Mesenteric Resistance Research Articles

Comprehensive MRI assessment of the cardiovascular responses to food ingestion in Fontan physiology.

In univentricular (Fontan) physiology, peripheral and splanchnic vascular tone may be raised to counteract reduced cardiac output (CO) and elevated central venous pressure and thus maintain vital organ perfusion. This could negatively affect the normal cardiovascular response to food ingestion, where mesenteric vasodilation and a concurrent rise in CO are central. We sought to elucidate this using rapid cardiovascular MRI. Thirty fasting subjects (50% controls, 40% women and 60% men) ingested a standardized meal. Responses over ~50 min in mean arterial pressure (MAP), CO, and blood flow in all major aortic branches were measured, and regional vascular impedance (Z0) was calculated. Differences from baseline and between groups were assessed by repeated-measures mixed models. Compared with the control group, the Fontan patient group had greater fasting Z0 of the legs and kidneys, resulting in greater systemic Z0 and similar MAP. They further had similar blood flow to the digestive organs at baseline, despite larger variation in mesenteric resistance. Postprandially, blood flow to the legs decreased in the control group but not in the Fontan patient group. Increases in CO and superior mesenteric blood flow were similar in both groups, but the celiac response was blunted in the Fontan patient group. No significant differences in MAP responses were observed. In conclusion, alterations in vascular tone to counteract adverse hemodynamics and raised hepatic afterload may blunt vasoreactivity in the legs and the celiac axis in Fontan physiology. Further study is needed to determine whether blunted celiac or mesenteric vasoreactivity is linked to deteriorating hemodynamics and poor prognosis in Fontan patients.NEW & NOTEWORTHY Novel data on cardiovascular physiology in response to a meal in Fontan patients are presented. Using a previously validated dynamic MRI protocol, we demonstrated that the usual increase in cardiac output and the dilation of the superior mesenteric artery are preserved in clinically well Fontan patients. In contrast, vasoconstriction of the legs may have prevented redistribution of blood flow from this region in response to the meal. This may also affect responses to other types of stress. Celiac vasodilation was also absent in Fontan patients. This may be due to abnormal hepatic circulation. The proposed protocol may be used to study Fontan complications secondary to abnormal regional hemodynamics.

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.

Hypotensive effect and vascular relaxation in different arteries induced by the nitric oxide donor RuBPY

NO donors are compounds that release NO that can be used when the endogenous NO bioavailability is impaired. The compound cis-[Ru(bpy)2(py)(NO2)](PF6) (RuBPY) is a nitrite-ruthenium, since it has a NO2 in its molecule. The aim of the present study was to evaluate the effect of RuBPY on arterial pressure, as well as on the vascular relaxation of different vascular arteries in renal hypertensive (2K-1C) and normotensive (2K) rats. We have evaluated the arterial pressure and heart rate changes as well as the RuBPY and SNP-induced relaxation (thoracic aorta, mesenteric resistance, coronary and basilar arteries). The administration of RuBPY in awake rats evoked a smaller but long lasting hypotensive effect when compared to SNP, with no increase in heart rate. The relaxation induced by RuBPY was similar between 2K-1C and 2K rats in thoracic aorta, mesenteric resistance and coronary arteries. However, the relaxation induced by RuBPY was smaller in basilar arteries from 2K-1C than in 2K. Taken together, our results show that RuBPY presents several advantages over SNP, since it does not induce hypotensive effect in normotensive animals, the hypotensive effect is slower, with no reflex tachycardia, and it is long lasting. In addition, RuBPY induces coronary artery relaxation (useful for angina) and presented only a small effect on basilar artery (may not induce headache).

Membrane Stretch and Angiotensin II type 1a Receptor: Causes and Role in the Myogenic Response

The ligand-independent activation of Angiotensin II type 1 receptors following vascular stretch plays very important (patho) physiological roles. Indeed, recent studies have implicated this mechanism in cardiac hypertrophy under conditions of pressure overload and it has shown to be indispensable in the regulation of the myogenic response in smooth muscle cells of small resistance arteries, as well as mesenteric and renal resistance arteries. The information discussed in here will highlight the involvement of the mechanoactivation of the Angiotensin II type I receptors in the development of the myogenic response and the molecular mechanisms modulating them following activation.

Neural programming of mesenteric and renal arteries.

There is evidence for developmental origins of vascular dysfunction yet little understanding of maturation of vascular smooth muscle (VSM) of regional circulations. We measured maturational changes in expression of myosin phosphatase (MP) and the broader VSM gene program in relation to mesenteric small resistance artery (SRA) function. We then tested the role of the sympathetic nervous system (SNS) in programming of SRAs and used genetically engineered mice to define the role of MP isoforms in the functional maturation of the mesenteric circulation. Maturation of rat mesenteric SRAs as measured by qPCR and immunoblotting begins after the second postnatal week and is not complete until maturity. It is characterized by induction of markers of VSM differentiation (smMHC, γ-, α-actin), CPI-17, an inhibitory subunit of MP and a key target of α-adrenergic vasoconstriction, α1-adrenergic, purinergic X1, and neuropeptide Y1 receptors of sympathetic signaling. Functional correlates include maturational increases in α-adrenergic-mediated force and calcium sensitization of force production (MP inhibition) measured in first-order mesenteric arteries ex vivo. The MP regulatory subunit Mypt1 E24+/LZ- isoform is specifically upregulated in SRAs during maturation. Conditional deletion of mouse Mypt1 E24 demonstrates that splicing of E24 causes the maturational reduction in sensitivity to cGMP-mediated vasorelaxation (MP activation). Neonatal chemical sympathectomy (6-hydroxydopamine) suppresses maturation of SRAs with minimal effect on a conduit artery. Mechanical denervation of the mature rat renal artery causes a reversion to the immature gene program. We conclude that the SNS captures control of the mesenteric circulation by programming maturation of the SRA smooth muscle.

Abstract 533: Vascular Smooth Muscle Na/Ca Exchanger-1 Modulates Myogenic Reactivity and Blood Pressure in Chronic Intermittent Hypoxia

Chronic intermittent hypoxia (CIH) results in systemic hypertension and altered vascular reactivity in human and rodents. We hypothesize that vascular smooth muscle (VSM) Na/Ca exchanger type-1 (NCX1) is a potential molecular mechanism mediating CIH-induced changes in vascular reactivity and blood pressure (BP). Wild type (WT) and transgenic (TG) mice with VSM-specific NCX1 overexpression were exposed to either CIH (1 min 5% nadir O 2 , followed by 1 min 21% O 2 ; 8 hrs/day for 5 weeks), or normoxia (constant 21% O 2 ). CIH resulted in greater BP elevation in TG (102 ± 3 mm Hg vs. 92 ± 6 mm Hg in normoxia, P < 0.05, n = 6 and 3, measured by intra-carotid artery catheterization under 1.5% isoflurane) than in WT (88 ± 4 mm Hg vs. 83 ± 2 mm Hg in normoxia, NS, n = 3 and 5) mice. Mesenteric small resistance arteries were then isolated and pressurized for diameter and wall thickness measurement. Compared to normoxia controls, CIH-exposed WT arteries exhibited increased resting myogenic tone (21 ± 2% vs. 16 ± 2% of PD in normoxia, P < 0.05, n = 5 each group). Moreover, myogenic reactivity in WT arteries of CIH-exposed mice shifted downward at lower range of intraluminal pressure (20-80 mm Hg), and upward at higher pressure (100-140 mm Hg). The effects of CIH were significantly greater in TG arteries compared to those in WT arteries, suggesting that VSM NCX1 augmented the myogenic response to CIH. Vasoconstrictions induced by phenylephrine (0.003-100 μM), greater in TG arteries, or high (60 mM) external K + solution, were similar between control and CIH groups in the same genotype, suggesting that arterial contractility to agonist stimulation was not affected by CIH. Arterial wall thickness or passive diameters under various intraluminal pressures in Ca 2+ -free solution were not different between control and CIH groups in either genotype, suggesting a lack of arterial stiffness or remodeling. In summary, 1) CIH results in greater BP elevation in TG mice; 2) CIH leads to biphasic changes in myogenic reactivity in small resistance arteries; 3) Overexpression of VSM NCX1 exaggerates BP elevation in CIH, likely by modulating myogenic reactivity, suggesting that VSM NCX1 is a potential mechanism mediating CIH-induced hypertension.

Activation of central α2-adrenoceptors mediates salivary gland vasoconstriction

ObjectivePeripheral treatment with the cholinergic agonist pilocarpine increases salivary gland blood flow and induces intense salivation that is reduced by the central injection of moxonidine (α2-adrenoceptors/imidazoline agonist). In the present study, we investigated the effects of the intracerebroventricular (i.c.v.) injection of pilocarpine alone or combined with moxonidine also injected i.c.v. On submandibular/sublingual gland (SSG) vascular resistance. In addition, the effects of these treatments on arterial pressure, heart rate and on mesenteric and hindlimb vascular resistance were also tested. DesignMale Holtzman rats with stainless steel cannula implanted into lateral ventricle and anaesthetized with urethane+α-chloralose were used. ResultsPilocarpine (500nmol/1μl) injected i.c.v. Reduced SSG vascular resistance and increased arterial pressure, heart rate and mesenteric vascular resistance. Contrary to pilocarpine alone, the combination of moxonidine (20nmol/1μl) and pilocarpine injected i.c.v. Increased SSG vascular resistance, an effect abolished by the pre-treatment with the α2-adrenoceptor antagonist yohimbine (320nmol/2μl). The increase in arterial pressure, heart rate and mesenteric resistance was not modified by the combination of moxonidine and pilocarpine i.c.v. ConclusionThese results suggest that the activation of central α2-adrenoceptors may oppose to the effects of central cholinergic receptor activation in the SSG vascular resistance.

The dorsomedial hypothalamus (DMH) plays a strain-dependent role in vascular responses to cocaine but not cold stress in conscious rats

s / Autonomic Neuroscience: Basic and Clinical 163 (2011) 1–133 56 P.039 The dorsomedial hypothalamus (DMH) plays a strain-dependent role in vascular responses to cocaine but not cold stress in conscious rats M.M. Knuepfer, M. Busauskas (St. Louis University School of Medicine Pharmacol. & Physiol. Science, USA) We demonstrated that cocaine or cold water stress (CWS) elicits systemic vasoconstriction in Brown-Norway (BN) rats but an increase in cardiac output in Dahl salt sensitive (DSS) rats. Since the DMH plays an important role in stress responsiveness, we sought to determine the role of the DMH to these disparate stressors on regional vascular hemodynamics. We hypothesized that inhibition of the DMH would attenuate greater hindquarters vasoconstriction to either stress in BN compared to DSS rats. BN and DSS rats were instrumented for determination of arterial pressure, heart rate, andwith pulsed Doppler flowprobes on the superiormesenteric and abdominal aorta. Bilateral guide cannulaswere implanted above the DMH. After recovery, we observed that cocaine (5 mg/kg, iv) elicited greater hindquarters andmesenteric vasoconstriction and greater bradycardia in BN rats compared toDSS rats. In contrast, CWS (1 cm deep for 1 min) elicited tachycardia in all rats and greater increases in mesenteric resistance in BN rats but hindquarters vasodilation that was greater in BN compared to DSS rats. Therefore, visceral and skeletalmuscle vascular responses differed between strains and stressors. We examined the dependence of these responses on the DMH with bilateral microinjections of muscimol (80 pmol in 100 nl) in theDMH.Muscimol attenuated thegreaterhindquarters andmesenteric vasoconstriction and tachycardia in BN rats without affecting responses in DSS rats in response to cocaine. Responses to CWSwere unaffected by muscimol except that tachycardia was selectively reduced in BN rats. Kainate (10 pmol) in the DMH elicited a similar response pattern as CWS. These studies demonstrate that the DMH plays a strainand stimulus-dependent role in mediating hemodynamic responses to stress. Our data suggest that there are significant variations in central neural pathways mediating stress that vary in different rat strains.

Renal- and calcium-dependent vascular effects of Polybia paulista wasp venom

In the present study, the effects of Polybia paulista venom (PPV) on renal and vascular tissues were investigated. Isolated kidneys perfused with PPV (1 and 3 μg/mL) had increased perfusion pressure, renal vascular resistance, urinary flow, and glomerular filtration rate; and reduced sodium tubular transport. Histological evaluation demonstrated deposits of proteins in Bowman's space and tubular lumen, and focal areas of necrosis. The venom promoted a cytotoxic effect on Madin-Darby canine kidney (MDCK) cells. A significant increase in lactic dehydrogenase levels was observed in response to venom exposure. In isolated mesenteric vascular beds, pressure and vascular resistance augmented in a dose-dependent manner. PPV increased the contractility of aortic rings maintained under basal tension. This contractile response was inhibited when preparations were maintained in Ca2+-free medium. Likewise, verapamil, a voltage-gated calcium channel blocker, also inhibited the contractile response. In this study, phentolamine, a blocker of α-adrenergic receptor blocker, significantly reduced the contractile effect of PPV in the aortic ring. In conclusion, PPV produced nephrotoxicity, which suggests a direct effect on necrotic cellular death in renal tubule cells. The vascular contractile effect of PPV appears to involve calcium influx through voltage-gated calcium channels via adrenergic regulation.

W1935 Rectal Distension Produces Increase in Mesenteric Vascular Resistance in Anesthetized Rats: A Compartment Syndrome and Attenuation by Topical Anesthetic

W1935 Rectal Distension Produces Increase in Mesenteric Vascular Resistance in Anesthetized Rats: A Compartment Syndrome and Attenuation by Topical Anesthetic

Exposure to chronic intermittent hypoxia in rats leads to exaggerated sympatho‐excitatory responses that are buffered by reduced adrenergic vasoconstriction in the mesentery

Chronic intermittent hypoxia (CIH) enhances sympatho‐excitatory reflexes in rats with blunted rises in arterial pressure (AP). Phenylephrine (PE; iv) evokes smaller rises in AP, suggesting adrenergic vascular reactivity is reduced. We examined if CIH reduces sympathetically‐mediated vasoconstriction in mesenteric (MES) vascular bed. Male Sprague‐Dawley rats were exposed to CIH (6% O2 for 40s, every 9 min, 8h/day, 2 wks). Under isoflurane rats were ventilated, paralyzed, prepared to record AP, splanchnic SNA, MES artery blood flow and then anesthesia was changed to urethane (750mg/kg)/chloralose (60mg/kg, iv). Compared to controls (n=9), rats with CIH (n=11) had higher AP (127±3 vs 107±7 mmHg, P<0.05) and SNA (85±11 vs 47±5 mV, P<0.05). After CIH, stimulation of brachial nerve evoked larger rises in SNA (137±21 vs 52± 11%, P<0.01) with blunted rises in AP and MES resistance (RES; 110±1 vs 117± 2%, P<0.05). Stimulation of brachial nerve after propranolol induced similar responses, suggesting beta adrenergic receptors were not mediating the blunted effects on AP and MES RES. After ganglionic block to eliminate SNA, PE evoked smaller rises in AP (n=5; 55±9 vs 83±7 mmHg, P<0.05) and MES RES (566±14 vs 971±234 %, P<0.05) in CIH rats. These data suggest CIH reduces sympathetically‐mediated alpha adrenergic vasoconstriction in the mesentery, perhaps as a buffer for chronically elevated SNA. AHA0755292, NIH‐HL075174

Reduction of Superior Mesenteric Hemodynamic Responsiveness to [Sar^1, Thr^8]-Angiotensin Ⅱ and Bradykinin, But Not Sodium Nitroprusside, in the Presence of Homocysteine Infusion

Hyperhomocysteinemia (HHcy) has been shown to be an independent risk factor for cardiovascular diseases, superior mesenteric thrombosis and inflammatory bowel disease. Superior mesenteric artery (SMA) supplies the intestine and reduced SMA blood flow results in intestinal ischemia. Although in vitro studies have shown that endothelium-dependent vasorelaxation of SMA is reduced in the presence of homocysteine incubation, it is not confirmed with in vivo studies. In this work, we evaluated responsiveness of SMA to endothelium-dependent or -independent vasodilators and a vasoconstrictor in the absence and presence of acute HHcy in vivo to clarify effect of HHcy on superior mesenteric vascular function. Sodium nitroprusside (SNP), bradykinin (BK), and [Sar1,Thr8]angiotensin II ([Sar1,Thr8]-ANG II) were intravenously administrated in sequence in male Sprague-Dawley rats with or without D,L-homocysteine infusion (6 mg/kg/min) through femoral vein. Agonists-induced changes in carotid artery blood pressure, superior mesenteric blood flow and vascular resistance were measured in the present study. We found that acute HHcy infusion had little effects on SNP-induced hemodynamic changes; however, BK-induced changes in blood pressure, blood flow and vascular resistance were significantly reduced in the presence of HHcy infusion. Additionally, HHcy also markedly decreased [Sar1,Thr8]-ANG II-induced superior mesenteric hemodynamic changes. These results demonstrated that responsiveness of SMA to vasoconstrictor, endothelium-dependent, but not endothelium-independent vasodilator, was inhibited in the presence of Hcy infusion. This HHcy-associated vascular hyporesponsiveness to vasoconstrictors and endothelium-dependent vasodilators may partially contribute to circulatory dysfunctions.

Systemic Activation of the Calcium Sensing Receptor Produces Acute Effects on Vascular Tone and Circulatory Function in Uremic and Normal Rats: Focus on Central versus Peripheral Control of Vascular Tone and Blood Pressure by Cinacalcet

Calcium-sensing receptor (CaR) activation decreases serum parathyroid hormone (PTH) and Ca2+ and, despite long-term reductions in mean arterial blood pressure (MAP), may produce acute hypertension in rats, an effect we hypothesized was mediated by constriction of multiple vascular beds. Rats were subjected to 5/6 nephrectomy (NX) or no surgery (Normal); at 7 to 8 weeks, uremia animals were anesthetized and instrumented to record MAP and regional blood flow (carotid, mesenteric, and hindlimb). Cinacalcet [N-(1-naphthalen-1-ylethyl)-3-[3-(trifluoromethyl)phenyl]-propan-1-amine; 1, 3, and 10 mg/kg; 30 min/dose] was infused over 90 min. In NX rats, cinacalcet dose-dependently decreased ionized calcium (iCa2+), elicited a 90% reduction in PTH, and produced dose-dependent self-limiting increases in MAP (from 119 +/- 6 to 129 +/- 5, 142 +/- 4, and 145 +/- 3 mm Hg at the end of each infusion). At 1 mg/kg, carotid vascular resistance (CVR) and mesenteric vascular resistance (MVR) increased to 16 +/- 6 and 18 +/- 6% above baseline, respectively. Hindlimb vascular resistance (HVR) also trended upward (13 +/- 8%). At 3 mg/kg, increases in CVR (38 +/- 10%), MVR (40 +/- 8%), and HVR (39 +/- 14%) were exacerbated; at 10 mg/kg, values remained at or near these levels. The effects of cinacalcet in Normal rats were similar to NX and were attenuated by ganglionic blockade with hexamethonium at low doses but remained significantly elevated at higher doses. Thus, CaR activation acutely increases MAP in uremic and nonuremic rats, responses that occur in parallel to vasoconstriction in multiple vascular beds through both a central and peripheral mechanism of action. Moreover, subsequent mechanistic studies suggest that increases in MAP produced by cinacalcet may be mediated by reduced tonic NO synthase-dependent NO production subsequent to reductions in blood iCa2+.

Serotonin and superior mesenteric artery resistance index

Objective. Serotonin is a vasoactive neuroendocrine substance and serotonergic drugs are promising agents for the treatment of functional gastrointestinal disorders. The effect of serotonin on superior mesenteric blood flow in humans is unknown. The aim of this study was to examine the effect of exogenous serotonin on superior mesenteric artery blood flow, as estimated by the resistance index with Doppler ultrasound, in healthy human volunteers. Material and methods. Six fasting healthy adult volunteers of both genders were studied. Transabdominal Doppler ultrasound was used to evaluate the effects of either a standard meal or intravenous infusion of serotonin (2.5–20 nmol kg−1 min−1) on the superior mesenteric artery resistance index, platelet‐depleted plasma levels of serotonin, blood pressure, heart rate and electrocardiogram. Results. All subjects had the same patterns of response to meal and serotonin stimulation. Meal stimulation decreased the mean resistance index from 0.84±0.04 to 0.72±0.02 (p = 0.0004) and increased platelet‐depleted‐plasma levels of serotonin from 50±36 to 61±46 nmol L−1 (p = 0.04). Serotonin stimulation increased the mean resistance index from 0.82±0.04 to 0.88±0.03 (p = 0.006) and mean platelet‐depleted‐plasma levels of serotonin from 44±24 to 83±37 nmol L−1 (p = 0.03). Most subjects reported minor short‐lived adverse effects. Electrocardiogram results were unchanged during all examinations. Conclusions. We conclude that intravenous infusion of serotonin increases the resistance index of the superior mesenteric artery (increases downstream resistance) in healthy adult volunteers.

THERMOREGULATORY ROLE OF PERIVENTRICULAR TISSUE SURROUNDING THE ANTEROVENTRAL THIRD VENTRICLE (AV3V) DURING ACUTE HEAT STRESS IN THE RAT

1. Thermoregulatory effector mechanisms are strongly influenced by hydration status. Dehydration delays the onset of evaporative heat loss and the redistribution of cardiac output in response to elevations in core temperature, yet very little is known about how and where thermal and non-thermal information is integrated. 2. The anteroventral third ventricular (AV3V) region encompasses several distinct neural structures, including the organum vasculosum of the lamina terminalis, the median preoptic nucleus, the preoptic periventricular nucleus and the medial aspects of the medial preoptic nucleus. In addition to its well-documented role in body fluid and cardiovascular homeostasis, recent anatomical and in vitro evidence has indicated the AV3V region may also be pivotal in the integration of thermal and osmotic information. 3. Electrolytic lesions of the AV3V region produce a markedly reduced thermal tolerance in rats. Elevations in mean arterial pressure, heart rate and mesenteric resistance were all attenuated in the AV3V-lesioned animals in response to a heat stress; however, hindquarter resistance was unaffected. Heat-induced salivation was also attenuated, severely reducing the ability of rats to lose heat via evaporation. 4. The AV3V region clearly has a functional role in thermoregulation, as well as cardiovascular and body fluid homeostasis. These data add further support to the hypothesis that thermal and non-thermal information may be integrated within this region.

Lesions of the anteroventral third ventricle region (AV3V) disrupt cardiovascular responses to an elevation in core temperature

Blood flow is redistributed from the viscera to the periphery during periods of heat stress to maximize heat loss. The heat-induced redistribution of blood flow is strongly influenced by nonthermal inputs such as hydration status. At present, little is known about where thermal and nonthermal information is integrated to generate an appropriate effector response. Recently, the periventricular tissue that surrounds the anteroventral third ventricle (AV3V) has been implicated in the integration of thermal and osmotic information. The purpose of the present study was to determine the effects of electrolytic lesions of the AV3V on the cardiovascular response to a passive heat stress in unanesthetized, free-moving male Sprague-Dawley rats. Core temperature was elevated at a constant rate of approximately 0.03 degrees C/min in sham- and AV3V-lesion rats using an infrared heat lamp. Changes in mesenteric and hindquarter vascular resistance were determined using Doppler flow probes, and heat-induced salivation was estimated using the spit-print technique. The rise in mean arterial pressure (MAP), heart rate (HR), and mesenteric resistance in response to elevations in core temperature were all attenuated in AV3V-lesion rats; however, hindquarter resistance was unaffected. Heat-induced salivation was also diminished. In addition, AV3V-lesion rats were more affected by the novelty of the experimental environment, resulting in a higher basal core temperature, HR, and MAP. These results indicate that AV3V lesions disrupt the cardiovascular and salivatory response to a passive heat stress in rats and produce an exaggerated stress-induced fever triggered by a novel environment.

Ouabain-induced hypertension alters the participation of endothelial factors in alpha-adrenergic responses differently in rat resistance and conductance mesenteric arteries.

1. This study compares the role of endothelial factors in alpha-adrenoceptor contractile responses in mesenteric resistance (MRA) and superior (SMA) mesenteric arteries from ouabain-treated (8.0 microg day(-1), 5 weeks) and untreated rats. The role of the renin-angiotensin system was also evaluated. 2. Ouabain treatment increased systolic blood pressure. In addition, ouabain reduced the phenylephrine response in SMA but did not alter noradrenaline responses in MRA. 3. Endothelium removal or the nitric oxide synthase (NOS) inhibitor (l-NAME, 100 microm) increased the responses to alpha-adrenergic agonists in both vessels. After ouabain treatment, both endothelial modulation and the l-NAME effect were increased in SMA, while only the l-NAME effect was increased in MRA. Endothelial NOS expression remained unaltered after ouabain treatment. 4. Indomethacin (10 microm) similarly reduced the noradrenaline contraction in MRA from both groups; in contrast, in SMA, indomethacin only reduced phenylephrine-induced contractions in segments from untreated rats. Co-incubation of l-NAME and indomethacin leftward shifted the concentration-response curves for noradrenaline more in MRA from ouabain-treated rats; tetraethylammonium (2 mm) shifted the noradrenaline curves further leftward only in MRA from untreated rats. 5.Losartan treatment prevents the development of hypertension but not all vascular changes observed after ouabain treatment. 6. In conclusion, a rise in endothelial NO and impaired prostanoid participation might explain the reduction in phenylephrine-induced contraction in SMA after ouabain treatment. An increase in the modulatory effect of endothelial NO and impairment of endothelium-dependent hyperpolarizing factor effect might explain why the ouabain treatment had no effect on noradrenaline responses in MRA.

Local metabolic effects of dopexamine on the intestine during mesenteric hypoperfusion.

This self-controlled experimental study was designed to test the hypothesis that dopexamine, a synthetic catecholamine that activates dopaminergic (DA-1) and beta2-adrenergic receptors, improves oxygenation in the jejunal mucosa during intestinal hypotension. In six normoventilated barbiturate-anesthetized pigs, controlled reductions in superior mesenteric arterial pressure (PSMA) was obtained by an adjustable clamp around the artery. Dopexamine infusions (0.5 and 1.0 microg.kg(-1).min(-1)) were administered at a freely variable PSMA (i.e., with the perivascular clamp fully open) and at a PSMA of 50 mmHg and 30 mmHg. We continuously measured superior mesenteric venous blood flow (QMES; transit-time ultrasonic flowmetry), jejunal mucosal perfusion (laser Doppler flowmetry), and tissue oxygen tension (PO2TISSUE; microoximetry). Jejunal luminal microdialysate of lactate, pyruvate, and glucose were measured every 5 min. Measurements of mucosal PCO2 (air tonometry), together with blood sampling and end-tidal PCO2 measurements, enabled calculations of pHi and PCO2 gap. Dopexamine reduced mesenteric vascular resistance and increased QMES at a PSMA of 50 mmHg and 30 mmHg. At a PSMA of 30 mmHg, dopexamine increased mesenteric oxygen delivery but did not influence mesenteric oxygen uptake or extraction. In this situation, dopexamine had no beneficial effect on jejunal mucosal blood flow. On the contrary, dopexamine increased mesenteric net lactate production and PCO2 gap, whereas PO2TISSUE and pHi decreased. Jejunal luminal microdialysate data demonstrated an increased lactate concentration and a pattern of decreased glucose concentration and increased luminal lactate-pyruvate ratio. These negative metabolic effects of dopexamine should be taken into account in situations of low perfusion pressures.

The effects of propofol on neural and endothelial control of in situ rat mesenteric vascular smooth muscle transmembrane potentials.

We indirectly assessed the in vivo effect of propofol on sympathetic neural and endothelial control of vascular smooth muscle (VSM) tone in Sprague-Dawley rats by measurement of in situ responses of VSM transmembrane potential (E(m)) in intact, small mesenteric arteries and veins superfused with physiologic salt solution. Measurements were made before, during, and after propofol infusion (10 and 30 mg x kg(-1) x h(-1)) in sympathetically innervated and locally denervated vessels. Propofol's effect on E(m) response to superfusion with acetylcholine (ACh), in physiologic salt solution also containing NG-nitro-L-arginine-methyl-ester and indomethacin, was determined in innervated vessels. At 30 mg x kg(-1) x h(-1), propofol caused greater arterial VSM hyperpolarization in innervated compared with denervated vessels (4.8 +/- 2.0 mV versus 2.8 +/- 1.5 mV, respectively). ACh hyperpolarized arterial, but not venous, VSM (e.g., 11.7 +/- 2.4 mV at 10(-4) M). ACh-induced hyperpolarization was eliminated by 30 mg x kg(-1) x h(-1) propofol. Assuming a close inverse correlation between magnitude of VSM E(m) and contractile force, these results suggest that propofol attenuates both sympathetic neural and nonneural regulation of VSM tone. They also suggest that propofol and ACh may act competitively in the second messenger cascade regulating VSM K+ channel activity in mesenteric resistance arteries. Vascular smooth muscle (VSM) contractile force responses to the IV anesthetic, propofol, were indirectly assessed by VSM membrane potential changes to clarify the mechanisms underlying attenuation of peripheral vascular control of arterial blood pressure. Results indicate that propofol-induced VSM membrane hyperpolarization and coupled reduction of VSM contractile force underlie such attenuation.

Role of Cl − channels in α-adrenoceptor-mediated vasoconstriction in the anesthetized rat

In vitro studies have provided evidence that Cl − ion currents are important for activation of vascular smooth muscle contraction. The stilbene, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), disrupts Cl − metabolism by blocking Cl − channels and by inhibiting Cl − bicarbonate exchange. The aims of this study were to: (i) characterize the hemodynamic responses produced by DIDS in pentobarbital anesthetized rats, and (ii) examine vasoconstrictor responses to norepinephrine before and after administration of DIDS. DIDS (2.5–50 μmol/kg, 92.5 μmol/kg total dose, i.v.) produced dose-dependent but transient reductions in mean arterial blood pressure and in hindquarter, renal and mesenteric vascular resistances. Prior to the administration of DIDS, norepinephrine (1.0–5.0 μg/kg, i.v.) produced dose-dependent increases in mean arterial pressure, renal resistance and mesenteric resistance, but decreases in hindquarter resistance that were inversely related to dose. After administration of DIDS, the peak pressor responses produced by norepinephrine were either slightly diminished (1.0, 2.5 μg/kg) or unchanged (5.0 μg/kg). Peak norepinephrine-induced changes in hindquarter and renal vascular resistance were unaffected by DIDS, while increases in mesenteric resistance were augmented. The total norepinephrine-induced increases in mean arterial pressure (mm Hg×s) were markedly reduced by DIDS. These effects of DIDS on norepinephrine-induced responses were similar, but not identical to those of the voltage-sensitive Ca 2+ channel blocker, nifedipine (500 nmol/kg, i.v.). These findings suggest that DIDS may interfere with norepinephrine-induced depolarization of resistance arteries, thereby preventing activation of voltage-sensitive Ca 2+ channels.