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Biomedical subjects

R Levi

Publications and source records attributed to R Levi.

At least 109 records · Page 6Linked to original sources
PubMed1994

Unmasking of activated histamine H3-receptors in myocardial ischemia: their role as regulators of exocytotic norepinephrine release.

We had previously found that histamine H3- receptors are negatively coupled to norepinephrine exocytosis in atrial tissue. We report here that in the presence of H1- and H2- receptor blockers, histamine significantly inhibits the tachycardia and norepinephrine release elicited by sympathetic nerve stimulation is isolated guinea pig hearts, an effect prevented by the H3 antagonist, thioperamide. Sympathetic nerve stimulation also caused a 1.5-fold increase in histamine overflow, which was insufficient to activate H3 receptors because thioperamide affected neither the tachycardia nor the norepinephrine release. Hence. We questioned whether H3 receptors become activated when adrenergic activity is greatly enhanced, as in myocardial ischemia. Guinea pig hearts underwent 10-min global ischemia. At reperfusion, norepinephrine exocytosis was markedly augmented and was associated with a 3.5-fold increase in histamine overflow. (R)alpha-methylhistamine, an H3 agonist, did not modify norepinephrine release, whereas thioperamide doubled it. Thus, in physiologic conditions, cardiac H3 receptors are quiescent, yet available for activation by exogenous ligands. In contrast, in the ischemic myocardium, H3 receptors appear to be fully activated by an endogenous ligand, probably histamine. Hence, cardiac H3 receptors may play an important role by negatively modulating exocytotic norepinephrine release associated with ischemic states.

Animals↗
PubMed1994

Histamine H3-receptor signaling in the heart: possible involvement of Gi/Go proteins and N-type Ca++ channels.

Discovered as inhibitory autoreceptors in central histaminergic pathways, histamine H3-receptors may also modulate peripheral cholinergic and central adrenergic function. Recently, H3-receptors were reported to inhibit adrenergic inotropic responses in guinea pig atria, possibly at prejunctional sites. We have assessed whether the H3-mediated modulation of cardiac adrenergic activities results from a reduction in norepinephrine release. We have found that (R) alpha-methylhistamine, the selective histamine H3-receptor agonist, attenuates the inotropic and chronotropic response of isolated guinea pig atria to transmural stimulation of adrenergic nerve endings. This attenuation was associated with a marked reduction in endogenous norepinephrine release. In contrast (R) alpha-methylhistamine did not modify the chronotropic effect of exogenous norepinephrine. The attenuation of adrenergic responses by (R) alpha-methylhistamine was 1) prevented by thioperamide, the selective H3-receptor antagonist; 2) attenuated by pertussis-toxin pretreatment and 3) potentiated by the N-type Ca(++)-channel blocker omega-conotoxin, which also potentiated the sympathetic modulatory effects of adrenergic-alpha 2 and adenosine-A1 receptor agonists. Our findings indicate that prejunctional histamine H3-receptors modulate the depolarization-dependent norepinephrine release from sympathetic nerve endings in the guinea pig myocardium. These receptors are probably coupled to a pertussis-toxin-sensitive Gi/Go protein and probably effect a reduction in Ca++ current. We have previously reported that sympathetic stimulation elicits a frequency-dependent release of cardiac histamine, whereas others had found that adrenergic activity regulates histamine's rapid turnover pool. Accordingly, presynaptic H3-receptors are likely to serve a modulatory role in cardiac adrenergic function.

Adrenergic Fibers↗
PubMed1993

Cholesterol enrichment of arterial smooth muscle cells upregulates cytokine-induced nitric oxide synthesis.

Endothelium-derived relaxing factor/nitric oxide (EDRF/NO) is produced by the vascular wall and is a key modulator of vascular tone and blood pressure. NO is also produced by vascular smooth muscle (VSMC) where it can inhibit proliferation. Since cytokine-activated VSMC proliferation is a major event in the development of atherosclerosis, we investigated the influence of cholesterol (CE)-enrichment of VSMC on cytokine-induced NO synthesis. Treatment of VSMC with native LDL for one week did not promote CE-accretion or alter NO production following exposure to endotoxin (LPS). In contrast, CE-enrichment by cationized LDL augmented LPS-induction of NO synthesis 2-5-fold. While TNF-alpha promoted little NO synthesis in control VSMC, it was very potent after CE-enrichment. Similarly, CE-enrichment augmented IL-1 alpha-induced NO synthesis. However, CE-enrichment did not affect the synergistic induction of NO synthesis by cytokines in combination with IFN-gamma. Our findings suggest that CE-enrichment of VSMC upregulates signal transduction pathways which mediate cytokine and LPS induction of NO synthase activity.

Animals↗
PubMed1993

Tetrahydrobiopterin synthesis is induced by LPS in vascular smooth muscle and is rate-limiting for nitric oxide production.

GTPCH1 mRNA and BH4 synthesis is increased by LPS in vascular smooth muscle. Our data suggest that induction of GTPCH1 and NOS represent two arms of a common pathway required for immunostimulant-evoked NO synthesis. This conclusion is consistent with the view that the major function of immunostimulant-evoked BH4 is to support NOS. Moreover, GTPCH1 and other enzymes of the de novo BH4 synthetic pathway may prove to be important targets for therapy of clinical conditions arising from NO overproduction. As we begin to reveal the molecular events governing the induction and expression of GTPCH1 and NOS, additional therapeutic approaches for treating NO overproduction are certain to be revealed.

Amino Acid Oxidoreductases↗
PubMed1993

Therapies for perioperative hypertension: pharmacodynamic considerations.

Cardiac output (CO) and peripheral resistance (PR), the two major determinants of systemic arterial blood pressure (BP), are regulated principally by the adrenergic (ADR) and renin-angiotensin-aldosterone (RAA) systems. Antihypertensive medications ultimately decrease CO, PR, or both, by acting at various sites in the ADR and RAA pathways or affecting cardiovascular functions directly. Beta-ADR-receptor blockers decrease heart rate (HR) and stroke volume (SV) by preventing the cardiostimulating effects of catecholamines and inhibiting renin release. Alpha-ADR-receptor blockers prevent the vasoconstricting effects of catecholamines and reduce PR (afterload). Angiotensin-converting enzyme inhibitors (ACEI) block the formation of angiotensin, a potent peripheral vasoconstrictor and aldosterone releaser. Hence, ACEI cause a decrease in both PR and CO, the latter by preventing salt and water retention by aldosterone, thereby reducing plasma volume and venous return. Direct vasorelaxation and, thus, a fall in PR can be achieved by vasodilators. These include drugs (e.g. calcium antagonists) that prevent the entry of calcium ions into vascular smooth muscle cells, and others (e.g. nitrovasodilators) that boost the intracellular levels of vasodilating second messengers (e.g. cyclic GMP). Antihypertensives from different classes are often combined to improve the ratio between therapeutic and adverse effects.

Antihypertensive Agents↗
PubMed1993

The effect of prone immersion on bronchial responsiveness in children with asthma.

We studied the effects of prone immersion on pulmonary function in children with asthma. Twelve children with asthma were subjected to prone immersion (WET) and standing upright on land (DRY) under controlled conditions regarding temperature and relative humidity of the inhaled air, minute ventilation, respiratory frequency, tidal volume, and the concentration of carbon dioxide in the exhaled air. Eight minutes of isocapnic hyperpnea was performed in random order either in the swimming pool (prone) or on land (upright), with the temperature and relative humidity of the inhaled air kept at 20 +/- 2 degrees C and 10 +/- 2%, respectively. The average accumulated ventilation for the 8 min of hyperpnea was 3151 for the WET treatment and 3101 for the DRY (P > 0.1). Average heart rates were 101 +/- 11 and 115 +/- 17 beats.min-1 for the WET and DRY treatments, respectively (P < 0.05). The decrease in FEV1 (delta FEV1) was 26.3 +/- 16.7% after the WET treatment (compared with pretreatment FEV1), and 26.4 +/- 11.3% after the DRY treatment (P > 0.1 between WET and DRY delta FEV1), with similar trend (insignificant differences between treatments), for delta FVC, delta PEF 50%, and delta PEF 25-75%. It is concluded that airway hyperactivity is not alleviated by whole body prone immersion.

Adolescent↗
PubMed1993

Pregnancy and delivery in women with a traumatic spinal cord injury in Sweden, 1980-1991.

OBJECTIVE: To evaluate the incidence of delivery in women after a traumatic spinal cord injury and to describe pregnancy outcome in this group of patients. METHODS: Between 1980-1991, 29 women with a traumatic spinal cord injury experienced 49 pregnancies and gave birth to 52 children in Sweden. A retrospective chart review of the antepartum, intrapartum, and perinatal records of these patients was performed. In addition, all patients participated in a telephone interview held by one of the authors. Of the 29 women, 12 had lesions above T5 and 17 had lesions at T5 or below. RESULTS: Antenatal complications occurred frequently in this group. Nine of 12 patients with lesions above T5 had symptoms of autonomic hyperreflexia during pregnancy and/or delivery. Only in a minority of the women was the problem recognized by the medical professionals. Nine of the infants (19%) were born preterm and two were small for gestational age. The perinatal mortality rate was two of 52 (3.8%) and occurred in two cases of abruptio placentae. Few of the patients were allowed to deliver vaginally. The cesarean delivery rate for women with lesions above T5 was 47% and for women with lesions below that level, 26%. CONCLUSION: The overall prognosis for these women was favorable. However, women with higher spinal cord lesions would probably benefit from referral to centers with a particular interest and expertise in the management of their problems.

Cesarean Section↗
PubMed1992

Tetrahydrobiopterin synthesis. An absolute requirement for cytokine-induced nitric oxide generation by vascular smooth muscle.

Nitric oxide (NO) synthesis is induced in vascular smooth muscle cells by lipopolysaccharide (LPS) where it appears to mediate a variety of vascular dysfunctions. In some cell types tetrahydrobiopterin (BH4) synthesis has also been found to be induced by cytokines. Because BH4 is a cofactor for NO synthase, we investigated whether BH4 synthesis is required for LPS-induced NO production in rat aortic smooth muscle cells (RASMC). The total biopterin content (BH4 and more oxidized states) of untreated RASMC was below our limit of detection. However, treatment with LPS caused a significant rise in biopterin levels and an induction of NO synthesis; both effects of LPS were markedly potentiated by interferon-gamma. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a selective inhibitor of GTP cyclohydrolase I, the rate-limiting enzyme for de novo BH4 synthesis, completely abolished the elevated biopterin levels induced by LPS. DAHP also caused a concentration-dependent inhibition of LPS-induced NO synthesis. Inhibition of NO synthesis by DAHP was reversed by sepiapterin, an agent which circumvents the inhibition of biopterin synthesis by DAHP by serving as a substrate for BH4 synthesis via the pterin salvage pathway. The reversal by sepiapterin was overcome by methotrexate, an inhibitor of the pterin salvage pathway. Sepiapterin, and to a lesser extent BH4, dose-dependently enhanced LPS-induced NO synthesis, indicating that BH4 concentration limits the rate of NO production by LPS-activated RASMC. Sepiapterin also caused LPS-induced NO synthesis to appear with an abbreviated lag period phase, suggesting that BH4 availability also limits the onset of NO synthesis. In contrast to the stimulation of LPS-induced NO synthesis, observed when sepiapterin was given alone, sepiapterin became a potent inhibitor of NO synthesis in the presence of methotrexate. This is attributable to a direct inhibitory action of sepiapterin on GTP cyclohydrolase I, an activity which is only revealed after blocking the metabolism of sepiapterin to BH4. Further studies with sepiapterin, methotrexate, and N-acetylserotonin (an inhibitor of the BH4 synthetic enzyme, sepiapterin reductase) indicated that the BH4 is synthesized in RASMC predominantly from GTP; however, a lesser amount may derive from pterin salvage. We demonstrate that BH4 synthesis is an absolute requirement for induction of NO synthesis by LPS in vascular smooth muscle. Our findings also suggest that pterin synthesis inhibitors may be useful for the therapy of endotoxin- and cytokine-induced shock.

Amino Acid Oxidoreductases↗
PubMed1992

Nitric oxide synthase in macula densa regulates glomerular capillary pressure.

Tubular-fluid reabsorption by specialized cells of the nephron at the junction of the ascending limb of the loop of Henle and the distal convoluted tubule, termed the macula densa, releases compounds causing vasoconstriction of the adjacent afferent arteriole. Activation of this tubuloglomerular feedback response reduces glomerular capillary pressure of the nephron and, hence, the glomerular filtration rate. The tubuloglomerular feedback response functions in a negative-feedback mode to relate glomerular capillary pressure to tubular-fluid delivery and reabsorption. This system has been implicated in renal autoregulation, renin release, and longterm body fluid and blood-pressure homeostasis. Here we report that arginine-derived nitric oxide, generated in the macula densa, is an additional intercellular signaling molecule that is released during tubular-fluid reabsorption and counters the vasoconstriction of the afferent arteriole. Antibody to rat cerebellar constitutive nitric oxide synthase stained rat macula densa cells specifically. Microperfusion of the macula densa segment of single nephrons with N omega-methyl-L-arginine (an inhibitor of nitric oxide synthase) or with pyocyanin (a lipid-soluble inhibitor of endothelium-derived relaxation factor) showed that generation of nitric oxide can vasodilate the afferent arteriole and increase glomerular capillary pressure; this effect was blocked by drugs that prevent tubular-fluid reabsorption. We conclude that nitric oxide synthase in macula densa cells is activated by tubular-fluid reabsorption and mediates a vasodilating component to the tubuloglomerular feedback response. These findings imply a role for arginine-derived nitric oxide in body fluid-volume and blood-pressure homeostasis, in addition to its established roles in modulation of vascular tone by the endothelium and in neurotransmission.

Amino Acid Oxidoreductases↗
PubMed1992

Inhibition of interleukin-1-alpha-induced nitric oxide synthase in vascular smooth muscle and full reversal of interleukin-1-alpha-induced hypotension by N omega-amino-L-arginine.

BACKGROUND: Interleukin-1-alpha (IL-1) is a cytokine with potentially therapeutic immunoproliferative and tumoricidal activities. Preliminary clinical studies suggest that use of IL-1 may be restricted by dose-limiting hypotension. PURPOSE: The purpose of this study was to investigate the role of nitric oxide (NO.) as a possible mediator of this hypotension. METHODS: Cytokine-treated rat aortic smooth muscle cells were assayed for nitrite production, a stable breakdown product of nitric oxide. Nitric oxide synthase from smooth muscle cells was partially characterized in cytosol preparations using a novel Fe(2+)-myoglobin method to test for nitric oxide production. To determine the role of NO. on the immunorestorative and antineoplastic activity of IL-1, N omega-amino-L-arginine (NAA) or N omega-monomethyl-L-arginine (NMA), inhibitors of nitric oxide synthase, were added to either cultures of IL-1-dependent T cells or A375 melanoma cells exposed to IL-1. To investigate the effects of NAA in vivo, pentobarbital anesthetized dogs, which were made hypotensive by administration of IL-1, received a single intravenous bolus dose of NAA. The effects of NAA were then reversed by the administration of L-arginine. RESULTS: Our results show that cultured IL-1-activated rat aortic smooth muscle cells synthesize nitric oxide, a potent vasodilator. Induction of nitric oxide synthase is augmented by interferon-gamma and blocked by IL-1 receptor antagonist and by inhibitors of RNA or protein synthesis. Nitric oxide synthesis by IL-1-activated smooth muscle cells is inhibited by NAA, NMA, and N omega-nitro-L-arginine (NNA) with ED50 (i.e., effective dose for 50% inhibition) values of 20, 60, and 1000 microM, respectively; this rank order of inhibition is characteristic of an agonist-unregulated, inducible isoform of nitric oxide synthase. In smooth muscle cells, inhibition of NO. synthesis by NAA is reversed by excess L-arginine. Consistent with the induction of unregulated NO. synthesis in vascular smooth muscle in vivo, administration of IL-1 (50 micrograms/kg) to dogs caused a 33.5% decrease in systemic vascular resistance and a 28% decrease in blood pressure within 3 hours. Subsequent administration of NAA (20 mg/kg) rapidly and completely reversed the hypotension and increased systemic vascular resistance; these effects of NAA were reversed by L-arginine. Neither the immunoproliferative nor the tumoricidal activity of IL-1 was diminished by NAA. CONCLUSIONS: Our results indicate that (a) vascular smooth muscle is a likely source as well as a target of IL-1-induced NO. synthesis, causing vasodilatation and hypotension, (b) nitric oxide synthase inhibitors can fully reverse this hypotension, and (c) the therapeutically useful properties of IL-1 are not diminished by nitric oxide synthase inhibitors. IMPLICATIONS: Administration of inhibitors of nitric oxide synthase can reverse the pathological cardiovascular effects of IL-1 at concentrations that do not interfere with the potentially useful immunoproliferative or tumoricidal effects of this cytokine. In the context of the current clinical trials of IL-1, this finding would represent a very significant advantage.

Amino Acid Oxidoreductases↗
PubMed1992

Synthetic recombinant vaccine expressing influenza haemagglutinin epitope in Salmonella flagellin leads to partial protection in mice.

The influenza virus haemagglutinin epitope 91-108, which is a conserved amino acid sequence in all type A H3 strains, was expressed in Salmonella flagellin, to evaluate its potential as a vaccine. For that purpose, a synthetic oligonucleotide comprising 54 bases coding for the corresponding sequence was inserted into the plasmid pLS408 and transformed into Escherichia coli JM101. Colonies containing the recombinant plasmid were used to transform Salmonella typhimurium LB5000 and were then transduced to a flagellin negative 'live vaccine' aroA mutant of Salmonella dublin. Rabbits immunized either with the live recombinant S. dublin or with the flagellin isolated from it, showed significant levels of IgG response against the synthetic peptide 91-108 as well as against the intact A/Texas/77 influenza virus. Mice immunized with the same preparations developed influenza-specific IgG antibodies in the blood and secreted IgA antibodies in their lungs. Furthermore, these mice showed about 50% protection against challenge infection with the virus. The most successful results were achieved by intranasal immunization with the isolated recombinant flagellin, when employed without the aid of adjuvant.

Amino Acid Sequence↗
PubMed1992

Peptide binding to class I molecules of the major histocompatibility complex on the surface of living target cells.

Molecules encoded by the class I major histocompatibility genes bind short (nonameric) peptides produced by intracellular proteolysis of antigens. These complexes formed intracellularly are then expressed on membranes of target cells and recognized by the antigen receptor of cytolytic T cells. No binding of externally added peptides could so far be monitored directly on the antigen presenting cells, although cytotoxicity experiments and indirect binding assays provided evidence for its existence. Here we report experiments where specific binding to class I molecules, of externally added peptides, has been monitored on living cells. N-terminal biotin-labelled Kd-restricted peptides (residues 147-155, residues 147-158, and an analogue lacking the arginine at position 156, derived from the sequence of the influenza A virus nucleoprotein) were incubated with murine H-2Kd mastocytoma cells (line P815) at 4 degrees C. The binding on surface of live, intact cells was then demonstrated fluorometrically via the interaction of a streptavidin-phycoerythrin conjugate with the biotin-labelled peptides. Thus, this binding does not involve processing, and its specificity in terms of peptide structure was established by competition with the respective unmodified peptides. The specificity of binding to class I molecules was demonstrated by blocking experiments using monoclonal antibodies specific for H-2Kd. Finally, a correlation was observed between the results of peptide binding measurements and those of cytotoxicity assays.

Amino Acid Sequence↗
PubMed1992

Episodic cluster headache. I: Personality and some neuropsychological characteristics in male patients.

The etiology and pathogenesis of cluster headache remain largely unknown. Some previous studies have focused on personality characteristics in cluster headache. However, no consistent personality profile has been found. The present study applied two personality inventories, the Karolinska Scales of Personality (KSP) and the Heart and Lifestyle Type A Measure (HALTAM), that have not previously been used in the context of cluster headache. A correlation has been suggested between left-handedness and early learning difficulties, and cluster headache. Thus, these variables were included and measured by inventory techniques. Forty-nine out of 51 consecutive male patients with episodic cluster headache participated in the present study. As compared to controls, the cluster headache patients were significantly more anxiety-prone (higher scores in the KSP Somatic anxiety and Muscular tension subscales), less successfully socialized (low scores in the KSP Socialization scale), and had a more hostile attitude towards others (higher scores in the HALTAM Hostility scale). No relationships between left-handedness or early learning difficulties, and cluster headache disease were found. The implications of the personality differences for the etiology of cluster headache disease are discussed.

Adult↗
PubMed1992

Episodic cluster headache. II: High tobacco and alcohol consumption in males.

Forty-nine out of 51 consecutive male patients with episodic cluster headache were studied with regard to their smoking and drinking habits in general and in relation to cluster headache periods. Questionnaires were constructed for data regarding tobacco intake. Situation-related smoking behavior was registered according to Frith (1971). Screening for alcohol over-consumption was made using the Malmö modification of the brief Michigan Alcoholism Screening Test (Mm-MAST). Eighty-three percent of the patients used tobacco on a regular basis at the time of the study, with an average consumption of 20 cigarettes per day. Only 3% had never used tobacco regularly. The smoking-related desire to smoke in different situations was consistent with what is found in a general population of smokers. Sixty-seven percent of the patients had scores on the Mm-MAST indicative of alcohol over-consumption (i.e. heavy social drinking or alcoholism). During active headache periods 79% decreased their alcohol intake, whereas no consistent change in tobacco consumption was reported for the group as a whole. These findings were further corroborated by the fact that alcohol, but not tobacco intake, was reported by the majority of patients to elicit headache attacks during periods. Thus, our study showed high alcohol and tobacco consumption to be prominent features in male patients with episodic cluster headache. Since neither alcohol nor tobacco appear to have properties of ameliorating headache periods or attacks, the addictive behavior in our patients more likely reflects certain personality characteristics.

Adolescent↗
PubMed1992

NG-methyl-L-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis, stimulates renal sympathetic nerve activity in vivo. A role for nitric oxide in the central regulation of sympathetic tone?

Continuous production of endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. NO is also formed in the brain upon activation of glutamate receptors, which are thought to mediate central autonomic reflexes. In the present study we assessed whether NO plays a role in central autonomic regulation. For this, we have investigated the effects of NG-methyl-L-arginine (NMA), a selective inhibitor of NO synthesis from L-arginine, on sympathetic renal nerve activity (RNA), blood pressure, and heart rate in the anesthetized rat. NMA elicited a dose-dependent sustained increase in blood pressure (approximately 20 and 30 mm Hg, 5 minutes after 10 and 50 mumol/kg i.v., respectively). Heart rate and RNA decreased transiently (15 beats per minute and 40%, respectively); RNA subsequently increased (100%) while blood pressure remained elevated. Baroreceptor deafferentation markedly altered these responses to NMA; the transient decreases in heart rate and RNA were abolished, whereas the increases in RNA and blood pressure were significantly potentiated. After spinal C-1-C-2 transection, there was no increase in RNA, and blood pressure increased to a smaller extent. L-Arginine blocked the NMA-induced increases in blood pressure and RNA. Thus, in addition to modulating vascular resistance by a peripheral action, NO may also play a role in the central regulation of sympathetic tone.

Animals↗
PubMed1992

Nitric oxide is a mediator of hypoxic coronary vasodilatation. Relation to adenosine and cyclooxygenase-derived metabolites.

Hypoxia is a potent coronary-vasodilating signal; its mechanisms are still controversial. We have assessed the possible role of nitric oxide (NO) in hypoxic coronary vasodilatation (HCVD) in isolated guinea pig hearts perfused at constant pressure. HCVD was elicited by a 1-minute 100% N2 exposure; coronary flow doubled within 1 minute of hypoxia (early phase) and returned to baseline within 40 seconds after reoxygenation (late phase). The early phase of HCVD was associated with a rapid approximately eightfold increase in cGMP overflow, an indication of NO release. The specific NO synthase inhibitor N omega-methyl-L-arginine (NMA, 0.1-1 mM) antagonized HCVD and the associated increase in cGMP spillover (maximum inhibition, approximately 65%); excess arginine (1.2 mM) prevented both effects. The late phase of HCVD was associated with an increase in adenosine overflow and was attenuated by the adenosine receptor antagonist BW A1433 (1 microM; maximum inhibition, approximately 45%). Indomethacin (10 microM) inhibited HCVD in spontaneously beating hearts by approximately 35% but had no effect in hearts paced at faster rates. NMA and BW A1433 were more effective in combination than alone (maximum inhibition, approximately 72%). However, irrespective of the concentrations used, there was no synergism among the anti-HCVD effects of NMA, BW A1433, and indomethacin, nor was HCVD completely inhibited by the antagonists, whether alone or in combination. Our findings indicate that NO is an important mediator of the early phase of HCVD, whereas additional mechanisms and/or factors, including adenosine and vasodilatatory prostaglandins, contribute to the late phase.

Adenosine↗