Analysis of the interaction between lacidipine and BAY K 8644 in two isolated rabbit arteries.

The calcium antagonist activity of the long-acting 1,4-dihydropyridine (DHP) lacidipine has been analyzed in rabbit ear artery (REA) and rabbit basilar artery (RBA). Its potency has been estimated from its interaction with BAY K 8644 using a three state gating model of the voltage-operated calcium channel. As a contractile agent, BAY K 8644 exhibited a bell-shaped concentration-response curve in both arteries. For fitting purposes, a second binding interaction between BAY K 8644 and the channel has been used to describe the descending part of the curve. The K(app)s for lacidipine and three other DHPs (nifedipine, nitrendipine and amlodipine) have been compared to pA2 values obtained from displacement of calcium concentration-response curves. In both REA and RBA the K(app)s for the four DHPs were not significantly different compared to their pA2s. The pK(app) values for lacidipine were estimated as 9.80 for REA and 10.20 for RBA.     

Positive inotropic effect of carbachol and inositol phosphate levels in mammalian atria after pretreatment with pertussis toxin

The m-cholinoceptor agonist carbachol elicits a negative inotropic effect in mammalian atria. Pretreatment with pertussis toxin converts the negative to a positive inotropic effect. In this study we investigated the time course of the effects of carbachol on force of contraction and phosphoinositide products in electrically driven left auricles from guinea pig hearts after pretreatment with pertussis toxin (180 micrograms/kg i.v.; 24 hr). Inositol phosphates and phosphatidylinositols were labeled with [3H]inositol and separated with high-performance liquid chromatography and thin-layer chromatography, respectively. All experiments were performed in the presence of LiCl (10 mmol/l). The positive inotropic effect of carbachol (10 mumol/l) began within 2 min and was maximal within 15 min. Inositol 1,4,5-trisphosphate rose within 1 min followed by an increase in inositol 1,3,4,5-tetrakisphosphate, inositol 1,3,4-trisphosphate, inositol 1,4-bisphosphate and inositol 1-phosphate beginning within 2 min. It is concluded that the carbachol-induced positive inotropic effect is associated with an increase in the presumed second messengers inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Since the increase in inositol 1,4,5-trisphosphate precedes the increase in force of contraction, it may initiate the positive inotropic effect. The increase in inositol 1,3,4,5-tetrakisphosphate may be involved in maintaining the positive inotropic effect of carbachol.     

Relationship between urinary concentrating ability, arginine vasopressin in plasma and blood pressure after renal transplantation

Arginine vasopressin (AVP) and serum osmolality (Sosm) were determined in plasma before and after a 24-h period of water deprivation in 19 patients with post-renal-transplant hypertension (group I), 14 patients with normal blood pressure after renal transplantation (group II), and 16 healthy control subjects (group III). Urine was collected in four periods of 6 h each for measurement of urine volume (V), urine osmolality (Uosm) and tubular capacity for reabsorption of water (Tc water). AVP and Sosm increased significantly in all groups. The AVP levels were the same in groups I and II, but higher in group I than III both before and after water deprivation. In group II, AVP was higher than in group III only after water deprivation; V was significantly reduced in all groups. In groups I and II, V, Tc water and Uosm were the same. In group III, V was significantly lower than in groups I and II in the last three 6-h periods, and in group III, Tc water was higher in the first 6-h period than in groups I and II. There was a significant positive correlation between AVP and Sosm in all groups. In conclusion, renal water excretion cannot be reduced as rapidly and to the same degree in renal transplant recipients as in control subjects because of a decreased renal capacity for reabsorption of water. The higher AVP level in the transplant recipients may be a compensatory phenomenon for the decreased responsiveness of the renal collecting ducts in the transplanted kidneys. The sensitivity of the osmoreceptors to changes in osmotic stimuli was normal.     

减毒百日咳杆菌注射部位与实验性变态反应性脑脊髓炎大鼠模型诱导效果的关系

背景：国外实验室一般选用近交系Lewis大鼠诱导实验性变态反应性脑脊髓炎模型，但国内缺乏Lewis大鼠。因此，本实验选用了国内数量充足、但不十分敏感的Wistar大鼠，在加用百日咳减毒活菌的情况下。成功地在Wistar大鼠中诱导出实验性变态反应性脑脊髓炎动物模型。 目的：探讨在不同部位加用减毒百日咳杆菌对实验性变态反应性脑脊髓炎非敏感品系Wistar大鼠模型诱导的影响。 设计：随机对照动物实验。 单位：山西大同大学脑科学研究所。 材料：实验于2003—03／10在山西大同大学脑科学研究所完成。雌性Wistar大鼠58只随机分为3组：（1）足背实验性变态反应性脑脊髓炎组24只。（2）腹腔实验性变态反应性脑脊髓炎组24只。（3）佐剂组10只。 方法：除常规免疫动物外。足背实验性变态反应性脑脊髓炎组大鼠于足背皮内或皮下注射减毒百日咳杆菌0．05mL／只（含5．0&;#215;10^10个菌体）；腹腔实验性变态反应性脑脊髓炎组大鼠于腹腔注射减毒百日咳杆菌0．05mL／只（含5．0&;#215;10^10个菌体）；佐剂组则以完全弗氏佐剂代替抗原。 主要观察指标：（1）发病时间。（3）体质量变化。（3）临床症状。（4）脑组织病理情况。 结果：58只大鼠均进入结果分析。（1）发病率和发病时间：足背实验性变态反应性脑脊髓炎组发病率为87．5％（21／24），发病时间为免疫后（10．25&;#177;1．67）d，而腹腔实验性变态反应性脑脊髓炎组分别为35．7％（9／24）和（14．8&;#177;1．79）d，两组比较差异有显著性意义（P〈0．05）。（爹体质量变化和临床症状：足背实验性变态反应性脑脊髓炎组体质量变化为（-16．00&;#177;7．30）g，症状评分为3．4&;#177;0．7；腹腔实验性变态反应性脑脊髓炎组体质量变化为（-9．14&;#177;13．11）g,症状评分为2．4&;#177;0．5。（3）脑组织病理情况：佐剂组大鼠脑脊髓组织没有或有少数单个核细胞浸润。实验性变态反应性脑脊髓炎大鼠炎症病灶侵犯脊髓腰膨大的自质以及灰白质交界处、软脊膜及脊髓实质，大脑皮质及皮髓质交界处甚至深部髓质、脑脊膜和侧脑室周围也被侵犯。病灶也累及小脑、脑干和视交叉。这与观察到的共济障碍、抽搐等表现相一致。苏木精-伊红染色显示病变血管周围有淋巴细胞和单核细胞浸润，呈典型的袖套样改变。足背实验性变态反应性脑脊髓炎和腹腔实验性变态反应性脑脊髓炎发病大鼠均有典型的袖套样改变，但足背实验性变态反应性脑脊髓炎大鼠病灶多。 结论：足背皮下注射百日咳毒索诱导实验性变态反应性脑脊髓炎模型病程、病理改变、临床表现都很典型，且发病率高，经济易行，是一种较为理想的实验性变态反应性脑脊髓炎模型诱导方法。     

减毒百日咳杆菌注射部位与实验性变态反应性脑脊髓炎大鼠模型诱导效果的关系

背景:国外实验室一般选用近交系Lewis大鼠诱导实验性变态反应性脑脊髓炎模型,但国内缺乏Lewis大鼠。因此,本实验选用了国内数量充足、但不十分敏感的Wistar大鼠,在加用百日咳减毒活菌的情况下,成功地在Wistar大鼠中诱导出实验性变态反应性脑脊髓炎动物模型。目的:探讨在不同部位加用减毒百日咳杆菌对实验性变态反应性脑脊髓炎非敏感品系Wistar大鼠模型诱导的影响。设计:随机对照动物实验。单位:山西大同大学脑科学研究所。材料:实验于2003-03/10在山西大同大学脑科学研究所完成。雌性Wistar大鼠58只随机分为3组:①足背实验性变态反应性脑脊髓炎组24只。②腹腔实验性变态反应性脑脊髓炎组24只。③佐剂组10只。方法:除常规免疫动物外,足背实验性变态反应性脑脊髓炎组大鼠于足背皮内或皮下注射减毒百日咳杆菌0.05mL/只(含5.0×1010个菌体);腹腔实验性变态反应性脑脊髓炎组大鼠于腹腔注射减毒百日咳杆菌0.05mL/只(含5.0×1010个菌体);佐剂组则以完全弗氏佐剂代替抗原。主要观察指标:①发病时间。②体质量变化。③临床症状。④脑组织病理情况。结果:58只大鼠均进入结果分析。①发病率和发病时间:足背实验性变态反应性脑脊髓炎组发病率为87.5%(21/24),发病时间为免疫后(10.25±1.67)d,而腹腔实验性变态反应性脑脊髓炎组分别为35.7%(9/24)和(14.8±1.79)d,两组比较差异有显著性意义(P<0.05)。②体质量变化和临床症状:足背实验性变态反应性脑脊髓炎组体质量变化为(-16.00±7.30)g,症状评分为3.4±0.7;腹腔实验性变态反应性脑脊髓炎组体质量变化为(-9.14±13.11)g,症状评分为2.4±0.5。③脑组织病理情况:佐剂组大鼠脑脊髓组织没有或有少数单个核细胞浸润。实验性变态反应性脑脊髓炎大鼠炎症病灶侵犯脊髓腰膨大的白质以及灰白质交界处、软脊膜及脊髓实质,大脑皮质及皮髓质交界处甚至深部髓质、脑脊膜和侧脑室周围也被侵犯。病灶也累及小脑、脑干和视交叉,这与观察到的共济障碍、抽搐等表现相一致。苏木精-伊红染色显示病变血管周围有淋巴细胞和单核细胞浸润,呈典型的袖套样改变。足背实验性变态反应性脑脊髓炎和腹腔实验性变态反应性脑脊髓炎发病大鼠均有典型的袖套样改变,但足背实验性变态反应性脑脊髓炎大鼠病灶多。结论:足背皮下注射百日咳毒素诱导实验性变态反应性脑脊髓炎模型病程、病理改变、临床表现都很典型,且发病率高,经济易行,是一种较为理想的实验性变态反应性脑脊髓炎模型诱导方法。     

Renal, haemodynamic and hormonal interactions between atrial natriuretic factor and arginine vasopressin in patients with congestive heart failure.

1. Nine patients with compensated heart failure were infused with synthetic arginine vasopressin at a rate of 0.1 m-units min-1 kg-1 for 60 min to increase their plasma arginine vasopressin concentration. Synthetic human atrial natriuretic factor (3 pmol min-1 kg-1) or placebo was co-infused with the arginine vasopressin in random order in a single-blind cross-over design. 2. The resultant plasma concentrations of arginine vasopressin and atrial natriuretic factor fell to within the upper range observed in congestive heart failure. Compared with the infusion of arginine vasopressin alone, atrial natriuretic factor co-infusion enhanced both the urine flow rate and the sodium excretion rate (both P less than 0.05) without significant haemodynamic and hormonal effects. 3. Systematic blood pressure was elevated by arginine vasopressin infusion (P less than 0.05) without any change in heart rate. Co-infusion of atrial natriuretic factor did not affect these haemodynamic parameters. 4. These results suggest that an increased release of atrial natriuretic factor maintains water and sodium excretion in the presence of arginine vasopressin-induced renal modulations, and that the pressor effect of arginine vasopressin is not antagonized by the increased plasma level of atrial natriuretic factor in patients with congestive heart failure.     

Effect of pertussis toxin treatment on postjunctional alpha-1 and alpha-2 adrenoceptor function in the cardiovascular system of the pithed rat

The role of pertussis toxin sensitive guanine nucleotide regulatory proteins (G-proteins) in the signal transduction processes involved in postjunctional vascular alpha-1 and alpha-2 adrenoceptor-mediated vasoconstriction has been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 micrograms/kg i.v., 3 days before experimentation) produced a marked inhibition of the alpha-2 adrenoceptor-mediated pressor response to B-HT 933. In contrast, pertussis toxin treatment had only a small effect on the alpha-1 adrenoceptor-mediated pressor response to cirazoline. However, after elimination of the alpha-1 adrenoceptor reserve for cirazoline with phenoxybenzamine (0.1 mg/kg i.v.), the pressor response to this agonist became highly sensitive to inhibition by pertussis toxin treatment. This pattern of inhibition of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by pertussis toxin is identical to that produced by inhibition of extracellular calcium influx by a high dose of the calcium channel antagonist, nifedipine (1.5 mg/kg i.a.), suggesting that those components of the alpha-1 and alpha-2 adrenoceptor-mediated vasoconstrictor processes that are dependent upon the translocation of extracellular calcium may involve a pertussis toxin sensitive G-protein.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of pertussis toxin on α1-adrenoceptor-mediated vasoconstriction by the full agonist, cirazoline, and the partial agonist, (-)-dobutamine, in pithed rats

The role of pertussis toxin-sensitive guanine nucleotide regulatory proteins (G-proteins) in the signal transduction process(es) involved in postjunctional vascular alpha 1-adrenoceptor-mediated vasoconstriction produced by the full agonist, cirazoline, and the partial agonist, (-)-dobutamine, have been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 micrograms/kg, iv, 3 days prior to experimentation) only slightly inhibited the pressor response of cirazoline, and the degree of inhibition produced by pertussis toxin was roughly equivalent to the inhibition produced by the calcium channel antagonist, nifedipine (1 mg/kg, ia). In contrast, pertussis toxin pretreatment produced marked inhibition of the alpha 1-adrenoceptor-mediated pressor response to the partial agonist, (-)-dobutamine, and this large degree of inhibition was qualitatively and quantitatively similar to the degree of inhibition produced by nifedipine. The differential pattern of inhibition of full and partial alpha 1-adrenoceptor agonists by pertussis toxin suggests that the vasoconstrictor response of an alpha 1-adrenoceptor partial agonist, which is more dependent upon the translocation of extracellular calcium than a full agonist, as evidenced by its sensitivity to inhibition by nifedipine, involves a pertussis toxin-sensitive G-protein that couples the alpha 1-adrenoceptor to the calcium channel. Furthermore, for alpha 1-adrenoceptor-mediated vasoconstriction by full agonists with high intrinsic efficacy, which involves both intracellular and extracellular pools of calcium, and particularly the former, pertussis toxin only inhibits that component of the alpha 1-adrenoceptor response which is dependent upon the translocation of extracellular calcium, accounting for the limited degree of inhibition of the response to cirazoline by pertussis toxin and by nifedipine. By inference, the other component of the alpha 1-adrenoceptor-mediated pressor response to a full agonist, which is dependent upon the mobilization of intracellular stores of calcium through a process believed to involve the activation of phospholipase C, likely utilizes a pertussis toxin insensitive G-protein that is distinct from that which we propose couples the alpha 1-adrenoceptor to the calcium channel. We conclude, therefore, that the alpha 1-adrenoceptor in the vasculature of the pithed rat may be coupled to 2 distinct G-proteins, only one of which is sensitive to inhibition by pertussis toxin and links the alpha 1-adrenoceptor to the membrane calcium channel, and which may be utilized by both full agonists and partial agonists.     

Agonist actions of Bay K 8644, a dihydropyridine derivative, on the voltage-dependent calcium influx in smooth muscle cells of the rabbit mesenteric artery

Actions of methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2- trifluoromethylphenyl)-pyridine-5-carboxylate (Bay K 8644) on the mechanical response evoked in intact and skinned mesenteric artery of the rabbit were investigated. The data were compared to that of nisoldipine, another dihydropyridine derivative Bay K 8644 increased the amplitudes of both the phasic and tonic components of the K+-induced contraction which is due to an increase in the voltage-dependent influx of Ca ion. Bay K 8644 antagonized competitively the actions of nisoldipine (a Ca antagonist) on the tonic but not on the phasic component of the K+-induced contraction. The contractions caused by high concentrations of norepinephrine were enhanced to a greater extent by Bay K 8644 than that evoked by lower concentrations of norepinephrine. Bay K 8644 had no effect on Ca++ extrusion from cells, which was estimated from the change in amplitudes of the norepinephrine-induced contractions in Na+- and Ca++-free solutions. This agent had no effect on the contractile proteins and Ca storage sites, as estimated from the Ca++- or caffeine-induced contraction observed in skinned muscles. The results suggested that Bay K 8644 acts primarily on the voltage-dependent Ca++ channel, presumably the same site at which other dihydropyridine derivatives (Ca antagonists) act, and that the influx of Ca++ is accelerated.     

Metabolic, humoral, and cellular responses in adult volunteers immunized with the genetically inactivated pertussis toxin mutant PT- 9K/129G

PT-9K/129G, a nontoxic mutant of pertussis toxin (PT) obtained by genetic manipulation, has been shown in animal models to be a promising candidate for new vaccines against whooping cough. To assess the safety and the immunogenicity of PT-9K/129G in humans, a pilot study has been performed in adult volunteers. The protein was found to be safe, capable of inducing high titers of toxin-neutralizing antibodies, and capable of generating immunological memory. In fact, vaccination caused an increase of cell-mediated response to PT, PT-9K/129G, S1 subunit, and B oligomer, indicating that memory T cells are induced by the vaccine. Since PT-9K/129G is mitogenic for T lymphocytes in vitro, it was investigated whether this activity is also present in vivo. No variation was observed in the proportion of T cells (CD3+), T helper cells (CD4+), and cytotoxic T cells (CD8+), as well as in that of other lymphoid populations, by FACS analysis. Interestingly, no thorough correlation was found between humoral and cellular responses. In one case, a very high cellular response was present in absence of detectable antibodies, suggesting that the antibody response, which is the only parameter measured in most clinical trials, may not give a complete picture of the response induced by a vaccine.     

Effect of endothelin-1 in man: pretreatment with nifedipine, with indomethacin and with cyclosporine A

The rise in blood pressure following the intravenous administration of endothelin-1 remained unchanged in healthy male volunteers pretreated with either the calcium-channel antagonist nifedipine (10 mg orally), the cyclo-oxygenase inhibitor indomethacin (150 mg day-1 for three days) or the immunosuppressive agent cyclosporine (5 mg kg-1 body weight for five days). Following administration of nifedipine the rise in plasma concentrations of endothelin-1 during the infusion of the peptide was markedly higher (P less than 0.01) than during control experiments without nifedipine. It is concluded that, in healthy men, nifedipine, indomethacin and cyclosporine do not exert a major influence on the pressor action of endothelin-1. However, nifedipine apparently influences the elimination of endothelin-1 from the circulation in healthy men.     

Renin, aldosterone and arginine vasopressin in patients with liver cirrhosis: the influence of ascites retransfusion

Plasma renin activity (PRA), and concentrations of aldosterone (PAL) and arginine vasopressin (AVP) in plasma were determined in 15 patients with ascites due to cirrhosis. The concentrations in ascites were analyzed simultaneously. Six patients were studied during extracorporeal ascites retransfusion. All but one patient with ascites showed elevated PAL (642 +/- 255 pg ml-1) and PRA (43 +/- 26 ng ml-1 h-1); all had increased AVP (7.3 +/- 5.1 pg ml-1). A low ascites to plasma ratio was found for aldosterone (0.023 +/- 0.023), but not for AVP (0.71 +/- 0.82). Retransfusion resulted in a normalization of central venous pressure (CVP), urinary volume, sodium/potassium ratio in urine, PAL and PRA, but not of AVP, serum sodium concentration and urinary sodium excretion. PRA and PAL increased again after cessation of treatment, while urinary output, CVP and sodium/potassium ratio in urine decreased. The results support the 'underfilling' concept, but give evidence that, in addition, other factors must be involved in the impaired natriuresis in cirrhotic patients. They further support the concept of volume expansion and increased renal perfusion as reason for the therapeutic efficacy of ascites retransfusion. Previous diuretic treatment seems not to be of importance for altered hormone metabolism in liver cirrhosis. Storage in a third compartment may be a factor in the persistently elevated AVP levels.     

左旋精氨酸对实验性心肌缺血/再灌注损伤中一氧化氮和内皮素的影响

目的　探讨一氧化氮 (NO)和内皮素 (ET)在心肌缺血 /再灌注损伤 (MIRI)中的作用及左旋精氨酸对其的影响。方法　实验兔分为假手术对照组 (n =10 )、心肌缺血 /再灌注组 (n =10 )及心肌缺血 /再灌注 左旋精氨酸组 (n =10 ) ;分别检测缺血前、缺血 4 0min和再灌注 2 0min 3个时点的指标变化。用硝酸还原酶法检测血浆及心肌组织一氧化氮代谢产物 (NOP)含量 ,放射免疫法测定ET水平 ,酶动力法测定乳酸脱氢酶 (LDH)活性 ,并行心肌电镜观察。结果　心肌缺血 4 0min、再灌注 2 0min血浆NOP明显低于、ET及LDH显著高于假手术对照组 ,尤以再灌注 2 0min变化显著 (均P <0 0 1) ;心肌组织NOP和LDH明显低于、ET显著高于假手术对照组 (P <0 0 5和P <0 0 1) ;心肌超微结构发生异常改变。左旋精氨酸可逆转上述指标的异常变化。结论　缺血 /再灌注导致血管内皮功能紊乱 (即NO水平下降和ET水平升高 ,在MIRI发生发展中起介导作用 ;左旋精氨酸通过保护冠脉内皮 ,提高机体内NO水平和降低机体内ET水平 ,从而减轻MIRI。     

Disturbed relationship between urinary prostaglandin E2 excretion, plasma arginine vasopressin and renal water excretion after oral water loading in early hepatic cirrhosis

An oral water load of 20 ml kg-1 body weight was given to 11 patients with early hepatic cirrhosis and to 16 healthy control subjects. Urinary output (V), free water clearance (CH2O), urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), and plasma concentration of arginine vasopressin (AVP) were determined before and during the first 4 h after loading. During basal conditions, PGE2 excretion was the same in patients (75 pg min-1, median, range 15-569) and controls (78 pg min-1, range 22-262), but during the first hour after water loading, PGE2 increased to a significantly higher level in cirrhotic patients (423 pg min-1, median) than in control subjects (162 pg min-1) (P less than 0.05). No difference in PGF2 alpha excretion was found between the two groups. Urinary output and CH2O were significantly lower after water loading in patients than in controls. Arginine vasopressin before water loading did not differ between patients and control subjects, but after loading it was unchanged in the patients, whereas a significant reduction (1.9 to 1.4 pmol l-1, P less than 0.01) was found in the control subjects. In controls, but not in patients, PGE2 was significantly positively correlated to V and CH2O, and negatively correlated to AVP after water loading. Thus, renal PGE2 excretion is increased and CH2O is decreased after water loading in patients with early hepatic cirrhosis, and a disturbed relationship seems to exist between PGE2 on the one hand, and AVP and renal water excretion, on the other, in these patients after water loading.(ABSTRACT TRUNCATED AT 250 WORDS)     

3H]BAY K 8644, a 1,4-dihydropyridine Ca++ channel activator: characteristics of binding to high and low affinity sites in cardiac membranes

The binding of [3H]BAY K 8644 [methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate] to high and low affinity sites in rabbit ventricular membranes was characterized. Binding affinities were 0.66 and 138 nM at 15 degrees C and 9.1 and 72 nM at 37 degrees C, for the high and low affinity sites, respectively, and binding site densities were 0.3 and 14 pmol/mg at 15 degrees C and 0.41 and 1.4 pmol/mg at 37 degrees C, for the respective sites. The modification of high affinity [3H]BAY K 8644 binding by verapamil, diltiazem, tiapamil, Ca++ and EDTA appeared to be the same as that for nitrendipine binding, consistent with the hypothesis that the high affinity binding site for [3H]BAY K 8644 on isolated membranes is the same as the 1,4-dihydropyridine antagonist binding site. The binding of [3H]BAY K 8644 to a low affinity binding site was modified by temperature, Ca++ and diltiazem, but the lack of stereoselectivity, lack of denaturation by heat and the large number of sites indicated that most of the low affinity binding sites were not associated with Ca++ channels. It is concluded that the high affinity binding site for BAY K 8644 is associated with Ca++ channels, and is modified by at least some of the factors that modify the binding site for Ca++ channel antagonists, whereas many or all of the low affinity binding sites detected are not related to Ca++ channels.     

Influence of the sympathetic nervous system and vasopressin on the blood pressure lowering effect of nifedipine in deoxycorticosterone acetate-salt hypertensive rats

1. The role of the sympathetic nervous system and the effect of vasopressin (AVP) on the hypotensive action of nifedipine (Nf) were evaluated in conscious, unrestrained normotensive and DOCA-salt hypertensive rats. 2. The hypotensive response to Nf was much greater in DOCA rats than in the controls. 3. Solitary blockade of the sympathetic nervous system or AVP, did not alter the Nf effect in either DOCA or control rats. However, a combination clearly diminished the effect of Nf in the DOCA group, but enhanced it in the controls. The inhibition of angiotensin II (ANG II) augmented the hypotensive effect of Nf in control animals, but not in the DOCA rats. The percentage fall in blood pressure with Nf was much the same in both groups after the combined inhibition of the sympathetic nervous system and AVP. 4. The enhanced hypotensive action of Nf in DOCA rats may be dependent on the hyperactivity of the sympathetic nervous system and AVP, which facilitates calcium influx, and in the normotensive animals the depressor response to Nf may relate to blockade of the calcium influx, independent of the sympathetic nervous system, AVP and ANG II.     

Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock

Arginine vasopressin (AVP) levels are increased in hemorrhagic and septic shock. Measurement of AVP levels has limitations due to its short half-life and cumbersome detection method. Copeptin is a more stable peptide derived from the same precursor molecule. We evaluated the plasma copeptin concentration in two independent studies: first, in an experimental baboon model of hemorrhagic shock, and second, in a prospective observational study of 101 consecutive critically ill patients at a university hospital. Copeptin was measured with a newly developed sandwich immunoassay using two polyclonal antibodies to the C-terminal region (amino acid sequence 132-164) of pre-pro-AVP. Copeptin concentrations in hemorrhagic shock increased markedly from median (range) of 7.5 [2.7-13) to 269 pM (241-456 pM). After reperfusion, copeptin levels dropped within hours to a plateau of 27 pM (15-78 pM). In the critically ill patient cohort, copeptin values increased significantly with the severity of the disease and were in patients without sepsis [27.6 pM [2.3-297 pM]), in sepsis [50.0 pM [8.5-268 pM]), in severe sepsis [73.6 pM [15.3-317 pM]), and in septic shock [171.5 pM (35.1-504 pM] compared with 4.1 pM (1.0-13.8 pM) in healthy controls (P for all vs. controls <0.001). On admission, circulating copeptin levels were higher in nonsurvivors (171.5 pM, 46.5-504.0 pM) as compared with survivors (86.8 pM, 8.5-386.0 pM; P = 0.01). Copeptin levels correlated with basal cortisol levels (r = 0.42; P < 0.001) and osmolality (r = 0.42; P < 0.001). In a logistic regression model including other covariates besides copeptin (e.g., determinants of fluid status) on survival, serum copeptin levels were the only independent significant predictor of outcome (P = 0.03). Copeptin concentrations are elevated in hemorrhagic and septic shock. Copeptin was higher on admission in nonsurvivors as compared with survivors, suggesting copeptin as a prognostic marker in sepsis. The availability of a reliable assay for the measurement of AVP release can also prove useful for the assessment of fluid and osmosis status in various diseases.     

Relationship between phospholipase C activation and prostaglandin E2 and cyclic adenosine monophosphate production in rabbit tubular epithelial cells. Effects of angiotensin, bradykinin, and arginine vasopressin.

By employing early-passaged rabbit kidney epithelial cells in tissue culture, we demonstrated that angiotensin II (AII) has unique mechanisms of signal transduction. First, unlike its action in other target tissues, micromolar concentrations of AII are required to induce small rises in cytosolic calcium, [Ca2+]i, an action which is not accompanied by the release of inositol phosphates (IP). In contrast, nanomolar bradykinin (BK) mobilizes [Ca2+]i through activation of phospholipase C and release of IP. Neither of these stimulated calcium responses exhibits pertussis toxin (PTx) sensitivity. Secondly, AII and BK at 10(-9) to 10(-7) M stimulate cAMP indirectly through PGE2 production in distal cells. AII- and BK-stimulated PGE2 release is PTx inhibitible, suggestive of the presence of a GTP binding protein mediating the response. By contrast, arginine vasopressin fails to elicit rises in [Ca2+]i but exerts its primary effect on cAMP production in distal cells via direct coupling to a stimulatory GTP binding protein, as evidenced by uncoupling with cholera toxin. Regulation of PGE2 synthesis appears to occur via phospholipase A2, not C, by all three peptides.     

Renal water excretion before and after remission of nephrotic syndrome: relationship between free water clearance and kidney function, arginine vasopressin, angiotensin II and aldosterone in plasma before and after oral water loading

An oral water load of 20 ml/kg body wt. was given to eight patients with nephrotic syndrome before and after remission of the syndrome, and to 13 healthy control subjects. Urine volume (D), free water clearance (C water), plasma concentrations of arginine vasopressin (AVP), angiotensin II (ANG II) and aldosterone (Aldo), were determined before and three times during the first 4 h after loading. D and C water increased to a significantly lower level (P less than 0.01) after water loading in patients with nephrotic syndrome than in control subjects, but D and C water were normal after remission of the syndrome. The maximum increase in C water (delta C water max.) was 1.07 ml/min (median) before remission and 7.93 ml/min after, compared with 8.01 ml/min in the control group. Creatinine clearance (Ccr) increased significantly after remission (63 ml/min to 88 ml/min, P less than 0.01), and the fractional excretion of sodium was enhanced. AVP was higher in the nephrotic syndrome both before (2.9 pmol/l) and after remission (2.9 pmol/l) compared with the control group (1.8 pmol/l). ANG II and Aldo did not change after remission and remained at the same level as in the control group. The elevation in delta C water max. after remission was accompanied by an increase in Ccr in all patients and delta C water max. and Ccr were significantly correlated (rho = 0.600, n = 16, P less than 0.05). No relationship was found between the change in delta C water max. and ANG II and Aldo.(ABSTRACT TRUNCATED AT 250 WORDS)