Mesenteric Vascular Resistance Research Articles

Functional symmetry of the aortic baroreflex in female spontaneously hypertensive rats.

Altered baroreflex function is well documented in hypertension; however, the female sex remains far less studied compared with males. We have previously demonstrated a left-sided dominance in the expression of aortic baroreflex function in male spontaneously hypertensive rats (SHRs) and normotensive rats of either sex. If lateralization in aortic baroreflex function extends to hypertensive female rats remains undetermined. This study, therefore, assessed the contribution of left and right aortic baroreceptor afferents to baroreflex modulation in female SHRs. Anesthetized female SHRs (total n = 9) were prepared for left, right and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, 0.4 mA for 20 s) and measurement of reflex mean arterial pressure (MAP), heart rate (HR), mesenteric vascular resistance (MVR) and femoral vascular resistance (FVR). All rats were also matched for the diestrus phase of the estrus cycle. Reflex (%) reductions in MAP, HR, MVR and FVR were comparable for both left-sided and right-sided stimulation. Bilateral stimulation evoked slightly larger ( P = 0.03) reductions in MVR compared with right-sided stimulation; however, all other reflex hemodynamic measures were similar to both left-sided and right-sided stimulation. These data show that female SHRs, unlike male SHRs, express similar central integration of left versus right aortic baroreceptor afferent input and thus show no laterization in the aortic baroreflex during hypertension. Marginal increases in mesenteric vasodilation following bilateral activation of the aortic baroreceptor afferents drive no superior depressor responses beyond that of the unilateral stimulation. Clinically, unilateral targeting of the left or right aortic baroreceptor afferents may provide adequate reductions in blood pressure in female hypertensive patients.

Differential frequency-dependent reflex summation of the aortic baroreceptor afferent input.

Reflex summation in the expression of left and right aortic baroreflex control of hemodynamic functions was investigated. In anesthetized Sprague-Dawley rats, mean arterial pressure (MAP), heart rate (HR), and mesenteric vascular resistance (MVR) were recorded following left, right, and bilateral stimulation of the aortic depressor nerve (ADN). Stimulation frequency was varied between low (1Hz), moderate (5Hz), and high (20Hz). At 1Hz, left and right ADN stimulation evoked similar depressor, bradycardic and MVR responses, whereas bilateral stimulation induced larger MAP, HR, and MVR reductions compared with stimulations of either side. The sum of the separate and combined stimulation effects on MAP, HR, and MVR was similar, indicating an additive summation. A similar additive summation was observed with HR responses at 5 and 20Hz. Left-sided and bilateral stimulation produced greater depressor and MVR responses than right-sided stimulation, with responses of the bilateral stimulation mimicking those of the left side. The bilateral MAP or MVR response was smaller than the sum of the separate responses, suggesting an inhibitory summation. In conclusion, reflex summation of the left and right aortic baroreceptor afferent input is differentially expressed in relation to the frequency of the input signal. Summation of baroreflex control of HR is always additive and independent of stimulation frequency. Summation of baroreflex control of MAP is additive when the frequency input is small and inhibitory when the frequency input is moderate to high, with MAP changes mainly driven by parallel baroreflex-triggered changes in vascular resistance.

Differential central integration of left versus right baroreceptor afferent input in spontaneously hypertensive rats.

The blood pressure (BP) regulatory impact of the arterial baroreflex has been well established in health and disease. Under normotensive conditions, we have previously demonstrated functional differences in the central processing of the left versus right aortic baroreceptor afferent input. However, it is unknown if lateralization in aortic baroreflex function remains evident during hypertension. We therefore, investigated the effects of laterality on the expression of baroreflex-driven cardiovascular reflexes in a genetic model of essential hypertension, the spontaneously hypertensive rat (SHR). Anesthetized male SHRs (total n = 9) were instrumented for left, right, and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, and 0.4 mA for 20 s) and measurement of mean arterial pressure (MAP), heart rate (HR), mesenteric vascular resistance (MVR), and femoral vascular resistance (FVR). Left right, and bilateral ADN stimulation evoked frequency-dependent decreases in MAP, HR, MVR, and FVR. Left and bilateral ADN stimulation evoked greater reflex reductions in MAP, HR, MVR, and FVR compared with right-sided stimulation. Reflex bradycardia to bilateral stimulation was larger relative to both left-sided and right-sided stimulation. Reflex depressor and vascular resistance responses to bilateral stimulation mimicked those of the left-sided stimulation. These data indicate a left-side dominance in the central integration of aortic baroreceptor afferent input. Furthermore, reflex summation due to bilateral stimulation is only evident on the reflex bradycardic response, and does not drive further reductions in BP, suggesting that reflex depressor responses in the SHRs are primarily driven by changes in vascular resistance. Together, these results indicate that lateralization in aortic baroreflex function is not only evident under normotensive conditions but also extends to hypertensive conditions.

PS-B05-3: CARDIOVASCULAR RESPONSES EVOKED BY LOW ENERGY CONTINUOUS VERSUS INTERMITTENT STIMULATION OF THE AORTIC BARORECEPTOR AFFERENTS IN HYPERTENSION

Objectives: Device-based neurostimulation of the carotid baroreceptors is a novel approach to control hypertension. We have previously demonstrated the significance of aortic baroreceptor afferent nerves as a viable alternative neuromodulation target to carotid baroreceptors in lowering mean arterial pressure (MAP) in hypertension. We have also shown that appreciable reductions in MAP do not necessarily require the use of ultrahigh stimulation parameters. In this study, we aimed to investigate if energy consumption for neuromodulation of aortic baroreceptor afferents could be lowered further by using intermittent as opposed to continuous stimulation. Design and method: In male anesthetized spontaneously hypertensive rats (SHRs), the effects of continuous (20 sec) versus intermittent (5 sec ON/3 sec OFF and 5 sec ON/5 sec OFF for 20 sec) stimulation of the left aortic depressor nerve (ADN) on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance were assessed using low (5 Hz) and high (15 Hz) frequencies delivered at 0.4 mA and 0.2 ms. Results: Continuous and intermittent low frequency stimulation produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. Conclusions: Low charge intermittent stimulation of the aortic baroreceptor afferents maintains the required reductions in MAP levels in hypertension and intermittent delivery of the electrical stimulus can further lower energy consumption for neuromodulation. Clinically, these findings may provide useful insight for studies using baroreflex modulation in resistant hypertension and other cardiovascular diseases.

Low intensity stimulation of aortic baroreceptor afferent fibers as a potential therapeutic alternative for hypertension treatment

Carotid baroreceptor stimulation has been clinically explored for antihypertensive benefits, but neuromodulation of aortic baroreceptor afferents remains unexplored for potential translation into the clinic. Published studies have used supramaximal stimulations, which are unphysiological and energy inefficient. The objective of the present study was to identify optimal low-charge nerve stimulation parameters that would provide a clinically-relevant (20–30 mmHg) decrease in mean arterial pressure (MAP) in anesthetized spontaneously hypertensive rats. Stimulations of 20 s were delivered to the left aortic depressor nerve (ADN) of these rats using low ranges of pulse amplitudes (≤ 0.6 mA), widths (≤ 0.5 ms) and frequencies (≤ 5 Hz). We also assessed the effects of continuous (20 s) versus intermittent (5 s ON/3 s OFF and 5 s ON/3 s OFF for 20 s) stimulation on MAP, heart rate (HR), mesenteric (MVR) and femoral (FVR) vascular resistance using low (5 Hz) and high (15 Hz) frequencies. Lower pulse amplitudes (0.2 mA) produced 9 ± 2 to 18 ± 2 mmHg decreases in MAP. Higher pulse amplitudes (0.4 mA) produced a median MAP reduction of 28 ± 4 mmHg at 0.2 ms and 5 Hz, with no added benefit seen above 0.4 mA. Continuous and intermittent low frequency stimulation at 0.4 mA and 0.2 ms produced similar sustained decreases in MAP, HR, MVR and FVR. Continuous high frequency stimulation at 0.4 mA and 0.2 ms produced larger reductions in MAP, HR, MVR and FVR compared with all low frequency and/or intermittent high frequency stimulations. We conclude from these findings that “low intensity intermittent” electrical stimulation is an effective alternate way for neuromodulation of the aortic baroreceptor afferents and to evoke a required restoration of MAP levels in spontaneously hypertensive rats. This approach enables low energy consumption and markedly lowers the excessive decreases in MAP and hemodynamic disturbances elicited by continuous high-charge injection protocols.

Resistance mesenteric arteries display hypercontractility in the resolution time of Strongyloides venezuelensis infection

The blood flow in the mesenteric region is crucial for nutrient absorption and immune response in the gastrointestinal tract. The presence of nematodes or their excreted/secreted products seems to provoke vascular dysfunction. However, it is unclear whether and how the intestinal nematodes with habitat in the intestinal niche could affect the mesenteric vascular resistance. In this study, male Wistar rats were infected with 2000 larvae of S. venezuelensis, and experiments were conducted at 0 (non-infected control), 10 or 30 days post-infection (DPI). Eggs were counted in rats’ feces and adult worms recovered from the small intestine. Second- or third-order mesenteric arteries were extracted for concentration-response curves (CRC) to phenylephrine [PE; in the presence or absence of L-NAME or indomethacin] and acetylcholine. The number of eggs and adult worms were significantly higher in the 10 DPI group than those of 30 DPI group. Augmented PE-induced contraction was seen after 30 DPI compared to 10 DPI or control group. Hypercontractility to PE was partially prevented by L-NAME and wholly abolished by indomethacin incubation. Endothelium-dependent relaxation and endothelial nitric oxide synthase expression were unchanged among groups. COX-1 and COX-2 display a different pattern of expression over the infection. Hypercontractility observed in mesenteric resistance arteries in the resolution time of S. venezuelensis infection may represent systemic damage, which can generate significant cardiovascular and gastrointestinal repercussions.

A Randomized Porcine Study in Low Cardiac Output of Vasoactive and Inotropic Drug Effects on the Gastrointestinal Tract.

ABSTRACTBackground:Splanchnic vasodilation by inodilators is an argument for their use in critical cardiac dysfunction. To isolate peripheral vasoactivity from inotropy, such drugs were investigated, and contrasted to vasopressors, in a fixed low cardiac output (CO) model resembling acute cardiac dysfunction effects on the gastrointestinal tract. We hypothesized that inodilators would vasodilate and preserve the aerobic metabolism in the splanchnic circulation in low CO.Methods:In anesthetized pigs, CO was lowered to 60% of baseline by partial inferior caval vein balloon inflation. The animals were randomized to placebo (n = 8), levosimendan (24 μg kg−1 bolus, 0.2 μg kg−1 min−1, n = 7), milrinone (50 μg kg−1 bolus, 0.5 μg kg−1 min−1, n = 7), vasopressin (0.001, 0.002 and 0.006 U kg−1 min−1, 1 h each, n = 7) or norepinephrine (0.04, 0.12, and 0.36 μg kg−1 min−1, 1 h each, n = 7). Hemodynamic variables including mesenteric blood flow were collected. Systemic, mixed-venous, mesenteric-venous, and intraperitoneal metabolites were analyzed.Results:Cardiac output was stable at 60% in all groups, which resulted in systemic hypotension, low superior mesenteric artery blood flow, lactic acidosis, and increased intraperitoneal concentrations of lactate. Levosimendan and milrinone did not change any circulatory variables, but levosimendan increased blood lactate concentrations. Vasopressin and norepinephrine increased systemic and mesenteric vascular resistances at the highest dose. Vasopressin increased mesenteric resistance more than systemic, and the intraperitoneal lactate concentration and lactate/pyruvate ratio.Conclusion:Splanchnic vasodilation by levosimendan and milrinone may be negligible in low CO, thus rejecting the hypothesis. High-dose vasopressors may have side effects in the splanchnic circulation.

Sympathetic Overactivity in CKD Disrupts Buffering of Neurotransmission by Endothelium-Derived Hyperpolarizing Factor and Enhances Vasoconstriction.

Hypertension commonly complicates CKD. Vascular smooth muscle cells (VSMCs) of resistance arteries receive signals from the sympathetic nervous system that induce an endothelial cell (EC)-dependent anticontractile response that moderates vasoconstriction. However, the specific role of this pathway in the enhanced vasoconstriction in CKD is unknown. A mouse model of CKD hypertension generated with 5/6-nephrectomy (5/6Nx) was used to investigate the hypothesis that an impaired anticontractile mechanism enhances sympathetic vasoconstriction. In vivo, ex vivo (isolated mesenteric resistance arteries), and in vitro (VSMC and EC coculture) models demonstrated neurovascular transmission and its contribution to vascular resistance. By 4 weeks, 5/6Nx mice (versus sham) had augmented increases in mesenteric vascular resistance and mean arterial pressure with carotid artery occlusion, accompanied by decreased connexin 43 (Cx43) expression at myoendothelial junctions (MEJs), impaired gap junction function, decreased EC-dependent hyperpolarization (EDH), and enhanced contractions. Exposure of VSMCs to NE for 24 hours in a vascular cell coculture decreased MEJ Cx43 expression and MEJ gap junction function. These changes preceded vascular structural changes evident only at week 8. Inhibition of central sympathetic outflow or transfection of Cx43 normalized neurovascular transmission and vasoconstriction in 5/6Nx mice. 5/6Nx mice have enhanced neurovascular transmission and vasoconstriction from an impaired EDH anticontractile component before vascular structural changes. These neurovascular changes depend on an enhanced sympathetic discharge that impairs the expression of Cx43 in gap junctions at MEJs, thereby interrupting EDH responses that normally moderate vascular tone. Dysregulation of neurovascular transmission may contribute to the development of hypertension in CKD.

Selepressin, a novel selective V1A receptor agonist: Effect on mesenteric flow and gastric mucosa perfusion in the endotoxemic rabbit

Intestinal or mesenteric ischemia generally leads to inflammation and injury, potentially developing hypoxia, causing cell death and tissue necrosis. This in turn can lead to sepsis and shock. Conversely, following shock, the intestinal tract is a main organ to experience ischemic/reperfusion injury. Increased intestinal cell-membrane permeability through mesenteric ischemia provoking bacterial translocation and gut-barrier injury can lead to sepsis and multi-organ failure. Hypotension induced by systemic vasodilation and vascular leak in systemic inflammatory response syndrome and sepsis is countered by immediate fluid resuscitation and vasopressor administration, primarily norepinephrine (NE), with possible arginine vasopressin (AVP) supplementation, an agonist of vasopressin V1A and V2 receptors. Selepressin is a selective V1A-receptor agonist, avoiding potential V2 receptor-associated adverse effects. Selepressin, non-selective AVP, and NE effects on mesenteric blood flow (MBF) and gastric mucosa perfusion (GMP) were compared in control rabbits and a lipopolysaccharide-induced, fluid-resuscitated rabbit endotoxemia model. AVP induced a pronounced decrease in MBF and GMP in non-endotoxemic and endotoxemic rabbits, whereas the reduction after selepressin treatment was significantly less for both indicators in the endotoxemic animals. By contrast, NE increased the MBF and did not affect GMP in both groups. Selepressin and AVP induced a pronounced dose-dependent increase in mesenteric vascular resistance in non-endotoxemic and endotoxemic rabbits, tending to be less in endotoxemic animals, whereas a minor increase in both groups was observed with NE. Therefore, in this safety study, the risk for mesenteric ischemia on selepressin treatment was not inferior to AVP, being less in endotoxemic than in non-endotoxemic animals.

Neuronal Nitric Oxide Mediates the Anti-inflammatory Effects of Intestinal Ischemic Preconditioning

BackgroundIschemic preconditioning (IPC) can provide a defense against ischemia–reperfusion (IR)-induced acute inflammation and barrier dysfunction in many organs. Because nitric oxide (NO) has been implicated as a trigger or mediator in the IPC mechanism and because neuronal NO synthase (nNOS) is a dominant isoform of NOS in the gastrointestinal tract, our aim was to investigate the role of nNOS in IPC-induced protection after mesenteric IR. Materials and methodsIntestinal IR was induced in sodium pentobarbital–anesthetized dogs by clamping the superior mesenteric artery for 60 min followed by 2 h of reperfusion (IR group; n = 7). In further groups, IPC was used (three cycles of 5-min ischemia/5-min reperfusion periods) before IR in the presence or absence of selective inhibition of nNOS with 7-nitroindazole (5 mg/kg, intravenously, in a bolus 15 min before IPC, n = 6 each). Changes in mesenteric vascular resistance, intramucosal pH (pHi), and small bowel motility were monitored. Plasma nitrite/nitrate levels, intestinal NO synthase activity, leukocyte accumulation, mast cell degranulation, and histologic injury were also determined. ResultsIschemia significantly decreased mesenteric vascular resistance and pHi, whereas IR induced a temporary bowel hypermotility and acute inflammatory reaction. IPC facilitated pHi recovery, attenuated motility dysfunction, elevated NOS-dependent NO production, and reduced leukocyte accumulation, mast cell degranulation, and mucosal injury. Pretreatment with 7-nitroindazole halted the IPC-induced increase in NO availability, pHi recovery, and the anti-inflammatory and morphologic effects. ConclusionsOur data demonstrate that NO generated by intestinal nNOS plays a pivotal role in IPC-linked tissue protection by inhibiting an IR-related acute inflammatory response.

SAT-114 ABERRANT RENAL AND MESENTERIC HEMODYNAMIC RESPONSES TO A HIGH SALT DIET AND BLOOD PRESSURE SALT-SENSITIVITY ARE ABOLISHED IN CONSOMIC SS.BN1 vs. DAHL SS RATS

The contribution of renal vs. systemic vascular dysfunction in the pathogenesis of salt-sensitive (SS) hypertension is a topic of considerable debate. The Dahl salt-sensitive (SS) rat is commonly used to investigate the genetic and pathophysiologic basis of SS hypertension. A consomic panel of rats in which individual chromosomes from the salt-resistant Brown-Norway (BN) rat are introgressed into the Dahl SS background have shown that genes on rat chromosome 1 play an important role in the pathogenesis SS hypertension. Here, we investigated renal injury as well as renal and mesenteric hemodynamics in conscious Dahl SS vs. consomic SS.BN1 rats fed low and high salt diets. Systolic blood pressure (BP, 24 hrs/day via telemetry), proteinuria and renal injury were assessed in 10-12 week old SS, BN and SS.BN1 rats fed a 0.4% or 4.0% NaCl diet for 3 weeks. Proteinuria and renal injury were also assessed in naïve 10-12 week vs. 5-6 month old SS, BN and SS.BN1 rats maintained on a 0.4% NaCl diet. BP (telemetry) and either renal blood flow (RBF, Transonic flow probe) or mesenteric blood flow (MBF, Transonic flow probe) were assessed (200 Hz, 2 hrs/day) in conscious 10-12 week old SS vs. SS.BN1 rats during 3 days of 0.4% NaCl feeding and during 5 days of 4.0% NaCl feeding. Finally, glomerular filtration rate (GFR) was assessed via creatinine clearance in 10-12 week old SS vs. SS.BN1 rats on a 0.4% NaCl diet and after 3 weeks of a 4.0% NaCl diet. SS hypertension was minimal and comparable in SS.BN1 and BN rats. In contrast, SS rats developed substantial increases in BP and proteinuria on a high salt diet. Glomerular and tubulointerstitial injury was prevalent in SS rats and correlated strongly with systolic BP. Significant renal injury and proteinuria was observed even in 10-12 week old SS, but not BN or SS.BN1, rats maintained on a 0.4% diet. Moreover, numerous abnormal tubules exhibiting enlarged hyperchromatic nuclei, non-isometric tubular vacuolization, loss of brush border and epithelial cell sloughing were observed in 10-12 week old SS rats. Frozen sections stained with H&E of kidneys from 10-12 week old SS rats showed protein plug formations within numerous tubule lumens. The magnitude of renal injury and proteinuria was substantially greater in 5-6 month old SS, but not BN or SS.BN1, rats fed a 0.4% NaCl diet as compared to respective 10-12 week old rats. When administered a 4.0% NaCl diet, SS.BN1 rats exhibited a significant decrease in renal vascular resistance (RVR) and increase in RBF but no change in mesenteric vascular resistance (MVR) or MBF. In contrast, RVR tended to increase and RBF decrease in SS rats fed a 4.0% high salt diet. Moreover, MVR significantly increased and MBF decreased in SS rats fed a high salt diet. GFR (normalized to body weight) tended to increase in SS.BN1 rats fed a high salt diet but no change was observed in SS rats. Introgression of chromosome 1 from the salt-resistant BN rat into the SS rat prevents SS hypertension. Such prevention is likely due, in large part, to a normal renal parenchyma and the ability of the renal vasculature to dilate and GFR to increase in response to a high salt diet. Moreover, the absence of aberrant increases in MVR during high salt feeding in SS.BN1 rats may further contribute to their resistance to SS hypertension.

Protein-Losing Enteropathy and Plastic Bronchitis After the Fontan Operation.

Protein-losing enteropathy and plastic bronchitis remain challenging to treat despite recent treatment advances. Protein-losing enteropathy and plastic bronchitis have been diagnosed in patients with cardiomyopathy, constrictive pericarditis, and congestive heart failure. This article focuses on patients with protein-losing enteropathy or plastic bronchitis following the Fontan procedure. Patients with single-ventricle physiology who have undergone the Fontan procedure are at risk for these conditions. Fontan physiology predisposes patients to chronically low cardiac output, increased central venous pressure, and congestive heart failure. These altered hemodynamics lead to increased mesenteric vascular resistance, resulting in venous hypertension and congestion in protein-losing enteropathy. Plastic bronchitis is a complex disease in which chronic high lymphatic pressures from Fontan physiology cause acellular bronchial casts to develop. These entities may also occur in patients with normal Fontan hemodynamics. This article also covers medical and surgical interventions for protein-losing enteropathy and plastic bronchitis. (Critical Care Nurse 2018;38[6]:e5-e12).

Evaluation of capillary leakage after vasopressin resuscitation in a hemorrhagic shock model

BackgroundHemorrhagic shock (HS) is a major threat to patients with trauma and spontaneous bleeding. The aim of the study was to investigate early effects of vasopressin on metabolic and hemodynamic parameters and endothelium permeability by measuring capillary leakage compared to those of other resuscitation strategies in a HS model.MethodsForty-five Sprague-Dawley rats were randomized into five groups: S group (n = 5), sham-operated rats without shock or resuscitation; HS group (n = 10), HS and no resuscitation; RL group (n = 10), HS and resuscitation with Ringer’s lactate (RL); RLB group (n = 10), HS and resuscitation with two-third shed blood plus RL; and vasopressin group (n = 10), HS and resuscitation with RL, followed by continuous infusion of 0.04 U/kg/min vasopressin. The effects of resuscitation on hemodynamic parameters [mean arterial pressure (MAP), superior mesenteric artery blood flow (MBF), and mesenteric vascular resistances (MVR)], arterial blood gases, bicarbonate, base deficit, and lactate levels as well as on capillary leakage in the lung, ileum, and kidney were investigated. Capillary leakage was evaluated with Evans blue dye extravasation.ResultsIn the vasopressin group, the MAP was higher than in the RL and RLB groups (p < 0.001), while MBF was decreased (p < 0.001). MVR were increased only in the vasopressin group (p < 0.001). Capillary leakage was increased in the lungs of the animals in the vasopressin group compared to that in the lungs of animals in the RLB group (p < 0.05); this increase was associated with the lowest partial pressure of oxygen (p < 0.05). Conversely, decreased capillary leakage was observed with vasopressin in the ileum (p < 0.05). Increased capillary leakage was observed in the kidney in the RLB and vasopressin groups (p < 0.05). Lastly, vasopressin use was associated with higher base deficit and lactate levels when compared to the RL and RLB groups (p < 0.001).ConclusionAlthough vasopressin was proposed as a vasoactive drug for provisional hemodynamic optimization in the early phase of HS resuscitation, the overall findings of this experimental study focus on the possible critical side effects of vasopressin on metabolic parameters and endothelium permeability.

Disappearance of a spontaneous intrahepatic portosystemic shunt managed by hepatic vein closure: Why?

Introduction Spontaneous intrahepatic portosystemic shunt (PSS) is uncommon. A few cases have been reported with its disappearance after outflow occlusion. It is unclear why it had disappeared, and the mechanism is closely related to the pathophysiology of PSS. The portal circulation is a ‘flow’ and governed by Ohm’s law (Flow=Pressure/Resistance). This can be explained through simulation using an electric circuit, which is also a flow system. Case description A 62-year old woman visited with hepatic encephalopathy. She had no history of chronic liver disease or liver trauma. Imaging studies revealed an intrahepatic aneurysmal PSS in Couinaud’s segment 6, formed between the posterior branch of right portal vein and the right inferior hepatic vein. She was managed by laparoscopic right inferior hepatic vein closure using an autostapling device. Her encephalopathic symptoms improved immediately after the operation, and she was discharged uneventfully. At her 8 month follow-up, she was symptom-free and her PSS disappeared entirely. Results and Conclusions The basic configuration of splanchnic circulation is essentially two resistors connected in series; the mesenteric vascular resistance and the portal vascular resistance. It is a pressure divider between the aortic pressure and systemic venous pressure. In turn, the portal vascular resistance can be seen as two resistors connected in parallel; the hepatic vascular resistance and the PSS resistance. A PSS means the shunt flow above zero, and according to Ohm’s law, there are two ways for the PSS to be formed. In one condition, the portal pressure increases sufficiently high and a PSS begins to form at a fixed shunt resistance. Once the shunt channel is established, portal pressure will decrease until equilibrium is reached between the portal pressure and the shunt flow. A clinical example is liver cirrhosis. In this condition, PSS will persist even if the outflow is occluded. In the other condition, the shunt resistance can decrease at a fixed portal pressure, such as an aneurysmal dilatation of PSS. In this case, PSS will disappear after outflow occlusion, because the shunt flow becomes zero. The puzzling phenomenon of the disappearance of PSS in our case can be easily explained by simulation using an electric circuit theory. Take home message Blood flow is similar to an electric current and is governed by Ohm’s law. By simulating splanchnic blood flow with an electric circuit, we can easily understand the underlying pathophysiology of many seemingly curious phenomena.

The Adenosinergic System as a Therapeutic Target in the Vasculature: New Ligands and Challenges.

Adenosine is an adenine base purine with actions as a modulator of neurotransmission, smooth muscle contraction, and immune response in several systems of the human body, including the cardiovascular system. In the vasculature, four P1-receptors or adenosine receptors—A1, A2A, A2B and A3—have been identified. Adenosine receptors are membrane G-protein receptors that trigger their actions through several signaling pathways and present differential affinity requirements. Adenosine is an endogenous ligand whose extracellular levels can reach concentrations high enough to activate the adenosine receptors. This nucleoside is a product of enzymatic breakdown of extra and intracellular adenine nucleotides and also of S-adenosylhomocysteine. Adenosine availability is also dependent on the activity of nucleoside transporters (NTs). The interplay between NTs and adenosine receptors’ activities are debated and a particular attention is given to the paramount importance of the disruption of this interplay in vascular pathophysiology, namely in hypertension., The integration of important functional aspects of individual adenosine receptor pharmacology (such as in vasoconstriction/vasodilation) and morphological features (within the three vascular layers) in vessels will be discussed, hopefully clarifying the importance of adenosine receptors/NTs for modulating peripheral mesenteric vascular resistance. In recent years, an increase interest in purine physiology/pharmacology has led to the development of new ligands for adenosine receptors. Some of them have been patented as having promising therapeutic activities and some have been chosen to undergo on clinical trials. Increased levels of endogenous adenosine near a specific subtype can lead to its activation, constituting an indirect receptor targeting approach either by inhibition of NT or, alternatively, by increasing the activity of enzymes responsible for ATP breakdown. These findings highlight the putative role of adenosinergic players as attractive therapeutic targets for cardiovascular pathologies, namely hypertension, heart failure or stroke. Nevertheless, several aspects are still to be explored, creating new challenges to be addressed in future studies, particularly the development of strategies able to circumvent the predicted side effects of these therapies.

Comprehensive assessment of the global and regional vascular responses to food ingestion in humans using novel rapid MRI.

Ingestion of food is known to increase mesenteric blood flow. It is not clear whether this increased flow demand is compensated by a rise in cardiac output (CO) alone or by redistribution of blood flow from other organs. We used a new comprehensive imaging method to assess the human cardiovascular response to food ingestion. Following a 12-h fast, blood flow in segments of the aorta and in organ-specific arteries, and ventricular volumes were assessed in 20 healthy adults using MRI at rest and following ingestion of a high-energy liquid meal. Systemic vascular resistance (SVR) fell substantially and CO rose significantly. Blood pressure remained stable. These changes were predominantly driven by a rapid fall in mesenteric vascular resistance, resulting in over four times more intestinal blood flow. Renal vascular resistance also declined but less dramatically. No changes in blood flow to the celiac territory, the brain, or the limbs were observed. In conclusion, this is the first study to fully characterize systemic and regional changes in vascular resistance after food ingestion in humans. Our findings show that the postprandial drop in SVR is fully compensated for by increased CO and not by redistribution of blood from other organs. With the exception of a modest increase in renal blood flow, there was no evidence of altered blood flow to nondigestive organs. The proposed oral food challenge protocol can be applied safely in an MRI environment and may be useful for studying the involvement of the gut in systemic or cardiovascular disease.

Early Impact of Fontan Operation on Enteric Protein Loss

Protein-losing enteropathy (PLE) is a challenging complication after a Fontan operation. Subclinical enteric protein loss may precede development of overt PLE. We evaluated the acute effects of Fontan circulation on enteric protein loss and mesenteric vascular resistance. A prospective cohort study was performed evaluating enteric protein loss in children undergoing Fontan operations. Stool alpha-1 antitrypsin (A1AT) concentration was measured in the preoperative, early postoperative, and intermediate postoperative (3-9 months) periods. The intestinal circulation was characterized by Doppler-derived resistance indices of the superior mesenteric artery (SMA), and serum albumin and protein levels were obtained. We enrolled 33 participants at a median age at operation of 3.0 years (interquartile range [IQR], 2.5-3.3 years). No clinical PLE was observed. Six of the 93 stool samples obtained had elevated A1AT levels (>54 mg/dL), with 2 abnormal samples at each of the 3 time points. Two of the 5 participants with elevated stool A1AT values had significant hemodynamic disturbances requiring intervention (junctional bradycardia or tricuspid stenosis). There was no difference in SMA resistance in the preoperative versus early postoperative periods (p = 0.9). Serum albumin levels were lower in the early postoperative period compared with the preoperative period (3.2 mg/dL [{IQR}, 2.9-3.5] versus 4.1 mg/dL; IQR, 3.4-4.5; p = 0.01) but did not correlate with abnormal stool A1AT concentration or SMA resistance indices. The Fontan operation does not commonly result in acute development of increased enteric protein loss. However, increased enteric protein loss may occur in children before or after a Fontan operation, particularly when hemodynamic disturbances are present.

Protective effects of l-alpha-glycerylphosphorylcholine on ischaemia–reperfusion-induced inflammatory reactions

Choline-containing dietary phospholipids, including phosphatidylcholine (PC), may function as anti-inflammatory substances, but the mechanism remains largely unknown. We investigated the effects of L-alpha-glycerylphosphorylcholine (GPC), a deacylated PC derivative, in a rodent model of small intestinal ischaemia-reperfusion (IR) injury. Anaesthetized Sprague-Dawley rats were divided into control, mesenteric IR (45 min mesenteric artery occlusion, followed by 180 min reperfusion), IR with GPC pretreatment (16.56 mg kg⁻¹ GPC i.v., 5 min prior to ischaemia) or IR with GPC post-treatment (16.56 mg kg⁻¹ GPC i.v., 5 min prior to reperfusion) groups. Macrohaemodynamics and microhaemodynamic parameters were measured; intestinal inflammatory markers (xanthine oxidoreductase activity, superoxide and nitrotyrosine levels) and liver ATP contents were determined. The IR challenge reduced the intestinal intramural red blood cell velocity, increased the mesenteric vascular resistance, the tissue xanthine oxidoreductase activity, the superoxide production, and the nitrotyrosine levels, and the ATP content of the liver was decreased. Exogenous GPC attenuated the macro- and microcirculatory dysfunction and provided significant protection against the radical production resulting from the IR stress. The GPC pretreatment alleviated the hepatic ATP depletion, the reductions in the mean arterial pressure and superior mesenteric artery flow, and similarly to the post-treatments with GPC, also decreased the xanthine oxidoreductase activity, the intestinal superoxide production, the nitrotyrosine level, and normalized the microcirculatory dysfunction. These data demonstrate the effectiveness of GPC therapies and provide indirect evidence that the anti-inflammatory effects of PC could be linked to a reaction involving the polar part of the molecule.

Hemodynamic responses elicited by systemic injections of isotonic and hypertonic saline in hemorrhaged rats

PurposeThe objectives of this study were (i) to characterize the hemodynamic responses caused by controlled hemorrhage (HEM) in pentobarbital-anesthetized rats, and (ii) to determine the responses elicited by systemic bolus injections of isotonic saline (0.15M) or hypertonic saline (3M) given 5min after completion of HEM. ResultsControlled HEM (4.3±0.2ml/rat at 1.5ml/min) resulted in a pronounced and sustained fall in mean arterial blood pressure (MAP) to about 40mmHg. The fall in MAP was associated with a reduction in hindquarter vascular resistance (HQR) but no changes in renal (RR) or mesenteric (MR) vascular resistances. Systemic injections of isotonic saline (96–212μmol/kg i.v., in 250–550μl) did not produce immediate responses but promoted the recovery of MAP to levels below pre-HEM values. Systemic injections of hypertonic saline (750–3000μmol/kg, i.v., in 250–550μl) produced immediate and pronounced falls in MAP, RR, MR and especially HQR of 30–120s in duration. However, hypertonic saline prompted a full recovery of MAP, HQR and RR to pre-HEM levels and an increase in MR to levels above pre-HEM values. ConclusionsThis study demonstrates that (i) HEM induced a pronounced fall in MAP which likely involved a fall in cardiac output and HQR, (ii) isotonic saline did not fully normalize MAP, and (iii) hypertonic saline produced dramatic initial responses, and promoted normalization of MAP probably by restoring blood volume and cardiac output through sequestration of fluid from intracellular compartments.

In Vivo Cardiovascular Pharmacology of 2′,3′-cAMP, 2′-AMP, and 3′-AMP in the Rat

The naturally occurring purine 2',3'-cAMP is metabolized in vitro to 2'-AMP and 3'-AMP, which are subsequently metabolized to adenosine. Whether in vivo 2',3'-cAMP, 2'-AMP, or 3'-AMP are rapidly converted to adenosine and exert rapid effects via adenosine receptors is unknown. To address this question, we compared the cardiovascular and renal effects of 2',3'-cAMP, 2'-AMP, 3'-AMP, 3',5'-cAMP, 5'-AMP, and adenosine in vivo in the rat. Purines were infused intravenously while monitoring mean arterial blood pressure (MABP), heart rate (HR), cardiac output, and renal and mesenteric blood flows. Total peripheral (TPR), renal vascular (RVR), and mesenteric vascular (MVR) resistances were calculated. Urine was collected for determination of urine excretion rate [urine volume (UV)]. When sufficient urine was available, the sodium excretion rate (Na(+)ER) and glomerular filtration rate (GFR) were determined. 2',3'-cAMP, 2'-AMP, and 3'-AMP dose-dependently and profoundly reduced MABP, HR, TPR, and MVR with efficacy and potency similar to adenosine and 5'-AMP. These effects of 2',3'-cAMP, 2'-AMP, and 3'-AMP were attenuated by blockade of adenosine receptors with 1,3-dipropyl-8-(p-sulfophenyl)xanthine. 2',3'-cAMP, 2'-AMP, 3'-AMP, adenosine, and 5'-AMP variably affected RVR, but profoundly (nearly 100%) decreased UV at higher doses. GFR and Na(+)ER could be measured at the lower doses and were suppressed by 2',3'-cAMP, 2'-AMP, and 3'-AMP, but not by adenosine or 5'-AMP. 2',3'-cAMP increased urinary excretion rates of 2'-AMP, 3'-AMP, and adenosine. 3',5'-cAMP exerted no adverse hemodynamic effects yet increased urinary adenosine as efficiently as 2',3'-cAMP. In vivo 2',3'-cAMP is rapidly converted to adenosine. Because both cAMPs increase adenosine in the urinary compartment, these agents may provide unique therapeutic opportunities.