Nitrite directly vasodilates hypoxic vasculature via nitric oxide-dependent and -independent pathways

Background and purpose:

It is postulated that nitrite requires reduction to nitric oxide in order to exert its relaxant effect upon isolated hypoxic vessels. Herein, we evaluate the relative contribution of nitric oxide and characterize the downstream mechanisms of nitrite-induced vasorelaxation.

Experimental approach:

Aortic rings were treated with pharmacological agents and exposed to hypoxia (<1% O₂). Following pre-constriction, nitrite (10 µM final) was added to appropriate baths; isometric tension was recorded throughout.

Key results:

Nitrite (under hypoxic conditions at physiological pH) is capable of exerting physiological effects that cannot be completely inhibited by the inhibitor of soluble guanylate cyclase (sGC), 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or a nitric oxide scavenger (carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide). Simultaneous blockade of both sGC and cyclooxygenase (COX) completely inhibited the response to nitrite. With regard to the nitric oxide-dependent component, we confirm that aldehyde oxidase, but not xanthine oxidase or endothelial nitric oxide synthase, was important for the actions of nitrite in our model.

Conclusions and implications:

Nitric oxide generated from nitrite is not exclusively responsible for the physiological actions observed in isolated hypoxic vessels. Nitrite operates via different pathways dependent on the presence or absence of endothelium to produce vasorelaxation. In intact vessels, both sGC and COX enzymes appear to be important. Irrespective of this difference in relaxation mechanism, nitrite is capable of producing the same maximum relaxation, regardless of the presence of endothelium. Having investigated possible nitrite reduction sites, we confirm that aldehyde oxidase is important for the actions of nitrite.     

Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.     

Analysis of short-term reproducibility of arterial vasoreactivity by pulse-wave analysis after pharmacological challenge

1. Pulse-wave analysis (PWA) is an established method to assess arterial wave reflections and arterial vasoreactivity in humans. A high short-term reproducibility of baseline augmentation index (AIx) has been reported. However, the short-term reproducibility of AIx changes following pharmacological challenge with either inhaled salbutamol (endothelium-dependent vasodilatation) or sublingual glyceryl trinitrate (GTN; endothelium-independent vasodilatation), using appropriate statistical methods, is largely unknown. 2. Baseline AIx and GTN- and salbutamol-mediated changes in AIx (all corrected for a heart rate of 75 b.p.m.) were measured on two separate occasions, 1 h apart, in 22 healthy controls (mean (+/-SD) age 52.0 +/- 13.4 years) and 11 elderly patients with chronic heart failure (CHF; 73.1 +/- 8.7 years). Reproducibility was assessed by measuring intraclass correlation coefficients (ICC), coefficients of variation (CV) and Bland-Altman plots. 3. Baseline AIx showed good short-term reproducibility with high ICC in both the control and CHF groups (0.90 and 0.87, respectively). In contrast, in the control and CHF groups, the ICC of GTN- (0.58 and 0.17, respectively) and salbutamol-mediated (0.18 and 0.04, respectively) changes in AIx were substantially low. The CV was relatively low for baseline AIx in control and CHF groups (25.0 and 22.5%, respectively), but not for GTN- (22.3 and 59.8%, respectively) or salbutamol-mediated (45.1 and 184.0%, respectively) changes in AIx. Bland-Altman analysis revealed poor reproducibility, with limits of agreement beyond either +15% or -15% for changes in AIx after GTN and salbutamol for both control and CHF groups. The changes in blood pressure and heart rate following pharmacological challenge were similar between the two measurements. 4. The poor reproducibility of changes in AIx following pharmacological challenge questions the use of this method in acute studies.     

Biphasic vasomotor reflex responses of the hand skin following intradermal injection of melittin into the forearm skin.

Melittin is the main toxin of honeybee venom. Previously, we have reported that intradermal injection of melittin into the volar aspect of forearm in humans produces a temporary pain and a subsequent sustained increase in the skin temperature due to axon reflex. To clarify the interaction between nociceptive inputs and vascular changes, we studied the influence of noxious stimulation by intradermal melittin on the vasomotor control of the distal extremities in human volunteers. Temperature changes of the bilateral palmar surface were recorded by means of a computer-assisted infrared thermography. Unexpectedly, we found a biphasic response of skin temperature. The skin temperature of both fingers and hands decreased immediately after the melittin injection and then increased well above the control level, prior to the injection. There was a considerable individual variation in the baseline skin temperature, prior to melittin. The skin temperature in a finger/hand with lower preinjection value increased more markedly in the second phase. Consequently, the individual variation in the peak temperature of the second phase was less pronounced. The initial decrease was interpreted as sympathetic vasoconstrictor reflex induced by noxious stimulation and the later increase as release of sympathetic vasomotor tone.     

Warifteine,a bisbenzylisoquinoline alkaloid,induces relaxation by activating potassium channels in vascular myocytes

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The effect of Hypericum perforatum on isolated rat aorta

Context: Different Hypericum species such as Hypericum perforatum (HP) L. and Hypericum triquetrifolium Turra are well known and widely used traditional medicine in Turkey.

Objectives: We investigated the effect of standardized HP extract on endothelium and vascular function.

Materials and methods: After suspending the aortas with endothelium in organ baths containing Krebs solution, contractile and relaxant responses were assessed in the absence and presence of HP (0.05?mg/ml).

Results: Although there were significant reductions in the contractile responses to phenylephrine (1113.73?±?164.11; 477.40?±?39.94; p?<?0.05) and potassium chloride (745.58?±?66.73; 112.58?±?26.58; p?<?0.05), no differences in the relaxant responses to acetylcholine (94.61?±?2.65; 87.79?±?9.40) and sodium nitroprusside (108.82?±?5.06; 106.43?±?7.45) were observed.

Discussion and conclusion: These data suggest that even the high dose of HP intervention does not bring any harmful effect on endothelium and smooth muscle function; meanwhile it might be beneficial on some of diseases accompanied with increased vascular contraction.     

Vasorelaxant and antihypertensive effects of formononetin through endothelium-dependent and -independent mechanisms

Aim:

To investigate the mechanisms underlying the vasorelaxant effect of formononetin, an O-methylated isoflavone, in isolated arteries, and its antihypertensive activity in vivo.

Methods:

Arterial rings of superior mesenteric arteries, renal arteries, cerebral basilar arteries, coronary arteries and abdominal aortas were prepared from SD rats. Isometric tension of the arterial rings was recorded using a myograph system. Arterial pressure was measured using tail-cuff method in spontaneously hypertensive rats.

Results:

Formononetin (1–300 μmol/L) elicited relaxation in arteries of the five regions that were pre-contracted by KCl (60 mmol/L), U46619 (1 μmol/L) or phenylephrine (10 μmol/L). The formononetin-induced relaxation was reduced by removal of endothelium or by pretreatment with L-NAME (100 μmol/L). Under conditions of endothelium denudation, formononetin (10, 30, and 100 μmol/L) inhibited the contraction induced by KCl and that induced by CaCl₂ in Ca²⁺-free depolarized medium. In the absence of extracellular Ca²⁺, formononetin (10, 30, and 100 μmol/L) depressed the constriction caused by phenylephrine (10 μmol/L), but did not inhibit the tonic contraction in response to the addition of CaCl₂ (2 mmol/L). The contraction caused by caffeine (30 mmol/L) was not inhibited by formononetin (100 μmol/L). Formononetin (10 and 100 μmol/L) reduced the change rate of Ca²⁺-fluorescence intensity in response to KCl (50 mmol/L). In spontaneously hypertensive rats, formononetin (5, 10, and 20 mg/kg) slowly lowered the systolic, diastolic and mean arterial pressure.

Conclusion:

Formononetin causes vasodilatation via two pathways: (1) endothelium-independent pathway, probably due to inhibition of voltage-dependent Ca²⁺ channels and intracellular Ca²⁺ release; and (2) endothelium-dependent pathway by releasing NO. Both the pathways may contribute to its antihypertensive effect.     

Targeting abnormal airway vascularity as a therapeutical strategy in asthma

Asthma is a chronic inflammatory disease of airways, characterized by airway hyperresponsiveness and airflow limitation with acute bronchoconstriction, swelling of the airway wall, chronic mucus plug formation and airway wall remodelling. Functional and structural changes in the vasculature of asthmatic airways have been documented, and the signalling mechanisms are complex and have recently attracted much attention. The vascular changes may affect inflammatory cell recruitment, airway hyperresponsiveness and the regulation of airway calibre, and further, the level of disease control. Many critical factors are involved in the pathophysiological regulation of vascular changes in bronchial asthma, and the actions of these factors must be very carefully orchestrated. By better understanding the complicated actions of each factor, we may be able to advance further in asthma treatment.     

Apigenin, a plant-derived flavone, activates transient receptor potential vanilloid 4 cation channel

BACKGROUND AND PURPOSE

Transient receptor potential vanilloid 4 (TRPV4) is a Ca²⁺-permeable channel with multiple modes of activation. Apigenin is a plant-derived flavone, which has potential preventive effects on the development of cardiovascular disease. We set out to explore the effects of apigenin on TRPV4 channel activity and its role in vasodilatation.

EXPERIMENTAL APPROACH

The effects of apigenin (0.01–30 µM) on TPRV4 channels were investigated in HEK293 cells over-expressing TRPV4, rat primary cultured mesenteric artery endothelial cells (MAECs) and isolated small mesenteric arterial segments using whole-cell patch clamp, fluorescent Ca²⁺ imaging, intracellular recording and pressure myography.

KEY RESULTS

Whole-cell patch clamp and fluorescent Ca²⁺ imaging in HEK cells over-expressing TRPV4 showed that apigenin concentration-dependently stimulated the TRPV4-mediated cation current and Ca²⁺ influx. In MAECs, apigenin stimulated Ca²⁺ influx in a concentration-dependent manner. These increases in cation current and Ca²⁺ influx were markedly inhibited by TRPV4-specific blockers and siRNAs. Furthermore, pressure myography and intracellular recording in small third-order mesenteric arteries showed that apigenin dose-dependently evoked smooth muscle cell membrane hyperpolarization and subsequent vascular dilatation, which were significantly inhibited by TRPV4-specific blockers. TRPV4 blocker or charybdotoxin (200 nM) plus apamin (100 nM) diminished the apigenin-induced dilatation.

CONCLUSION AND IMPLICATIONS

This is the first study to demonstrate the selective stimulation of TRPV4 by apigenin. Apigenin was found to activate TRPV4 channels in a dose-dependent manner in HEK cells over-expressing TRPV4 and in native endothelial cells. In rat small mesenteric arteries, apigenin acts on TRPV4 in endothelial cells to induce EDHF-mediated vascular dilatation.