Biomedical subjects

E Vicaut

Publications and source records attributed to E Vicaut.

At least 73 records · Page 4Linked to original sources

PubMed1999

Acute modulation of albumin microvascular leakage by advanced glycation end products in microcirculation of diabetic rats in vivo.

Advanced glycation end products (AGEs) are nonenzymatic glycosylated adducts of proteins that accumulate in vascular tissue during diabetes and aging. The aim of this work was to study the role of AGEs and of the oxidative mechanisms in diabetes-induced changes in vascular permeability. Intravital videomicroscopy was used to study albumin microvascular leakage in cremaster muscle. The extravasation of a fluorescent macromolecular tracer (fluorescein isothiocyanate-albumin) was measured for 1 h and, after computer-aided image analysis, was expressed as variations of normalized gray levels (arbitrary units). Extravasation of the macromolecular tracer was much higher in diabetic rats than in control rats (slope of extravasation versus time increased by >100%, P < 10(-4)). This increase was significantly inhibited when we blocked AGEs binding to their endothelial receptor by intravenous bolus of soluble recombinant receptor to AGEs (rR-RAGE) (slope of extravasation versus time decreased by 19, 30, and 40%, for 0.5, 2.5, and 5.15 mg/kg rR-RAGE, respectively) or by a 6 mg/kg intravenous bolus of antibody against RAGE (slope decreased by 53%). Systemic injection of probucol (an antioxidant) also significantly inhibited the increase in the extravasation of the macromolecular tracer occurring in experimental diabetes (slope decreased by 51%, P < 10(-4)). These results strongly suggest that in experimental diabetes the interaction of circulating AGEs and endothelial RAGE mediates albumin micro-vascular leakage, possibly via AGE-RAGE-dependent enhanced oxidant stress.

Albumins↗

PubMed1999

Microcirculation and arterial hypertension.

A large part of the pressure gradient takes place in the microvascular network (which corresponds to vessels less than 150 microns in diameter). Most of the changes in the peripheral resistance associated with hypertension affect the microvascular network. From the brief review presented here, it appears that the functional characteristics of arterioles are significantly modified in hypertension. Sensitivity to numerous vasoconstrictive substances is increased. Local ACE activity is considerably higher, and endothelium-dependent dilation is lower, in genetically hypertensive animals than in control models. The myogenic response, which represents the vasoconstriction of arterioles in response to a stepped increase in pressure, is also amplified by mechanisms dependent on both prostanoids and endothelin. Changes also affect the structure of the microvascular network. Morphological alterations in the arteriolar wall are not observed for all types of hypertension. Conversely, arteriolar and capillary rarefaction appears to be the most commonly observed change affecting the structure of the microvascular network. The first stage of rarefaction is functional and affects the number of vessels perfused but not the total number of vessels of the microvascular network. At this stage, potent dilators can induce a recruitment of microvessels, which may cancel the difference between the number of perfused vessels in hypertensive and normotensive animals. The second stage is the anatomical rarefaction corresponding to a decrease in arterioles and/or the total number or density of capillaries. Microvascular rarefaction has also been described in patients even in the early stages of hypertension. This led us to consider the microvascular network not only as one of the putative factors responsible for increased pressure but also as a key target of hypertension. Consequently, antihypertensive drugs should also be assessed and differentiated in terms of their efficacy in preventing or reversing the microcirculatory damage associated with hypertension.

Animals↗

PubMed1999

Microcirculation and arterial hypertension.

Animals↗

PubMed1999

[Role of microcirculation in hypertension].

A large share of the pressure gradient in the vascular system is situated in the microcirculation. Most of the mechanisms resulting in an increase of peripheral resistances during hypertension are also located in this network. Experimental studies have shown that the functional characteristics of arterioles are profoundly modified in most hypertension models. The sensitivity to vasoconstrictor agonists is increased. The activity of the angiotensin-converting enzyme, situated in the arteriolar wall, is considerably greater in genetically hypertensive animals than in control animals. Endothelium-dependent vasodilator mechanisms are also decreased in these animals, while endothelium-derived vasoconstrictor factors are responsible for an increased smooth muscle response. These functional disorders are associated with structural modifications of the microvascular network. Changes of wall thickness are observed only inconstantly, but an initially functional then anatomical rarefaction of arterioles and capillaries has been observed in most experimental models of hypertension and in several clinical studies. This phenomenon reduces the capacities of adaptation of perfusion condition to changes in metabolic requirements of the various organs, reflecting the fact that the microcirculation is a target of hypertensive disease. Antihypertensive drugs should therefore be assessed not only in terms of the reduction of blood pressure figures, but also in terms of their capacity to prevent or correct structural changes of the microvascular network.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1998

Comparison of the prognostic value of C-reactive protein and troponin I in patients with unstable angina pectoris.

This study assessed the prognostic value of cardiac troponin I (cTnI) and C-reactive protein (CRP) in unstable angina, and specifically in patients with angiographically proven coronary artery disease. These biochemical parameters, which are related to myocardial injury or to systemic inflammation, may help in short-term risk stratification of unstable angina. We prospectively studied 195 patients with unstable angina, 100 of whom had angiographically proven coronary artery disease (with normal creatine kinase [CK] and CK-MB mass). Serum concentrations of cTnI (N < 0.4 ng/ml) and CRP (N < 3 mg/L) were measured at admission, 12, and 24 hours later. The rate of in-hospital major adverse cardiac events (death, myocardial infarction, or emergency revascularization) was higher in patients with increased cTnI within the first 24 hours, regardless of the results of coronary angiography (23% vs 7%; p < 0.001). Conversely, events occurred at similar rates in patients with or without increased CRP. In patients with angiographic evidence of coronary artery disease, multivariate analysis showed that increased cTnI within 24 hours of admission (35 patients) was an independent predictor of major adverse cardiac events (odds ratio 6.7, range 1.7 to 27.3), but not cTnI levels at admission and CRP at 0, 12, and 24 hours. Thus, both in unselected patients with unstable angina and in patients with angiographically proven coronary artery disease, increased cTnI within 24 hours of admission, but not CRP, is a predictor of in-hospital clinical outcome. We also found a temporal link between cTnI increase and late elevation of CRP, suggesting that systemic inflammation may partially be a consequence of myocardial injury.

Angina, Unstable↗

PubMed1998

Early increase of von Willebrand factor predicts adverse outcome in unstable coronary artery disease: beneficial effects of enoxaparin. French Investigators of the ESSENCE Trial.

BACKGROUND: The pathogenesis of unstable angina and non-Q-wave myocardial infarction is still poorly understood, and early evaluation of prognosis remains difficult. We therefore studied the predictive value of 5 biological indicators of inflammation, thrombogenesis, vasoconstriction, and myocardial necrosis, and we examined the effects of enoxaparin and unfractionated heparin on these markers after 48 hours of treatment. METHODS AND RESULTS: Sixty-eight patients with unstable angina or non-Q-wave myocardial infarction randomized in the international ESSENCE trial participated in this French substudy. C-reactive protein, fibrinogen, von Willebrand factor antigen, endothelin-1 and troponin I were measured on admission and 48 hours later. The composite end point of death, myocardial infarction, recurrent angina, or revascularization was significantly lower at 14 and 30 days of follow-up in patients allocated to enoxaparin compared with unfractionated heparin. All acute-phase reactant proteins were elevated on admission and increased further at 48 hours. Multivariate analysis demonstrated that the rise of von Willebrand factor over 48 hours was a significant and independent predictor of the composite end point at both 14 days and 30 days. Moreover the early increase of von Willebrand factor was more frequent and more severe with unfractionated heparin than with enoxaparin (mean change was +8.7+/-8.8% with enoxaparin versus +93.9+/-11.7% with unfractionated heparin, P<0.0001). The other clinical and biological variables did not predict outcome. CONCLUSIONS: In patients with unstable angina or non-Q-wave myocardial infarction, the acute-phase proteins increase over the first 2 days despite medical treatment. The early rise of von Willebrand factor is an independent predictor of adverse clinical outcome at 14 days and at 30 days. Enoxaparin provides protection as evidenced by the reduced release of von Willebrand factor, which represents a favorable prognostic finding.

Aged↗

PubMed1998

CD28 expression in T cell aging and human longevity.

Functional decrements of the immune system have a major contribution to aging and age-related diseases. Here, we further characterize the decline in proportion of CD28-positive T cells previously identified in centenarians. Cohorts of 97 centenarians, 40 subjects aged 70-90 (ELD group), and 40 young adults (under age 40) were phenotyped for T cell surface expression of CD28, CD4, and CD8 antigens. The significant decline in T cells expressing CD28 (p < 10(-4) for comparisons between adults and either ELD or centenarians) affects preferentially the CD8+ subset of T cells. This decline accounts largely for the age-related diminution of T cell responsiveness to mitogenic signals. CD28 expression is modulated in T cell cultures in a growth-related fashion and this modulation is dampened in cultures from centenarians. We propose that the decrease in CD28 expression reflects a compensatory adaptation of the immune system during aging in the face of chronic stimulation.

Adult↗

PubMed1998

Theophylline dilates rat diaphragm arterioles via the prostaglandins pathway.

1. We investigated by intravital microscopy in rats, the in vivo direct effects of theophylline on the diameters of second and third order diaphragm arterioles. 2. Theophylline (1-100 microM) dilated second and third order diaphragm arterioles significantly, and with an amplitude which was not statistically different from the one obtained with adenosine (1-100 microM). Enprofylline (1-100 microM), a theophylline analogue with poor adenosine-receptor antagonism but with similar or higher phosphodiesterases inhibition properties than theophylline, also dilated diaphragm arterioles, causing however, a significantly smaller dilatation than theophylline. 3. Neither the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 50 nM), nor the A2 adenosine receptor antagonist 3,7-dimethyl-1-proparglyxanthine (DMPX, 10 microM) reduced significantly theophylline-induced arteriolar dilatation. 4. Theophylline (100 nM) abolished adenosine-induced arteriolar dilatation. 5. The dilatation induced by theophylline was unchanged by the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine (NNA, 300 microM). 6. Theophylline-induced arteriolar dilatation was abolished by the prostaglandin synthesis inhibitors mefenamic acid or indomethacin (20 microM). 7. These findings show that theophylline induced a significant dilatation of diaphragm arterioles via the release of prostaglandins.

Adenosine↗

PubMed1998

Assessment of the acute arterial effects of converting enzyme inhibition in essential hypertension: a double-blind, comparative and crossover study.

In subjects with essential hypertension, angiotensin-converting enzyme (ACE) inhibition increases arterial diameter, compliance and distensibility of peripheral muscular arteries in association with blood pressure reduction. Whether pulse pressure amplification is modified by ACE inhibition and whether changes in compliance and distensibility are due to a drug effect on the arterial wall, to the blood pressure reduction or to a combination of both factors, is largely ignored. In a randomised, double-blind crossover trial, we used the ACE inhibitor quinapril as a marker to evaluate the changes in: pulse pressure amplification (applanation tonometry), carotid compliance and distensibility (echo-tracking technique), and aortic distensibility (measured from pulse wave velocity). Quinapril decreased in the same extent carotid and brachial pulse pressure, thus causing a resetting of pulse pressure amplification toward normal values. Carotid compliance and distensibility as well as aortic distensibility increased significantly. Based on three-way analysis of variance, it was shown that, whereas the changes in carotid stiffness were exclusively due to blood pressure reduction and not to a drug-induced relaxation of the arterial wall, the changes in aortic distensibility were due to the combination of both factors. Thus, using an atraumatic non-invasive procedure, it was possible to show that: (i) ACE inhibition is able to maintain pulse pressure amplification, an important factor contributing to reduce the afterload of the heart; and (ii) ACE inhibition alters the hypertensive arterial wall in a very heterogeneous manner, with a maximal drug effect on muscular large arteries like the abdominal aorta, and not on elastic arteries like the carotid artery and the thoracic aorta.

Adult↗

PubMed1998

Characterization of the specific response to serotonin of mouse tumour-feeding arterioles.

PURPOSE: To investigate the role of tumour versus non-tumour factors in the specific response to serotonin (5-HT) of tumour-feeding arterioles (TFA). MATERIALS AND METHODS: Using mouse models of intra-vital microscopy, the response to topical administration of 5-HT was studied in arterioles feeding tumours: fibrosarcoma (Meth A), murine mammary adenocarcinoma (EMT6) and human colo-rectal carcinoma (HRT18) intra-cutaneously implanted. RESULTS: For all types of tumour, 5-HT induced a far more pronounced constriction of TFA than of control arterioles. The presence of a tumour implanted in the connective tissue between the skin and the cremaster muscle also affected the reactivity of muscle arterioles. Conversely, the response to serotonin by neovessels grown after implantation of an exogenous element under the skin did not differ from that of control arterioles. CONCLUSIONS: Changes in reactivity to serotonin were not dependent on the type of tumour implanted in the skin and were not present for a non-tumour implant. The presence of the tumour can alter the reactivity of vessels from tissue in contact with the tumour even if these vessels did not feed the tumour. This phenomenon is local and was not found in the vessels at a distance from the tumour.

Animals↗

PubMed1998

Effects of etomidate, propofol and thiopental anaesthesia on arteriolar tone in the rat diaphragm.

We have assessed, by intravital microscopy in rats, the effects of different anaesthetics on diaphragmatic arteriolar diameter. Rats were anaesthetized with etomidate, propofol or thiopental (groups E, P and T, respectively) and the diameters of the arterioles were measured sequentially at baseline and after topical application of either mefenamic acid (MA, 20 mumol litre-1) or N omega-nitro-L-arginine (NNA, 300 mumol litre-1), inhibitors of prostaglandins and nitric oxide, respectively. In group E, baseline arteriolar diameters were significantly higher than those in the two other groups (P < 0.01). MA and NNA induced significant constriction in the three groups (P < 0.001). However, whereas constriction induced by NNA was similar in the three groups, constriction induced by MA was significantly higher in group E compared with groups P and T (P < 0.05). We conclude that diaphragmatic arteriolar diameters in rats were greater during etomidate than during thiopental or propofol anaesthesia. This phenomenon may be mediated by prostaglandins.

Anesthetics, Intravenous↗

PubMed1998

HLA-DR alleles display sex-dependent effects on survival and discriminate between individual and familial longevity.

In an effort to reassess the contribution of HLA-DRB1 polymorphisms to inter-individual variations of human longevity, we have compared their genotypic distributions between longevous and adult control groups in the French population. The longevous groups included two independent cohorts totalling 533 centenarians, and 163 nonagenarian siblings. Allelic distributions were significantly different between controls and longevous groups. Three individual alleles were mostly responsible for these differences: DR7, DR11 and DR13. Multivariate logistic analyses were performed in order to sort out interactions between gender- and age-specific genetic effects. DR7 frequency was elevated in longevous men, in centenarians as well as nonagenarian siblings [OR = 1.72 (1.2-2.5)]. DR11's influence on longevity displayed a significant interaction with sex, with an increase in women from longevous sibships [OR = 2.03 (1.4-3.0)]. DR13's frequency was increased in centenarians of both genders [OR = 1.46 (1.2-1.75)]. These results are discussed in the context of other pathophysiological effects of the implicated alleles. Our data support the direct involvement of three HLA-DR alleles in survival at very old ages. Two allele-specific effects on longevity appear to depend on gender and one on familial status for aggregation of this trait. The latter is an original finding for humans.

Adult↗

PubMed1998

In vivo study of the effect of systemic hypoxia on leukocyte-endothelium interactions.

To evaluate the effect of systemic hypoxia on leukocyte-endothelium interactions in peripheral tissues, we studied by intravital microscopy leukocyte rolling velocity and adherence in venules of rat cremaster muscle. We examined the possible roles of changes in blood oxygenation, peripheral tissue oxygenation, changes in local shear rate, and the involvement of integrins. Six groups of rats submitted to either control normoxic conditions, or systemic hypoxia (PO2 = 51 mm Hg) associated with either low O2 tension of Krebs superfusing the muscle, high O2 tension of the Krebs superfusing the muscle, anti-lymphocyte function-associated antigen (LFA)-1beta antibody, pentoxifylline, or normoxic conditions associated with partial occlusion of the artery perfusing the muscle. We found that: (1) systemic moderate hypoxia resulting from purely respiratory disturbance even in the absence of local stop-flow phenomenon or circulatory shock can induce an increase in leukocyte adhesion and a decrease in leukocyte rolling velocity in the microcirculation of peripheral tissues; (2) to be present, this increase in leukocyte adhesion does not require tissue hypoxia of the peripheral tissue but the effect of systemic hypoxia on rolling velocity is prevented by tissue oxygenation; (3) this increase in leukocyte adhesion is mediated by CD11/CD18 integrins but is not due to changes in local shear rate.

Animals↗

PubMed1997

Prediction of head-up tilt test result by analysis of early heart rate variations.

BACKGROUND: Head-up tilt testing is a useful test for investigating vasovagal syncope. The determination of early, accurate, predictive criteria for a negative result would permit a reduction in the duration of the tilt test. METHODS AND RESULTS: Patients with no drug use and no illnesses other than recurrent unexplained syncope were recruited. In an initial study (110 consecutive patients), we aimed to determine a predictive criterion based on heart rate variations during the first minutes of upright tilting that could distinguish between patients with positive and negative tilt tests (patients with an early continual decrease in heart rate or blood pressure were excluded). Then we tested the predictive value of the established criterion in a second independent sample of patients with unexplained syncope (109 consecutive patients). An early sustained increase in heart rate < or = 18 bpm during the first 6 minutes of upright tilting at a 60 degree angle allowed us to predict negative tilt tests with 100% specificity, 100% positive predictive value, and 88.6% sensitivity. This criterion was validated in the second, prospective arm of the study (96.4% specificity, 98.4% positive predictive value, and 87.3% sensitivity), even with subsequent use of isoproterenol in low doses. CONCLUSIONS: In patients with no drug use and no illnesses other than recurrent unexplained syncope, a simple clinical criterion identifies patients who will not develop syncope during a prolonged upright tilt.

Adult↗

PubMed1997

Specific response of mouse tumor-feeding arterioles to stimulation by 5-HT1 agonists.

Using intravital microscopy, we compared the responses to 5-HT1 receptor stimulation by the host-modified arterioles feeding a Meth-A tumor implanted in the flank of female Balb/c mice with the responses of tumor-independent arterioles (TIA) and those of control arterioles from mice without tumor. Topical administration of 5 x 10(-5) M serotonin in the presence of 10(-4) M ketanserin (5-HT2 receptors inhibitor) induced arteriolar vasodilation in TIA (+13%) and in the control arterioles (+19%), but induced constriction (-14%) in the tumor-feeding arterioles (TFA). Topical administration of the general 5-HT1 agonist 5-carboxamidotryptamine maleate (10(-6) to 10(-4) M) or the 5-HT1A agonist buspirone (2 x 10(-6) to 2 x 10(-4) M) induced vasoconstriction that was dramatically higher in TFA than in TIA or control arterioles (p < 0.0001 in both cases). In addition, topical administration of the 5-HT1B agonist M-trifluoromethylphenylpiperazine (2 x 10(-6) to 2 x 10(-4) M) produced opposite responses, i.e., dose-dependent vasodilation in TIA and control arterioles, and dose-dependent constriction in TFA. Since we observed the same degree of vasodilation in response to 10(-4) M acetylcholine in all three groups of arterioles, the differences between the responses to 5-HT1 receptor stimulation were not due to the absence of endothelial-dependent dilatory mechanisms in the tumor-feeding arterioles. We conclude that 5-HT1 agonists are interesting pharmacologic tools for the modulation of tumoral blood flow, since they more dramatically constrict the microvasculature feeding the tumors than that feeding normal tissue.

Acetylcholine↗

PubMed1997

Benefit of active compression-decompression cardiopulmonary resuscitation as a prehospital advanced cardiac life support. A randomized multicenter study.

BACKGROUND: We compared short-term prognosis of active compression-decompression (ACD) and standard (STD) cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrests. METHODS AND RESULTS: We randomized advanced cardiac life support (ACLS) with ACD ACLS CPR on odd days and STD ACLS CPR on even days. We measured the rates of return of spontaneous circulation (ROSC), survival at 1 hour (H1), at 24 hours (H24), and at 1 month (D30): hospital discharge (HD); neurological outcome; and complications. Mean times from collapse to basic cardiac life support CPR was 9 minutes and from collapse to ACLS CPR was 21 minutes. Compared with the STD ACLS patients (n = 258), ACD ACLS patients (n = 254) had higher survival rates (ROSC, 44.9% versus 29.8%, P = .0004; H1, 36.6% versus 24.8%, P = .003; H24, 26% versus 13.6%, P = .002; HD without neurological impairment, 5.5% versus 1.9%, P = .03) and a trend for improvement in neurological outcome at D30 (Glasgow-Pittsburgh Outcome Categories = 1.6 +/- 0.8 versus 2.3 +/- 1.1. P = .09). Sternal dislodgements (2.9% versus 0.4%, P = .03) and hemoptysis (5.4% versus 1.3%, P = .01) were more frequent in the ACD ACLS group. CONCLUSIONS: Despite long time intervals, ACD significantly improved short-term survival rates in out-of-hospital cardiac arrests compared with STD CPR.

Adult↗

PubMed1997

Scanning laser ophthalmoscope imaging of fluorescein-labelled blood cells.

PURPOSE: To demonstrate the feasibility of a technique for the visualization by scanning laser ophthalmoscope (SLO) of fluorescein-labelled autologous leukocytes and platelets in retinal vessels. METHOD: Individual blood samples from rats and rabbits were centrifuged to isolate platelets and leukocytes, then passively labelled with fluorescein and reinjected into the same animal. An SLO was used to visualize and record cell displacement in the retinal circulation. Labelled platelets were analysed by flow cytometry. RESULTS: By SLO, platelets appeared as a heterogeneous particle flow, and individual leukocytes appearing as brighter spots could easily be traced. Flow cytometry showed that after labelling platelets were well individualized and their size was slightly increased. CONCLUSION: Circulating blood cells can be visualized in retinal vessels by a simple method consisting of passive labelling of autologous platelets and leukocytes by fluorescein. No platelet toxicity was detected. This method could be applied to the study of blood cell movement in human retinal vascular diseases.

Animals↗

PubMed1997

Predominant role of A1 adenosine receptors in mediating adenosine induced vasodilatation of rat diaphragmatic arterioles: involvement of nitric oxide and the ATP-dependent K+ channels.

1. We investigated, by intravital microscopy in rats, the role of the subtypes of adenosine receptors A1 (A1/AR) and A2 (A2AR) in mediating adenosine-induced vasodilatation of second and third order arterioles of the diaphragm. 2. Adenosine, and the A1AR selective agonists R(-)-N6-(2-phenylisopropyl)-adenosine (R-PIA) and N6-cyclo-pentyl-adenosine (CPA) induced a similar concentration-dependent dilatation of diaphragmatic arterioles. The non selective A2AR subtype agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl]adenosine (DPMA) also dilated diaphragmatic arterioles but induced a significantly smaller dilatation than adenosine. By contrast the selective A(2a)AR subtype agonist 2-[p-(2-carboxyethyl)phenyl amino]-5'-N-ethyl carboxamido adenosine (CGS 21680) did not modify diaphragmatic arteriolar diameter. 3. The non selective adenosine receptor antagonist 1,3-dipropyl-8-p-sulphophenylxanthine (SPX, 100 microM) and the selective A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 50 nM) significantly attenuated adenosine-induced dilatation of diaphragmatic arterioles. By contrast, adenosine significantly dilated diaphragmatic arterioles in the presence of A2AR antagonist 3,7-dimethyl-1-propargylxanthine (DMPX, 10 microM). 4. The dilatation induced by adenosine was unchanged by the mast cell stabilizing agent sodium cromoglycate (cromolyn, 10 microM). 5. The nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (L-NOARG, 300 microM) attenuated the dilatation induced by adenosine, and by the A1AR and A2AR agonists. 6. The ATP-dependent K+ channel blocker glibenclamide (3 microM) significantly attenuated diaphragmatic arteriolar dilatation induced by adenosine and by the A1AR agonists R-PIA and CPA. By contrast, glibenclamide did not significantly modify arteriolar dilatation induced by the A2AR agonist DPMA. 7. These findings suggest that adenosine-induced dilatation of diaphragmatic arterioles in the rat is predominantly mediated by the A1AR, via the release of NO and activation of the ATP-dependent K+ channels.

Adenosine↗