4'-甲基立可定对冠脉血流和家兔实验性心肌梗塞的影响

实验表明4′-甲基立可定具有增加家免冠脉血流量和小白鼠心肌营养性血流量的作用,但对家兔心肌收缩力和心率无明显影响。通过对家兔实验性心肌梗塞疗效的观察,证明4′-甲基立可定可改善结扎冠脉后引起的心电图变化,表现为∑ST明显降低,NST和TO显著减少,NBT染色法也证明用药后梗塞心肌的重量明显减轻。与立可定进行对比研究指出,二者作用基本相似,唯后者增加心肌营养性血流的作用不够明显。     

A COMPARISON OF THE EFFECTS OF END-TO-SIDE PORTACAVAL SHUNTING AND SIDE-TO-SIDE MESOCAVAL SHUNTING ON HEPATIC HAEMODYNAMICS IN THE DOG

Functional liver blood flow and hepatic artery flow were measured before and after either end-to-side portacaval or side-to-side mesocaval shunting in dogs. Functional liver blood fell by approximately 50% following both portacaval and mesocaval shunting. The hepatic artery response was variable after both portacaval and mesocaval shunts. It is concluded that side-to-side mesocaval shunts do not preserve hepatic blood flow or produce a greater compensatory increase in hepatic artery flow than conventional portacaval shunts.     

ACUTE EFFECT OF PHYSIOLOGICAL CONCENTRATIONS OF VASOPRESSIN ON RAT RENAL FUNCTION

1. The antidiuretic, pressor and electrolyte transport effects of arginine vasopressin (AVP) were simultaneously evaluated in the anaesthetized water diuretic rat. Increasing concentrations of AVP (7.5, 75 and 750 ng/kg bolus and per h), were used to produce plasma levels which approximate the physiological range (4.8 ± 2.4, 35.7 ± 12.5, 85.2 ± 16.1 pg/mL respectively). 2. Administration of a minimally effective antidiuretic dose (7.5 ng) increased mean urine osmolality (from 101 ± 7 to 312 ± 89 mosmol/kg) without altering mean arterial pressure (MAP), renal plasma flow (RPF) or glomerular filtration rate (GFR). A maximal antidiuretic dose of AVP (75 ng) increased mean urine osmolality to 2002 ± 109 mosmol/kg and was associated with significant mean increases in MAP (9 mmHg), RPF and GFR (25%) by 30–60 min. A further ten-fold increase in AVP (750 ng) produced a greater increase in MAP (116 ± 6 to 134 ± 7 mmHg; P < 0.01) as well as increasing RPF and GFR by 35.5 and 38.9% respectively. 3. Increasing concentrations of AVP also progressively increased the fractional excretion of sodium, potassium and phosphate. However, fractional calcium and magnesium excretion was significantly decreased with maximal and supramaximal concentrations. 4. These studies support evidence that AVP is a pressor hormone in physiological concentrations in baroreceptor intact animals. Its role in renal electrolyte transport is unclear. Measured increases in RPF and GFR with the maximal and supramaximal AVP concentrations appear to be correlated with the increase in MAP.     

A METHOD OF DETERMINING INTRINSIC HEPATIC CLEARANCE FROM THE FIRST-PASS EFFECT

1. The relation between systemic hepatic clearance, intrinsic hepatic clearance and hepatic blood flow is considered from the point of view of the sinusoidal perfusion (parallel tube) model of the liver. 2. It is shown how intrinsic hepatic clearance may be calculated, for substrates eliminated in the liver and the kidney only, from data obtained by introducing successively an oral and an intravenous dose (i.e., by using the first-pass effect) without the clinically cumbersome catheterization of the liver vein. 3. The rate of hepatic blood flow is shown to follow from the same data.     

THE HEPATIC TRANSPORT OF SODIUM TAUROCHOLATE IN THE RAT: EFFECT OF PHENOBARBITONE

SUMMARY 1. The effect of pretreatment with phenobarbitone on the hepatic transport of sodium ¹⁴C-taurocholate was studied in the Sprague Dawley rat. Taurocholate solutions were injected into the portal vein in a volume of 0.2 ml in 2 s.
2. Biliary secretion of taurocholate injected into the portal vein in a concentration of 25 μM was not altered by pretreatment with phenobarbitone. This concentration of taurocholate corresponds to that occurring normally in portal venous blood.
3. When taurocholate was injected in a much larger concentration (13 mM), biliary secretion of taurocholate was significantly slower in phenobarbitone-pretreated rats than in control rats.
4. Changes in hepatic bile salt transport do not appear to contribute to the choleresis that occurs with phenobarbitone.     

THE NATURE OF THE PRESSOR RESPONSE TO CAROTID ARTERY OCCLUSION IN THE HEXAMETHONIUM-TREATED RAT

1. The blood pressure monitored from the cannulated right carotid artery and heart rate responses to occlusion of the intact left carotid artery were investigated in rats. 2. Hexamethonium abolished the response to ganglion stimulants but not that to carotid occlusion, although the time course and nature of the response were altered. 3. The pressor response to carotid occlusion in the presence of hexamethonium was not abolished by carotid sinus denervation, vagal section, tubocurarine, atropine, ethyl alcohol or an angiotensin II antagonist, but it was abolished by high doses of phenoxybenzamine. In six out of eight experiments the response was not abolished by cervical cord section. 4. It was concluded that the pressor response to carotid occlusion in the presence of hexamethonium in the rat involves an adrenergic mechanism which is at least in part independent of the autonomic ganglia, and which is mediated by an agent liberated from the brain, possibly under conditions of cerebral ischaemia.     

ACUTE EFFECT OF ETHANOL ON RENAL ELECTROLYTE TRANSPORT IN THE RAT

1. Despite human and animal studies, the direct effect of ethanol on renal water and electrolyte transport is poorly understood. The acute effect of increasing plasma concentrations of ethanol was evaluated in a water diuretic anaesthetized rat model which inhibits endogenous arginine vaso-pressin (AVP) release. 2. Ethanol at a plasma concentration of 1.69 ±0.28 mmol/L produced an immediate increase in urine flow (174 ± 11 μL/min pre-ethanol and 189 ± 13 and then 206 ± 12 μL/min during the ethanol infusion; P<0.001) as well as an increase in fractional sodium excretion (0.17 ± 0.04 to 0.28 ± 0.05 and 0.27 ± 0.05%; P<0.001). There was also a brief phosphaturia. These increases in electrolyte excretion had returned to control values by 20 min despite a further increase in the plasma ethanol concentration. 3. The urinary excretion of potassium, calcium and magnesium was not altered nor was glomerular filtration rate or renal plasma flow. 4. Ethanol at a mean concentration of 1.60 mmol/L did not alter the action of a maximal concentration of AVP (75 ng/kg) on water or electrolyte transport. However, the antidiuretic effect of a submaximal concentration of AVP (7.5 ng/kg) was augmented by ethanol at concentrations of 1.63 and 0.98 mmol/L. 5. These studies suggest that the ethanol induced diuresis commonly ascribed to inhibition of AVP secretion may also be due to other intrarenal effects of ethanol, possibly acting within the proximal tubule. These results also confirm recent in vitro findings that while ethanol does not inhibit the action of a maximal concentration of AVP, it does modulate the effects of lower AVP concentrations.     

EFFECT OF BILE DUCT OBSTRUCTION ON HEPATIC UPTAKE OF 1-METHYL-4-PHENYLPYRIDINIUM IN THE RAT

Previous studies have demonstrated that the organic cation 1-methyl-4-phenylpyridinium (MPP⁺) is avidly taken up by rat freshly isolated hepatocytes through at least two distinct transport mechanisms: the type I hepatic transporter of organic cations and P-glycoprotein. In this study, the effects of extrahepatic cholestasis induced by bile duct ligation for 4 days on the uptake of [³H]MPP⁺by rat freshly isolated hepatocytes and liver slices were determined. Bile duct ligation produced no significant alterations in the characteristics of [³H]MPP⁺uptake by freshly isolated hepatocytes. The strong correlation found between the effect of various drugs on [³H]MPP⁺uptake by hepatocytes from control and treated rats (r=0.958;P<0.0001;n=15) suggests that neither the type I hepatic transporter of organic cations nor P-glycoprotein were affected by bile duct ligation. On the contrary, uptake of [³H]MPP⁺by liver slices was markedly changed after bile duct ligation: (1) there was a significant increase (≅40%) in the amount of [³H]MPP⁺taken up by liver slices from bile duct-ligated rats; (2) there was no correlation between the effect of various drugs on [³H]MPP⁺uptake by liver slices from control and treated rats (r=0.772;P=0.072;n=6). On the basis of (1) the lack of effect of bile duct ligation on [³H]MPP⁺uptake by isolated hepatocytes; and (2) the profound morphological alterations of liver tissue observed 4 days after bile duct ligation (increase in volume density of bile ductules, ductular cells and infiltration of inflammatory cells), we suggest that non-parenchymal liver cells have an important participation in the hepatic uptake of [³H]MPP⁺after bile duct ligation in the rat.     

HEPATIC SINUSOIDAL RESPONSES TO INTRAPORTAL INJECTIONS OF PHENYLEPHRINE AND ISOPRENALINE IN THE RAT

1. Specific α- and β-adrenoreceptor agonists, phenylephrine and isoprenaline, were injected intraportally into the intact rat liver under direct microscopic observation by an in viva transillumination technique. 2. The diameter of a hepatic sinusoid and the intra-sinusoidal erythrocyte velocity were quantitatively measured, and the sinusoidal volume flow was calculated from these two parameters. 3. Results show that phenylephrine causes a sinusoidal constriction and an increased sinusoidal blood flow, whereas isoprenaline causes the opposite effects on the sinusoids. 4. All the sinusoidal responses to phenylephrine and isoprenaline were dose-dependent and were possibly related to the direct effect of these drugs on the sinusoids.     

THE HEPATIC TRANSPORT OF TAUROCHOLIC ACID IN THE RAT: DEVELOPMENT OF A MATHEMATICAL MODEL

1. The transport of taurocholic acid from portal blood to bile was studied in the anaesthetized rat by injecting a radiolabeled pulse of bile acid. 2. The transport process was very rapid, 50% of the dose being secreted within 5 min, and the total dose within 15 min. 3. The transport process had a large capacity. The secretory profile was little modified by a 500-fold increase in the injected dose. 4. The transport process was modelled with both analogue and digital computers. The simplest model which fitted the data comprised rapid uptake from portal blood, slow transport across the cell and rapid secretion into bile. The digital computer simulation suggested that this model is not unique, but will require further testing.     

INTERACTION OF VASOPRESSIN, ANGIOTENSIN AND α-ADRENERGIC SYSTEM IN SODIUM DEPLETION IN THE RAT

1. The role of vasopressin in cardiovascular adaptation to sodium depletion was examined in rats after 6 days on a low sodium diet. Studies were performed after selective or combined blockade with d(CH2)5 Tyr(Me)AVP (AVPA), enalaprilat (CEI) and phentolamine (PHENTOL). AVPA alone had no effect on systemic haemodynamics or regional blood flow distribution. After CEI or PHENTOL pretreatment, AVPA led to significant falls in peripheral resistance and increases in cardiac output and renal blood flow. In sodium depletion, endogenous vasopressin acts as a vasoconstrictor hormone, particularly in the kidney, when either the renin-angiotensin or alpha-adrenergic system is inhibited.     

肝动脉栓塞微球的研究

本文用乳化聚合法制备了明胶和聚乙烯醇两种微球,通过正交试验,确定了制备特定粒径微球的最佳工艺条件。以氟脲嘧啶和甲氨喋呤为模型药物,对明胶微球的体外溶出特性进行了探讨,结果表明,经复合交联能延缓药物的体外溶出。实验狗灌注微球前后的肝动脉造影表明术后肝动脉分枝有不同程度的减少;病理检查表明微球沉积于肝血窦前的肌性小动脉;γ-射线扫描也证实锝标记微球在肝内的特异性分布。     

肝动脉栓塞微球的研究

本文用乳化聚合法制备了明胶和聚乙烯醇两种微球,通过正交试验,确定了制备特定粒径微球的最佳工艺条件。以氟脲嘧啶和甲氨喋呤为模型药物,对明胶微球的体外溶出特性进行了探讨,结果表明,经复合交联能延缓药物的体外溶出。实验狗灌注微球前后的肝动脉造影表明术后肝动脉分枝有不同程度的减少;病理检查表明微球沉积于肝血窦前的肌性小动脉;γ-射线扫描也证实锝标记微球在肝内的特异性分布。     

ROLE OF THE MESOLIMBIC DOPAMINE SYSTEM IN CARDIOVASCULAR HOMEOSTASIS. STIMULATION OF THE VENTRAL TEGMENTAL AREA MODULATES THE EFFECT OF VASOPRESSIN ON BLOOD PRESSURE IN CONSCIOUS RATS

1. The possible role of the ventral tegmental area (VTA) and its dopaminergic projections in cardiovascular regulation is reviewed. 2. Our own work has shown that stimulation of the VTA by local microinjection of the substance P analogue DiMe-C7 caused an increase in blood pressure. The mechanism of the pressor response was an interaction of central dopaminergic activation, most likely at the level of the baroreflex, with the circulatory actions of vasopressin. 3. These findings are important for a possible role of the mesolimbic dopamine system in cardiovascular homeostasis. Several studies reviewed here show that neuronal activity of the VTA and its mesolimbic projections is altered by changes in blood pressure, salt and electrolyte balance, stress and food and water intake. 4. The VTA and mesolimbic dopamine system, while playing a widely accepted role in locomotor activity, cognition and reward mechanisms, may also be involved in the integration of sensory and behavioural information with cardiovascular homeostasis.     

HUMAN INTERNAL MAMMARY ARTERY RESPONSES TO NON-PEPTIDE VASOPRESSIN ANTAGONISTS

1. OPC-21268 and OPC-31260 are newly developed orally active non-peptide vasopressin (AVP) V₁ and V₂ receptor antagonists, respectively. The effects of the two compounds on human vessels have not been studied. 2. The effects of the two compounds on AVP-induced contraction of human internal mammary arteries (IMA) were investigated. Their effects were compared with the peptide V₁ and V₂ antagonists d(CH₂)_sSar⁷AVP (SAVP) and d(CH₂)₅D-Ileu²11eu⁴AVP (Ileu² Ileu⁴AVP), respectively. 3. The V₁ antagonist OPC-21268 failed to antagonize AVP-induced contraction at low concentrations and potentiated the contraction at higher concentration (3 × 10^?-⁷ mol/L, P<0.05). It also caused a mild direct contractile effect on IMA. In contrast, the peptide V₁ antagonist SAVP potently inhibited the AVP-induced contraction, indicating that functionally constrictor V₁ receptors exist in IMA. Both the nonpeptide and peptide V₂ antagonists OPC-31260 (3X10^?-⁶ mol/L) and Ileu²Ileu⁴AVP significantly antagonized the AVP-induced contraction (P<0.01). 4. The AVP-induced contraction was reversed by high concentrations of OPC-31260 (10^?-⁶ mol/L-3×10^?-⁵ mol/L) but not by OPC-21268 (up to 3X 10^?-⁵ mol/L). 5. These studies indicate that, in human IMA, OPC-21268 is a partial VI receptor agonist with no V₁ receptor antagonist activity, while OPC-31260 is a V1 receptor antagonist. The results also indicate that Ileu² Ileu⁴AVP may be a V_l receptor antagonist in humans.     

EFFECTS OF TOTAL AND SELECTIVE PORTASYSTEMIC SHUNTING ON HEPATIC HAEMODYNAMICS AND SOME ASPECTS OF LIVER FUNCTION IN THE CIRRHOTIC RAT

The effects of total and selective portasystemic shunting on hepatic haemodynamics and some aspects of liver function were studied in rats with dimethylnitrosamine-induced cirrhosis. Immediately following end-to-side portacaval shunting there were significant reductions in wedged hepatic venous pressure (WHVP) and liver blood flow. After side-to-side mesocaval shunting liver blood flow and wedged hepatic venous flow fell by approximately the same magnitude. Selective shunting (mesocaval 'H'-grafts and splenopancreaticocaval) preserved liver blood flow to a greater extent than total portasystemic shunting but had a less marked effect on WHVP. Furthermore, selective portasystemic shunting prevented liver atrophy and deterioration in liver function which was observed in rats following total portasystemic shunting. These results suggest that in the cirrhotic rat, selective portasystemic shunts which preserve functional liver blood flow and prevent liver atrophy and a deterioration in liver function do not produce such a marked decrease in WHVP as total shunts. Further studies in man are required to evaluate the relative advantages of total and selective portasystemic shunts.     

EFFECT OF ARGININE VASOPRESSIN AND PARATHYROID HORMONE-RELATED PROTEIN ON RENAL FUNCTION IN THE OVINE FOETUS

1. The effects of intravenous infusions of arginine vasopressin (AVP), parathyroid hormone-related protein (PTHrP) and AVP + PTHrP on renal function in intact ovine foetuses at 100–125 days of gestation were examined. 2. A low dose of AVP (5.5 ± 0.9 pmol/h) increased plasma AVP concentrations from 0.6 pmol/L to 2.1 ± 0.4 pmol/L (mean ± s.e.m; n= 8). This dose caused a significant reduction in free water clearance (C_H2O; P<0.001), without any significant change in fetal arterial blood pressure, glomerular filtration rate (GFR), or the urinary excretion rates of sodium, calcium or 3', 5'-cyclic adenosine monophosphate (CAMP). 3. Infusions of PTHrP (1 nmol/h), with or without 1 nmol bolus dose, significantly increased (P<0.05) urine osmolality (Uosm), but did not synergize with AVP in reducing C_H2O. 4. It is concluded that AVP and PTHrP do not act synergistically on the kidney of the intact ovine foetus.     

THE EFFECT OF ADRENALECTOMY ON WATER PERMEABILITY IN RAT PAPILLARY COLLECTING DUCT

1. Chronic adrenal insufficiency impairs maximal urine concentration, probably in part due to reduced medullary tonicity but also possibly by inhibition of distal nephron water transport. This latter defect has been demonstrated in rabbit but not in rat. 2. Since the time between adrenalectomy and experiment was different in rabbit and rat studies, diffusional water permeability was evaluated in the papillary collecting duct in the absence and presence of submaximal (20 μU/mL) and supramaximal (200 μU/mL) arginine vasopressin (AVP) in adrenalectomized rats at 7, 14 and 21 days. 3. Experimentation 7 days after adrenalectomy failed to demonstrate significantly altered basal or AVP-induced water permeability which increased by 23 and 78% with submaximal and supramaximal concentrations, respectively. Submaximal AVP concentrations also induced a comparable change in water permeability in adrenalectomized rats at 14 days; however, 21 days after adrenalectomy, diffusional water permeability was not increased by 20 μU/mL AVP (3.31 ±.22 to 3.31 ±.24 μm/s). Nevertheless, the effect of a supramaximal AVP concentration (200 μU/mL) was not altered by adrenalectomy (4.54 ±.39 to 8.08 ±.96; P<0.01). Incubation of collecting ducts in aldosterone for 2 h did not reverse the inhibitory effect of chronic adrenalectomy on AVP-stimulated water transport. 4. These studies suggest that mineralocorticoid withdrawal does impair the hydro-osmotic action of AVP in the rat papillary collecting duct but that this effect takes between 14 and 21 days to occur.     

THE MEASUREMENT OF GLOMERULAR BLOOD FLOW IN THE RAT KIDNEY: INFLUENCE OF MICROSPHERE SIZE

1. Radioactively labelled microspheres were used to determine glomerular blood flow in glomerular populations with distinct vascular characteristics. Two batches of microspheres (15 ± 5.0 μm diameter and 7.0–10 μm diameter) were utilized. 2. The results show that the larger microspheres overestimate the superficial glomerular blood flow (414 ± 61 nl/min, mean ± s.e.m.) and underestimate the deep glomerular blood flow (98 ± 10 nl/min), when compared with the data obtained with 7.0–10 μm diameter microspheres (317 ± 30 nl/min and 209 ± 23 nl/min, respectively). 3. The rheological artefact associated with the use of larger microspheres is confirmed by finding an uneven size distribution of microspheres lodged in the glomeruli. In each of three experiments, the mean diameter of 200 microspheres lodged in the superficial glomeruli (16.43 ± 0.27 μm, 15.87 ± 0.23/mi and 16.58 ± 0.27 Jim) was significantly greater than that found in the deep glomeruli (15.36 ± 0.15μm, 15.25 ± 0.21 μm and 15.73 ± 0.24μm; P<0.01, <0.05 and < 0.01, respectively). No such difference was detected when the 7.0–10 μm spheres were used. 4. Glomerular blood flow can be measured at all depths of the rat's cortex and the demonstrated rheological artefact associated with use of the larger spheres is circumvented with the use of 7.0–10 μm microspheres.