Purinergic receptors in the splanchnic circulation

There is considerable evidence that purines are vasoactive molecules involved in the regulation of blood flow. Adenosine is a well known vasodilator that also acts as a modulator of the response to other vasoactive substances. Adenosine exerts its effects by interacting with adenosine receptors. These are metabotropic G-protein coupled receptors and include four subtypes, A(1), A(2A), A(2B) and A(3). Adenosine triphosphate (ATP) is a co-transmitter in vascular neuroeffector junctions and is known to activate two distinct types of P2 receptors, P2X (ionotropic) and P2Y (metabotropic). ATP can exert either vasoconstrictive or vasorelaxant effects, depending on the P2 receptor subtype involved. Splanchnic vascular beds are of particular interest, as they receive a large fraction of the cardiac output. This review focus on purinergic receptors role in the splanchnic vasomotor control. Here, we give an overview on the distribution and diversity of effects of purinergic receptors in splanchnic vessels. Pre- and post-junctional receptormediated responses are summarized. Attention is also given to the interactions between purinergic receptors and other receptors in the splanchnic circulation.     

Prostaglandins in the circulation of the fetal lamb

Prostaglandin E and PGF have been measured in the plasma of chronically catheterized fetal lambs throughout the last 20–35 days (0.73 onwards) of gestation. The mean concentration of PGE was higher than that of PGF. There was a significant increase in the concentration of PGE but little change in the concentration of PGF in samples of fetal plasma taken within 24 h of parturition. In contrast, at this time in maternal utero-ovarian venous plasma, there was a large increase in PGF, but relatively little change in PGE. There was a significant decrease in the concentration of PGE and PGF in the plasma of lambs within 12 h after birth compared to the levels found in the same animals as fetuses a few hours previously. The physiological importance of these changes is discussed.     

Prostaglandins in the human fetal circulation in mid-trimester and term pregnancy

Concentrations of prostaglandins in fetal and maternal plasma during mid-pregnancy and fetal plasma at term have been measured. Fetal levels at both gestations were higher than found in maternal blood. The stable chemical breakdown product of prostacyclin, 6-keto-prostaglandin F_1∝, was consistently considerably higher in the fetus during mid-pregnancy compared with at term. Prostaglandin F levels were also significantly higher in mid-pregnancy, though there was no difference in the concentrations of the major circulating prostaglandin F metabolite, PGFM. Concentrations of prostaglandin E were similar at the two stages of pregnancy. The physiological significance of these findings is discussed.     

A lumped parameter mathematical model of the splanchnic circulation.

A lumped parameter mathematical model to describe the propulsion of blood in the splanchnic circulation was developed by integrating the principles of mechanics and physiology. A set of governing equations by derived by specifically considering the contractility of the portal vein, hepatic vein, liver sinusoids, and of the draining lymphatics. These equations were then simulated on a computer. The present simulation results substantiate previous experimental observations that hepatic venous pressure leads to portal hypertension and increased liver interstitial fluid volume.     

Heat acclimation alters nitric oxide response in the splanchnic circulation

The role of nitric oxide (NO) mediated vasorelaxation in splanchnic blood flow during heat stress was studied in rats before and after heat acclimation (1 month, at 34°C). Superior mesenteric artery and portal vein blood flows were measured on-line in the conscious rats during heat stress at 40°C and 42°C before and after LNNA administration. NO mediated vasorelaxation in these vessels was studies in vitro, in response to pilocarpine, Ca ionophore and Na nitroprusside stimulation. The data suggest that NO is an integral part of the thermoregulatory splanchnic vasomotor response, and that heat acclimation enhances its regulatory importance.     

Effect of acidification of the duodenal contents on splanchnic circulation and metabolism

Portal vein (PF) and superior mesenteric artery blood flows (SMAF), arterial and portal venous oxygen concentrations were measured in dogs before and after duodenal introduction of 3 ml/kg 0.1 mol HCl. The duodenal acidification increased PF by 30% and SMAF by 35%. The change of mesenteric oxygen utilisation, from 0.80 +/- 0.10 to 0.81 ml/kg was not significant. It is concluded that the circulatory changes after acidification of the duodenal contents are not secondary to a metabolic effect.     

Effects of angiotensin blockade on the splanchnic circulation in normotensive humans

The effects of angiotensin-converting enzyme inhibition (ACE-I) by enalapril on splanchnic (n = 10) and central hemodynamics (n = 9) were examined in moderately salt-depleted healthy volunteers, at rest and during 15-20 min of lower body negative pressure (LBNP), reducing mean arterial pressure by 10 mmHg. During LBNP before ACE-I, both splanchnic and total peripheral vascular resistances increased. During ACE-I, splanchnic and total peripheral vascular resistances decreased. After enalapril administration, splanchnic vascular resistance did not increase during LBNP. Total peripheral vascular resistance still increased but not to the same extent as during LBNP before ACE-I. The increases in heart rate and plasma norepinephrine during LBNP were attenuated after ACE-I compared with LBNP before ACE-I. The effectiveness of the ACE-I was clearly demonstrated by unchanged and low plasma angiotensin II levels during ACE-I. We conclude that, in normal sodium-depleted humans, acute ACE-I decreases splanchnic vascular resistance at rest and abolishes splanchnic vasoconstriction during LBNP. Furthermore, it may interfere with autonomic nervous system control of the circulation.     

Effect of synthetic physalaemin on splanchnic circulation in dogs

Physalaemin has been reported as one of the most potent vasodilator and hypotensive peptides (1-4). In spite of these studies, however, the effect of the peptide on splanchnic circulation is not known precisely. In the present study, the effect of synthetic physalaemin on superior mesenteric arterial blood flow, portal venous blood flow and pancreatic capillary blood flow was investigated in dogs. Dose dependent increases of superior mesenteric arterial blood flow and portal venous blood flow were induced in response to physalaemin (0.1-10.0 ng/kg). Superior mesenteric arterial blood flow and portal venous blood flow attained maximal increases of 77 +/- 8.9% and 70 +/- 8.6%, respectively, at a dose of 5 ng/kg. Physalaemin caused a dose-related decrease in systemic arterial blood pressure. Pancreatic capillary blood flow did not show significant change with the administration of physalaemin. These data suggest that physalaemin may play some physiological roles in the regulation of splanchnic circulation.     

Influence of central command and ergoreceptors on the splanchnic circulation during isometric exercise

The splanchnic circulation can make a major contribution to blood flow changes. However, the role of the splanchnic circulation in the reflex adjustments to the blood pressure increase during isometric exercise is not well documented. The central command and the muscle chemoreflex are the two major mechanisms involved in the blood pressure response to isometric exercise. This study aimed to examine the behaviour of the superior mesenteric artery during isometric handgrip (IHG) at 30% maximal voluntary contraction (MVC). The pulsatility index (PI) of the blood velocity waveform of the superior mesenteric artery was taken as the study parameter. A total of ten healthy subjects [mean age, 21.1 (SEM 0.3) years] performed an IHG at 30% MVC for 90 s. At 5 s prior to the end of the exercise, muscle circulation was arrested for 90 s to study the effect of the muscle chemoreflex (post exercise arterial occlusion, PEAO). The IHG at 30% MVC caused a decrease in superior mesenteric artery PI, from 4.84 (SEM 1.57) at control level to 3.90 (SEM 1.07) (P = 0.015). The PI further decreased to 3.17 (SEM 0.70) (P = 0.01) during PEAO. Our results indicated that ergoreceptors may be involved in the superior mesenteric artery vasodilatation during isometric exercise.     

Role of NPY for vasoregulation in the splanchnic circulation during portal hypertension

Vascular dysfunction in the splanchnic circulation during portal hypertension is characterized by enhanced NO-mediated vasorelaxation and vascular hyporeactivity to norepinephrine that lead to arterial vasodilation. NPY most likely counteracts both of these key features. Firstly, NPY appears to inhibit Ach- and PNS-induced vasorelaxation in mesenteric arteries. This effect is more pronounced in portal hypertensive rats as compared to control, and most likely reflects the inhibition of increased e- and nNOS-derived NO-synthesis during portal hypertensive conditions. Secondly, NPY sensitizes the mesenteric vasculature to alpha(1)-adrenergic vasoconstriction. Most importantly, in portal hypertensive rats but not in sham rats NPY markedly augments vascular contractility and thereby corrects vascular hyporeactivity. Both actions of NPY increase vascular tone and may well act synergistically in the splanchnic circulation during portal hypertension. Moreover, the vasoconstrictive effects of NPY are most pronounced at particularly high levels of alpha(1)-adrenergic activity. Therefore, it appears that NPY becomes increasingly important for optimizing adrenergic vasoconstriction at particularly high adrenergic drive and also for playing a predominant role for vascular homeostasis. Cirrhotic patients present with elevated circulating plasma levels of NPY, which appears to be independent from the severity of liver dysfunction and to correlate with portal pressure. This finding indicates enhanced NPY release during portal hypertension that may represent a compensatory mechanism aimed at counterbalancing arterial vasodilation by restoring the efficacy of endogenous catecholamines and inhibiting vasodilative drive in the splanchnic circulation.     

Effects of synthetic kassinin on splanchnic circulation and exocrine pancreas in dogs

Effects of intravenously administered synthetic kassinin on splanchnic circulation and exocrine pancreatic secretion were examined in six anesthetized dogs. Kassinin caused dose-related increases in the blood flow in superior mesenteric artery and portal vein, and produced an initial increase followed by a decrease in pancreatic blood flow, but did not affect the exocrine pancreatic secretion. This study demonstrates that kassinin affects splanchnic blood flow in dogs, and suggests that kassinin or a kassinin-like substance functions as a neuropeptide controlling the splanchnic circulation in mammalian species.     

Impulse-response function of splanchnic circulation with model-independent constraints: theory and experimental validation

Modeling physiological processes using tracer kinetic methods requires knowledge of the time course of the tracer concentration in blood supplying the organ. For liver studies, however, inaccessibility of the portal vein makes direct measurement of the hepatic dual-input function impossible in humans. We want to develop a method to predict the portal venous time-activity curve from measurements of an arterial time-activity curve. An impulse-response function based on a continuous distribution of washout constants is developed and validated for the gut. Experiments with simultaneous blood sampling in aorta and portal vein were made in 13 anesthetized pigs following inhalation of intravascular [15O]CO or injections of diffusible 3-O-[11C]methylglucose (MG). The parameters of the impulse-response function have a physiological interpretation in terms of the distribution of washout constants and are mathematically equivalent to the mean transit time (T) and standard deviation of transit times. The results include estimates of mean transit times from the aorta to the portal vein in pigs: T = 0.35 +/- 0.05 min for CO and 1.7 +/- 0.1 min for MG. The prediction of the portal venous time-activity curve benefits from constraining the regression fits by parameters estimated independently. This is strong evidence for the physiological relevance of the impulse-response function, which includes asymptotically, and thereby justifies kinetically, a useful and simple power law. Similarity between our parameter estimates in pigs and parameter estimates in normal humans suggests that the proposed model can be adapted for use in humans.     

Prostaglandins and the thyroid

Prostaglandins (PG), PGE in particular, exert an effect similar to the stimulating one of thyroidotropic hormone (TTH), a basic regulator of the thyroid function, on the thyroid gland cells. Specific finding of the above compounds with plasma membranes of the gland cells is the first stage of their action. In most cases formation of the PGE-receptor complexes, is followed by the corresponding increase in the intracellular content of cAMP due to adenylate cyclase activation. PGE can be regarded as original extracellular local regulating agents formed in neighbouring (or the same) cells under the TTH effect and modulating the action of the latter on the regulated gland. In this case the regulating action of the hormone and PGE can be realized through the same mechanisms. Under conditions of the thyroid gland pathology against the background of the thyrotropic control weakening it is impossible to exclude the possibility of the independent PGE action on different parameters of the thyroid function or their participation in realization of the effects of other regulating agents.     

Prostaglandins and the alpha-cell

Experimental evidence has recently accumulated indicating that administration of some prostaglandins (PGs), particularly those of the E series, can evoke release of glucagon by the pancreatic alpha-cells. Virtually, all the in vitro studies (isolated perfused rat pancreas, isolated guinea-pig islets) agree that PGs can increase both basal and stimulated glucagon release. On the other hand, inhibition of PG synthesis with indomethacin blocks glucagon release. In rats and in normal humans, PGE₁, but not PGA₁ or PGF_2a, causes a progressive rise of plasma glucagon levels. While in the rat this response seems independent of the adrenergic nervous system, in man the hyperglucagonemia induced by PGE₁ is easily suppressed by propranolol, suggesting an interaction between the prostaglandin and the beta-receptors of the alpha-cell. Studies with inhibitors of PG synthesis in vivo have yielded conflicting results, depending on the particular experimental protocol used and o the type of inhibitor tested. In normal humans, it seems that acetylsalicylic acis (ASA) has no effect on glucagon response to arginine, tolbutamide and insulin-induced hypoglycemia. Conversely, a stimulator of PG synthesis, such as furosemide, increases glucagon response to an arginine pulse in man. In insulin-dependent diabetics, who present an exaggerated glucagon response to stimulants, ASA fails to alter glucagon response to arginine, but completely blunts the glucagon response to salbutamol, a weak beta-2 receptor agonist. In conclusion, these observations provide evidence in support of a role for PGs, at least PGE, in the contro of glucagon release.