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PubMed1991

Future directions in vasodilator therapy for heart failure.

Vasodilator therapy has become a major pharmacologic approach for improving left ventricular function, and consequently, vasodilator drugs are being used increasingly in the treatment of heart failure. Ideally, vasodilator drugs used in the long-term management of heart failure should show clearly defined pharmacodynamic effects. These include reduced impedance to left ventricular ejection, increased venous capacitance, increased left ventricular ejection fraction and reduced heart size, absence of neurohormonal stimulation, and slowed progression of left ventricular dysfunction. The mechanisms of action and sites of activity of the various vasodilator drugs currently available vary considerably, and none as yet has proved ideal for the treatment of heart failure or hypertension. The complexity surrounding the multiple vasoconstrictor mechanisms involved in heart failure has led to a rationale for combined vasodilator therapy and certain combinations are discussed. From a therapeutic standpoint, the development of drugs with multiple mechanisms of action is particularly attractive. Flosequinan is a new vasodilator agent whose cellular mechanism of action remains uncertain. Flosequinan has the advantage of being able to relax both arterial and venous beds and as such may be particularly beneficial in the treatment of heart failure.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1981

Mechanisms and implications of vasodilator tolerance in the treatment of congestive heart failure.

Vasodilators play an important role in the treatment of the patient with severe heart failure and increased systemic vascular resistance. However, there are both clinical data and theoretic reasons to anticipate that some degree of tolerance may develop during the long-term use of most agents. The cause of the increased vascular resistance of heart failure is not completely understood, but it appears to be related to a number of neuroendocrine, molecular and physical mechanisms including increased activity of the sympathetic nervous and renin-angiotensin systems, and increased vascular stiffness due to intra- and extracellular sodium and fluid accumulation. Not surprisingly, a lowering of systemic vascular resistance either by direct smooth muscle relaxers or by blockade of specific neuroendocrine systems may result in a number of compensatory responses at the neuroendocrine and/or molecular level. The over-all effectiveness of a particular vasodilator is the net sum of its direct pharmacologic action, and the neuroendocrine and molecular responses to the drug. The specific compensatory mechanisms activated depend on several factors including the type of vasodilator used, the dose employed, the baseline neuroendocrine status of the patient, the severity of heart failure and the functional integrity of various reflex systems. Although not directly applicable to patients with heart failure, much information derived from the use of these agents to treat patients with hypertension and angina pectoris suggests several potential mechanisms by which tolerance may develop to virtually all classes of vasodilators. The major types of vasodilators are discussed with regard to their potential mechanisms of tolerance. Finally, the evidence currently available from long-term studies is reviewed in order to assess the potential relevance of vasodilator tolerance to the clinical management of the patient with heart failure.

Adrenergic alpha-Antagonists↗

PubMed1984

Conceptual dilemmas in the classification of vasodilator drugs for severe chronic heart failure. Advocacy of a pragmatic approach to the selection of a therapeutic agent.

Two distinct systems of classifying vasodilator drugs have been developed over the past decade in an attempt to guide the choice of a therapeutic agent for the patient with severe heart failure, but the merits and utility of these systems have not been critically evaluated. Vasodilator drugs may be categorized according to their peripheral site of action: an agent may exert its effects preferentially on systemic arteries, systemic veins, or on both circulations. However, changes in the peripheral circulation cannot be directly translated into an improvement in central hemodynamic variables; furthermore, immediate hemodynamic responses may not be predictive of long-term clinical efficacy. Hence, there is no evidence that characterization of patients into hemodynamic subsets determined by the findings of right heart catheterization improves the clinical outcome of vasodilator therapy in chronic heart failure. An alternative classification system groups vasodilator drugs according to their mechanism of action: an agent may possess direct vasodilating effects or may exert its actions via selective neurohumoral inhibition. However, attempts to identify patients who might be most responsive to neurohumoral antagonism by measuring plasma renin activity or circulating levels of catecholamines before treatment have not been successful in predicting the clinical responses to therapy. Because neither system of drug classification provides the clinician with useful therapeutic guidelines, patients with severe heart failure appear to be best managed using a pragmatic approach in which specific drugs that produce predictable therapeutic benefits with a low frequency of side effects are utilized preferentially. Among presently available vasodilator agents, only captopril and oral isosorbide dinitrate have been shown to produce consistent hemodynamic and clinical improvement with an acceptable degree of adverse reactions.

Captopril↗

PubMed1990

Changes in calcitonin gene-related peptide (CGRP)-containing vasodilator nerve activity in hypertension.

The role of calcitonin gene-related peptide (CGRP)-containing vasodilator nerves in maintenance of hypertension was investigated in the perfused mesenteric vascular beds isolated from spontaneously hypertensive rats (SHR), deoxycorticosterone-salt-induced hypertensive rats (DOCA-Salt-HR) and corresponding normotensive control rats (Wistar Kyoto rats, WKY and Wistar rats, NR). In the mesenteric artery with an active tone, the neurogenic vasodilation induced by perivascular nerve stimulation (PNS, 0.5-8 Hz), which was mediated by CGRP nerves, was markedly decreased in adult SHR (15-week-old) when compared with age-matched WKY, whereas the vasodilation in DOCA-Salt-HR was similar in magnitude to that in NR. The vasodilator response to exogenously applied CGRP was greater in SHR than in WKY, whereas no difference was found between DOCA-Salt-HR and NR. The neurogenic release of CGRP-like immunoreactivity (CGRP-LI) induced by PNS of the mesenteric artery was significantly decreased in SHR compared to that of WKY. In addition, immunohistochemical studies showed decreased populations of CGRP-LI fibers in the mesenteric artery of SHR compared to those in WKY. These results suggest that CGRP-containing vasodilator innervation is greatly decreased in SHR with established hypertension. It is also suggested that the decreased vasodilator mechanism by CGRP-containing nerves contributes to the maintenance of hypertension.

Animals↗

PubMed1983

Hemodynamic effects of the arteriolar vasodilators hydralazine, dihydralazine and endralazine in the conscious spontaneously hypertensive rat.

The hemodynamic effects of the vasodilators hydralazine, dihydralazine and endralazine were studied in conscious, unrestrained spontaneously hypertensive rats (SHR) equipped for chronic hemodynamic measurements. The arteriolar vasodilators hydralazine (0.3 mg/kg i.a.) and dihydralazine (0.3 mg/kg i.a.) caused a rapid fall in blood pressure and peripheral resistance, lasting up to 24 h in the case of dihydralazine. Immediately after injection, the cardiac output and heart rate were increased significantly. These effects only lasted for 1-2 h. The hemodynamic pattern of the new vasodilator endralazine (0.1-1 mg/kg i.a.) was very similar, with a duration of action similar to that of dihydralazine. The role of baroreceptor reflexes in the early hemodynamic effects of vasodilators was studied by comparing the effects of 0.3 mg/kg hydralazine in baroreflex-denervated and non-denervated SHR. The decrease in blood pressure and peripheral resistance was significantly larger in the denervated SHR, whereas increases in cardiac output and heart rate were almost completely absent in these animals. These data suggest that baroreceptor reflexes oppose the early fall in blood pressure and peripheral resistance induced by vasodilators. However, the activity of the baroreflex seems of very short duration, suggesting a rapid adaptation to the prevailing blood pressure. Moreover, the data show that endralazine is an effective arteriolar vasodilator in conscious SHR.

Animals↗

PubMed1991

Effect of opioid receptor antagonists on vasodilator nerve actions in the perfused rat mesentery.

Our previous work suggests that opioid peptides modulate sensory nerves in the perfused rat mesentery. Therefore we tested the hypothesis that opioids are involved in the ongoing regulation of sensory nerve activity using selective opioid receptor antagonists. In the presence of guanethidine and methoxamine, transmural nerve stimulation caused a vasodilator response which was potentiated significantly by naloxone (3 x 10(-7) M). However, naloxone did not affect vasodilator responses to exogenous calcitonin gene related peptide. IC1 174.864 (3 x 10(-7) M), a selective delta receptor antagonist, had no effect on vasodilator responses to transmural nerve stimulation. In contrast CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2) (3 x 10(-7) M), a selective mu receptor antagonist, significantly inhibited vasodilator responses to transmural nerve stimulation, effects which were abolished by naloxone treatment. In preparations pretreated with beta-FNA (beta-funaltrexamine HCl), an irreversible mu receptor antagonist, naloxone no longer potentiated vasodilator responses to transmural nerve stimulation. These results suggest that potentiation of vasodilator responses to transmural nerve stimulation by naloxone may be due to blockade of mu receptors, resulting in a reduced inhibitory modulation by endogenous opioids. These findings support the contention that prejunctional opioid receptors on sensory nerves may play a role in modulating activity of the cardiovascular system.

Animals↗

PubMed1993

Characterization of muscarinic receptors mediating vasodilation in rat perfused kidney.

The muscarinic receptor mediating vasodilation of resistance vessels in the rat isolated, constant-pressure perfused kidney (preconstriction by 10(-7) M cirazoline) was characterized by subtype-preferring agonists and selective antagonists. The agonists produced vasodilation with the following rank order of potency: arecaidine propargyl ester (APE) > 5-methylfurtrethonium = methacholine = oxotremorine > (S)-aceclidine > arecaidine 2-butyne-1,4-diyl bisester > 4-Cl-McN-A-343 = (R)-nipecotic acid ethyl ester = N-ethyl-guvacine propargyl ester approximately (R)-aceclidine = (S)-nipecotic acid ethyl ester > McN-A-343. Agonist-induced vasodilation disappeared after destruction of the endothelium with detergent. Highly significant correlations of agonist potencies for vasodilation were found between rat kidney and guinea-pig ileum submucosal arterioles as well as agonist potencies at smooth muscle muscarinic M3 receptors of the guinea-pig ileum. The rank order of antagonist potencies (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > (R)-hexahydro-difenidol approximately hexahydro-sila-difenidol > pirenzepine approximately p-fluoro-hexahydro-sila-difenidol approximately himbacine approximately AF-DX 384 approximately AQ-RA 741 > (S)-hexahydro-difenidol) to attenuate vasodilation to APE in rat kidney, correlated significantly with affinities at M3 receptors in submucosal arterioles and in smooth muscle of the guinea-pig ileum, but differed from those at M1 and M2 receptors in rabbit vas deferens. The agonist and antagonist potencies suggest that vasodilation elicited by muscarinic stimuli in endothelium-intact rat renal vasculature is mediated by functional muscarinic M3 receptors.

Animals↗

PubMed1994

Vasodilator action of the isopropyl ester of palmitoyl carnitine in the rat coronary circulation and mesenteric vascular bed.

The vasodilator action of the isopropyl ester of palmitoyl carnitine (P1Pi) has been examined in perfused rat hearts and mesenteric vessels. The coronary vasodilator effect P1Pi was not significantly inhibited by flurbiprofen (10 microM), BW755C (10 microM), glibenclamide (10 microM) or the bradykinin B2 receptor antagonist D-Arg0[Hyp3,Thi5,8,D-Phe7]bradykinin (1 microM), indicating that the action of P1Pi is not mediated via arachidonic acid metabolites, ATP-dependent K+ channels or bradykinin B2 receptors. L-NG-Nitro arginine (100 microM) did not inhibit the vasodilator action of P1Pi whilst superoxide dismutase (20 and 50 U.ml-1) attenuated its vasodilator action. Methylene blue (10 microM) caused inhibition in three out of four hearts, while haemoglobin (1 microM) caused an irreversible inhibition of the action of P1Pi which was associated with a depression of myocardial contractility. In air-damaged mesenteric vascular beds the vasodilator action of P1Pi was not attenuated, whilst that of acetylcholine was abolished. In K(+)-depolarised mesenteric vascular beds the constrictor action of Ca2+ was attenuated by P1Pi. Therefore the vasodilator effect of P1Pi appears to be the result of a direct effect on smooth muscle.

Adenosine Triphosphate↗

PubMed1981

Inhibition of vasoconstrictor and vasodilator responses by PGE1 in the intestinal vascular bed of the cat.

The effects of PGE1 on vascular resistance, vasoconstrictor responses to sympathetic nerve stimulation and pressor hormones and vasodilator responses to bradykinin and nitroglycerin were investigated in the feline mesenteric vascular bed. Infusions of PGE1, 1.0 and 0.1 micrograms/min, into the superior mesenteric artery dilated the mesenteric vascular bed and markedly inhibited vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine and angiotensin and to vasodilator responses to bradykinin and nitroglycerin. The response to the highest dose of bradykinin was reversed to a pressor response during infusion of PGE1. In contrast, mesenteric perfusion pressure and vasoconstrictor responses to nerve stimulation and pressor hormones and vasodilator responses to bradykinin and nitroglycerin were unchanged during the lowest rate of infusion of PGE1, 0.01 microgram/min. When the decrease in (initial value) vascular resistance was taken into account by expressing vasodilator responses on a percent decrease basis, infusion of PGE1 reduced or reversed the vasodilator responses to bradykinin whereas the vasodilator responses to nitroglycerin were not altered. Results of these studies suggest that PGE1 may influence vasomotor tone and responses to pressor hormones and bradykinin in the mesenteric vascular bed of the cat.

Alprostadil↗

PubMed1992

Neurogenic cutaneous vasodilation in the cat forepaw.

The present experiments were undertaken to determine, using Laser Doppler flowmetry, if elimination of efferent constrictor mechanisms would unmask cutaneous vasodilator responses following preganglionic sympathetic nerve stimulation in the forepaw of anesthetized cats. We also addressed the question of a potential causal relationship between neurally evoked vasodilator and sudomotor responses. Three separate anti-adrenergic regimens were utilized: (1) acute guanethidine administration (1-2 mg/kg); (2) chronic monoamine depletion with reserpine (5 mg/kg) and alpha-methyl-para-tyrosine (2 x 300 mg/kg); and (3) alpha-adrenoceptor blockade with prazosin (300 micrograms/kg) and yohimbine (0.5 mg/kg). Guanethidine treatment produced a significant depression of basal cutaneous blood flow whereas alpha-adrenoceptor blockade did not. In all three groups, stimulation of the preganglionic thoracic sympathetic nerve trunk produced intensity-dependent increases of digital skin blood flow along with near-maximal sympathetic-cholinergic sudomotor (electrodermal) responses recorded simultaneously from the same paw. Vasodilator responses were not altered by intravenous propranolol (1 mg/kg) or atropine (1 mg/kg); however, evoked sudomotor responses were totally blocked by atropine. Low doses (1.5 mg/kg i.v.) of hexamethonium selectively abolished the cutaneous vasodilator responses but not concomitantly evoked sudomotor responses. These results demonstrate, using direct measurements of blood flow, that cutaneous digital vasodilation can be measured in cats following removal of vasoconstrictor mechanisms either pre- or postjunctionally. Neither muscarinic nor beta-adrenoceptor mechanisms appear to be involved. These experiments also suggest that cutaneous vasodilation is not a consequence of concomitant sudomotor activation.

Adrenergic alpha-Antagonists↗

PubMed1993

Gastric vasodilator and motor responses to splanchnic stimulation and tachykinins in the dog.

1. Gastric blood flow and motor responses to greater splanchnic nerve stimulation and intra-arterial injection of tachykinins were studied in anaesthetized dogs. 2. Splanchnic nerve stimulation (40 V, 10 Hz) with pulse durations of 0.05 and 1 msec caused a gastric relaxation and contraction, respectively. Both types of stimulation produced a decrease followed by an increase in blood flow. The responses to stimulation with a pulse duration of 0.05 msec were inhibited by hexamethonium. 3. After treatment with hexamethonium, stimulation with 1 msec caused frequency-dependent gastric contraction and vasodilation. Both responses had two components, sensitive and resistant to atropine. 4. Intra-arterial injection of substance P (SP), neurokinin A (NKA), neurokinin B (NKB), physalaemin (PHY) or eledoisin (ELE) elicited dose-dependent gastric contraction and vasodilation. The order of potency for contraction was SP = PHY = ELE = NKA >> NKB and that for vasodilation was SP = PHY > ELE > NKA > NKB. 5. Atropine partly inhibited the tachykinin-induced gastric contraction but not gastric vasodilation. Spantide partly inhibited the atropine-resistant vasodilation but not contraction in response to splanchnic nerve stimulation and SP. 6. It is concluded that splanchnic nerve stimulation produced cholinergic and SPergic vasodilation after ganglionic blockade in the dog stomach.

Animals↗

PubMed1994

Impaired endothelium-dependent vasodilation in patients with essential hypertension: evidence that the abnormality is not at the muscarinic receptor level.

OBJECTIVES: The purpose of this study was to determine whether the impaired endothelium-dependent vasodilation of hypertensive patients is related to a specific defect of the muscarinic receptor or to a broader abnormality of the vascular endothelium. BACKGROUND: Patients with essential hypertension have abnormal endothelium-dependent vasodilator response to acetylcholine. However, whether this results from an isolated dysfunction of the endothelial cell muscarinic receptor is unknown. METHODS: The responses of the forearm vasculature to acetylcholine and substance P (endothelium-dependent agents acting on different receptors) and to sodium nitroprusside (a direct dilator of vascular smooth muscle) were studied in eight hypertensive patients (six men, two women; mean age [+/- SD] 50 +/- 12 years) and eight normal control subjects (four men, four women; mean age 49 +/- 9 years). To determine the nitric oxide contribution to substance P-induced vasodilation, the vascular responses to substance P were also measured after inhibition of nitric oxide synthesis with NG-monomethyl-L-arginine. Drugs were infused into the brachial artery, and forearm blood flow was measured by strain gauge plethysmography. RESULTS: The response to acetylcholine was significantly blunted in hypertensive patients (highest blood flow [mean +/- SD] 8.4 +/- 4 vs. 13.8 +/- 4 ml/min per 100 ml in control subjects, p < 0.03). Similarly, the vasodilator effect of substance P was significantly reduced in hypertensive patients (highest blood flow [mean +/- SD] 8.8 +/- 4 vs. 13.9 +/- 4 ml/min per 100 ml in control subjects, p < 0.03). A significant correlation was found between the maximal blood flow with acetylcholine and that with substance P (r = 0.68, p < 0.004). The vasodilator response to sodium nitroprusside was similar in patients and control subjects. The nitric oxide contribution to substance P-induced vasodilation was reduced in hypertensive patients, such that the responses to substance P measured during infusion of NG-monomethyl-L-arginine were not significantly different between the two groups. CONCLUSIONS: These findings indicate that the endothelial abnormality of patients with essential hypertension is not restricted to the muscarinic cell receptor.

Acetylcholine↗

PubMed1996

Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus.

OBJECTIVES: This study sought to determine whether nitric oxide-mediated vasodilation is abnormal in patients with non-insulin-dependent diabetes mellitus. BACKGROUND: Multiple investigations, both in experimental models and in patients with insulin-dependent diabetes mellitus, demonstrate impaired endothelium-dependent vasodilation. Decreased availability of endothelium-derived nitric oxide may contribute to the high prevalence of vascular disease in diabetes. METHODS: Vascular reactivity was measured in the forearm resistance vessels of 21 patients with non-insulin-dependent diabetes mellitus and 23 matched healthy control subjects. No patient had hypertension or hypercholesterolemia. Each subject was pretreated with aspirin to inhibit endogenous production of vasoactive prostanoids. Methacholine chloride (0.3 to 10 microg/min) was administered through a brachial artery cannula to assess vasodilation to endothelium-derived nitric oxide. Sodium nitroprusside (0.3 to 10 microg/min) was infused to evaluate vasodilation to an exogenous nitric oxide donor. Verapamil (10 to 300 microg/min) was administered to distinguish impaired nitric-oxide-mediated vasodilation from general dysfunction of vascular smooth muscle. Forearm blood flow was determined by venous occlusion plethysmography, and dose-response curves were generated for each agent. To assess the role of vasoconstrictor prostanoids, a subset of eight diabetic subjects were reexamined in the absence of aspirin treatment. RESULTS: Basal forearm blood flow in diabetic and nondiabetic subjects was comparable. The forearm blood flow responses to both methacholine chloride and nitroprusside were significantly attenuated in diabetic compared with nondiabetic subjects (p < 0.005 by analysis of variance for both agents). In contrast, the response to verapamil was not significantly different between the groups (p > 0.50). The forearm blood flow responses to these agents were not significantly affected by cyclooxygenase inhibition. CONCLUSIONS: Nitric oxide-mediated vasodilation is impaired in non-insulin-dependent diabetes mellitus. Vasoconstrictor prostanoids do not contribute significantly to vascular dysfunction. The attenuated response to exogenous as well as endogenous nitric oxide donors suggests that the abnormality is due to increased inactivation of nitric oxide or to decreased reactivity of the vascular smooth muscle to nitric oxide.

Adult↗

PubMed1990

Inhibition by nitric oxide and nitric oxide-producing vasodilators of DNA synthesis in vascular smooth muscle cells.

Effects of nitric oxide (NO) and NO-producing vasodilators such as glyceryl trinitrate and sodium nitroprusside were tested on DNA synthesis in the clonal rat aortic smooth muscle cells, RACS-1. DNA synthesis was estimated by [3H]thymidine incorporation to DNA. NO and NO-producing vasodilators inhibited the DNA synthesis that was induced by 10% fetal calf serum. NO and NO-producing vasodilators also inhibited the basal level of DNA synthesis that occurred possibly as a result of autocrine mechanisms. NO-producing vasodilators also inhibited the fetal calf serum-induced proliferation of cells. Sodium nitroprusside inhibited the endothelin-mediated DNA synthesis. In another mesenchymal cell line, Chinese hamster fibroblast V79 cells, NO and NO-producing vasodilators failed to inhibit DNA synthesis, excluding the possibility of general cell toxicity. An exposure to NO and NO-producing vasodilators resulted in an increase of cyclic GMP (cGMP) content in the RACS-1 cells. A cGMP analog, 8-bromo-cGMP, inhibited DNA synthesis in the RACS-1 cells. These results suggest that EDRF/nitric oxide released from endothelium possibly contributes to inhibition of the DNA synthesis in vascular smooth muscle cells.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2007

Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure.

BACKGROUND: Treatment of decompensated heart failure often includes the use of intravenous vasoactive medications, but the effect on outcome has not been clearly defined. METHODS: Data from 433 patients enrolled in the ESCAPE trial were analyzed to determine 6-month risks of all-cause mortality and all-cause mortality plus rehospitalization associated with the use of vasodilators, inotropes, and their combination. Patients had a mean left ventricular ejection fraction of 19%, 6-minute walk distance of 414 ft, and systolic blood pressure of 106 mm Hg. The main outcome measure was multivariable risk-adjusted 6-month hazard ratios (HRs). RESULTS: Overall 6-month mortality was 19%. Risk-adjusted HRs were not statistically significant for vasodilators (1.39, 95% CI 0.64-3.00), but were significant for inotropes (2.14, 95% CI 1.10-4.15) and the combination (4.81, 95% CI 2.34-9.90). Risk-adjusted 6-month mortality plus rehospitalization HRs were not significant for vasodilators (1.20, 95% CI 0.81-1.78, P = .37), but were significant for inotropes (1.96, 95% CI 1.37-2.82, P < .001) and their combination (2.90, 95% CI 1.88-4.48, P = .001). The decision to use vasodilators or inotropes was determined by hemodynamic parameters and renal function, but the main factor was treatment site. CONCLUSIONS: In ESCAPE, the choice of medications was mainly determined by the treatment site. Use of inotropic agents was associated with adverse outcomes, whereas the use of vasodilators was not. Inotropes in combination with vasodilators identified a group with the highest mortality. Prospective studies are needed to establish the appropriate use of vasoactive medications in this population.

Adult↗

PubMed2005

Tetrahydrobiopterin improves aging-related impairment of endothelium-dependent vasodilation through increase in nitric oxide production.

Deficiency of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthase, decreases NO production and increases reactive oxygen species. The purpose of this study was to elucidate the effects of aging on endothelial function and to determine whether the degree of BH4 deficiency is related to aging and oxidative stress. We evaluated forearm blood flow (FBF) responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, before and after co-infusion of BH4 (500 mg/min) in 37 healthy men (mean age, 41+/-18 yr; range, 19-81 yr). FBF was measured using strain-gauge plethysmograph. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) and serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) were measured as indices of oxidative stress. Both ACh and ISDN increased the FBF in a dose-dependent manner in all subjects. Co-infusion of BH4 resulted in a significant increase in ACh-induced vasodilation (from 22.3+/-6.7 to 30.1+/-7.5 mL/min/100 mL tissue, P<0.05). Aging was found to be significantly correlated with ACh-induced vasodilation (r=-0.47, P=0.006), urinary 8-OHdG (r=0.38, P=0.02), serum MDA-LDL (r=0.36, P=0.02), and the change in ACh-induced vasodilation after co-infusion of BH4 (r=0.45, P=0.007). The FBF response to ISDN did not correlate with any parameters. Infusion of N(G)-monomethyl-L-arginine, an NO synthase inhibitor, abolished the BH4-induced enhancement of forearm vasorelaxation evoked by ACh. The increase in FBF after ISDN was not altered by BH4. These findings suggest that a deficiency of BH4 may be involved in the pathogenesis of disturbances in endothelium-dependent vasodilation related to aging through decrease in NO production and increase in oxidative stress.

Acetylcholine↗

PubMed2005

Angiotensin II type 1 (AT1)-receptor blocker prevents impairment of endothelium-dependent cerebral vasodilation by acute cigarette smoking in rats.

Our aim was to test for smoking-induced endothelial dysfunction in rat cerebral vessels, then to evaluate the effect of valsartan [angiotensin II type I (AT1)-receptor blocker] on that impairment. In pentobarbital-anesthetized, mechanically ventilated Sprague-Dawley rats, we used a cranial window preparation to measure changes in pial vessel diameters following topical applications of acetylcholine (Ach) (before and after smoking or intravenous nicotine infusion; n = 6 in each group), and adenosine (n = 6 for before and after smoking). Then, after intravenous valsartan pretreatment we reexamined the pial vasodilator response to topical Ach (before and after cigarette smoking). Under control conditions, cerebral arterioles were dilated by 6.9 +/- 4.2% and 13.6 +/- 4.8% by topical Ach (10(-6) M and 10(-5) M, respectively) and by 6.4 +/- 2.5% and 12.2 +/- 3.1% by topical adenosine (10(-5) M and 10(-4) M, respectively). One hour after a 1-min inhalation of mainstream smoke (1-mg nicotine cigarette), 10(-5) M Ach constricted cerebral arterioles (-4.4 +/- 4.1%), while 10(-4) M adenosine dilated them by 13.4 +/- 3.4%. One hour after a 1-min nicotine infusion (0.05 mg), 10(-5) M Ach dilated cerebral arterioles by 9.9 +/- 2.4%. Thus, vasodilator response to topical Ach was impaired after smoking, whereas that to adenosine was unaffected. However, the vasodilator response to Ach was unaffected by intravenous nicotine. Valsartan prevented smoking from impairing Ach-induced vasodilation. In conclusion, acute single-cigarette smoking causes a dysfunction of endothelium-dependent, but not endothelium-independent, vasodilation of rat cerebral vessels in vivo, and the effect was not mimicked by intravenous nicotine. AT1-receptor blockade prevented the above smoking-induced impairment of endothelium-dependent vasodilation.

Acetylcholine↗

PubMed2004

Role of potassium channels in the nitric oxide-independent vasodilator response to acetylcholine.

Stimulation of vascular endothelial muscarinic receptors by acetylcholine (ACh) leads to the formation of an endothelium-derived relaxing factor (EDRF), which is generally accepted to be nitric oxide (NO). Recent evidence, however, suggests that NO may be only one of several EDRFs mediating the vasodilator response to ACh. Since this NO-independent vasodilator response to ACh has been hypothesized to be dependent upon K(+) channel activation, the current study was undertaken to investigate the role of K(+) channels in mediating the hindlimb vasodilator responses to ACh in vivo. Additionally, since variations in vascular tone can complicate the analysis of responses, the level of vascular tone was maintained at a similar level throughout the study so that responses could be compared directly. The results of the present study demonstrate that the vasodilator response to ACh possesses a significant component that is independent of NO production. The K(Ca) channel blockers charybdotoxin and apamin, but not K(+)-ATP channel blocker U37883A or the COX antagonist meclofenamate, attenuated the NO-independent component of the vasodilator response to ACh. This suggests that K(Ca) channels, but not K(+)-ATP channels or COX products, are involved in mediating the L-NAME resistant response to ACh. Further, the inhibition of the ACh vasodilator response by the K(+)-ATP opener BRL55834 suggests that the response is dependent upon membrane hyperpolarization. These data suggest that the mechanism mediating ACh responses in the hindlimb vascular bed of the rat are complex and may involve several signaling pathways.

Acetylcholine↗