Effects of Tetramethylpyrazine on Portal Hypertensive Rats

The effects of tetramethylpyrazine, an alkaloid isolated from a Chinese herb Ligusticum wallichii Franch have been assessed in portal hypertensive rats. Portal hypertension was induced by partial portal vein ligation in Sprague-Dawley rats. Two weeks after ligation, when the hyperdynamic state had stabilized, rats were anaesthetized after an overnight fast and cannulated for measurement of mean arterial pressure, portal venous pressure, cardiac index and heart rate. Tetramethylpyrazine (3·0, 9·9 and 30mgkg^?1) induced dose-dependent reductions of portal venous pressure and mean arterial pressure after intravenous infusion. The maximum percentage reduction of portal venous pressure after tetramethylpyrazine was 6·0±0·8, 9·3±1·6 and 20±2% of baseline for doses of 3·0, 9·9 and 30·0mgkg^?1, respectively. Also, total peripheral resistance was significantly reduced by tetramethylpyrazine and cardiac index was slightly increased. Our results showed that tetramethylpyrazine induced portal pressure reduction in portal hypertensive rats.     

Effects of β-Adrenoceptor Antagonists on Portal Vein Hypertension and Ethanol-induced Gastric Mucosal Damage in Rats

Abstract— The effects of various β-adrenoceptor antagonists, with different pharmacological properties, on systemic and portal vein blood pressure and on ethanol-induced gastric mucosal damage were examined in surgically-induced portal hypertensive rats. Propranolol (5, 10 or 20 mg kg^?1), nadolol (5 or 10 mg kg^?1), metoprolol (10 or 20 mg kg^?1), labetalol (20 or 40 mg kg^?1) and pindolol (3 or 6 mg kg^?1) reduced systemic blood pressure to a similar degree in both portal vein-ligated and sham-operated rats. All β-adrenoceptor antagonists, except for pindolol, significantly reduced portal venous pressure and ethanol-induced macroscopic gastric mucosal damage in portal hypertensive animals. Sham-operated rats had lower portal venous pressure and less gastric damage compared with portal hypertensive rats, but both were unaffected by β-adrenoceptor antagonist pretreatment. We conclude that: propranolol, nadolol, metoprolol and labetalol are effective in reducing the portal venous pressure and ethanol-induced gastric mucosal damage in portal hypertensive rats, but not in portal normotensive animals; there was no direct relationship between the reduction of portal vein and systemic blood pressure; and local anaesthetic action is probably important in reducing the portal vein pressure and ethanol-induced gastric mucosal lesions, while the intrinsic sympathomimetic effect can counteract the actions of the β-adrenoceptor antagonists on portal venous pressure and gastric mucosa.     

Influence of the baroreceptor reflex on the modulation of noradrenaline overflow through prejunctional receptors in the portal vein of freely moving rats

1 The effects of alterations in mean arterial blood pressure (MAP), as induced by vasoactive drugs, on heart rate (HR), basal noradrenaline concentration and electrically evoked noradrenaline overflow and on blood flow in the portal vein of freely moving rats, were investigated. 2 By infusion of sodium nitroprusside or phenylephrine (0.5, 1.0 and 2.5 μg kg^?1 min^?1), MAP was altered over a range of 50 to 150 mmHg. The resulting changes in HR showed a sigmoidal relationship with MAP. Noradrenaline overflow increased linearly when MAP was decreased; when MAP was increased, however, noradrenaline levels only decreased to 70% and reached a plateau from 125 mmHg onwards. 3 Nitroprusside (2.5 μg kg^?1 min^?1) and fenoterol (0.25 mg kg^?1) decreased MAP to the same extent (– 46 mmHg). HR and basal noradrenaline concentration, however, were increased to a higher extent by fenoterol (+ 192 beats min^?1; + 373 pg ml^?1, respectively) than by nitroprusside (+ 78 beats min^?1; + 206 pg ml^?1, respectively). Electrically evoked overflow was not changed at all after nitroprusside, whereas fenoterol induced an increase to 206% of control. 4 Phenylephrine (2.5 μg kg^?1 min^?1) and angiotensin II (1 μg kg^?1 min^?1) increased MAP to the same extent (to 155 and 161 mmHg, respectively). Basal noradrenaline concentration decreased by 30% after phenylephrine, whereas angiotensin II increased noradrenaline levels to 226% of control. Evoked noradrenaline overflow was not changed after phenylephrine but was increased to 204% of control after angiotensin II. 5 Portal venous blood flow (15.3 ml min^?1) was not affected after brisk changes in MAP induced by nitroprusside (2.5 μg kg^?1 min^?1), fenoterol (0.25 mg kg^?1) or phenylephrine (2.5 μg kg^?1 min^?1). 6 The results showed that the electrically evoked overflow of endogenous noradrenaline in the portal vein of the freely moving rat is not influenced by baroreceptor reflex-induced changes in basal noradrenaline overflow. As a consequence, the prejunctional effects of drugs on the electrically evoked overflow are only of local origin. Portal venous blood flow is not changed by brisk changes in MAP or electrical stimulation, therefore no changes in noradrenaline spillover from nerve terminals are expected. However, the enhancement of basal noradrenaline overflow from numerous peripheral sympathetic junctions as seen with fenoterol and angiotensin II, is augmented or dampened, respectively, by baroreceptor reflexmediated changes of sympathetic activity.     

Comparative effects of calcium channel blockers and indomethacin on insulin secretion and blood pressure increase derived from α1-adrenoceptor stimulation in the rabbit

1 In conscious, fasted rabbits the intravenous infusion of the α₁-adrenoceptor agonist, amidephrine (3 and 10 μg kg^?1 min^?1) induced a dose related increase in insulin plasma levels. This effect was accompanied by a minor hypo- or hyperglycaemic response, depending on the dose of agonist infused. 2 A dose related increase in mean arterial pressure and reduction in heart rate were also found after amidephrine administration. 3 The insulin secretory response to amidephrine was not prevented in rabbits previously treated with atropine (5.26 μg kg^?1 min^?1). However, in the presence of muscarinic receptor blockade the bradycardic effect of amidephrine was either suppressed or attenuated. 4 Pretreatment with the calcium channel antagonist elgodipine (35 ng kg^?1 min^?1) or with indomethacin (0.66 mg kg^?1 min^?1) clearly blocked the effect of amidephrine on insulin secretion. 5 The haemodynamic changes induced by amidephrine were preserved in the presence of either verapamil (0.17 μg kg^?1 min^?1) or indomethacin, whereas the hypertensive response was antagonized by elgodipine. 6 Our results suggest that the metabolic and haemodynamic changes mediated by amidephrine are two independent effects, insulin secretion requiring the presence of extracellular calcium and the synthesis of arachidonic acid metabolites.     

Cardiovascular actions of nitric oxide synthase inhibition in the portal hypertensive rat

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The Transhepatic Response to Noradrenaline in the Rabbit Liver: the Influence of Arterioportal Pressure Gradient

The dose-related responses of the hepatic arterial and portal venous vascular beds to bolus administration of noradrenaline (10^?10?10^?4mol), injected into the hepatic artery and portal vein, were studied in the isolated dual-perfused rabbit liver at both basal and raised tone. The transhepatic ratio, defined as the ratio between the intra-arterial molar ED50 dose and the intraportal dose required to give the same arterial response, was calculated for arterial and venous responses to noradrenaline. At basal tone, the transhepatic ratio for hepatic arterial vasoconstrictive responses was 500. Portal venous vasoconstrictive responses were similar in potency independent of injection site but differed significantly in analysis of dose-response slope and maximal response. At raised tone, the arterio-portal pressure gradient increased by 68·5 mmHg and there was a 10-fold increase in the transhepatic ratio for hepatic arterial responses, while the portal venous responses remained unchanged. These results demonstrate that arterio-portal pressure gradient has a powerful effect on transhepatic action of noradrenaline, and suggest a pre-sinusoidal site for the generation of both hepatic arterial and portal venous vascular resistance.     

Changes in vascular reactivity in experimental hypertensive animals following treatment with indapamide

Indapamide at doses of 8–16 mg kg^?1 day^?1, orally, lowered arterial blood pressure (9–26 mm Hg) in conscious renal hypertensive cats during a two week treatment period. The antihypertensive effect was sustained for 5–7 h after dosing and was not accompanied by reflex tachycardia. Antihypertensive responses to injection of clonidine (20 μg, i.c.v.) were significantly enhanced one week after the completion of indapamide treatment but had returned to normal two weeks later. In DOCA/saline hypertensive rats, administration of indapamide 10 mg kg^?1 day^?1, orally, or hydrochlorothiazide, 5 mg kg^?1 day^?1, intraperitoneally, for 10 days produced similar falls in blood pressure (40–45 mm Hg) as measured by an indirect method. Pressor responses to intravenous noradrenaline or tyramine or electrical stimulation of the sympathetic outflow in the pithed rat preparation were much reduced by pretreatment with indapamide (10 mg kg^?1, orally) for 10 days. However, cardiovascular reactivity was unaffected by hydrochlorothiazide pretreatment (5 mg kg^?1 day^?1, i.p.). Isolated perfused mesenteric artery***/preparations from indapamide-treated rats showed no changes in reactivity to noradrenaline, 5-hydroxytryptamine or adenosine-5′-triphosphate from those of control DOCA/saline hypertensive rats. Isolated portal veins from rats pretreated with indapamide showed contractile responses to noradrenaline similar to those of control animals although the frequency of spontaneous contractions was reduced in the former group. The results support a vascular site of action for indapamide and suggest a mode of action different from that of hydrochlorothiazide.     

Hemodynamic effects of synephrine treatment in portal hypertensive rats

Synephrine, a sympathomimetic alpha1-adrenoceptor agonist, has been shown to induce dose-dependent portal hypotensive effects after acute intravenous infusion. The present study was undertaken to investigate the hemodynamic effects of 8-day administration of synephrine in portal hypertensive rats. Portal hypertension was induced by either partial portal vein ligation (PVL) or bile duct ligation (BDL). Portal hypertensive rats were allocated into one of two groups: vehicle group (0.1 N HCl, 0.5 ml/12 h) or synephrine group (1 mg/kg per 12 h), with 7 rats in each group. Synephrine or vehicle was administered by gavage into PVL and BDL rats for 8 consecutive days. Systemic as well as splanchnic hemodynamic parameters were measured thereafter. Synephrine significantly ameliorated the hyperdynamic state in both PVL and BDL rats. The portal venous pressure in PVL and BDL rats (-13.5% and -10.1%, respectively), portal tributary blood flow (-19.5% and -20.4%) and cardiac index (-12.1% and -18.8%) were significantly reduced, while mean arterial pressure (10.4% and 23.4%) and systemic (26.3% and 51.0%) as well as portal territory (47.1% and 67.7%) vascular resistance were enhanced by treatment of synephrine as compared with vehicle treatment. Our results showed that eight-day administration of synephrine exerted beneficial hemodynamic effects in two models of portal hypertensive rats.     

Intravenous verapamil kinetics in rats: Marked arteriovenous concentration difference and comparison with humans

The pharmacokinetics of verapamil, a calcium channel blocker, were studied in male Sprague—Dawley rats following i.v. administration at a dose of 1 mg kg^?1. Both arterial and venous blood were collected and the plasma drug concentrations were determined by reversed-phase high-performance liquid chromatography. Verapamil was distributed to the extravascular tissues very rapidly as indicated by the large V_dss (2.99±0.57 1 kg^?1) and V_dβ (5.08 ± 0.541 kg^?1). The apparent terminal plasma T_1/2, MRT_iv, and CL_p were 1.59 ± 0.46, 1.26 ± 0.12 h, and 40.4 ± 9.73 ml min^?1 kg^?1, respectively. Marked arterial/venous differences were found with a considerable influence on the MRT and V_dss, and the terminal phase venous levels were higher than arterial levels by 103, 69, and 90%, respectively, for the three rats studied. The distribution of verapamil between plasma and erythrocytes occurred very rapidly and was identical in vitro and in vivo. The average blood to plasma and plasma to blood cell concentration ratios were 0.85 and 1.47, respectively. In contrast to propranolol, blood data rather than plasma data should be used to predict the hepatic extraction ratio of verapamil (0.87). The plasma protein binding of verapamil in humans (90%) and rats (95%) were quite similar and constant over the wide concentration range studied. A comparison of some pharmacokinetic parameters between rats and humans is presented and the potential shortcomings of using T_1/2 or CL_p and the advantage of using CL_u (unbound plasma clearance) in interspecies scaling is also discussed.     

Pharmacodynamics of ZM 241385, a Potent A2a Adenosine Receptor Antagonist,after Enteric Administration in Rat,Cat and Dog

4-(2-[7-Amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) is currently the most selective for the A_2a adenosine receptor antagonist. This paper describes the in-vivo activity of ZM 241385 after administration by both oral and intraduodenal routes. In conscious spontaneously hypertensive rats, ZM 241385 (1–10 mg kg^?1) selectively attenuated the mean arterial blood pressure response produced by exogenous adenosine (1 mg kg^?1 min^?1, i.v.) by up to 45% after oral administration. Activity of ZM 241385 was maintained for at least 6 h after 3 and 10 mg kg^?1 (p.o.). In conscious normotensive cats, ZM 241385 attenuated the blood pressure responses to adenosine (0.6–10 mg kg^?1, i.v.) by 94% after 10 mg kg^?1 (p.o.) and by up to 74% after 0.3 mg kg^?1 (i.v.). Duration of action of ZM 241385 up to 12 h (36% inhibition) was observed after 3 mg kg^?1 (p.o.). In anaesthetized dogs and cats, ZM 241385, after intraduodenal administration (1–10 mg kg^?1), produced a rapid (dose ratio 100-fold 15 min after administration of 10 mg kg^?1 in the cat) and prolonged (dose ratio of 14 at 6 h after administration of 10 mg kg^?1) attenuation of the vasodilatation responses to adenosine receptor stimulation. When administered by this route ZM 241385 was six times more potent than theophylline in the cat and at least twice as potent as theophylline in the dog. In conclusion, ZM 241385 is a potent, selective A_2a adenosine receptor antagonist which is orally active, with a good duration of action by the enteric route in cat, rat and dog. It could therefore be used to evaluate the role of adenosine A_2a receptors in the action of adenosine in-vivo.     

Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension

BACKGROUND: Carvedilol is a non-selective vasodilating beta-blocker with weak alpha1 receptor antagonism. Recent studies have demonstrated its potential as a portal hypotensive agent. AIM: To assess the haemodynamic effects and patient tolerability of the acute and chronic administration of low-dose carvedilol. METHODS: Haemodynamic measurements were performed in ten cirrhotic patients before and 1 h after the administration of 12.5 mg oral carvedilol. The study was repeated 4 weeks after daily administration of 12.5 mg carvedilol. RESULTS: After acute administration of carvedilol, there was a 23% reduction in the hepatic venous pressure gradient from 16.37 +/- 2.14 to 12.56 +/- 3.91 mmHg (P < 0.05), with significant falls in the heart rate, mean arterial pressure and cardiac output. Chronic administration resulted in a further fall in the hepatic venous pressure gradient from a baseline of 16.37 +/- 0.71 to 9.27 +/- 1.40 mmHg (P < 0.001) with the mean arterial pressure being unaffected. The drug was well tolerated with only one patient experiencing asymptomatic hypotension. CONCLUSIONS: The results show that low-dose carvedilol is an extremely potent portal hypotensive pharmacological agent, and is worthy of further investigation in large randomized trials to assess its effect in preventing variceal haemorrhage.     

Selective effect of fentanyl on group III and IV somatosympathetic reflexes

The effect of fentanyl on sympathetic reflexes evoked by supramaximal electrical stimulation of the radial nerve, and the subsequent reversal of its effects by naloxone, have been observed in 10 dogs anaesthetized with α-chloralose, paralysed with suxamethonium and artiflcally ventilated. During infusions of 5 μg/kg^?1 min^?1 the late, long-latency, sympathetic response evoked by unmyelinated fibres was abolised at a mean dose of 27 μg/kg^?1 (SD 12.6 μg/kg^?1) after which the early, short-latency response evoked by small myelinated fibres was eliminated at a mean dose of 90.3 μg/kg^?1 (SD 54.6 μg/kg^?1) so that there was no longer any response to stimulation of the radial nerve. During a subsequent infusion of naloxone (200 μg/kg^?1) the late response returned to control values at a mean dose of 0.5mg and subsequently the early response reappeared to return to control values at a total dose of 1.6 mg. In 2 preparations phrenic nerve activity was abolished after 6.1 and 17.4 μg/kg^?1 of fentanyl and returned immediately before the late response, during the infusion of naloxone. In 2 preparations, induced tolerance occurred so that the early response could not be eliminated.     

Effects of Endotoxin on Neurally-mediated Gastric Acid Secretion in the Rat

The effects of a peripheral administration of E. coli endotoxin on neurally-mediated gastric acid secretion and the role of endogenous opioids or PAF receptors in endotoxin effects have been evaluated in the continuously perfused stomach of the anaesthetized rat. Gastric acid secretion stimulated by distension (20 cm H₂O) was reduced dose-dependently by single intravenous bolus injection of endotoxin (0.1–10 μg kg^?1). Doses of 5 μg kg^?1 induced a peak reduction of distension-stimulated acid output and significantly reduced the secretory response induced by an intravenous bolus of 2-deoxy-d -glucose (150 mg kg^?1). This dose of endotoxin did not significantly modify mean systemic arterial blood pressure throughout the experimental period. Pretreatment with the opioid receptor antagonist naloxone (1 mg kg^?1, i.v.) or the platelet-activating factor (PAF) receptor antagonist WEB 2086 (2 mg kg^?1, i.v.) did not reverse the inhibitory effects of endotoxin (5 μg kg^?1, i.v.) on acid secretion stimulated by both distension and 2-deoxy-d -glucose. These findings suggest that endotoxin-induced acute inhibition of neurally-mediated acid responses, stimulated by gastric distension or administration of 2-deoxy-d -glucose, do not involve the activation of endogenous opioids or PAF receptors.     

Review of recent guidelines for the management of severe sepsis and septic shock

Severe sepsis and septic shock affect millions of patients and are major causes of mortality worldwide. Advancements in treatment and disease management led to a decline in in-hospital mortality from 27.8% (1979–1984) to 17.9% (1995 to 2000). In this article, we systemically review recent guidelines for the management of severe sepsis and septic shock published in 2008 by the International Surviving Sepsis Campaign Guidelines Committee. The 2008 Surviving Sepsis guidelines recommend protocolized resuscitation with goals to maintain central venous pressure ⩾ 8–12 mmHg, mean arterial pressure ⩾ 65 mmHg, urine output ⩾ 0.5 mL·kg⁻¹·h⁻¹ and central venous oxygen saturation ⩾ 70% (or mixed venous ⩾ 65%). Further fluid administration, transfusion of packed red blood cells to achieve a hematocrit of ⩾ 30% and/or infusion of dobutamine max 20 μg·kg⁻¹·min⁻¹ are advised if venous O₂ saturations remain below 70%. In patients with decreased ventricular compliance or mechanical ventilation, a target central venous pressure of 12–15 mmHg is recommended. Intravenous antibiotic administration within the first hour of recognizing severe sepsis and septic shock is essential, while use of corticosteroids in sepsis is controversial. The mechanisms by which activated protein C improves clinical outcomes in sepsis are unknown. Therapy with activated protein C is approved for patients with severe sepsis and an increased risk of death [Acute Physiology and Chronic Health Evaluation II (APACHE II) > 25]. Bicarbonate therapy is discouraged. Intravenous insulin should be used to control hyperglycemia in patients with severe sepsis following stabilization in the intensive care unit.     

The In-vivo Cardiovascular Effects of a Putative Class III Anti-arrhythmic Drug,AM 92016

AM 92016(1-(4-methanesulphonamidophenoxy)-3-(N-methyl-3–4-dichlorophenethylamino)-2-propanol benzoic acid salt), an oxypropanolamine analogue of sotalol, has been shown to possess Class III antiarrhythmic properties in-vitro at concentrations showing 1000 times more potency than sotalol. The aim of this study was to characterize the effects of AM 92016 in-vivo. When administered to anaesthetized guinea-pigs, AM 92016 (10 μg kg^?1-5 mg kg^?1) significantly increased heart rate, systolic arterial blood pressure, left ventricular systolic pressure and the contractile index dp/dt_max. AM 92016 also significantly decreased the QT interval of the electrocardiogram from 135 ± 10 to 105 ± 4 ms (5 mg kg^?1). The time to onset of the first arrhythmia and ventricular fibrillation, induced by intravenous infusion of ouabain, was shortened in the presence of AM 92016. Ouabain-induced ventricular fibrillation occurred at 18 ± 5 and 12 ± 3 min (P < 005) in control and AM 92016-(1 mg kg^?1) treated guinea-pigs, respectively. An infusion of AM 92016 (2.5 μg kg^?1 min^?1) to anaesthetized pigs significantly increased the total number of arrhythmias occurring following coronary artery occlusion from 266 ·26 in control pigs to 535 ± 148 (P < 005) in those receiving AM 92016. The time to onset of ventricular fibrillation was also significantly reduced in anaesthetized pigs from 24 ± 1 to 18 ± 3 min in the presence of AM 92016. The drug did not change haemodynamics in the anaesthetized pig. We conclude that AM 92016 exhibited proarrhythmic rather than antiarrhythmic activity when administered in-vivo to either guinea-pigs or pigs.     

Attenuation of adenylate cyclase-induced increases in renal sodium excretion by the dopamine D-2 receptor agonist SK&F 89124

1 Although the existence of D-2 receptor binding sites in kidney has been identified, their functional significance in terms of influencing renal sodium excretion is not clear. In the present study we have examined the renal effects of a selective D-2 receptor agonist, SK&F 89124, in anaesthetized rats. 2 Intravenous infusion of SK&F 89124 (0.3, 1 and 3 μg kg^?1 min^?1 respectively) produced dose-dependent decreases in mean arterial blood pressure, heart rate and renal blood flow without causing any significant changes in urine output, urinary sodium excretion, renal vascular resistance or glomerular filtration rate. The changes in blood pressure, heart rate and renal blood flow caused by SK&F 89124 were abolished by a selective D-2 receptor antagonist, domperidone (50 μg kg^?1 i.v. bolus; 10 μg kg^?1 min^?1). 3 Treatment with 3-isobutyl-l-methylxanthine (IBMX, 1 mg kg^?1 bolus i.v.) or forskolin (200 μg kg^?1 bolus i.v.) produced increases in heart rate, urine output and urinary sodium excretion, but there was no change in mean blood pressure. The natriuretic and diuretic response, but not tachycardiac response to IBMX or forskolin, was attenuated by SK&F 89124 (0.3 μg kg^?1 min^?1). 4 These results suggest that the selective D-2 receptor agonist, SK&F 89124, produced a significant decrease in blood pressure and heart rate via prejunctional D-2 receptor-mediated inhibition of noradrenaline release from postganglionic sympathetic nerve terminals. Although activation of renal tubular D-2 receptors had no significant effect on renal excretory function under basal conditions, it is likely that these receptors may exert an opposing effect on cAMP-mediated increases in renal sodium and water excretion.     

Physostigmine and modulators of nitric oxide system on the mean arterial pressure of the spontaneously hypertensive rat

• 1.1. A slow intravenous infusion of L-arginine (3 mg kg⁻¹) lasting one hr produced significant hypotension in urethane-anaesthetized spontaneously hypertensive rats (SHRs).
• 2.2. A slow intravenous infusion of N^G-nitro-l-arginine methyl ester (l-NAME) (3 mg kg⁻¹ h⁻¹) did not produce any significant change in the mean arterial pressure during infusion. After stopping infusion of l-NAME, a slowly developing increase of the mean arterial pressure was observed during the following 40 min.
• 3.3. The pressor response to physostigmine (20, 40 and 80 μg kg⁻¹, IV), injected during a slow intravenous infusion of either l-arginine or l-NAME, was not changed.
• 4.4. l-arginine and l-NAME depressed the pressor responses to physostigmine, if physostigmine was injected after the end of a 1-hr infusion.
• 5.5. Acute pretreatment with increasing doses of physostigmine markedly affected the blood pressure response to L-arginine (i.e., L-arginine-caused hypotension was more pronounced), but only slightly that to l-NAME.
• 6.6. In conclusion, l-arginine, as a donor of NO, produced hypotension by itself and also decreased, but not significantly, the central cholinergically-mediated hypertension (CCMH) produced by physostigmine. It is quite possible that the peripheral NO released by l-arginine antagonized the increased adrenergic activity in the CCMH. This does happen in normotensive rats, but to a lesser degree than in SHRs, as shown in the current experiments.
• 7.7. Also, our results show that inhibition of endogenous NO biosynthesis using l-NAME does not necessarily lead to pressor response in vivo, at least in SHRs. It is concluded that l-arginine-nitric oxide pathways operate in SHRs, as well as in normotensive Wistar rats, but their role in modulating cholinergically-mediated regulation of the mean arterial pressure is less pronounced in SHRs than in normotensive animals.

     

The Acute Effects of FK-506 on Renal Haemodynamics,Water and Sodium Excretion and Plasma Levels of Angiotensin II,Aldosterone, Atrial Natriuretic Peptide and Vasopressin in Pigs

FK-506 has been shown to be an effective immunosuppressive drug with possible nephrotoxic side effects. In this study we have investigated the acute effects of FK-506 on renal haemodynamics, water, sodium and lithium excretion rates and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide (ANP) and vasopressin in 29 anaesthetized Lancaster/Yorkshire female pigs. A continuous intravenous infusion was given over a 2-h period to 4 groups: A: 0.075 mg kg^?1 (n = 7), B: 0.15 mg kg^?1 (n = 8), C: 0.3 mg kg^?1 (n = 6) and P: placebo vehicle (n = 8). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion clearance technique using 125-I-iothalamate and 131-I-hippuran as reference substances. Hormonal parameters were measured by radioimmunoassay. In all three FK-506 groups, fractional lithium excretion was significantly decreased 2 h after FK506 infusion (P: + 0.4%, A: ? 8.8% (P < 0.05), B: ?12.9% and C: ?11.2% (P < 001 for both). Mean arterial blood pressure (MBP) was significantly increased in the two highest dosage groups (B,C) at 2 h of infusion: (MBP; P: +2.9%, A: +3.5%, B: +12.0%, C: + 15.3% (P < 0.01 for both). GFR and RPF showed minor and inconsistent changes while all other parameters measured showed similar or no changes. In conclusion, acute infusion of FK-506 to pigs does not change overall renal function significantly, but increases mean arterial blood pressure and decreases fractional excretion of lithium.     

Acute hemodynamic effects of tetramethylpyrazine and tetrandrine on cirrhotic rats

The hemodynamic effects of tetramethylpyrazine (TMP) and tetrandrine (TET), both alkaloids isolated from Chinese herbs Ligusticum wallichii Franch and Stephania tetrandra S. Moore, respectively, were assessed in anesthetized cirrhotic rats. TMP induced dose-dependent decreases of portal venous pressure (P.V.P.) and mean arterial pressure (M.A.P.) after intravenous infusion. The maximum percentage reduction of P.V.P. after TMP was 3.6 +/- 0.8%, 6.8 +/- 0.5%, and 17.8 +/- 0.6% of baseline, respectively, for the dosages given (3.0, 9.9 and 30.0 mg/kg). Similarly, TET induced dose-dependent decreases of P.V.P. and M.A.P. The maximum percentage reduction of P.V.P. after TET was 5.4 +/- 1.0%, 9.2 +/- 0.8%, and 23.7 +/- 1.2% of baseline, respectively, for the dosages given (2.0, 6.6 and 20.0 mg/kg). Total peripheral resistance was also reduced by TMP as well as TET. Our results showed that TMP and TET induced P.V.P. reduction in cirrhotic rats, together with reduction in M.A.P. and total peripheral resistance.     

Effect of bis(maltolato) oxovanadium on experimental vascular endothelial dysfunction

The study has been designed to investigate the effect of bis(maltolato) oxovanadium (BMOV), a protein tyrosine phosphatase inhibitor, on hypercholesterolemia and hypertension-induced vascular endothelial dysfunction. High fat diet (8 weeks) and deoxycorticosterone acetate (DOCA; 40 mg kg⁻¹, s.c.) were administered to rats to produce hypercholesterolemia and hypertension (mean arterial blood pressure >120 mmHg) respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) were estimated to assess oxidative stress. BMOV (0.2 mg/ml in drinking water) or atorvastatin (30 mg kg⁻¹, p.o.) markedly improved acetylcholine-evoked endothelium-dependent relaxation, lining of vascular endothelium, serum nitrite/nitrate concentration, and serum TBARS in hypercholesterolemic and hypertensive rats. However, this ameliorative effect of BMOV has been prevented by L-NAME (25 mg kg⁻¹, i.p.), an inhibitor of NOS, or by glibenclamide (5 mg kg⁻¹, i.p.), a blocker of ATP-sensitive K⁺ channels. It may be concluded that BMOV-induced inhibition of PTPase may improve vascular endothelial dysfunction.