Superior Mesenteric Vascular Beds Research Articles

The association between liver fat and systemic calcified atherosclerosis

BackgroundThe association of nonalcoholic fatty liver disease (NAFLD) with systemic calcified atherosclerosis, other than the coronary arteries, has not been clearly elucidated. We investigated the association between NAFLD and calcification in eight different vascular beds. MethodsIn a community-based cohort with computed tomography scans for carotid artery, coronary artery, thoracic aorta, abdominal aorta, iliac artery, renal artery, celiac trunk, and superior mesenteric artery, the association between NAFLD and arterial calcification was evaluated with adjustment for age, sex, hypertension, dyslipidemia, diabetes, obesity, current smoking status, and family history of heart disease in the first-degree relatives. ResultsIn age- and sex-adjusted models, NAFLD was significantly associated with calcification in the coronary artery, carotid artery, thoracic aorta, celiac trunk, and superior mesenteric artery vascular beds (P < .05). However, adjustment for the traditional chronic venous disease risk factors attenuated the associations, except in the case of the thoracic aorta (odds ratio [OR], 1.38; 95% confidence interval [CI], 1.09-1.78) and celiac trunk (OR, 2.05; 95% CI, 1.16-3.65). In addition, NAFLD was independently associated with multiarterial calcification (four or more [OR, 1.33; 95% CI, 1.01-1.74], five or more [OR, 1.46; 95% CI, 1.09-1.97], and six or more [OR, 1.58; 95% CI, 1.09-2.30] of eight evaluated arterial segments). ConclusionsThe association between NAFLD and arterial calcification is mainly mediated by conventional risk factors. The independent association between NAFLD and calcification in the thoracic aorta and celiac trunk as well as in a larger number of vascular beds needs confirmation in future prospective studies in diverse populations.

Ischemia/Reperfusion-Induced Low Reactivity of the Rat Superior Mesenteric Vascular Bed is Associated With Expression of Nitric Oxide Synthases

Our objective was to investigate the mRNA and protein expressions of eNOS and iNOS in the mesenteric vascular bed after ischemia and reperfusion of the rat superior mesenteric artery (SMA) and the role of nitric oxide (NO) in the response of the vascular bed to vasoconstrictors following reperfusion of the SMA. Methods Real-time polymerase chain reaction and immunohistochemistry were used to monitor the mRNA and protein expression of eNOS and iNOS after I/R challenge to the rat SMA. Ischemia was induced by clamping the SMA for 40 minutes, after which the flow was restored and the vessels were reperfused for 300 minutes. Blood samples were collected for assays of lactic dehydrogenase, tumor necrosis factor (TNF), hydroxyl radical, and NO. After ischemia/reperfusion, the vascular beds were separated for analysis of the expression of eNOS and iNOS. The SMA with its associated intestinal tissue was isolated and perfused in vitro with Tyrode’s solution ( N = 8) then challenged with phenylephrine. Results Reperfusion of the SMA induced an increase in blood concentrations of lactic dehydrogenase ( P < .001; N = 8), hydroxyl radical ( P < .05), TNF ( P < .001), and NO ( P < .05). ENOS and iNOS mRNA expression increased 1.3 ± 0.1-fold and 19.6 ± 3.5-fold, respectively when compared to the sham-operated group. Protein expression increased 1.9 ± 0.4-fold and 12.6 ± 3.1-fold, respectively, after reperfusion (N = 3) when compared with sham-treated rats. In vitro challenge showed that administration of phenylephrine (10 −8 ∼ 10 −4 nmol) produced vasoconstriction in a dose-related manner. Maximum contractile responses to phenylephrine were attenuated in reperfused SMA. Addition of the NOS inhibitor N G-nitro-L-arginine (L-NNA, 10 −4 M) resulted in full recovery of the response to phenylephrine. Conclusions Ischemia/reperfusion of the SMA results in a decrease in vascular reactivity of the mesenteric vessels that is dependent on NOS expression by the intestinal vascular bed.

Role of endothelin in regulation of resistance, fluid-exchange, and capacitance functions of the systemic circulation.

This article reviews data at the in vivo whole animal and human level. The importance of both flow and pressure recordings and of the methods used to record these variables is emphasized. Exogenous administration of endothelin-1 evokes a transient depressor response mediated by endothelial endothelinB receptors, but the predominate effect of endothelin-1 is a sustained increase in blood pressure resulting from increases in total peripheral resistance. Resistance in the superior mesenteric, renal, and hindquarter vascular beds of animals and forearm resistance in humans is increased. Both endothelinA and, to a lesser extent, endothelinB receptors on vascular smooth muscle mediate the increases in resistance. Endothelin-1 evokes decreases in the precapillary/postcapillary resistance ratio, resulting in increased capillary pressure and net transcapillary filtration. Endothelin-1 evokes increases in mean circulatory filling pressure in animals and in constriction of the human dorsal hand vein. This venoconstrictor activity is mediated primarily through endothelinA and to a lesser extent endothelinB receptors. Endogenously generated endothelin contributes to the hemodynamic effects of angiotensin and vasopressin in certain animal models of hypertension. Antagonists of endothelin evoke modest hemodynamic changes in healthy humans and in some healthy animals, and they decrease vascular resistance dramatically in several salt-sensitive rat models of hypertension and also in some hypertensive human subjects. Thus, endogenously generated ET appears to play a modest role in the healthy organism, but it likely plays a major role in many pathophysiological states as described in companion articles in this issue.

Tonic inhibitory control exerted by opioid peptides in the paraventricular nuclei of the hypothalamus on regional hemodynamic activity in rats.

1. Systemic and regional cardiovascular changes were measured following bilateral microinjection of specific and selective opioid-receptor antagonists into the paraventricular nuclei of the hypothalamus (PVN) of awake, freely moving rats. 2. PVN microinjection of increasing doses of the specific opioid antagonist naloxone - methiodide (1 - 5.0 nmol), or a selective mu-opioid receptor antagonist, beta-funaltrexamine (0.05 - 0.5 nmol), evoked important cardiovascular changes characterized by small and transient increases in heart rate (HR) and mean arterial pressure (MAP), vasoconstriction in renal and superior mesenteric vascular beds and vasodilation in the hindquarter vascular bed. 3. No significant cardiovascular changes were observed following PVN administration of the highly selective delta-opioid-receptor antagonist, ICI 174864 (0.1 - 1 nmol), or the selective kappa-opioid-receptor antagonist, nor-binaltorphine (0.1 - 1 nmol). 4. Most of the cardiovascular responses to naloxone (3 nmol) and beta-funaltrexamine (0.5 nmol) were attenuated or abolished by an i.v. treatment with a specific vasopressin V(1) receptor antagonist. 5. These results suggest that endogenous opioid peptides and mu-type PVN opioid receptors modulate a tonically-active central depressor pathway acting on systemic and regional haemodynamic systems. Part of this influence could involve a tonic inhibition of vasopressin release.

Cardiovascular Action of Insulin-like Growth Factor-1 Is Not Mediated by Calcitonin Gene-Related Peptide Neurons

Calcitonin gene-related peptide (CGRP) is a potent vasodilator located in the peripheral nerves including the perivascular nerves. Previous studies in our laboratory determined that the vasodilatory action of insulin is mediated in part by CGRP-containing neurons. Since insulin-like growth factor-1 (IGF-1) and insulin share molecular and receptor structural similarity as well as functional similarity, we investigated the role of the CGRP-containing neurons in IGF-1-mediated vasodilation. Wistar rats were made CGRP deficient by treatment with capsaicin (50 mg/kg) 1-3 d after birth. Vehicle-treated controls and CGRP-deficient rats were maintained for 12 to 13 wk. At this time rats were fasted overnight, anesthetized with urethane and chloralose, and prepared for cardiovascular recordings. The basal mean arterial pressure (MAP) was higher in CGRP-deficient rats when compared with controls. The infusion of IGF-1 resulted in an equivalent decrease in MAP in both the CGRP-deficient and control rats. IGF-1 infusion did not change the heart rate in control rats but decreased it in CGRP-deficient rats. IGF-1 also increased flow as determined by conductance in the iliac, renal, and superior mesenteric vascular beds in both vehicle controls and CGRP-deficient rats. We concluded that unlike insulin the IGF-1-mediated vasodilatory response is not mediated by the CGRP-dependent perivascular neurons.

Effects of the novel selective endothelin ET(A) receptor antagonist, SB 234551, on the cardiovascular responses to endotoxaemia in conscious rats.

1. In conscious, freely moving, male, Long Evans rats, regional haemodynamic responses to exogenous endothelin-1 (ET-1; 25, 50 and 250 pmol kg(-1) i.v.) were assessed in the presence of vehicle, or the selective ET(A)-receptor antagonist, SB 234551. On the following day, the effects of SB 234551 on the haemodynamic responses to lipopolysaccharide (LPS) infusion (150 microg kg(-1) h(-1), i.v.) were determined. 2. When SB 234551 was given i.v. by primed infusion at a dose of 0.3 mg kg(-1) bolus, 0.3 mg kg(-1) h(-1) infusion, it caused selective inhibition of the vasoconstrictor effects of exogenous endothelin-1, whereas at a dose of 1 mg kg(-1), 1 mg kg(-1) h(-1), SB 234551 also inhibited some of the vasodilator effects of endothelin-1. 3. Infusion of LPS, in the presence of vehicle, caused a short-lived (1 - 2 h) hypotension, tachycardia, and vasodilatation in renal, superior mesenteric and hindquarters vascular beds. Thereafter, blood pressure, heart rate and mesenteric vascular conductance returned to baseline values, but renal vasodilatation persisted, and there was vasoconstriction in the hindquarters. 4. In the presence of SB 234551 (0.3 mg kg(-1), 0.3 mg kg(-1) h(-1)), the early (1 - 2 h) cardiovascular responses to LPS infusion were unaffected, but the subsequent recovery of mean arterial blood pressure was impaired, due to developing vasodilatation in the mesenteric and, to a lesser extent, hindquarters, vascular beds. SB 234551 had no effect on the renal haemodynamic responses to LPS infusion. 5. The results confirm an important, regionally-selective, vasoconstrictor role for endogenous endothelin in this model of endotoxaemia.

Possible Contribution of Central Gamma‐Aminobutyric Acid Receptors to Resting Vascular Tone in Freely Moving Rats

Previous studies have shown that central administration of GABA (gamma -aminobutyric acid), an inhibitory neurotransmitter, preferentially reduces hindquarters and carotid vascular resistances but not renal and coeliac vascular resistances in conscious rats. This study tested the hypothesis that these preferential actions of central GABA receptors are related to differences between vessels in resting autonomic vascular tone in freely moving rats. Rats were chronically implanted with intracisternal cannulas and/or electromagnetic probes to measure regional blood flows. In response to GABA administration, the changes in vascular resistance (arterial blood pressure/regional blood flow) of the hindquarters (n = 23) and carotid (n = 12) vascular beds were significantly and negatively correlated with basal vascular resistance. No such relationship was found for the renal (n = 21), coeliac (n = 13) and superior mesenteric (n = 23) vascular beds. This finding indicates that the responsiveness to GABA of brainstem pathways controlling the hindquarters and carotid vascular beds co-varies with resting resistance in hindquarters and carotid vessels. A similar analysis was performed, correlating the ongoing vascular resistance of each vessel with its response to ganglionic blockade by chlorisondamine. In this case, a significant negative correlation was also found for the hindquarters (n = 26) and carotid (n = 15) vascular beds, but not for the coeliac (n = 17) or superior mesenteric (n = 19) vessels. Together, these findings suggest that central GABA receptors accessible from the cisterna magna preferentially affect two vascular beds which, in the freely moving rat, show resting autonomic vascular tone.

Isradipine and insulin sensitivity in hypertensive rats.

The present study was designed to investigate the effect of a reduction in blood pressure, by using the calcium channel antagonist isradipine, on insulin sensitivity and vascular responses to insulin in conscious spontaneously hypertensive male rats (SHR). The rats were instrumented with intravascular catheters and pulsed Doppler flow probes to measure blood pressure, heart rate, and blood flows. Insulin sensitivity was assessed by the euglycemic-hyperinsulinemic clamp technique. Two groups of rats received isradipine at a dose of 0.05 or 0.15 mg. kg-1. h-1, whereas a third group received a continuous infusion of vehicle (15% DMSO). Both doses of isradipine were found to decrease mean blood pressure (-25 +/- 4 mmHg at the dose of 0.05 mg. kg-1. h-1 and -20 +/- 2 mmHg at the dose of 0.15 mg. kg-1. h-1) and to improve insulin sensitivity. Moreover, in the rats treated with the low dose of isradipine, we observed vasodilations in renal, superior mesenteric, and hindquarter vascular beds. In the untreated group, the euglycemic infusion of insulin (4 mU. kg-1. min-1) was found to cause vasoconstrictions in superior mesenteric and hindquarter vascular beds, but no changes in mean blood pressure, heart rate, or renal vascular conductance were found. In contrast, in the isradipine-treated groups, the same dose of insulin was found to produce vasodilations in the renal vascular bed and to abolish the vasoconstrictor responses previously observed. We concluded that short-term treatment with isradipine in SHR can lower blood pressure and improve insulin sensitivity, mainly through hemodynamic factors, as supported by experiments with hydralazine as a positive vasodilator control.

Effects of salt-loading on membrane potentials in mesenteric arteries of spontaneously hypertensive rats.

Although salt intake and blood pressure are correlated, with hypertensives tending to exhibit higher blood pressure sensitivity to salt than normotensives, the precise mechanisms underlying this relationship remain unclear. This study aimed to determine whether salt-loading affects arterial membrane properties of spontaneously hypertensive rats (SHR). SHR and age-matched Wistar Kyoto rats (WKY) received either an 8% high salt diet or standard rat chow from 6 to 16 wk of age. Systolic blood pressure was significantly higher in salt-loaded SHR than in control SHR (267+/-7 vs. 235 +/- 5 mmHg, p < 0.05). The membrane potential of isolated conduit and resistance arteries of the superior mesenteric vascular bed, measured with microelectrodes, was less negative in salt-loaded SHR than in control SHR or salt-loaded WKY (conduit arteries, -39.9 +/- 0.3 vs. -44.5 +/- 0.4 or -47.4 +/- 0.4 mV, respectively, p < 0.05 for each; resistance arteries, -55.5 +/- 0.5 vs. -62.5 +/- 0.5 or -67.0 +/- 0.5 mV, respectively, p < 0.05 for each). Furthermore, conduit arteries of salt-loaded SHR exhibited spontaneous electrical activity (4-13 mV, 1-3/min), which was sensitive to ONO-3708, a thromboxane A2/prostaglandin H2 receptor antagonist. These findings suggest that salt-loading in SHR leads to a membrane depolarization in both conduit and resistance arteries, as well as to spontaneous electrical activity, presumably mediated by eicosanoids, in conduit arteries. These alterations in membrane properties might contribute to the exacerbation of hypertension and/or the target organ damage after salt loading in SHR.

Preparation and application of an isolated superior mesenteric arterial vascular preparation.

Our laboratory developed an isolated perfused superior mesenteric arterial vascular bed preparation to study and correlate vascular smooth-muscle mechanics with associated biochemical events. This preparation provides consistent dose-dependent contractile responses, contains most of the superior mesenteric artery as well as first-, second-, and third-generation arterioles, and has been used for concurrent functional and biochemical analysis of vascular smooth muscle. Preparations isolated from Sprague-Dawley rats produced rapid, dose-related vasoconstrictor responses to norepinephrine (NE) and KCl, while appearing to be unresponsive to periarterial nerve stimulation. Endothelial relaxations to bolus doses of acetylcholine (ACh) in the presence of a constant infusion of NE (10 microM) were limited, producing reductions of perfusion pressures of <25%. Receptor-binding studies conducted to evaluate alpha1-adrenoceptor subtypes revealed high- and low-affinity binding sites composing 91 and 9% of the overall population, respectively. A 60-s time course for contractile response and inositol 1,4,5-triphosphate (IP3) production revealed a significant but transient increase of IP3 that paralleled the contractile response generated by using bolus injections of NE (30 microg). This preparation offers the capacity to conduct perfusion studies investigating vasoconstrictor responses, as well as biochemical studies including receptor-binding and second-messenger assays in the same tissue.

Neurally-mediated vasodilatation in normal and portal hypertensive rats: role of nitric oxide and calcitonin gene-related peptide

Background/Aims: Portal hypertension is associated with systemic vasodilatation and vascular hyporeactivity, and is reversed by inhibiting nitric oxide biosynthesis. Nitric oxide and calcitonin gene-related peptide are neurotransmitters of non-adrenergic non-cholinergic nerves. The role of nitric oxide and calcitonin gene-related peptide in nerve-stimulated vasodilatation in portal hypertension is unknown. Methods: We tested (i) if in vitro perfused superior mesenteric arterial vascular beds of portal hypertensive rats (induced by partial portal vein ligation) showed an increased vasodilatation to periarterial nerve stimulation compared to normal controls, and (ii) if this vasodilatation was modulated by nitric oxide and calcitonin gene-related peptide antagonism. Results: Vasodilatatory responses to periarterial nerve stimulation (10 V, 1 ms) with increasing frequencies (Hertz, 2–12) in preconstricted vessels (methoxamine and guanethidine) were significantly smaller in vessel preparations of control ( n=8) compared to portal hypertensive ( n=7) rats, values with 8 Hertz being 32.3±3.6% and 44.9±3.6%, respectively ( p<0.05). This difference was reversed by inhibiting nitric oxide and calcitonin gene-related peptide action with the nitric oxide-biosynthesis inhibitor N ω-Nitro-L-arginine, values for 8 Hertz being 28.7±4.8% (controls) and 37.8±3.3% (portal hypertensive, ns) or with the calcitonin gene-related peptide antagonist CGRP 8–37, values being 25.2±2.8% (controls) and 27.8±4.2% (portal hypertensive, ns), respectively ( n=4–6 per group). Vasodilatation to the β-agonist isoproterenol was not significantly different between groups with and without calcitonin gene-related peptide and nitric oxide antagonism. Conclusion: Portal hypertensive rats display a significantly enhanced vasodilatation to periarterial nerve stimulation, which is reversed by inhibiting the non-adrenergic non-cholinergic neurotransmitters nitric oxide and especially calcitonin gene-related peptide.

Regional Blood Flow Dynamics in Response to Insulin and IGF-1 in Diabetic Animals

Vascular changes in diabetes characterized by increased contractile or decreased dilator responses have been demonstrated in isolated blood vessels as well as in vivosystems. Previous studies in our laboratory have demonstrated that insulin and insulin like growth factor-1 (IGF-1) can decrease mean arterial pressure (MAP) and increase blood flow in vascular beds. In this study we evaluated the regional hemodynamic responses to insulin and IGF-1 in normal and diabetic rats. Normal male rats were made diabetic with streptozotocin (55 mg/kg) i.v. and maintained 60 to 70 days. On the day of the study the rats were anesthetized with urethane/chloralose, the femoral artery and vein cannulated for blood pressure monitoring and blood sampling or infusion, respectively. Pulsed-Doppler flow probes were placed around the iliac artery, renal artery and superior mesenteric artery to monitor blood flow. Insulin (16 nmol/kg) was infused as a bolus via the femoral vein and it decreased the MAP approximately 17% in both normal and diabetic rats. Insulin enhanced vascular flow (expressed as conductance) in the iliac and renal vascular bed but not the superior mesenteric vascular bed in normals. In diabetic rats the flow response to insulin compared to normals was attenuated in the iliac and renal vascular beds and increased in the superior mesenteric vascular bed. A bolus infusion of IGF-1 (16 nmol/kg) also decreased the MAP in normals and diabetics. IGF-1 increased vascular flow in all three vascular beds in normals but in the diabetics the response to IGF-1 was artenuated in the iiiac, increased in h e renal vascular bed and suppressed in the superior mesenteric vascularure. From these studies we conciude that diabetes is associated with an anenllared vascular response to insulin and IGF-1 in the iliac and renal vessels while insulin augments and IGF-1 decreases blood flow in the superior mesenteric vasculature

Purines and the nucleus tractus solitarius: effects on cardiovascular and respiratory function.

1. The roles of adenosine and adenosine 5'-triphosphate in cardiorespiratory regulation by the nucleus tractus solitarius (NTS) have been evaluated in a range of experiments, using micro-injections of selective agonists and antagonists of purinoceptors. 2. Adenosine injected into the caudal NTS decreases heart rate (HR), arterial blood pressure (BP) and respiratory frequency by an action at A2a receptors on glutamatergic nerve terminals. Microinjections of the A2a agonist CGS21680 caused falls in arterial BP and HR which were selectively antagonized by the A2a antagonist CGS15943. Injection of the A1 agonist CPA in the caudal NTS elevated BP and HR and its actions were selectively antagonized by the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine. Adenosine enhanced glutamate release in the NTS. 3. In the rostral NTS, adenosine administration resulted in an elevation of BP. 4. ATP microinjection into the subpostremal NTS depressed HR and BP by an action on P2x purinoceptors, which are blocked by saramin. ATP microinjections differentially affected vascular conductance in regional peripheral vascular beds, with the most marked increases in conductance in the iliac bed and lesser effects in the superior mesenteric and renal vascular beds. 5. Recordings from renal and lumbar sympathetic nerves have demonstrated marked dose-dependent decreases in efferent activity following alpha, beta-methylene ATP injections into the NTS; however, only renal but not lumbar sympathetic nerve activity was inhibited following CGS21680 injections into the same site of the NTS. 6. ATP may function as a fast-acting neurotransmitter in the baroreceptor afferent pathway or in interneurons in the NTS. Adenosine is likely to play a role as a modulator of activity in baroreceptor and chemoreceptor pathways, fine tuning the functional output of both systems.

Intracerebroventricular administration of NPY increases sympathetic tone selectively in vascular beds.

NPY is widely distributed and has broad regulatory actions in the peripheral and central nervous system (CNS) and is especially important in the regulation of cardiovascular responses. CNS administered NPY has been demonstrated to produce both increases and decreases in cardiovascular tone. In this study we evaluated the effect of intracerebroventricular (ICV) administered NPY on cardiovascular tone, regional blood flow dynamics, as well as the mechanism of this action in normal animals. Male rats were instrumented with ICV cannulas and allowed to recover. At the time of the experiment the rats were anesthetized with urethane/chloralose and the femoral artery cannulated for blood pressure determinations. The abdomen was opened and Doppler flow probes were placed around the iliac, renal, and superior mesenteric artery. Mean arterial pressure (MAP), heart rate (HR), iliac, renal, and superior mesenteric flow, as well as the calculated iliac, renal, and superior mesenteric conductance were determined. ICV administered NPY resulted in an increase in MAP and HR, which was associated with decreased flows in the iliac and superior mesenteric vessels while increasing renal flow. Conductance was decreased in the iliac and superior mesenteric vascular beds but not the renal artery. ICV administration of NPY in the presence of a systemically administered alpha1-adrenergic inhibitor, prazosin, attenuated the NPY-mediated effects on MAP as well as vascular conductance in the iliac and superior mesenteric vessels. Additionally, ICV administration of NPY in the presence of a systemically administered beta1-adrenergic inhibition, atenolol, also attenuated the NPY-mediated increase in HR and MAP. Blood flow responses and iliac and superior mesenteric vascular conductance were also attenuated by atenolol pretreatment. In these studies we conclude that lateral ventricular administration of NPY acts to increase systemic MAP and HR and the response is mediated by an increase in sympathetic tone to the heart and especially the splanchnic and skeletal muscle vasculature.

Insulin sensitivity and hemodynamic responses to insulin in Wistar-Kyoto and spontaneously hypertensive rats.

The insulin-mediated vasodilator effect has been proposed as an important physiological determinant of insulin action on glucose disposal in normotensive humans. The present study was designed to further examine the acute regional hemodynamic effects of insulin in different vascular beds and to explore the relationships between insulin vascular effects and insulin sensitivity during euglycemic hyperinsulinemic clamps in conscious normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The rats were instrumented with intravascular catheters and pulsed Doppler flow probes to measure blood pressure, heart rate, and regional blood flows. In WKY rats, the euglycemic infusion of insulin (4 and 16 mU.kg-1.min-1) causes vasodilations in renal and hindquarter vascular beds but no changes in mean blood pressure, heart rate, or superior mesenteric vascular conductance. In contrast, in SHR, the same doses of insulin produce vasoconstrictions in superior mesenteric and hindquarter vascular beds and, at high doses, increase blood pressure. Moreover, at the lower dose of insulin tested, we found a reduction in the insulin sensitivity index in the SHR compared with the WKY rats. The present findings provide further evidence for an association between insulin sensitivity and insulin-mediated hemodynamic responses.

Activation of purinergic receptor subtypes in the nucleus tractus solitarius elicits specific regional vascular response patterns

The nucleus tractus solitarius (NTS) is a major integrative site in the brain stem involved in central autonomic control. Several lines of evidence indicate that ATP, acting at P 2x purinoceptors, and adenosine, acting at A 2a adenosine (P 1) purinoceptors, play synchronous roles as transmitter substances in NTS-mediated mechanisms of cardiovascular control. The purpose of this study was to examine regional vascular response patterns elicited by selective activation of purinergic receptor subtypes in the NTS. Adult male rats were anesthetized with a mixture of α-chloralose and urethane. Pulsed-Doppler flow probes were placed on the iliac, renal and superior mesenteric arteries via a midline laparotomy for measurement of regional blood flow velocities. The animal was then mounted prone in a stereotaxic unit and the dorsal surface of the medulla was surgically exposed in the region of the obex. Microinjections of α,β-methylene ATP (α,β-MeATP), a selective P 2x purinergic receptor agonist, or 2- p-(2-carboxyethyl)Phenethylamino-5′- N-ethylcarboxamidoadenosine (CGS 21680), a selective A 2a adenosine (P 1) receptor agonist, were made into the subpostremal region of the NTS via multibarrel glass micropipettes. Both α,β-MeATP (25 and 100 pmoles/rat) and CGS 21680 (2 and 20 pmoles/rat) produced significant dose-related reductions in blood pressure and heart rate. These agonist-elicited depressor response patterns were associated with a pronounced and preferential dilation of the iliac vascular bed. However, α,β-MeATP, but not CGS 21680, also caused significant dilation of the renal and superior mesenteric vascular beds, although lesser in magnitude compared to the iliac bed, whereas the hypotensive actions of CGS 21680 were considerably more prolonged compared to the very rapid and transient effects of α,β-MeATP. These resutls support the view that extracellular ATP and adenosine via synchronous actions at specific purinergic receptor subtypes in the NTS may be functionally linked as neural signalling substances to selectively coordinate the regulation of regional vasomotor tone.

Long-term octreotide treatment prevents vascular hyporeactivity in portal-hypertensive rats

Chronically portal-hypertensive rats show in vitro vascular hyporeactivity in large part mediated by the endothelium-derived vasodilator nitric oxide. We tested whether long-term octreotide treatment (15 micrograms/kg subcutaneously in 5% D/W, 8-hourly) corrects the in vitro vascular hyporeactivity. Increases in perfusion pressures (delta mm Hg) to potassium chloride (30-300 mmol/L) of in vitro perfused superior mesenteric arterial vascular beds of partial portal vein-ligated (PVL) rats were significantly (P < .05) higher in octreotide (n = 9) compared with placebo (n = 10, 5% D/W) treated animals. Octreotide significantly (P < .05) increased mean arterial pressure compared with placebo, the values being 129 +/- 3 and 117 +/- 4 mm Hg, respectively. Furthermore, a significant (P < .001) correlation was observed between in vitro vascular reactivity and mean arterial pressure. Incubation of separate vascular beds (n = 7 for both PVL and sham-operated rats) with octreotide (10-6 mol/L) did not enhance pressure responses to 125 mmol/L potassium chloride, and failed to increase perfusion pressures in preconstricted vessel preparations (n = 6), excluding a direct inhibitory effect on NO. In summary, long-term octreotide treatment prevents in vitro vascular hyporeactivity in prehepatic portal-hypertensive rats, and octreotide does not exert its action through direct effects on endothelium-derived NO. (Hepatology 1996 May;23(5):1218-23)

Long-term octreotide treatment prevents vascular hyporeactivity in portal-hypertensive rats.

Chronically portal-hypertensive rats show in vitro vascular hyporeactivity in large part mediated by the endothelium-derived vasodilator nitric oxide. We tested whether long-term octreotide treatment (15 micrograms/kg subcutaneously in 5% D/W, 8-hourly) corrects the in vitro vascular hyporeactivity. Increases in perfusion pressures (delta mm Hg) to potassium chloride (30-300 mmol/L) of in vitro perfused superior mesenteric arterial vascular beds of partial portal vein-ligated (PVL) rats were significantly (P < .05) higher in octreotide (n = 9) compared with placebo (n = 10, 5% D/W) treated animals. Octreotide significantly (P < .05) increased mean arterial pressure compared with placebo, the values being 129 +/- 3 and 117 +/- 4 mm Hg, respectively. Furthermore, a significant (P < .001) correlation was observed between in vitro vascular reactivity and mean arterial pressure. Incubation of separate vascular beds (n = 7 for both PVL and sham-operated rats) with octreotide (10(-6) mol/L) did not enhance pressure responses to 125 mmol/L potassium chloride, and failed to increase perfusion pressures in preconstricted vessel preparations (n = 6), excluding a direct inhibitory effect on NO. In summary, long-term octreotide treatment prevents in vitro vascular hyporeactivity in prehepatic portal-hypertensive rats, and octreotide does not exert its action through direct effects on endothelium-derived NO.

Effects of gamma-aminobutyric acid on regional vascular resistances of conscious spontaneously hypertensive rats.

1. The regional vascular effects of a central injection of gamma-aminobutyric acid (GABA) in conscious spontaneously hypertensive rats (SHR) were compared with normotensive control rats (NCR), including Wistar-Kyoto rats (male, 10-20 weeks of age). One week or more after insertion of a cannula into the cisterna magna, an electromagnetic flow probe was implanted around one of five arteries, and a catheter for measurement of blood pressure and heart rate was inserted into the terminal aorta or common carotid artery. Cardiovascular changes were observed in the conscious animal after recovery from the surgery. Peripheral resistance was calculated as pressure divided by flow. 2. Ten min following intracisternal injection of 10 mu mol of GABA, mean arterial pressure and heart rate were significantly lowered (P < 0.05; t-test): - 29 and -16% (70 d.f.) in SHR versus -23 (116 d.f.) and -19% (112 d.f.) in NCR. Hindquarters, carotid, superior mesenteric and renal, but not coeliac, vascular resistances were significantly lowered (P < 0.05; t-test, 21, 9, 18 d.f.) in SHR. However, when comparing the effect of GABA injection in SHR and NCR, there were no significant differences in coeliac, carotid and hindquarters vascular resistances, but there were significant decreases in superior mesenteric and renal vascular resistances in SHR. 3. These results indicate that: (i) a cisternal injection of GABA in SHR decreases both peripheral vascular resistance and heart rate, and thereby lowers blood pressure; (ii) the vascular resistance of the superior mesenteric and renal vascular beds was more decreased in SHR than in NCR. This suggests that the GABAergic control of regional vascular resistance differs in the SHR and the NCR.

Regional haemodynamic effects of mu-, delta-, and kappa-opioid agonists microinjected into the hypothalamic paraventricular nuclei of conscious, unrestrained rats.

1. The cardiovascular effects of bilateral injection into the hypothalamic paraventricular nuclei of selective mu-, delta-, and kappa-opioid receptor agonists were investigated in conscious, unrestrained Wistar Kyoto rats, chronically instrumented with pulsed Doppler flow probes for measurement of regional haemodynamics. 2. The selective mu-agonist [D-Ala2,MePhe4,Gly5ol]enkephalin (DAMGO), injected bilaterally into the hypothalamic paraventricular nuclei (0.01-1.0 nmol), caused increases in blood pressure, tachycardias, vasoconstriction in renal and superior mesenteric vascular beds and substantial vasodilatation in the hindquarter vascular bed. 3. The administration of increasing doses (0.01-5.0 nmol) of the selective delta-agonist [D-Phe2,5]enkephalin (DPDPE) or the selective kappa-agonist, U50488H into the paraventricular nuclei (PVN) had no significant effect on blood pressure, heart rate, or regional haemodynamics. 4. Together, the present results are further evidence of a role for opioid peptides, especially acting at mu-receptors in the PVN, in the central regulation of the cardiovascular system, whereas a role for opioid peptides, acting at delta- and kappa-receptors in the PVN, seems less obvious from the present results.