of pulmonary endothelial function in pulmonary hypertension.

Acetylcholine↗
PubMed2005

Altered arachidonic acid metabolism impairs functional vasodilation in metabolic syndrome.

These studies tested the hypothesis that in obese Zucker rats (OZRs), a model of metabolic syndrome, the impaired functional vasodilation is due to increased thromboxane receptor (TP)-mediated vasoconstriction and/or decreased prostacyclin-induced vasodilation. Spinotrapezius arcade arterioles from 12-wk-old lean (LZR) and OZR were chosen for microcirculatory observation. Arteriolar diameter (5 LZR and 6 OZR) was measured after 2 min of muscle stimulation in the absence or presence of 1 microM SQ-29548 (TP antagonist). Additionally, arteriolar diameter (6 for each group) was measured after application of iloprost (prostacyclin analog; 0.28, 2.8, and 28 microM), arachidonic acid (10 microM), and sodium nitroprusside (0.1, 1, and 10 microM) in the absence or presence of 1 microM SQ-29548. A 10 microM concentration of adenosine was used to induce a maximal dilation. Basal diameters were not different between LZRs and OZRs. Functional hyperemia and arachidonic acid-mediated vasodilations were significantly attenuated in OZR compared with LZR, and treatment with 1 microM SQ-29548 significantly enhanced the dilations in OZRs, although it had no effect in LZRs. Vasodilatory responses to iloprost and sodium nitroprusside (1 and 10 microM) were significantly reduced in OZR. Adenosine-mediated vasodilation was not different between groups. These results suggest that the impaired functional dilation in the OZR is due to an increased TP-mediated vasoconstriction and a decreased PGI2-induced vasodilation.

Animals↗
PubMed1997

Adrenomedullin-(22-52) antagonizes vasodilator responses to CGRP but not adrenomedullin in the cat.

The effects of adrenomedullin (ADM)-(22-52), a putative ADM receptor antagonist, on vasodilator responses to ADM and the structurally related peptide, calcitonin gene-related peptide (CGRP), were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. ADM-(22-52) had no significant effect on hindlimb perfusion pressure when injected in doses up to 120 nmol; after administration of ADM-(22-52), vasodilator responses to ADM were unchanged, whereas vasodilator responses to CGRP were inhibited. The inhibitory effects of ADM-(22-52) on responses to CGRP were selective and reversible and were similar to the inhibitory effects of the CGRP antagonist CGRP-(8-37). Hindlimb vasodilator responses to CGRP and to ADM were increased in duration by the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor rolipram but were not altered by inhibitors of guanosine 3',5'-cyclic monophosphate phosphodiesterase, nitric oxide synthetase, K(+)-ATP channels, the cyclooxygenase pathway, or the adrenergic nervous system. These results demonstrate that ADM-(22-52) is a selective CGRP receptor antagonist in the hindlimb vascular bed of the cat. The present data suggest that vasodilator responses to CGRP and ADM are mediated by different receptors but that these peptides dilate the hindlimb vascular bed of the cat by a similar cAMP-dependent mechanism.

Adrenomedullin↗
PubMed1997

Vasodilator responses to acetylcholine, bradykinin, and substance P are mediated by a TEA-sensitive mechanism.

The effects of tetraethylammonium (TEA), a K+ channel antagonist, on vasodilator responses were investigated in the hindquarters vascular bed of the cat under constant-flow conditions. After administration of TEA in a total dose of 60 mg/kg into the hindquarters perfusion circuit, vasodilator responses to acetylcholine, bradykinin, and substance P were reduced, whereas vasodilator responses to the NO donors, diethylamine-NO complex, S-nitroso-N-acetylpenicillamine, and sodium nitroprusside, and to prostaglandin E1, albuterol, vasoactive intestinal polypeptide, isradipine, and levcromakalim were not altered. The inhibitory effect of TEA on responses to the endothelium-dependent vasodilators was reversible with time, and vasoconstrictor responses to norepinephrine, U-46619, angiotensin II, and BAY K 8644 were enhanced by the K+ channel antagonist. Although TEA had no sustained effect on baseline systemic arterial and hindquarters perfusion pressures, the NO synthase inhibitor, N omega-nitro-L-arginine methyl ester, increased these pressures in the presence of TEA. The results of the present investigation suggest that TEA attenuates vasodilator responses to acetylcholine, bradykinin, and substance P by inhibiting the release of endothelium-derived relaxing factor. These data suggest that the acetylcholine-, bradykinin-, and substance P-stimulated release of endothelium-derived relaxing factor may involve the opening of a TEA-sensitive K+ channel in the endothelium in the hindlimb vascular bed of the cat, but that a TEA-sensitive mechanism is not involved in the maintenance of baseline tone in this vascular bed.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2003

Urotensin II is a nitric oxide-dependent vasodilator and natriuretic peptide in the rat kidney.

Recent studies have indicated that urotensin II (UII), a cyclic peptide, is vasoactive and may be involved in cardiovascular dysfunctions. It remains unknown, however, whether UII plays a role in the control of renal vascular tone and tubular function. In the present study, a continuous infusion of synthetic human UII (hUII) into the renal artery (RA) in anesthetized rats was found to increase renal blood flow (RBF) and urinary water and sodium excretion (UV and UNaV) in a dose-dependent manner. At a dose of 20 ng. kg-1. min-1, it increased RBF by 20% and UV and UNaV by 94 and 109%, respectively. Nitric oxide (NO) synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) completely abolished hUII-induced increases in RBF and water/sodium excretion. In isolated, pressurized, and phenylephrine-precontracted small RA with internal diameter of approximately 200 microm, hUII produced a concentration-dependent vasodilation with a maximal response of 55% at 1.5 microM. l-NAME significantly blocked this hUII-induced vasodilation by 60%. In denuded RA, hUII had neither vasodilator nor vasoconstrictor effect. With the use of 4,5-diaminofluorescein diacetate-based fluorescence imaging analysis of NO levels, hUII (1 microM) was shown to double the NO levels within the endothelium of freshly dissected small RA, and l-NAME blocked this UII-induced production of endothelial NO. These results indicate that UII produces vasodilator and natriuretic effects in the kidney and that UII-induced vasodilation is associated with increased endothelial NO in the RA.

Animals↗
PubMed1993

Maintained endothelium-dependent pulmonary vasodilation following chronic hypoxia in the rat.

We have previously demonstrated that arginine vasopressin (AVP) dilates the preconstricted pulmonary vasculature via the release of nitric oxide (NO). However, recent evidence suggests that NO release in response to other agents may be suppressed in lungs from animals that have been chronically exposed to hypoxia. The purpose of the present experiment was to determine whether vasopressinergic pulmonary vasodilation is similarly affected by chronic exposure to hypoxia (barometric pressure = 380 Torr for 4 wk). Inhibition of NO synthesis with N omega-nitro-L-arginine (L-NNA) had no effect on baseline perfusion pressure in isolated salt-perfused lungs from either control or chronically hypoxic rats. Similarly, pulmonary vasodilatory responses to AVP and the calcium ionophore A23187 were unaffected by chronic hypoxic exposure. Pretreatment with the cyclooxygenase inhibitor meclofenamate did not alter vasopressinergic pulmonary vasodilation in lungs from either control or chronically hypoxic animals, ruling out involvement of vasodilator prostaglandins in the response to AVP. In contrast, vasodilatory responses to both AVP and A23187 were inhibited by L-NNA pretreatment not only in lungs from control animals but also in lungs from chronically hypoxic rats, suggesting the involvement of NO in the vasodilatory response. The inhibition by L-NNA was reversible by prior addition of excess L-arginine but not by D-arginine. In addition, vasodilatory responses to the endothelium-independent vasodilators sodium nitroprusside and isoproterenol were unaffected by chronic hypoxic exposure. We conclude that endothelium-dependent vasodilation remains intact in male Sprague-Dawley rats after chronic hypoxic exposure.

Air Pressure↗
PubMed2004

Effect of COX-1/COX-2 inhibition versus selective COX-2 inhibition on coronary vasodilator responses to arachidonic acid and acetylcholine.

The effect of a nonselective COX-1/COX-2 inhibitor, naproxen, was compared with a COX-2-selective inhibitor (SC-58236) on coronary vasodilatory responses in the anesthetized dog. Coronary vasodilation was induced by direct intracoronary injection of acetylcholine (ACH) and arachidonic acid (AA) in control animals and in those treated with either naproxen (1, 3, or 10 mg/kg p.o. 24 h prior to the experiment) or SC-58236 (1, 5, or 15 mg/kg p.o. 24 h prior to the experiment). Naproxen, at 10 mg/kg, significantly attenuated the AA-induced vasodilation (prostacyclin dependent) with no effect on ACH-induced vasodilation (nitric oxide dependent). SC-58236 failed to attenuate either AA- or ACH-induced vasodilation. Ex vivo assays were utilized to establish inhibition of COX-2 (lipopolysaccharide-stimulated prostaglandin E2 formation) and COX-1 (serum thromboxane B2) in blood taken from dogs administered 1, 3, or 10 mg/kg naproxen or 15 mg/kg SC-58236. Naproxen (3 and 10 mg/kg) and SC-58236 (15 mg/kg) markedly reduced the lipopolysaccharide-induced prostaglandin E2 formation, whereas SC- 58236 (15 mg/kg) had no effect on serum thromboxane B2. Naproxen significantly reduced thromboxane B2 at all three doses studied. Furthermore, naproxen (10 mg/kg p.o.) significantly inhibited the AA-induced platelet aggregation (thromboxane B2 dependent), whereas SC-58236 had no effect. Collectively, these results demonstrate that SC-58236 is selective for COX-2, while naproxen is a nonselective inhibitor. These data also suggest that vasodilatory responses to AA in the dog are primarily COX-1 dependent. Selective COX-2 inhibition does not affect either prostacyclin or nitric oxide mediated vasodilation in the canine coronary circulation.

Acetylcholine↗
PubMed1993

Vasodilator effect of tertatolol in isolated perfused rat kidneys: involvement of endothelial 5-HT1A receptors.

The aim of the studies was to examine the mechanism of the renal vasodilator action of the beta-adrenoceptor antagonist tertatolol. In isolated Tyrode perfused rat kidneys, constricted with norepinephrine, serotonin (5-HT) or BaCl2, tertatolol evokes dilatations; these vasodilator responses are not due to an interaction of tertatolol with alpha- or beta-adrenoceptors, muscarinic or nicotinic receptors, opioid receptors, dopamine or histamine receptors and they are independent of prostaglandin release. In the presence of ritanserin and ICS 205930, to block 5-HT2 and 5-HT3 receptors, tertatolol, 5-HT, 5-carboxamidotryptamine (5-CT) and 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DPAT) all evoked renal vasodilator responses that were significantly reduced by the nonselective 5-HT antagonist metergoline and by the selective 5-HT1A antagonist BMY 7378 suggesting that 5-HT1 receptors resembling the 5-HT1A subtype were involved. The nitric oxide (NO) inhibitors hemoglobin and nitro-L-arginine (L-NNA), as well as the guanylate cyclase inhibitor methylene blue also inhibited the vasodilator responses to tertatolol and to the serotonergic agonists, suggesting the involvement of the NO-cyclic GMP pathway. These data suggest that 5-HT receptors located on the vascular endothelium of the rat renal circulation are involved in the vasodilator responses caused by tertatolol and these receptors resemble the 5-HT1A subtype.

Adrenergic beta-Antagonists↗
PubMed1999

Vasodilation to bradykinin is mediated by an ouabain-sensitive pathway as a compensatory mechanism for impaired nitric oxide availability in essential hypertensive patients.

BACKGROUND: In essential hypertension, endothelium-dependent vasodilation is impaired because of reduced nitric oxide (NO) availability, which is mainly caused by oxidative stress. The present study was designed to identify the mechanism(s) responsible for NO-independent vasodilation to bradykinin in patients with essential hypertension. METHODS AND RESULTS: In 16 healthy subjects (49.5+/-5.8 years; 118.6+/-3.5/78.9+/-2.9 mm Hg) and 16 patients with essential hypertension (47.9+/-4.8 years; 154.6+/-4.5/102.9+/-3.2 mm Hg), we measured modifications in forearm blood flow (strain-gauge plethysmography) during intrabrachial infusion of bradykinin (5, 15, or 50 ng/100 mL of forearm tissue per minute) in the presence of saline, N(omega)-monomethyl-L-arginine (L-NMMA; used to inhibit NO synthase; 100 microg/100 mL of forearm tissue per minute), and ouabain (to block Na(+)K(+)/ATPase and prevent hyperpolarization; 0.7 microg/100 mL of forearm tissue per minute). In healthy subjects, vasodilatation to bradykinin was significantly blunted by L-NMMA and unaffected by ouabain. In hypertensive patients, vasodilatation to bradykinin was not modified by L-NMMA, but it was significantly reduced by ouabain. In an adjunctive group of 8 hypertensive patients (49.9+/-3.8 years; 155.9+/-5.5/103.7+/-3.9 mm Hg), the response to bradykinin was repeated during the administration of intrabrachial vitamin C (a scavenger for oxygen free radicals; 8 mg/100 mL of forearm tissue per minute). In these patients, L-NMMA-induced inhibition of vasodilation to bradykinin was restored, and ouabain was no longer effective. In a final group of 6 normotensive controls (45.9+/-4.1 years; 115.1+/-2.9/79.3+/-2.1 mm Hg), vasodilation to bradykinin residual to L-NMMA blockade was further inhibited by simultaneous ouabain infusion. CONCLUSIONS: Vasodilation to bradykinin is impaired in essential hypertensive patients because of an NO-system alteration caused by oxidative stress, and it is mediated by an alternative pathway, possibly involving endothelium-dependent hyperpolarization.

Adaptation, Physiological↗
PubMed2000

Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea.

BACKGROUND: Patients with obstructive sleep apnea (OSA) experience repetitive episodic hypoxemia with consequent sympathetic activation and marked blood pressure surges, each of which may impair endothelial function. We tested the hypothesis that patients with OSA have impaired endothelium-dependent vasodilation, even in the absence of overt cardiovascular disease. METHODS AND RESULTS: We studied 8 patients with OSA (age 44+/-4 years) and 9 obese control subjects (age 48+/-3 years). Patients with OSA were newly diagnosed, never treated for OSA, on no medications, and free of any other known diseases. All obese control subjects underwent complete overnight polysomnographic studies to exclude occult OSA. Resistance-vessel function was tested by use of forearm blood flow responses to intra-arterial infusions of acetylcholine (a vasodilator that stimulates endothelial release of nitric oxide), sodium nitroprusside (an exogenous nitric oxide donor), and verapamil (a calcium channel blocker). Conduit-vessel function was also evaluated by ultrasonography. Brachial artery diameter was measured under baseline conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). Patients with OSA had a blunted vasodilation in response to acetylcholine (P:<0.007), but responses to sodium nitroprusside and verapamil were not significantly different from those of control subjects. No significant difference in conduit-vessel dilation was evident between OSA patients and obese control subjects. CONCLUSIONS: Patients with OSA have an impairment of resistance-vessel endothelium-dependent vasodilation. This may be implicated in the pathogenesis of hypertension and heart failure in this condition.

Acetylcholine↗
PubMed1988

Modulation of arteriolar blood flow by inhibitors of arachidonic acid oxidation after thermal injury: possible role for a novel class of vasodilator metabolites.

To examine the contribution of arachidonic acid (AA) metabolites to the maintenance of cutaneous vasomotor tone after thermal injury, enzyme inhibitors were topically applied to the hamster cheek pouch before and after a spot burn. By use of video microscopy, blood flow was measured in adjacent arterioles that supplied the injured site. Ringer's solutions containing no drug (vehicle), indomethacin (cyclooxygenase inhibitor), BW755c (cyclooxygenase/lipoxygenase inhibitor), or ketoconazole (lipoxygenase/cytochrome P450 inhibitor) continuously suffused the entire tissue. There were no effects of these drugs on preburn blood flow at concentrations that blocked the vascular effects evoked by topical AA. In all groups, blood flow transiently increased after burn and thereafter decreased to levels that were altered by treatment. These results could not be attributed to alterations in vascular reactivity because neither the burn nor the drugs altered the vasodilation evoked by adenosine or prostacyclin. Relative to Ringer's, indomethacin had no effect, BW755c caused vasodilation, and ketoconazole caused vasoconstriction, which suggests that cytochrome P450 products might be vasoactive mediators in injured tissue. Therefore, purified synthetic compounds were compared with known vasodilators. The potency was prostacyclin greater than 12R-hydroxyeicostetraenoic acid greater than adenosine = 5,6 epoxyeicosatrienoic acid greater than AA, which supports the hypothesis that AA can be the source of a novel class of nonprostaglandin vasodilator compounds. In addition, at least one of the vasodilator responses was stereospecific. Nevertheless, the exact explanation for the differential effects of AA inhibitors on postburn blood flow is unknown.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed2002

Interaction of sildenafil with cAMP-mediated vasodilation in vivo.

Sildenafil inhibits cGMP breakdown by phosphodiesterase 5. In vitro, increased cGMP levels inhibit cAMP breakdown by phosphodiesterase 3. It is uncertain, however, whether sildenafil increases biological effects of interventions increasing cAMP levels in vivo. The objective of the present study in 40 healthy male volunteers was to determine the existence and extent of interactions with sildenafil and vasodilators acting via cGMP or cAMP or independently from these mediators on the arterial tone of the human forearm. Forearm blood flow (FBF) responses (plethysmography) to brachial artery infusions of 3 doses each of nitroglycerin, which increases cGMP levels; of isoprenaline and milrinone, which increase cAMP levels; and of verapamil as a control were assessed at baseline and 80 minutes after 50 mg oral sildenafil in 10 volunteers each. Sildenafil increased FBF (2.5+/-0.1 to 3.5+/-0.2 mL/min per 100 mL, P<0.001; n=40). At equipotent vasodilator dosages, sildenafil increased FBF from 7.5+/-1.0 to 9.8+/-1.2 mL/min per 100 mL for nitroglycerin, from 8.3+/-1.0 to 10.4+/-1.4 mL/min per 100 mL for isoprenaline, and from 8.1+/-1.0 to 10.3+/-1.2 mL/min per 100 mL for milrinone and slightly decreased FBF from 7.7+/-1.3 to 7.1+/-1.2 mL/min per 100 mL for verapamil. ANOVA for repeated measures revealed a significant interaction between sildenafil and the type of vasodilator on FBF (P<0.01). The responses of FBF to nitroglycerin, milrinone, and isoprenaline after sildenafil were similarly increased compared with the response to verapamil (P<0.01). Sildenafil markedly enhanced the arterial vasodilator response to nitroglycerin, milrinone, and isoprenaline. The response to milrinone and isoprenaline is compatible with an interaction between cGMP and phosphodiesterase 3 or an enhancement of the NO component of cAMP-mediated vasodilation, and raises the possibility of enhanced biological effects of interventions leading to increases of cAMP in the presence of sildenafil.

Adrenergic beta-Agonists↗
PubMed1996

Indigo carmine inhibits endothelium-dependent and -independent vasodilation.

To investigate the potential mechanisms by which indigo carmine produces hypertension, we tested the hypothesis that indigo carmine inhibits endothelium-dependent vasodilation and determined the possible site of the inhibition (endothelium versus smooth muscle). Using isolated rat thoracic aortic rings that were precontracted with phenylephrine, we examined vasodilatory responses to acetylcholine, histamine, and Ca2+ ionophore A23187 (in endothelium-intact rings) and sodium nitroprusside and isoproterenol (in endothelium-denuded rings) in the presence and absence of indigo carmine. In addition, the effects of methylene blue on the acetylcholine- and sodium nitroprusside-induced vasodilation were compared with those of indigo carmine. Indigo carmine (10(-6), 10(-5), and 10(-4) mol/L) significantly inhibited receptor- and non-receptor-mediated endothelium-dependent vasorelaxation. Indigo carmine (10(-4) mol/L) also inhibited endothelium-independent vasorelaxation induced by sodium nitroprusside (an activator of vascular smooth muscle soluble guanylyl cyclase), although to a lesser extent than vasodilation from acetylcholine, histamine, and Ca2+ ionophore A23187. In contrast, indigo carmine (10(-4) mol/L) had no effect on the vasodilation induced by isoproterenol (an activator of adenylyl cyclase), indicating that indigo carmine selectively inhibits nitric oxide-mediated responses. Methylene blue, a known inhibitor of soluble guanylyl cyclase, inhibited both acetylcholine- and sodium nitroprusside-induced vasorelaxation. The inhibition was also greater in the acetylcholine- than the sodium nitroprusside-induced vasodilation. These results suggest that indigo carmine, like methylene blue, may inhibit endothelium-dependent relaxation by a mechanism that involves two levels. The major action of indigo carmine appears to be at the level of nitric oxide generation and/or release from the endothelial cell. In addition, indigo carmine appears to inhibit vascular smooth muscle guanylyl cyclase. Thus, indigo carmine may elevate blood pressure by interfering with these nitric oxide-mediated vasodilatory mechanisms.

Acetylcholine↗
PubMed2001

Effect of medroxyprogesterone acetate on endothelium-dependent vasodilation in postmenopausal women receiving estrogen.

BACKGROUND: Estrogen increases endothelium-dependent vasodilation in postmenopausal women. However, use of progestins in combination with estrogen may counter beneficial effects of estrogen on endothelium. We investigated the effect of medroxyprogesterone acetate (MPA) on estrogen-induced increase in endothelium-dependent vasodilation in postmenopausal women. METHODS AND RESULTS: Postmenopausal women were treated daily with conjugated equine estrogen (CEE) 0.625 mg (n=14), CEE 0.625 mg and MPA 2.5 mg (n=15) or CEE 0.625 mg and MPA 5.0 mg (n=16) for 3 months. Plasma lipids and hormones were measured before and after treatment. Vasodilatory responses of the brachial artery were evaluated by measuring flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation by use of high-resolution ultrasonography. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO(4) while kinetics of conjugated diene formation was monitored. Plasma total and LDL cholesterol concentrations were decreased significantly in all groups. CEE increased FMD significantly, from 4.5+/-1.7% to 8.5+/-2.8% (P<0.001). Addition of MPA reversed this effect in a concentration-dependent manner (for MPA 2.5 mg, from 5.0+/-3.2% to 6.2+/-3.1%; for MPA 5.0 mg, from 4.9+/-3.4% to 3.6+/-3.7%; P=NS for each). No treatment significantly altered nitroglycerin-induced dilation. Lag time for conjugated diene formation was prolonged significantly in all groups, and the oxidation rate was significantly reduced. CONCLUSIONS: Concurrent MPA administration may offset favorable effects of estrogen on endothelial function in postmenopausal women. Because MPA did not diminish LDL-lowering and antioxidant effects of estrogen, MPA-induced inhibition of endothelium-dependent vasodilation may be independent of changes in oxidative susceptibility and plasma concentration of LDL.

Blood Flow Velocity↗
PubMed1998

Specific impairment of endothelium-dependent vasodilation in subjects with type 2 diabetes independent of obesity.

In subjects with type 2 diabetes in whom an impaired response to an endothelial-dependent vasodilator has been characterized, the populations have also been at least moderately obese. Obesity has been characterized as an independent predictor of endothelial dysfunction in nondiabetic subjects. We hypothesized that in normotensive subjects with type 2 diabetes compared with age-matched control subjects, 1) endothelium-dependent vasodilation, as demonstrated by the forearm blood flow (FABF) response to intraarterial acetylcholine, would be decreased; 2) endothelium-independent vasodilation, as demonstrated by the FABF response to intraarterial nitroprusside, would be similar; 3) the degree of insulin resistance, as measured by the insulin sensitivity index (SI), would predict greater impairment in the FABF response to acetylcholine; and 4) these relationships would be independent of obesity. We measured FABF by venous occlusion plethysmography during brachial arterial infusions of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroprusside in 20 control and 17 subjects with type 2 diabetes. We measured SI using the frequently sampled i.v. glucose tolerance test. Among the diabetic relative to the control subjects we identified a decrease in the acetylcholine-mediated percent increase in FABF (P = 0.02). Using the absolute FABF response to acetylcholine and including adjustments for body mass index and other covariates, the overall group difference remained and was noted to be greatest in those subjects who had lower baseline FABFs. In contrast, no significant difference in the nitroprusside-mediated increase in the percent change FABF was identified between groups (P = 0.30). Finally, the degree of insulin resistance, as measured by SI, did not independently predict greater impairment of the FABF response to acetylcholine. This study is the first to identify specific endothelial cell dysfunction that remains significant after adjustment for obesity in a population of normotensive subjects with type 2 diabetes.

Acetylcholine↗
PubMed2000

Plasma free fatty acids and endothelium-dependent vasodilation: effect of chain-length and cyclooxygenase inhibition.

Free fatty acids (FFA) are known to interfere with glucose metabolism. Moreover, it has been shown that they are able to impair the endothelium-dependent vasodilation. Therefore, we sought to determine whether their negative effect on endothelial function depends on their chain length or on their ability to modify PG production. Fourteen normal volunteers were studied under baseline conditions and then randomly allocated to two of the following four studies: 1) long chain triglyceride (LCT) emulsion and heparin infusion (n = 7), 2) infusion of an emulsion containing 56% medium chain triglycerides (MCT) and 44% LCT plus heparin (n = 7), 3) infusion of LCT and heparin preceded by an i.v. bolus of 900 mg lysine-salicylate (ASA; n = 7), and 4) after an i.v. bolus of ASA (n = 7). Basal forearm blood flow (FBF), endothelium-dependent vasodilation in response to intraarterial acetylcholine (Ach), and endothelium-independent vasodilation in response to intraarterial nitroprusside were assessed by venous occlusion plethysmography. Both LCT and MCT infusions significantly increased basal FBF from 1.58 +/- 0.35 to 2.60 +/- 0.76 and 2.28 +/- 0.56 mL/min 100 mL tissue, respectively (both P < 0.05). This increase was also observed for LCT plus heparin, but not after ASA alone. The percent increase in FBF during Ach was lowered during both LCT (252 +/- 34% of the ratio infused/control arm at maximal Ach dose) and MCT (255 +/- 41%) compared to the baseline conditions (436 +/- 44%; both P < 0.05). The response to Ach was also lower during LCT plus ASA, whereas it was similar to baseline with ASA alone. No differences were observed in the response to nitroprusside among the experimental conditions. In conclusion, 1) the effect of FFA on endothelium-dependent vasodilation is independent of their chain length; 2) both LCT and MCT increase baseline FBF, independently from cyclooxygenase inhibition; and 3) acute ASA administration does not affect endothelium-dependent vasodilation. The FFA effect on the endothelial response to Ach may contribute to altered endothelial function and, hence, to the development and progression of atherosclerotic cardiovascular disease.

Acetylcholine↗
PubMed2003

Vitamin C improves attenuated angiotensin II-induced endothelium-dependent vasodilation in human forearm vessels.

Endothelial dysfunction might be related to an increase in superoxide anion production in patients with hypertension, hypercholesterolemia, diabetes mellitus, and heart failure. Studies in animal models indicate that angiotensin II increases superoxide anion production by vascular tissues. We examined whether angiotensin II attenuates endothelium-dependent vasodilation via an increase in superoxide anion production in human forearm vessels in vivo. Forearm blood flow was measured in 23 healthy young men. We examined forearm vasodilator responses to an intra-arterial infusion of acetylcholine (4, 8, and 16 microg/min) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min) before and during an intra-arterial infusion of anglotensin II (n=8), angiotensin II plus vitamin C (n=8), and vitamin C alone (n=4). Angiotensin II attenuated the forearm vasodilatory response to acetylcholine (p<0.05), and this attenuated response was abolished by vitamin C. Angiotensin II did not alter the forearm vasodilatory response to sodium nitroprusside, and vitamin C infusion did not affect the forearm vasodilatory response to either acetylcholine or sodium nitroprusside. The forearm vasodilator response to acetylcholine did not change during infusion of norepinephrine (n=3), which reduced forearm blood flow to a degree similar to that by angiotensin II infusion. These results suggest that angiotensin II attenuates endothelium-dependent forearm vasodilation, and vitamin C improves this impairment. Thus, angiotensin II likely attenuates endothelium-dependent vasodilation via an increase of superoxide anion production in the human forearm in vivo.

Adult↗
PubMed1988

Temporal response of the fetal pulmonary circulation to pharmacologic vasodilators.

To determine the temporal response of the fetal pulmonary circulation to pharmacologic vasodilators and to assess vasoreactivity following vasodilation, we infused either acetylcholine, histamine, or bradykinin directly into the left pulmonary artery of 21 chronically prepared fetal sheep. Blood flow (Q) to the left lung was measured by electromagnetic flow transducer. Left pulmonary artery infusion of acetylcholine at 1.5 micrograms.min-1 for 2 hr produced an increase in Q from 59 +/- 8 ml.min-1 to a peak of 113 +/- 10 ml.min-1 at 20 min into the infusion (P less than 0.001). After the peak at 20 min, Q steadily declined toward baseline to 66 +/- 7 ml.min-1 at the end of the 2-hr infusion period (P less than 0.01). Q in the 1/2-hr period following infusion was significantly less than the baseline period (47 +/- 6; P less than 0.04) with no change in pulmonary artery pressure. Similar patterns were seen with 2-hr infusions of histamine (150 ng.min-1) and bradykinin (100 ng.min-1). After a 2-hr infusion of one of the agents, a repeat infusion with that agent or a different one resulted in a diminished response. We conclude that fetal pulmonary vasodilation in response to local infusion of acetylcholine, histamine, or bradykinin is not sustained over a 2-hr period, and that following 2-hr exposure to vasodilators, pulmonary vascular resistance is increased and pulmonary vasoreactivity to pharmacologic vasodilators is decreased.

Acetylcholine↗