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PubMed1999

Effects of cytokines on nitric oxide pathways in human vasculature.

Proinflammatory cytokines exert a number of important effects on vascular reactivity. At one end of the spectrum, certain cytokines may induce vascular paresis leading to profound vasodilatation and hyporesponsiveness to constrictor stimuli. This may be relevant to the pathogenesis of septic shock and other types of inflammatory vasodilatation. At the other end of the spectrum, inflammatory cytokines can impair endothelium-dependent dilatation and the endothelium may lose its ability to respond to circulating hormones or autacoids. This effect may case a predisposition to vessel spasm, thrombosis or atherogenesis. Studies in human vessels suggest that interleukin-1 is particularly important as a mediator of inflammatory dilatation; the underlying mechanisms include induction of the inducible isoform of nitric oxide synthase in vascular smooth muscle, or over-production of nitric oxide from the endothelial isoform of nitric oxide synthase. Induction of the enzyme GTP cyclohydrolase 1 and consequent production of tetrahydrobiopterin contributes to the increase in the activity of endothelial nitric oxide synthase. In contrast, tumour necrosis factor-alpha considerably impairs endothelium-dependent relaxation. The mechanisms of these effects are not yet fully understood, but tumour necrosis factor can induce endothelial dysfunction in human endothelial cells in culture, and human blood vessels in vitro and in vivo. The implications of these observations for cardiovascular disease are discussed.

Animals↗
PubMed1999

Hepatorenal syndrome and its treatment today.

The pathogenesis of ascites, a severe and the most frequent complication during cirrhosis, is still not completely understood, but present evidence indicates that portal hypertension principally triggers renal sodium and water retention. Ascites is associated with profound disturbances of splanchnic and systemic haemodynamics, which in turn may influence renal function. Within the kidney the balance between vasoconstricting and vasodilating factors is critical for the maintenance of renal function. As the disease progresses, vasoconstricting factors (mainly angiotensin II, catecholamines, thromboxane, leucotrienes and endothelins) prevail, probably due to the exhaustion of the vasodilating renal autacoid system (mainly prostaglandins). In this setting, vasoconstriction of the intrarenal vascular system induces marked and often irreversible sodium and water retention, leading to refractory ascites, a progressive rise in plasma creatinine levels and reduction of renal clearances (hepatorenal syndrome, HRS). This persistent renal hypoxia may also favour the occurrence of tubular damage due to several causes. A careful therapeutic approach is first based on sequential diuretic treatment (and the addition of adequate plasma expansion with human albumin for patients with diuretic resistant ascites), which may lead to control of ascites for years. However, when HRS occurs, all the proposed treatments (such as paracentesis, administration of renal vasodilators, systemic vasoconstrictors, calcium channel antagonists, TIPS, surgical portosystemic shunts) have been shown to moderately or temporarily improve renal function only, leaving liver transplantation as the only choice of treatment for patients.

Angiotensin II↗
PubMed1996

Forskolin Stimulates Aggrecan Gene Expression in Cultured Bovine Chondrocytes.

Prostaglandins are autacoids that elevate intracellular 3prime prime or minute:5prime prime or minute-cyclic adenosine monophosphate (cAMP) levels in chondrocytes and other cells in culture. To facilitate intracellular cAMP accumulation, bovine chondrocytes were incubated with forskolin alone or forskolin and isobutylmethylxanthine. Both significantly increased proteoglycan synthesis, which was inhibited by the cAMP-dependent protein kinase inhibitor H89. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE) on 3--16% gels revealed the presence of two large proteoglycan core proteins which migrated more slowly than the 200-kDa marker protein and two small proteoglycan core proteins which migrated slightly slower than the 46-kDa marker. Northern blot hybridization, employing (32)P-labeled cDNA probes, showed that aggrecan steady-state mRNA levels were increased by forskolin and isobutylmethylxanthine after 1 h and 5 h incubation. Decorin and type II collagen mRNA levels were not altered under these conditions. Link protein mRNA levels were slightly elevated, but only at the 5-h time point. These results indicated that stimulation of intracellular cAMP accumulation by forskolin or forskolin and isobutylmethylxanthine resulted in augmented proteoglycan synthesis via increased steady-state aggrecan mRNA levels. Suppression of proteoglycan synthesis by the cAMP-dependent protein kinase inhibitor H89 suggested that cAMP-dependent protein kinase may also play a role in regulating the synthesis and completion of newly synthesized proteoglycans.

Journal Article↗
PubMed2006

Effect of salt intake on progression of chronic kidney disease.

PURPOSE OF REVIEW: The attempt of this review is to bring into focus the potential role of dietary salt intake in progression of chronic kidney disease. RECENT FINDINGS: Ongoing work has elucidated a role for dietary salt intake in modulating intrarenal production of transforming growth factor-beta1. The mechanism is independent of angiotensin II and systemic blood pressure and involves activation of vascular endothelium by dietary salt intake with release of this growth factor. In this model, transforming growth factor-beta1 serves an autacoid function by stimulating nitric oxide production by the endothelium. In turn, endothelium-derived nitric oxide modulates production of this growth factor. The model further predicts that individuals who have lost the requisite endothelial cell flexibility to adapt to this environmental stress (a high salt diet) are potentially at increased risk of developing end-organ damage from excess salt intake. Animal and human studies are presented to support this working hypothesis. SUMMARY: Overproduction of transforming growth factor-beta1 permits excess biological activity of this important fibrogenic growth factor with subsequent development or acceleration of vascular and kidney damage. In patients with diseases whose pathogenesis is related to excess production of transforming growth factor-beta1, such as chronic allograft nephropathy and diabetic nephropathy, increased salt intake may hasten loss of function, particularly if nitric oxide production does not increase. The role that endothelial cell plasticity plays in altering vascular tone and renal function, especially in response to changes in dietary salt intake, should be examined further in chronic kidney disease.

Animals↗
PubMed2006

Hormonal and cytokine effects of uric acid.

PURPOSE OF REVIEW: Current evidence supports the role of soluble uric acid as a true mediator of injury, exerting its effects through the induction of growth factors, cytokines, hormones and autacoids. In the present review, we summarize recent studies on the mechanisms involved in the uric acid deleterious effects. RECENT FINDINGS: Although uric acid is considered an antioxidant in plasma, recent clinical and epidemiological studies have found that hyperuricemia is associated with mortality and development of hypertension, cardiovascular and chronic renal diseases. Experimental studies suggest that uric acid induce its detrimental effects at the cellular level entering to vascular smooth muscle cells (VSMC) via an organic anion transport system, and followed by the activation of specific MAP kinases, nuclear transcription factors, with stimulation of COX-2, PDGF A and C chain, PDGF alpha receptor, and various inflammatory mediators, including C-reactive protein and monocyte chemoattractant protein-1. Physiologically, these effects translate into a rise of arterial pressure, VSMC hypertrophy, tubulointerstitial infiltration and glomerular hypertension in the setting of renal vasoconstriction. Uric acid also promotes endothelial dysfunction through inactivation of NO and arresting the proliferation of endothelial cells. Thus, arteriosclerosis induced by hyperuricemia may be a novel mechanism for the development of essential hypertension. SUMMARY: Soluble uric acid has important biologic roles. While it acts as an antioxidant, there is also evidence that uric acid has pro-inflammatory and proliferative effects on VSMC, and causes dysfunction of endothelial cells. These cellular mechanisms may translate into why uric acid is associated with renal and cardiovascular disease.

Antioxidants↗
PubMed2007

Adenosine A1 receptor expression during the transition from compensated pressure overload hypertrophy to heart failure.

OBJECTIVES: Myocardial adenosine is increased in pressure-overload hypertrophy (POH) and exerts important cardioprotective effects that delay transition to left ventricular failure. Adenosine-mediated signaling is attenuated in POH, but whether this depends on receptor or postreceptor defects is unknown. We therefore examined left ventricular adenosine A1-receptor gene and protein expression in experimental POH. METHODS: Six week-old Sprague-Dawley rats were subjected to abdominal aortic banding (group B) or sham operation (group S). Echocardiography and left ventricular catheterization were performed 10 weeks later under ketamine anesthesia. Left ventricular and lung weight indices were obtained postmortem. A1-Receptor mRNA and protein expression were measured in samples from left ventricular, right ventricular and aortic arch tissue. Group B rats were subgrouped as having compensated or decompensated hypertrophy according to the absence or presence of lung congestion (lung weight index below or above mean +/- 2SD compared with group S rats). RESULTS: Both mRNA and protein A1-receptor expression were significantly increased in compensated group B versus group S rats (by, respectively, 37 and 77%; both P < 0.01). This was not observed in decompensated group B rats. No consistent gene or receptor expression changes were observed in right ventricular or aortic tissues. CONCLUSIONS: In compensated POH, increased interstitial adenosine concentrations are accompanied by increased expression of the specific receptor mediating the major cardioprotective effects of this autacoid. Such overexpression is no longer detectable once the transition from POH to left ventricular failure has occurred. These observations may have pathophysiological and, in perspective, therapeutic relevance to the course of hypertensive heart disease.

Animals↗
PubMed2007

The role of the renal kallikrein-kinin system in diabetic nephropathy.

PURPOSE OF REVIEW: Diabetic nephropathy is one of the most common complications in diabetes mellitus. Multiple pathogenic mechanisms are now believed to contribute to this disease, including inflammatory cytokines, autacoids and oxidative stress. Numerous studies have shown that the kallikrein-kinin system may be involved in these mechanisms. This review focuses on recent research advance on the potential role of the kallikrein-kinin system in the development of diabetic nephropathy, and its clinical relevance. RECENT FINDINGS: A collection of recent studies has shown that angiotensin-converting enzyme inhibitors, which inhibit angiotensin II formation and degradation of bradykinin, and vasopeptidase inhibitors attenuated the development of diabetic nephropathy in experimental animals and clinical settings. The role of the kallikrein-kinin system in diabetes is further supported by findings that diabetic nephropathy is worsened in diabetic mice lacking bradykinin B2 receptors. Although long-acting bradykinin B2 receptor agonists have been shown to have renal protective effects, their therapeutic benefits have not been well studied. SUMMARY: Current experimental investigations demonstrated that pharmacological intervention of the kallikrein-kinin system improved renal conditions in diabetes mellitus. These findings suggest that the kallikrein-kinin system may be a therapeutic target in preventing and treating diabetic nephropathy.

Animals↗
PubMed1995

Enhancement of delayed hypersensitivity inflammatory reactions in guinea pig skin by 12(R)-hydroxy-5,8,14-eicosatrienoic acid.

Delayed-type hypersensitivity (DTH) reactions are initiated by sensitized T cells. Their progression is dependent upon the local release of various autacoids, including cytokines and eicosanoids, by T cells, infiltrating inflammatory cells, and resident tissue cells. 12(R)-hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE], an eicosanoid produced by skin and cornea, possesses potent proinflammatory properties at picomolar concentrations including vasodilation, increase in membrane permeability, neutrophil chemotaxis, and angiogenesis. Because DTH reactions are associated with many of these same phenomena, we examined the effect of 12(R)-HETrE and related 12-hydroxyeicosanoids on the expression of DTH to purified protein derivative of tuberculin in sensitized guinea pigs. In the absence of purified protein derivative of tuberculin, none of the eicosanoids evoked erythema or edema after intradermal injection at doses up to 100 pmol. When injected together with purified protein derivative of tuberculin, 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid [12(R)-HETE], but not its enantiomer 12(S)-HETE, significantly inhibited macroscopic expression of delayed reactivity (erythema) only at the highest dose tested, 10 pmol. In contrast, 12(R)-HETrE significantly enhanced expression of DTH at doses between 1 fmol and 1 pmol (50% and 30% increases above control, respectively). Its stereoisomer, 12(S)-HETrE, did not enhance DTH at any tested dose, but was able to block the activity of 12(R)-HETrE when injected simultaneously. Enhancement or inhibition of visible skin responses was not associated with qualitative or quantitative changes in cellular infiltrates at the reaction site. 12(R)-HETrE had no effect on the nonimmunologic inflammatory skin reaction induced by phorbol myristate acetate, suggesting selectivity toward DTH. We conclude that 12(R)-HETrE enhances DTH via a yet to be determined mechanism and that its stereoisomer, 12(S)-HETrE, may be a useful antagonist for studying the inflammatory actions of this eicosanoid.

8,11,14-Eicosatrienoic Acid↗
PubMed1984

Preliminary pharmacological characterization of ovine mesenteric vasculature.

Spirally cut strips of ovine mesenteric vein and artery were studied in isolated organ baths. No qualitative differences were observed in the autonomic and autacoid reactivity of these blood vessels. Both arterial and venous preparations responded in a dose-related manner to 5HT greater than or equal to adrenaline greater than phenylephrine greater than histamine. The responses of venous and arterial strips to 5HT were antagonized by methysergide while mepyramine inhibited histamine-induced contractions. Phentolamine competitively inhibited adrenaline on arteries. Vascular preparations, incubated with mepyramine (2 X 10(-7) M) and contracted half-maximally with 5HT, responded with relaxations to the higher doses of histamine. Specific H2-agonists, impromidine and dimaprit also caused relaxations of half-maximally contracted venous and arterial strips. Impromidine was approximately 500-5000 times more potent than histamine and dimaprit. Trimetaquinol effectively relaxed both venous and arterial preparations while isoproterenol had either no effect or produced weak contractions/relaxations. This investigation suggested the presence of (i) both excitatory and inhibitory receptors for histamine, (ii) D-tryptaminergic receptors mediating contractile effects of 5HT, and (iii) a predominance of alpha-adrenergic receptors, in the mesenteric vasculature of sheep.

Animals↗
PubMed1987

Antiallergic activity of loratadine, a non-sedating antihistamine.

Loratadine is a new non-sedating antihistamine. The present studies compared loratadine and terfenadine, another non-sedating antihistamine, for their ability to inhibit the bronchial response to histamine and other autacoids which have been implicated as contributing to the symptoms of an allergic reaction. In addition, the two antihistamines were evaluated in models of immunologically mediated allergic reactions. Loratadine is a more potent inhibitor of histamine-induced bronchospasm in guinea pigs than is terfenadine. Both antihistamines exhibit marked antiserotonin activity at doses 10 times their antihistamine ED50 values. In contrast, loratadine and terfenadine produce little or no inhibition of the bronchial responses to methacholine, leukotriene C4 or platelet-activating factor. An allergic bronchospasm in guinea pigs is inhibited by loratadine (ED50 = 0.40 mg/kg, p.o.) and terfenadine (ED50 = 1.7 mg/kg, p.o.). The bronchospasm associated with allergic anaphylaxis in rats is significantly inhibited by 10 mg/kg, p.o. loratadine and 30 mg/kg, p.o. terfenadine. Loratadine exhibits antiallergy activity in vitro. At micromolar concentrations, loratadine inhibits the release of histamine from Con A and A23187-stimulated rat peritoneal mast cells and the release of histamine and leukotriene C4 from a Con A-stimulated cloned murine mast cell line.

Animals↗
PubMed1987

Prostaglandin E1 binds to Z protein of rat liver.

Z protein or fatty-acid-binding protein is abundant in the cytosol of many cell types including liver cells. It is considered to play an important role in intracellular transport and metabolism of long-chain fatty acids and other organic anions. We studied the role of Z protein in the metabolism of prostaglandin E1 (PGE1). Binding of tritiated prostaglandin E1 to this fatty-acid-binding protein (Z protein) purified from rat liver was determined. The binding of [3H]prostaglandin E1 to Z protein is rapid, saturable and reversible. Scatchard analysis of [3H]PGE1 binding to Z protein showed a single class of binding sites with a dissociation constant (Kd) of 37 nM. The binding capacity is 110 nmol/mg Z protein. Optimal [3H]PGE1 binding occurred at pH 7.4. The presence of 3 mM MgCl2 stimulated the prostaglandin E1 binding to Z protein. Competition experiments show that the binding of this autacoid to Z protein is highly specific. It could not be displaced by other prostaglandins (PGA1, PGA2, PGE2, PGB1, PGI2, PGD2, PGF2 alpha, and 6-keto PGF1 alpha). Z protein might be involved in the metabolism of prostaglandins in the cytosol.

Alprostadil↗
PubMed1992

The evolution of hypertensive therapy.

1. During the past 30 years many antihypertensive agents, acting at differing levels on the mechanisms controlling arterial blood pressure, have been introduced. 2. Whereas the usefulness of early drugs was limited by side effects, the discovery of successive classes of agents has resulted in the gradual introduction of drugs causing fewer adverse effects with consequent improvements in patient compliance. 3. The recent appearance of angiotensin II antagonists and potassium channel openers, together with increased knowledge of the roles played by atrial natriuretic factor and endothelial cell-derived autacoids in control of vascular tone, hold prospects for still further improvements in therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

The physiology of pre-eclampsia.

1. Pre-eclampsia is a multisystem disorder of human pregnancy with a genetic predisposition. It occurs more commonly in first pregnancies and primarily affects maternal renal, cerebral, hepatic and clotting functions while elevating blood pressure. The foetus is affected through placental insufficiency arising from abnormal 'placentation', that is, failure to adequate trophoblast invasion of maternal vasculature, and possible from abnormal autacoid production. 2. Pre-eclampsia is caused by the placenta; delivery of the placenta is the only known cure. Its manifestations are considered secondary to organ hypoperfusion which arises as a result of vasoconstriction, intravascular coagulation and reduced maternal blood volume. 3. Current hypotheses propose that pre-eclampsia is due to widespread maternal endothelial cell damage, perhaps secondary to a cytotoxic factor released by the placenta. This hypothesis has gained wide acceptance, but scientific evidence is lacking. 4. Defining the abnormal balance of vasoactive factors in pre-eclampsia has proved a difficult task. There is enhanced pressor activity to infused angiotensin II (AII) despite reduced plasma concentrations of AII, renin and aldosterone. Prostacyclin production appears reduced, and the balance of thromboxane/prostacyclin favours vasoconstriction and platelet aggregation. There is no convincing evidence for enhanced endothelin or reduced nitric oxide production. Plasma concentrations of atrial natriuretic peptide are paradoxically elevated in the face of plasma volume contraction. An intriguing observation, which remains unexplained, is why some vascular beds are affected predominantly in one patient (eg. hepatic ischaemia) while another has a similar degree of hypertension but involvement of a different organ system (eg. renal insufficiency yet normal liver function). 5. Volume homeostasis is disturbed with redistribution of intravascular volume to the interstitial fluid space due to increased capillary permeability and in some cases reduced plasma oncotic pressure. This redistribution is not always clinically apparent as peripheral oedema. Whether this change in volume is compensated for by venoconstriction and maintenance of adequate cardiac output is undetermined. 6. Improved understanding of the pathophysiology of pre-eclampsia is necessary to allow better clinical management of this serious disorder.

Biological Factors↗
PubMed1997

Contractile properties of afferent and efferent arterioles.

1. The balance of vascular tone of the afferent and efferent arteriole is a crucial determinant of glomerular haemodynamics. Despite their intimate anatomical relationship in the juxtaglomerular apparatus, the mechanisms that regulate afferent and efferent arteriolar tone are different. 2. In the afferent arteriole, two intrinsic mechanisms, the myogenic response and macula densa-mediated tubuloglomerular feedback (TGF) play a dominant role, maintaining the glomerular filtration rate (GFR) at a constant level over a wide range of renal perfusion pressure. Studies have shown that these two mechanisms are modulated by nitric oxide (NO). In addition, an interaction between TGF and angiotensin II (AngII) seems to be essential to maintaining GFR despite large variations in daily intake of salt and water. 3. In the efferent arteriole, neither myogenic response nor TGF seems to be important, while AngII is one major factor involved in the control of vascular resistance. In addition, recent studies have provided evidence that NO and prostaglandins produced by the glomerulus may control resistance of the downstream efferent arteriole. 4. As the early segment of the efferent arteriole resides within the glomerulus, various autacoid hormones produced by the glomerulus may reach and directly act on this segment, thereby controlling the glomerular capillary pressure. Thus, it would be important to understand the differences in the mechanisms operating at the afferent and efferent arteriole, as well as their alterations in various physiological and pathological conditions.

Angiotensin II↗
PubMed1998

Nitric oxide in atherosclerosis: vascular protector or villain?

1. Nitric oxide (NO) has important roles in physiological vasodilatation, cytotoxicity and vascular disease. Nitric oxide and prostacyclin (PGI2), both released from the endothelium, act synergistically to inhibit platelet aggregation and adhesion. These autacoids also inhibit the adhesion and migration of leucocytes and, in some arteries, they synergize in terms of vasodilation. 2. The development of atherosclerosis and hyperlipaemia per se is accompanied by impairment of endothelium-dependent vasodilation. 3. Atherosclerosis is associated with marked changes in the activity of isoforms of NO synthase (NOS) in the artery wall, including increased expression of the NOS2 (inducible) isoform in complex human lesions as well as in the neointima of experimental animal models. 4. Failure of NO release from the endothelium with normal physiological stimuli, which has been attributed to a defect in the operation of the endothelial NOS (NOS3), provides conditions propitious for leucocyte adhesion, vasospasm, thrombosis and, in addition, may promote increased proliferation of intimal cells. 5. Nitric oxide and superoxide anions generated by inflammatory cells in atherosclerosis react to form cytodestructive peroxynitrite radicals, potentially causing injury to the endothelium and myocytes, and this may be a factor in apoptosis of cells leading to plaque rupture. 6. We have been able to reverse these NO defects with therapeutic agents, including angiotensin-converting enzyme inhibitors, antagonists of platelet-activating factor and NO donor compounds, all offering promise in protecting against some manifestations of vascular disease.

Animals↗
PubMed2003

Role of angiotensin AT1 and AT2 receptors in cardiac hypertrophy and cardiac remodelling.

1. Left ventricular hypertrophy (LVH) is an independent cardiovascular risk factor. Angiotensin AT1 receptor antagonism has been considered as a specific approach to block the renin-angiotensin system and been demonstrated to be able to prevent or regress LVH by interfering with the remodelling process of the heart. 2. Angiotensin AT1 receptor blockade induces a marked increase in angiotensin (Ang) II, which may stimulate the AT2 receptors. Gene expression of AT1 and AT2 receptors increases in a time-dependent manner in cardiac remodelling following myocardial infarction. 3. Considerable efforts have been made to clarify the role of AT2 receptors in cardiac hypertrophy and remodelling since the mid-1990s, resulting in controversial reports: the AT2 receptor mediates actions either opposite to or in coordination with those of the AT1 receptor. Moreover, there are many reports of no significant effects mediated by AT2 receptors. 4. Based on the studies reviewed in the present article, we assume that the predominant effect of AngII in cardiac hypertrophy and cardiac remodelling is growth promoting and that this effect is mediated mainly via AT1 receptors. The AT2 receptors may affect the hypertrophic process by interacting with other cardiac membrane proteins, enzymes and autacoids. Before coming to a conclusion as to whether AT2 receptor stimulation or antagonism is beneficial to the heart, more studies should be performed in different LVH models, especially long-term treatment protocols in vivo.

Angiotensin II↗
PubMed1971

Cardiovascular effects of morphine, pethidine, diamorphine and nalorphine on the cat and rabbit.

1. The predominant effect of morphine, diamorphine, pethidine or nalorphine on the blood pressure of the anaesthetized cat or rabbit is hypotension although, occasionally, a pressor action may predominate or intervene.2. Possible mechanisms of the depressor phases of action have been studied on cardiac and vascular preparations both in situ and in vitro.3. While in the whole animal, catecholamine release from the adrenal medulla and histamine liberation may be implicated in the responses, the vasodilator and vascular relaxant actions of morphine and, probably, pethidine, nalorphine and diamorphine on the isolated preparations are not mediated by the liberation of known peripheral transmitters or autacoids or by interaction with their specific receptors.

Acetylcholine↗
PubMed1978

Responses of the simultaneously-perfused hepatic arterial and portal venous vascular beds of the dog to histamine and 5-hydroxytryptamine.

1 The sympathetically-innervated hepatic arterial and portal venous vascular beds of the dog were perfused simultaneously in situ. 2 Histamine and 5-hydroxytryptamine (5-HT) were injected intra-arterially and intraportally in graded, increasing doses. 3 Intra-arterial histamine evoked decreases in hepatic arterial vascular resistance (HAVR) and increases in hepatic portal vascular resistance (HPVR). 4 Intraportal injections of histamine caused increases in HPVR and decreases in HAVR. 5 The time courses of the arterial responses to intraportal histamine and of the portal responses to intra-arterial histamine, compared with any systemic effects, showed that these effects on the liver vasculature could not be the result of recirculation of histamine. 6 Intra-arterial 5-HT evoked biphasic changes in HAVR and small falls in HPVR. Intraportal 5-HT caused falls in HPVR at low doses and rises at high doses, together, typically, with biphasic effects on HAVR. 7 It is unlikely that the arterial effects of intraportal 5-HT and the portal effects of intra-arterial 5-HT were due to recirculation of the vasoactive material. 8 Pathophysiologically, both histamine and 5-HT are released from the gastrointestinal tract into the portal vein. These experiments show that such release may affect the hepatic arterial vascular resistance (and therefore blood flow) even though vasoactive levels of the autacoids are not attained in the systemic circulation.

Animals↗