Mesenteric Vascular Conductance Research Articles

P-Aminobenzamidine attenuates cardiovascular dysfunctions in spontaneously hypertensive rats

AimsDiminazene aceturate, a putative ACE2 activator, is susceptible to cleavage resulting in the formation of p-aminobenzamidine (PAB). This study aimed to investigate the effects of PAB in addressing cardiovascular dysfunctions in spontaneously hypertensive rats (SHR). Main methodsAcute effects of PAB on mean arterial pressure (MAP), heart rate (HR), and aortic (AVC) and mesenteric vascular conductance (MVC) were evaluated in anesthetized SHR. Isolated aortic rings and the Langendorff technique were used to investigate the acute and chronic effects of PAB in the artery and heart. Chronic treatment with PAB (1 mg/kg, gavage) was carried out for 60 days. During this period, systolic blood pressure (SBP) and HR were measured by tail-cuff plethysmography. After the treatment, the left ventricle was collected for histology analyses, western blotting, and ACE2 activity. Key findingsBolus infusion of PAB acutely reduced MAP and increased both AVC and MVC in SHR. Additionally, PAB induced coronary and aorta vasodilation in isolated organs from Wistar and SHR in an endothelial-dependent manner. The chronic PAB treatment in SHR significantly attenuated the increase of SBP and improved the aorta vasorelaxation induced by acetylcholine and bradykinin-induced coronary vasodilation. In addition, chronic treatment with PAB attenuated the cardiomyocyte hypertrophy and extracellular matrix deposition in hearts from SHR. PAB did not alter the protein expression of the AT1, AT2, Mas, ACE, ACE2, or ACE2 activity. SignificancePAB induced beneficial effects on cardiovascular dysfunctions induced by hypertension, suggesting that this molecule could be used in the development of new drugs for the treatment of cardiovascular diseases.

Exploring the Haemodynamic Effects of BAY60‐6583, in Conscious, Freely‐Moving Rats

IntroductionThe adenosine A2B receptor (A2BR) is a potential novel therapeutic target for cancer treatments, however, the effects of A2BR ligands on the cardiovascular system have yet to be fully elucidated [1]. This project explored haemodynamic responses to a selective A2BR agonist, BAY60‐6583, in conscious rats. Previous, unpublished studies have shown that BAY60‐6583 causes tachycardia and vasodilatations in the renal and mesenteric vascular beds, that are attenuated by the A2BR selective antagonist, PSB1115, proving that the effects of BAY60‐6583 are caused by agonism of the A2BR. It is not known, however, if the tachycardic response is caused directly by A2BRs situated on the heart, or by indirect catecholamine mediated homeostatic reflexes to maintain mean arterial pressure (MAP) in the presence of regional arterial vasodilatations. In this study, the haemodynamic response to BAY60‐6583 in the presence or absence of the beta‐adrenergic blocking agent propranolol was investigated to test if the tachycardic response is caused by catecholamine mediated reflexes.MethodsSprague‐Dawley rats were anaesthetised, before being implanted with pulsed Doppler flow probes for the measurement of vascular conductance in the renal, mesenteric, and hindquarter vascular beds. Subsequently, intra‐arterial and intra‐venous catheters were implanted, allowing measurements of heart rate (HR) and MAP, and drug administration, respectively. 24 hours after surgery, a bolus of either the beta‐blocker, propranolol (0.1 mL, 1.0 mg/kg), or vehicle (0.1 mL) was followed by infusion with either propranolol (0.5 mg/kg/hr) or vehicle, respectively. After 90 minutes, three doses (4, 13.3, 40 μg/kg/min) of BAY60‐6583 was consecutively infused, each for 3 minutes, respectively. Recordings were made for a further 4 hours after drug administration. BAY60‐6583 was administered on two separate experimental days, in the presence or absence of propranolol, with a washout day in between, allowing each rat to act as their control. Procedures were approved by the University of Nottingham Animal Welfare Ethical Review Board, under Home Office Project and Personal License Authority, and follow the FASEB statement of principles for the use of animals in research.ResultsInfusion of BAY60‐6583 (4, 13.3, 40 μg/kg/min) caused a dose‐dependent increase in HR, no significant change in MAP and was accompanied by an increase in renal and mesenteric vascular conductance, but no significant change in hindquarter vascular conductance (Figure 1). Treatment with propranolol attenuated the tachycardic effects of BAY60‐6583. Propranolol caused no changes to the effects of BAY60‐6583 on regional vascular beds (Figure 1).ConclusionsThe tachycardia caused by BAY60‐6583 administration can be attenuated by beta‐blockade, suggesting that BAY60‐6583 may cause catecholamine mediated reflex countermeasures to maintain MAP in the presence of vasodilatations in the renal and mesenteric vascular beds, in conscious rats.Support or Funding InformationThis work was funded by The Centre of Membrane Proteins and Receptors (COMPARE).Responses to BAY60‐6583, ± propranolol, in conscious rats. A 0.1 mL bolus of propranolol (1.0 mg/kg) or vehicle was administered, before a 90‐minute infusion of either propranolol (0.5 mg/kg/hr) or vehicle, respectively. After infusion, three doses (4, 13.3, 40 μg/kg/min, each for 3 minutes) of BAY60‐6583 was administered. *Friedman’s test, P<0.05 accepted for significance versus baseline. #Wilcoxon test, P<0.05 accepted for significance between conditions. Data: mean ± SEM, n=8.Figure 1

S-nitrosothiols dilate the mesenteric artery more potently than the femoral artery by a cGMP and L-type calcium channel-dependent mechanism

S-nitrosothiols (SNOs) are metabolites of NO with potent vasodilatory activity. Our previous studies in sheep indicated that intra-arterially infused SNOs dilate the mesenteric vasculature more than the femoral vasculature. We hypothesized that the mesenteric artery is more responsive to SNO-mediated vasodilation, and investigated various steps along the NO/cGMP pathway to determine the mechanism for this difference. In anesthetized adult sheep, we monitored the conductance of mesenteric and femoral arteries during infusion of S-nitroso-l-cysteine (L-cysNO), and found mesenteric vascular conductance increased (137 ± 3%) significantly more than femoral conductance (26 ± 25%). Similar results were found in wire myography studies of isolated sheep mesenteric and femoral arteries. Vasodilation by SNOs was attenuated in both vessel types by the presence of ODQ (sGC inhibitor), and both YC-1 (sGC agonist) and 8-Br-cGMP (cGMP analog) mediated more potent relaxation in mesenteric arteries than femoral arteries. The vasodilatory difference between mesenteric and femoral arteries was eliminated by antagonists of either protein kinase G or L-type Ca2+ channels. Western immunoblots showed a larger L-type Ca2+/sGC abundance ratio in mesenteric arteries than in femoral arteries. Fetal sheep mesenteric arteries were more responsive to SNOs than adult mesenteric arteries, and had a greater L-Ca2+/sGC ratio (p = 0.047 and r = −0.906 for correlation between Emax and L-Ca2+/sGC). These results suggest that mesenteric arteries, especially those in fetus, are more responsive to SNO-mediated vasodilation than femoral arteries due to a greater role of the L-type calcium channel in the NO/cGMP pathway.

Splenic neurohormonal modulation of mesenteric vascular tone

In portal hypertension, development of a hyperdynamic circulation is preceded by transient mesenteric vasoconstriction. Portal hypertension increases splenic venous outflow pressure. We hypothesized that this causes direct reflex activation of mesenteric vasoconstrictor nerves and splenorenal reflex-mediated activation of the renin-angiotensin system. In anaesthetized male rats, we measured mesenteric efferent nerve activity and mesenteric vascular conductance (MVC) after selectively elevating splenic venous pressure. Partial splenic vein occlusion raised splenic venous pressure (from 4.8 ± 0.4 to 24.1 ± 0.3 mmHg; n = 18) and induced a significant increase in mesenteric efferent nerve activity (from 23.2 ± 3.3 to 31.6 ± 3.5 spikes s(-1); n = 11); this response was abolished by prior splenic denervation (from 32.4 ± 2.4 to 31.2 ± 1.6 spikes s(-1); n = 7). Mesenteric vascular conductance, the ratio of superior mesenteric artery blood flow to mean arterial pressure, fell upon splenic vein occlusion (ΔMVC = -0.0120 ± 0.0014 ml min(-1)mmHg(-1); P < 0.05, n = 10). This was attenuated by splenic denervation (ΔMVC = -0.0044 ± 0.0018 ml min(-1)mmHg(-1); P < 0.05, n = 8), but unaffected by mesenteric denervation (ΔMVC = -0.0145 ± 0.0020 ml min(-1)mmHg(-1); n = 6) or bilateral renal denervation (ΔMVC = -0.0106 ± 0.0021 ml min(-1)mmHg(-1); n = 5). Localized blockade of mesenteric vascular angiotensin II type 1 (AT(1)) receptors significantly attenuated the response (ΔMVC = -0.0058 ± 0.0017 ml min(-1)mmHg(-1); P < 0.05, n = 5), whereas blockade of both AT(1) and α(1)-adrenergic receptors caused a significant increase in mesenteric conductance (ΔMVC = +0.0033 ± 0.0010 ml min(-1)mmHg(-1); P < 0.05, n = 6). Our evidence suggests that increased splenic venous outflow pressure reflexly activates adrenergic/angiotensinergic mesenteric nerves, vasodilator mesenteric nerves and the renin-angiotensin system. We propose that obstruction to splenic venous outflow, such as would normally accompany portal hypertension, induces reflex mesenteric vasoconstriction independently of the increase in portal venous pressure.

Inhibition of nitric oxide synthase in the paraventricular nucleus prevents the hyperthermia-induced reduction of mesenteric blood flow in rats

Increasing body core temperature reflexly decreases mesenteric blood flow (MBF), and the hypothalamic paraventricular nucleus (PVN) plays an essential role in this response. Nitric oxide (NO) is involved in temperature regulation and is concentrated within the PVN. The present study investigated whether NO in the PVN contributes to the cardiovascular responses elicited by hyperthermia. Anesthetized rats were microinjected bilaterally in the PVN (100 nl/side) with saline or N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (100 or 200 nmol/100 nl) (n = 5/group). Body core temperature was then elevated from 37 degrees C to 39 degrees C, and blood pressure (BP), heart rate (HR), MBF, and mesenteric vascular conductance (MVC) were monitored. In separate groups, L-NAME (200 nmol) (n = 5) or saline (n = 5) was microinjected in the PVN, but body core temperature was not elevated. In control rats, increasing body core temperature resulted in no marked change of BP but an increase in HR and significant decreases in MBF (15%) and MVC. Pretreatment with 100 nmol L-NAME did not affect the responses. In contrast, 200 nmol L-NAME prevented the normal reduction in MBF and MVC but did not significantly affect the BP and HR responses. In rats in which body core temperature was not increased, L-NAME reduced MBF by 19%. The present results suggest that endogenous NO in the PVN is important in mediating the reduction of MBF induced by hyperthermia. In the absence of hyperthermia, however, endogenous NO in the PVN may play a role in maintaining mesenteric vasodilation.

Chronic administration of angiotensin II (AngII) to rats consuming a high salt diet causes mesenteric vasoconstriction by increasing sympathetic tone

We previously reported that AngII induced hypertension in rats consuming a high salt diet is accompanied by a sustained decrease in mesenteric vascular conductance (MVC). We tested the hypothesis that this vasoconstrictor response is mediated by increased sympathetic tone. Rats (n=5) were fed a high (2%) NaCl diet and instrumented for measurement of mean arterial pressure (MAP) and superior mesenteric artery blood flow (SMABF) during 4 days of control, and 14 days of AngII infusion (150ng/kg/min, sc). The contribution of sympathetic tone to MAP and MVC (SMABF/MAP) was assessed during control, and days 3, 7, and 13 of AngII by ganglionic blockade (hexamethonium; 20mg/kg, iv). MAP increased from a control level of 102±2 mmHg to 133±4, 141±4, and 140±12 on days 3, 7, and 13 of AngII. MVC decreased from 0.108±0.008 mL/mmHg·min during control to 0.065±0.004, 0.076±0.009, and 0.09±0.01 over the same time course. The decrease in MAP to ganglionic blockade was similar during control (−39±3) and on Day 3 (−37±12), but then increased significantly on Day 7 (−68±8) and Day 13 (−81±12) of AngII. The increase in MVC to ganglionic blockade was 0.04±0.01 during control and was 0.01±0.01 on Day 3, but then increased on Day 7 (0.06±0.01) and Day 13 (0.064±0.007) of AngII. We conclude that mesenteric vasoconstriction in AngII‐salt induced hypertension is mediated, in part, by a delayed increase in sympathetic tone (HL076312).

Factors influencing the regional haemodynamic responses to methanandamide and anandamide in conscious rats

In vitro evidence suggests that metabolism of anandamide by cyclooxygenase-2 (COX-2) may be more important when the primary metabolic pathway [i.e. fatty acid amide hydrolase (FAAH)] is inhibited. Thus, the first aim of the present study was to assess the effects of COX-2 and/or FAAH inhibition, on the cardiovascular actions of anandamide. The second aim was to compare the effects of anandamide with those of the metabolically stable analogue (i.e. methanandamide) and investigate mechanisms involved in responses to the latter in conscious rats. Rats were chronically instrumented for recording blood pressure, heart rate and renal, mesenteric and hindquarters vascular conductances in the freely moving state. Inhibition of FAAH with URB597 (cyclohexycarbamic acid 3'-carbamoyl-biphenyl-3-yl-ester) augmented the haemodynamic actions of anandamide, but there was no effect of COX-2 inhibition with parecoxib, either in the absence or the presence of URB597. Methanandamide caused CB(1) receptor-mediated renal and mesenteric vasoconstriction and evoked beta(2)-adrenoceptor-mediated hindquarters vasodilatation. No evidence for an involvement of COX-2 in the systemic cardiovascular actions of anandamide could be demonstrated. Vasoconstrictor actions of methanandamide were shown to involve CB(1) receptors, whereas no involvement of CB(1) receptors in such actions of anandamide has been shown. However, beta(2)-adrenoceptor-mediated hindquarters vasodilatation, independent of CB(1) receptors, observed here with methanandamide, has previously been seen with anandamide and differs from previous results with other synthetic cannabinoids for which the response was CB(1) receptor-dependent. Thus, mechanisms underlying the cardiovascular actions of endocannabinoids and synthetic analogues appear to be agonist-specific.

Alosetron, cilansetron and tegaserod modify mesenteric but not colonic blood flow in rats

As the use of the 5-HT(3) receptor antagonist alosetron (GlaxoSmithKline) and the 5-HT(4) receptor agonist tegaserod (Novartis) in patients with irritable bowel syndrome has been associated with cases of ischaemic colitis, the effects of alosetron, cilansetron (Solvay) and tegaserod on the rat splanchnic circulation were evaluated. Phenobarbital-anaesthetised rats were instrumented to record blood flow in the superior mesenteric artery and transverse colon and to calculate mesenteric and colonic vascular conductance. Intravenous alosetron (0.03-0.3 mg.kg(-1)) did not alter blood pressure or heart rate but reduced mesenteric blood flow and vascular conductance by 15-20%. This activity profile was also seen after intraduodenal alosetron and shared by the 5-HT(3) receptor antagonist cilansetron. In contrast, blood flow, vascular conductance and intraluminal pressure in the colon were not modified by alosetron and cilansetron. Intravenous or intraduodenal tegaserod (0.3-1.0 mg.kg(-1)) had no inhibitory effect on mesenteric and colonic blood flow. Peroral treatment of rats with alosetron or tegaserod for 7 days did not modify mesenteric haemodynamics at baseline and after blockade of nitric oxide synthesis. Mild inflammation induced by dextran sulphate sodium failed to provoke a vasoconstrictor effect of cilansetron in the colon. Alosetron and cilansetron, not tegaserod, caused a small and transient constriction of the rat mesenteric vascular bed, whereas blood flow in the colon remained unaltered. The relevance of these findings to the treatment-associated occurrence of ischaemic colitis in patients with irritable bowel syndrome remains open.

Sinoaortic denervation differentially reverses iliac, renal and mesenteric vasoconstriction evoked by stimulation of A1 adenosine receptors in the Nucleus of the Solitary Tract (NTS)

Activation of NTS A1 adenosine receptors evokes transient vasodilation followed by differential neural and vasopressinergic vasoconstriction in the iliac, mesenteric and renal vascular beds (FASEB, 21: A466, 2007). These responses may be partially mediated via inhibition of NTS baroreflex mechanisms (Am J Physiol 294: H172‐82, 2008). Therefore, in the present study we assessed the contribution of baroreflex mechanism to the regional vascular responses evoked by stimulation of NTS A1 adenosine receptors (CPA 330pmol/50nl) in urethane/chloralose anesthetized male Sprague Dawley rats. We compared the responses in iliac, mesenteric and renal vascular conductance evoked in intact vs. sinoaortic denervated (SAD) animals. SAD abolished vasoconstriction and accentuated vasodilation (iliac=mesenteric&gt;renal). Inasmuch as NTS A1 adenosine receptor mediated activation of the adrenal medulla partially persisted after SAD plus vagotomy or blockade of glutamatergic transmission in the NTS (Am J Physiol 283: H1588‐99, 2002) we conclude that the differential regional vasodilation observed in SAD animals is mediated mostly via non‐baroreflex activation of the adrenal medulla.

Otolithic activation on visceral circulation in humans: effect of aging

Engagement of the otolith organs elicits differential activation of sympathetic nerve activity and vascular responses to muscle and skin in humans. Additionally, aging attenuates the otolith organ-mediated increases in muscle sympathetic nerve activity in older adults. In this study, we hypothesized that 1) the vestibulosympathetic reflex (VSR) would elicit visceral vascular vasoconstriction and 2) visceral vascular response to the VSR would be attenuated in older subjects compared with young. To test these hypotheses, heart rate, mean arterial blood pressure, and renal, celiac trunk, and superior mesenteric arterial blood velocity (Doppler ultrasound) were measured in 22 young (25+/-1 yr) and 18 older (65+/-2 yr) healthy subjects during head-down rotation (HDR), which selectively activates the otolith organs. Mean arterial pressure and heart rate did not change from baseline during HDR in young or older subjects. Renal blood velocity (Delta -2+/-1 cm/s) and vascular conductance (Delta -0.03+/-0.01 cm.s(-1).mmHg(-1)) significantly decreased from baseline during HDR (P<0.05) in young subjects. In contrast, renal blood velocity and conductance did not change in older subjects (Delta -0.2+/-1 cm/s and Delta0.02+/-0.08 mmHg.cm(-1).s(-1), respectively) during HDR. Superior mesenteric and celiac blood velocity and vascular conductance did not change in response to HDR in either the young or older subjects. These data suggest that renal vasoconstriction occurs during otolith organ activation in young but not older humans. Together with our previous studies, we conclude that the VSR elicits a diverse patterning of sympathetic outflow that results in heterogeneous vascular responses in humans and that these responses are significantly attenuated in older humans.

Splenic neural modulation of mesenteric vascular tone

Portal hypertension impedes outflow from the splanchnic vascular beds. We hypothesized that the increase in splenic intravascular pressure may initiate a neural reflex to increase mesenteric arterial tone and reduce blood flow into the plethoric mesenteric vascular bed. Splenic venous pressure was selectively increased by partial splenic vein occlusion (6.9±0.5 to 22.5±0.3 mmHg, n=47). During the 3 minutes following occlusion, mesenteric vascular conductance fell (−0.01±0.002 mmHg/mL·min‐1; p&lt;0.05 n=7), an effect which was unchanged by renal denervation (−0.01±0.009 mmHg/mL·min‐1; n=6) and exacerbated by mesenteric denervation (−0.02±0.004 mmHg/mL·min‐1; p&lt;0.05, n=7). The fall in conductance was abolished by splenic denervation (−0.002±0.002 mmHg/mL·min‐1; p&lt;0.05 n=6). Similarly, the significant increase in mesenteric efferent nerve activity observed during splenic venous occlusion (22.2±2.8 to 27.9±3.8 spikes/sec, p&lt;0.05 n=13) was absent after splenic denervation (32.4±2.4 to 31.2±1.6 spikes/sec, n=7). Although the spleen is thus integral to initiating the reflex, the accompanying increase in mesenteric nerve activity is not wholly responsible for increasing mesenteric arterial tone. (HSFC,CIHR).

Vascular pharmacology of a novel cannabinoid‐like compound, 3‐(5‐dimethylcarbamoyl‐pent‐1‐enyl)‐N‐(2‐hydroxy‐1‐methyl‐ethyl)benzamide (VSN16) in the rat

A putative novel cannabinoid receptor mediates vasorelaxation to anandamide and abnormal-cannabidiol and is blocked by O-1918 and by high concentrations of rimonabant. This study investigates VSN16, a novel water-soluble agonist, as a vasorelaxant potentially acting at non-CB1, non-CB2 cannabinoid receptors in the vasculature. VSN16 and some analogues were synthesized and assayed for vasodilator activity in the rat third generation mesenteric artery using wire myography. Also carried out with VSN16 were haemodynamic studies in conscious rats and binding studies to CB1 receptors of rat cerebellum. VSN16 relaxed mesenteric arteries in an endothelium-dependent manner. The vasorelaxation was antagonized by high concentrations of the classical cannabinoid antagonists, rimonabant and AM 251, as well as by O-1918, an antagonist at the abnormal-cannabidiol receptor but not at CB1 or CB2 receptors. It did not affect [3H]CP55,940 binding to CB1 receptors in rat cerebellum. The vasorelaxation was not pertussis toxin-sensitive but was reduced by inhibition of nitric oxide synthesis, Ca(2+)-sensitive K+ channels (KCa) and TRPV1 receptors. In conscious rats VSN16 transiently increased blood pressure and caused a longer-lasting increase in mesenteric vascular conductance. Structure-activity studies on vasorelaxation showed a stringent interaction with the target receptor. VSN16 is an agonist at a novel cannabinoid receptor of the vasculature. It acts on the endothelium to release nitric oxide and activate KCa and TRPV1. As it is water-soluble it might be useful in bringing about peripheral cannabinoid-like effects without accompanying central or severe cardiovascular responses.

Exaggerated Cardiovascular Stress Responses and Impaired β-Adrenergic–Mediated Pressor Recovery in Obese Zucker Rats

Clinical studies have demonstrated that the pressor response to acute stress is larger in obese versus lean individuals. We therefore tested the hypotheses that the pressor response to behavioral stress is greater in obese (OZRs) versus lean Zucker rats (LZRs) and that reduced beta-adrenergic-mediated vasodilation contributes to the enhanced pressor response. Animals were restrained and subjected to acute pulsatile air jet stress (3 minutes), followed by a poststress period of 20 minutes; beta-adrenergic blockade was achieved with propranolol (5 mg/kg, IV) given 15 minutes before the start of air jet stress. Mean arterial pressure (MAP) was continuously monitored by telemetry. Untreated OZRs responded with a greater integrated pressor response (area under the curve [AUC]) to acute stress (41.2+/-6.1 versus 21.2+/-3.3 mm Hgx3 minutes, OZR versus LZR; P<0.05) and significantly reduced poststress recovery of MAP. Beta-adrenergic blockade had no effect on stress AUC in either LZRs or OZRs but significantly attenuated the poststress recovery of MAP in LZRs only (poststress AUC: -100.1+/-48.1 versus 49.0+/-13.5 mm Hgx20 minutes, untreated versus propranolol; P<0.05). In anesthetized animals, significantly smaller increases in mesenteric vascular conductance contributed to blunted depressor responses to isoproterenol in OZRs versus LZRs, suggesting that beta-adrenergic stimulation causes a greater reduction in total peripheral resistance in lean versus obese animals. We conclude that beta-adrenergic-mediated vasodilation facilitates blood pressure recovery after stress and that this pathway is compromised in an animal model of morbid obesity, resulting in the impaired ability to regulate blood pressure during stress.

Differentiated hemodynamic changes controlled by splanchnic nerve

The splanchnic (SPL) nerve is a postganglionic sympathetic nerve involved in the tonic regulation of the cardiovascular system. Electrical stimulation of this nerve produces mesenteric vasoconstriction and it has been assumed that vasodilatory responses are dependent on inhibition of the vasoconstrictor tone. Several different central stimuli have been shown to dilate the hindquarter vascular bed and constrict the mesenteric vascular bed. To determine whether vasodilatory and vasoconstrictor effects in different vascular beds are elicited by activation of different sympathetic nerves, we investigated the hemodynamic changes in hindquarter, mesenteric and renal vascular beds evoked by electrical stimulation of the SPL nerve. Stimulation of the intact or sectioned SPL nerve in chloralose-anesthetized, artificially ventilated rats evoked increases in the hindquarter vascular conductance and simultaneously decreased the mesenteric and renal vascular conductance. Intravenous (i.v.) administration of l-NAME prior to stimulation of the proximal end of the sectioned SPL nerve abolished the increase in hindquarter conductance, suggesting the involvement of nitric oxide in this response. In assessing the hemodynamic effects of tonic activity on the SPL nerves, no significant changes were observed after unilateral section of the SPL nerve, but bilateral section of the SPL nerves decreased hindquarter conductance and did not significantly change the mesenteric conductance simultaneously. No consistent response was observed in the renal vascular bed after unilateral and subsequent contralateral section of the SPL nerves. These findings demonstrate that electrical stimulation of the SPL nerve produces mesenteric vasoconstriction and simultaneous hindquarter vasodilatation, which is mediated by nitric oxide. Moreover, the present data suggest that SPL nerves may provide a tonic vasodilatory tone in the hindquarter vascular bed and simultaneously a vasoconstrictor tone in another, undetermined vascular bed.

Mesenteric Vasoconstriction and Hindquarters Vasodilatation Accompany the Pressor Actions of Exendin-4 in Conscious Rats

The hemodynamic effects of the glucagon-like peptide-1 (GLP-1) receptor agonist, exendin-4, and putative underlying mechanisms were assessed in conscious male Sprague-Dawley rats. At a dose of 25 ng kg(-1) i.v., exendin-4 had little effect, but doses of 250 and 2500 ng kg(-1) had significant tachycardic effects (+66 +/- 9 and +95 +/- 16 beats min(-1) at 5 min, respectively) and pressor actions (+10 +/- 2 and +12 +/- 1 mm Hg), accompanied by substantial falls in mesenteric vascular conductance (-38 +/- 3% and -47 +/- 3%) and increases in hindquarters vascular conductance (+82 +/- 14% and +126 +/- 15%). The latter were likely due to adrenaline-mediated activation of beta(2) adrenoceptors since they were abolished by the beta(2) adrenoceptor antagonist, ICI 118551 [(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol) hydrochloride], or propranolol [(RS)-1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-2-propanol], and absent in adrenal-demedullated rats. In the presence of beta-adrenoceptor antagonism, the tachycardic effects of exendin-4 were suppressed, but the pressor action was enhanced. Enhancement of the pressor action of exendin-4 was not seen in adrenal-demedullated rats or in animals given phentolamine in addition to propranolol, consistent with a component of the pressor action of exendin-4 being due to an adrenaline-mediated positive inotropic effect mediated by alpha-adrenoceptors. The mesenteric vasoconstrictor effect of exendin-4 was unaffected by antagonism of alpha-adrenoceptors, vasopressin receptors, angiotensin receptors, or GLP-1 receptors, although antagonism of the latter substantially inhibited the hindquarter vasodilator effects of exendin-4. These results are consistent with exendin-4 having cardiovascular effects through GLP-1 receptor-dependent and -independent mechanisms, some of which involve sympathoadrenal activation.

Impact of Nitric Oxide Synthase Inhibitor and Chloride Channel Antagonist on Mesenteric Vascular Conductance in Anesthetized Dahl Normotensive and Hypertensive Rats

The effects of nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) and chloride channel antagonist niflumic acid on vascular responsiveness to the effect of alpha1-adrenoceptor stimulation in the mesenteric bed of Dahl salt-resistant normotensive (SRN) and salt-sensitive hypertensive (SSH) rats were examined. Dahl salt-resistant and salt-sensitive rats were fed a high-salt diet (4% NaCl) for 7 weeks, and blood pressure, heart rate, and mesenteric blood flow were measured before and after treatment with L-NAME (0.3 mg/kg, IV) and/or niflumic acid (10 mg/kg, IV). Morphometry of the primary mesenteric blood vessel was also assessed. Administration of alpha1-adrenoceptor agonist cirazoline produced a dose-dependent increase in blood pressure, decrease in heart rate, mesenteric blood flow, and mesenteric vascular conductance in SRN and SSH rats. L-NAME significantly increased basal blood pressure and decreased basal mesenteric blood flow and vascular conductance in SRN but not in SSH rats. Niflumic acid attenuation of cirazoline-mediated decreases in mesenteric blood flow and vascular conductance was more pronounced in the SRN than SSH rats. This difference in the inhibitory actions of niflumic acid was absent following its concomitant administration with L-NAME. It seems that tonic release of nitric oxide modulates niflumic acid-sensitive chloride channels in vascular muscle. Blood vessels from SSH rats had significantly larger smooth muscle thickness and lumen diameter, but the ratio of the 2 were not different between the SRN and SSH. Our findings support the view that alterations in receptor-mediated signal transduction, rather than just changes in blood vessel architecture, are responsible for differences in behavior of blood vessels in salt-induced hypertensive rats.

Hemodynamic effects of phosphodiesterase 5 and angiotensin-converting enzyme inhibition alone or in combination in conscious SHR.

The regional hemodynamic responses to continuous 4-day infusion of UK-357,903 [1-ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-2-(2-methoxyethoxy)-5-pyridylsulphonyl}piperazine] (266 microg kg(-1) h(-1)) alone and in combination with a low dose of enalapril (10 microg kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats to test the hypothesis that the renin-angiotensin system may influence the cardiovascular consequences of inhibition of phosphodiesterase 5 (PDE5) by UK-357,903 or vice versa. UK-357,903 alone caused a fall in mean blood pressure (-12.1 mm Hg) associated with vasodilatation in the mesenteric and hindquarters vascular beds. The only way in which the effects of enalapril given alone differed significantly from those of the vehicle was in causing mesenteric vasodilatation, which developed over the 4 days of infusion. UK-357,903 given in combination with enalapril caused hypotension (-17.8 mm Hg) and vasodilatation in the renal, mesenteric, and hindquarter vascular beds. There was evidence of a significant interaction between the effects of the two compounds on renal Doppler shift and vascular conductance with the combined action of the two compounds being greater than the sum of their individual effects. However, although there was a trend for the combination to have greater effects than either of the individual agents on blood pressure and mesenteric vascular conductance, there was no statistical evidence of an interaction. The results indicate that inhibition of the renin-angiotensin system uncovers additional renal vasodilator effects of UK-357,903, and/or inhibition of PDE5 enhances the renal vasodilator effects of angiotensin-converting enzyme inhibition.

Lumbar sympathetic nerve activity and hindquarter blood flow during REM sleep in rats.

The present study aimed to investigate the response of lumbar sympathetic nerve activity (LSNA) to the onset of rapid eye movement (REM) sleep and its contribution to the regulation of muscle blood flow during REM sleep in rats. Electrodes for the measurements of LSNA, electroencephalogram, electromyogram and electrocardiogram and a Doppler flow cuff for the measurements of blood flow in the common iliac and mesenteric arteries, also catheters for the measurements of systemic arterial and central venous pressures were implanted chronically. REM sleep resulted in a step increase in LSNA, by 22 +/- 9% (mean +/-S.E.M., P < 0.05), a reduction of iliac vascular conductance, by -16 +/- 3% (P < 0.05) and a gradual increase in systemic arterial pressure, reaching a maximum value of 8.1 +/- 2.0 mmHg (P < 0.05) at 89 s after onset of REM sleep, while mesenteric vascular conductance increased simultaneously by 5 +/- 2% (P < 0.05). There was a significant (Pearson's correlation coefficient = 0.94, P < 0.05) inverse linear relationship between LSNA and the iliac blood flow. Unilateral lumbar sympathectomy blunted the reduction of iliac blood flow induced by the onset of REM sleep. The present observations suggest that the onset of REM sleep appears to be associated with a vasodilation in viscera and a vasoconstriction in skeletal muscle, such that systemic arterial pressure increases during REM sleep in rats.

Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats.

1. The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically-instrumented, male, Sprague-Dawley rats. 2. CsA (5.9 mg kg(-1) bolus i.v.) caused rapid-onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects. 3. Pretreatment with the angiotensin (AT(1)) receptor antagonist, losartan, and the endothelin (ET(A) and ET(B)) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the alpha-adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA. 4. Tacrolimus (450 microg kg(-1) bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response. 5. Sirolimus (450 microg kg(-1) bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances. 6. The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects.

A comparative study of the effects of Cl − channel blockers on mesenteric vascular conductance in anaesthetized rat

There is evidence to suggest that niflumic acid is capable of selectively inhibiting Ca 2+-dependent Cl − channels. Furthermore, it has been demonstrated that niflumic acid is capable of antagonizing contractile responses due to activation of α 1-adrenoceptor in mesenteric vasculature. Here, we have examined the effects of three Cl − channel blockers, niflumic acid, indanyloxyacetic acid 94 (IAA-94) and diphenylamine-2-carboxylic acid (DPC) on cirazoline-mediated vasoconstriction in mesenteric blood vessel in vivo. Infusion of cirazoline produced a dose-dependent increase in blood pressure, decrease in superior mesenteric blood flow, mesenteric vascular conductance and heart rate. While niflumic acid and IAA-94 did not have any impact on cirazoline-induced changes in blood pressure, DPC accentuated the pressor effect of cirazoline. Neither agent affected cirazoline-mediated reflex reduction in the heart rate. Niflumic acid, IAA-94 and DPC attenuated α 1-adrenoceptor mediated decrease in mesenteric blood flow and vascular conductance. Based on the profile of the actions of these compounds, it may be suggested that IAA-94 did not appear to act as selective inhibitor of Ca 2+-activated Cl − channels when compared to niflumic acid in the mesenteric blood vessels. In addition, while DPC seems to be as effective as niflumic acid in its effects on mesenteric blood vessels, its actions may be attributed to other pharmacological effects.