Cyclooxygenase 2 (COX-2) as a target for therapy and noninvasive imaging.

Prostaglandins modulate a wide range of biologic functions, including wound healing, temperature regulation, reproduction, and many aspects of immune function. Exaggerated production of prostaglandins contributes to a large number pathophysiologies. The critical enzyme in prostaglandin biosynthesis is prostaglandin synthase, also known as cyclooxygenase (COX). The nonsteroidal anti-inflammatory drugs (NSAIDs), one of the largest classes of pharmaceutical agents, exert most of their biologic effects by inhibiting cyclooxygenase production of prostaglandins. The discovery of a second, inducible form of cyclooxygenase, now known as COX-2, responsible for the production of prostaglandins in most pathological states, revived a relatively moribund research area in biochemistry, physiology, and pharmacology, and led to the search for and discovery of a new class of pharmacologic agents. The coxibs have greater efficacy and substantially ameliorated side effects when compared to the classic NSAIDs. Because of the pervasive role of COX-2 in a wide range of human pathologies, the coxibs have been the most successful entry into the pharmaceutical market in history, responsible for 6-10 billion dollars in sales annually. The ability to noninvasively monitor COX-2 expression with molecular imaging probes will provide a corresponding advance in diagnosing COX-2-based disease, monitoring progression of such diseases, and evaluating alternative therapies.     

Increased intracellular cyclic adenosine monophosphate inhibits T lymphocyte-mediated cytolysis by two distinct mechanisms

Cholera toxin (CT), but not pertussis toxin (PT), treatment of cloned murine CTL inhibited target cell lysis in a dose-dependent fashion. The effects of CT were mimicked by forskolin and cyclic adenosine monophosphate (cAMP) analogues. Inhibition of cytotoxicity by CT and cAMP analogs was mediated in part by attenuation of conjugate formation. Additionally, both CT and cAMP analogs blocked the increase in intracellular Ca2+ induced by stimulation of the TCR complex by mAbs. These findings indicate that cAMP inhibits the activity of CTL by two distinct mechanisms and suggests a role for this second messenger in CTL-mediated cytolysis.     

Effects of milrinone on contractility and cyclic adenosine monophosphate production induced by beta1- and beta2-adrenergic receptor activation in human myocardium

BACKGROUND: Because milrinone is a widely used phosphodiesterase-3 (PDE3) inhibitor, it would be of interest to know whether it interacts with beta1- and beta2-adrenergic receptor (AR) agonists in human myocardium. OBJECTIVES: This in vitro study was conducted to test whether milrinone differentially regulates cyclic adenosine-3',5'-monophosphate (cAMP) production and to examine the effect of milrinone on the positive inotropic responses and cAMP production induced by activation of the beta1-AR with norepinephrine (NE) and activation of the beta2-AR with epinephrine (EPI) in human atrial myocardium. METHODS: Right atrial trabeculae were obtained from patients undergoing cardiac surgery for valve repair. Concentration-response curves for inotropic responses mediated through the beta1-AR (NE in the presence of the beta2-blocker ICI 118, 551) and the beta2-AR (EPI in the presence of the beta1-blocker CGP 20712A) were obtained in the absence and presence of milrinone 1 micromol/L. This concentration of milrinone was chosen because it corresponded to its 50% inhibitory concentration as a PDE3 inhibitor and its therapeutic plasma concentration. The production of cAMP induced by exposure to selective beta1- and beta2-AR stimulation was also measured in the absence and presence of milrinone. RESULTS: Right atrial tissue samples were obtained from 12 white patients (7 women, 5 men; mean [SE] age, 64.6 [6.3] years) undergoing cardiac surgery for valve repair (8 mitral, 4 aortic). The presence of milrinone was associated with leftward shifts in the concentration-response curves for both NE and EPI. cAMP production in myocardial tissue samples in the presence of milrinone was increased only with NE induction (mean [SEM], 745.0 [136.7] pmol/g in the absence of milrinone vs 1620.5 [372.3] pmol/g in the presence of milrinone; P < 0.05). CONCLUSIONS: In this preliminary study in human atrial myocardium, milrinone potentiated the contractile responses to both NE and EPI. However, only the effect of NE on tissue levels of cAMP was increased in the presence of milrinone.     

复方丹参滴丸干预短暂性脑缺血发作时对血浆环磷酸腺苷和环磷酸鸟苷的影响

背景：在缺血性脑卒中急性期和恢复期皆可见血小板处于活化状态，环磷酸腺苷和环磷酸鸟苷与血小板功能密切相关。目的：观察复方丹参滴丸预防治疗短暂性脑缺血发作的临床疗效及对血浆环磷酸腺苷、环磷酸鸟苷的影响。设计：随机对照实验。单位：滨州医学院附属医院神经科。对象：选择2000-09／2001—04滨州医学院附属医院神经科门诊180例自愿参加本实验的短暂性脑缺血发作患者。采用随机数字表将患者按给予复方丹参滴丸剂量大小分为3组。给药10粒／d组60例，男35例，女25例；年龄50～70岁，平均（54．3&;#177;7．2）岁；给药20粒／d组60例，男32例，女28例；年龄49～62岁，平均（55．7&;#177;5．1）岁。给药30粒／d组60例，男33例，女27例；年龄52&;#177;69岁，平均（54．9&;#177;5．5）岁。方法：给药10粒／d组，1次／d，10粒／次；给药20粒／d组，2次／d，10粒／次；给药30粒／d组，3次／d，10粒／次。患者均在服药4周后，晨抽血3mL，采用放射免疫分析法，测定三组血浆中的环磷酸腺苷、环磷酸尿苷含量。每例患者均3个月随访一次，共随访18个月：①观察短暂性脑缺血发作的发作次数及发作形式。②发生缺血性脑卒中例数（包括心、脑卒中）。（④副作用：消化道反应，牙龈出血、鼻出血、皮下出血、口麻、头痛、头晕等。主要观察指标：①各组患者短暂性脑缺血发作的发作形式。②各组患者发生缺血性脑卒中例数。③各组患者副作用发生情况。④各组患者血浆中环磷酸腺苷，环磷酸鸟苷水平。结果：180例患者均进入结果分析。①发生短暂性脑缺血发作的发作例数：给药10粒／d组，发生颈内动脉系统短暂性脑缺血发作的1例；发生椎动脉系统短暂性脑缺血发作的2例；发生脑梗死的1例；发生心肌梗死的2例；给药20粒／d组，分别为2，2，1例；给药30粒／d组．分别为1，2，1例。②发生缺血性脑卒中例数：3组分别发生脑卒中的例数为6．5，4例。⑨各组患者副作用发生情况：三组不良事件及副反应分别为1．2，4例，其中给药10粒／d组出现口周麻木1例，给药20粒／d组出现口周麻木和头痛各1例，给药30粒／d组出现胃肠道反应1例，口周麻木2例，头晕1例；末出现牙龈出血、鼻出血及皮下出血病例，同时患者亦未因上述副作用退出治疗。各组比较，无显著性差异（P〉0．05）。（少各组患者血浆中环磷酸腺苷，环磷酸鸟背水平：3组环磷酸腺苷分别为（21．22&;#177;3．94），（22．5&;#177;3．67），（23．1&;#177;7．7）ng/L；环磷酸鸟苷分别为（3．67&;#177;1．18）．（4．74&;#177;2．12）．（4．6&;#177;0．7）ng／L，（P〉0．05）．结论：复方丹参滴丸在短暂性脑缺血发作的二级预防中，有肯定的疗效，各剂量比较疗效基本一致，同时无明显副作用。     

复方丹参滴丸干预短暂性脑缺血发作时对血浆环磷酸腺苷和环磷酸鸟苷的影响

背景在缺血性脑卒中急性期和恢复期皆可见血小板处于活化状态,环磷酸腺苷和环磷酸鸟苷与血小板功能密切相关.目的观察复方丹参滴丸预防治疗短暂性脑缺血发作的临床疗效及对血浆环磷酸腺苷、环磷酸鸟苷的影响.设计随机对照实验.单位滨州医学院附属医院神经科.对象选择2000-09/2001-04滨州医学院附属医院神经科门诊180例自愿参加本实验的短暂性脑缺血发作患者.采用随机数字表将患者按给予复方丹参滴丸剂量大小分为3组.给药10粒/d组60例,男35例,女25例;年龄50～70岁,平均(54.3±7.2)岁;给药20粒/d组60例,男32例,女28例;年龄49～62岁,平均(55.7±5.1)岁.给药30粒/d组60例,男33例,女27例;年龄52～69岁,平均(54.9±5.5)岁.方法给药10粒/d组,1次/d,10粒/次;给药20粒/d组,2次/d,10粒/次;给药30粒/d组,3次/d,10粒/次.患者均在服药4周后,晨抽血3mL,采用放射免疫分析法,测定三组血浆中的环磷酸腺苷、环磷酸尿苷含量.每例患者均3个月随访一次,共随访18个月①观察短暂性脑缺血发作的发作次数及发作形式.②发生缺血性脑卒中例数(包括心、脑卒中).③副作用消化道反应,牙龈出血、鼻出血、皮下出血、口麻、头痛、头晕等.主要观察指标①各组患者短暂性脑缺血发作的发作形式.②各组患者发生缺血性脑卒中例数.③各组患者副作用发生情况.④各组患者血浆中环磷酸腺苷,环磷酸鸟苷水平.结果180例患者均进入结果分析.①发生短暂性脑缺血发作的发作例数给药10粒/d组,发生颈内动脉系统短暂性脑缺血发作的1例;发生椎动脉系统短暂性脑缺血发作的2例;发生脑梗死的1例;发生心肌梗死的2例;给药20粒/d组,分别为2,2,1例;给药30粒/d组,分别为1,2,1例.②发生缺血性脑卒中例数3组分别发生脑卒中的例数为6,5,4例.③各组患者副作用发生情况三组不良事件及副反应分别为1,2,4例,其中给药10粒/d组出现口周麻木1例,给药20粒/d组出现口周麻木和头痛各1例,给药30粒/d组出现胃肠道反应1例,口周麻木2例,头晕1例;未出现牙龈出血、鼻出血及皮下出血病例,同时患者亦未因上述副作用退出治疗.各组比较,无显著性差异(P＞0.05).④各组患者血浆中环磷酸腺苷,环磷酸鸟苷水平3组环磷酸腺苷分别为(2122±3.94),(22.5±3.67),(23.1±7.7)ng/L;环磷酸鸟苷分别为(3.67±1.18),(4.74±2.12),(4.6±0.7)ng/L,(P＞0.05).结论复方丹参滴丸在短暂性脑缺血发作的二级预防中,有肯定的疗效,各剂量比较疗效基本一致,同时无明显副作用.     

Evidence that parathyroid hormone-mediated calcium transport in rat brain synaptosomes is independent of cyclic adenosine monophosphate.

In vivo PTH administration to rats resulted in increased brain synaptosomal Ca++ transport, while parathyroidectomy (PTX) resulted in decreased transport. To determine the mechanism of action of PTH on Ca++ transport in rat brain synaptosomes, we performed transport studies by the Na-Ca exchanger and also measured cAMP generation in synaptosomes from PTX rats. Ca++ transport was studied after in vivo additions of either bovine (b)PTH, cAMP, or forskolin, and adenylate cyclase activity was assessed after additions of either bPTH, forskolin, sodium fluoride (NaF), or isoproterenol. In the presence of 1-34 bPTH [10(-7) M], Ca++ uptake was significantly increased by 55% (P less than 0.001) above control, while 3-34 bPTH [10(-7) M] had no effect on uptake. Both 8br,cAMP [10(-6) M] and dibut,cAMP [10(-6) M] also significantly increased (P less than 0.001) Ca++ uptake above control by 63 and 44%, respectively. Similarly, forskolin [10(-5) M], the adenylate cyclase activator, increased Ca++ uptake by 41%. We next evaluated Ca++ efflux, and found that 1-34 bPTH [10(-7) M], 1-84 bPTH [10(-7) M], and forskolin [10(-5) M] also increased Ca++ efflux by 50, 73, and 120%, respectively, above control. Since Ca++ transport was increased by either PTH, cAMP, or forskolin, we decided to determine if PTH action on Ca++ transport in synaptosomes was dependent on cAMP. This was investigated by measuring cAMP production during the conversion of 32P-ATP to 32P-cAMP in the presence of an ATP regenerating system (30 micrograms creatine phosphokinase, 10 mM creatine phosphate), and the cyclic nucleotide phosphodiesterase inhibitor (1 mM IBMX). Whereas forskolin [10(-4) M] and NaF [100 mM] significantly increased (P less than 0.001) adenylate cyclase activity in synaptosomes by eight- and fourfold, respectively, neither 1-34 bPTH nor 1-84 bPTH increased synaptosomal cyclase activity. However, in canine renal cortical plasma membranes (CRCPM), we observed significant increases in cAMP production with either forskolin, NaF, or PTH. Finally, to determine if synaptosomes contain an intact adenylate cyclase system, we measured cAMP production in the presence of the beta adrenergic agent, isoproterenol. Isoproterenol significantly increased adenylate cyclase activity in both synaptosomes (90%) and CRCPM (50%). These data suggest that although there is an intact adenylate cyclase system in rat brain synaptosomes, PTH-stimulated calcium transport in synaptosomes appears to be independent of this system.     

Effects of atrial natriuretic factor on cyclic guanosine monophosphate and cyclic adenosine monophosphate accumulation in microdissected nephron segments from rats.

Atrial natriuretic factor (ANF) (1 microM) markedly increased cyclic guanosine monophosphate (cGMP) content in microdissected glomeruli (35-fold) and in microdissected inner medullary collecting ducts (IMCD) (20-fold). ANF caused little or no increase in cGMP content in other nephron segments. The threshold concentration for increased cGMP accumulation by ANF was 0.1-1 nM in IMCD, which is in the range reported for rat plasma. Sodium nitroprusside (1 mM), which selectively stimulates soluble guanylate cyclase, increased cGMP content in glomeruli but not in IMCD. ANF did not alter cAMP accumulation in the absence or presence of vasopressin (AVP) or parathyroid hormone (PTH) in outer and inner medullary tubule suspensions, or in microdissected proximal convoluted tubules (PCT), medullary thick ascending limbs (MAL) or IMCD. These data are compatible with the hypothesis that cGMP is a second messenger for a physiologic action of ANF in the inner medullary collecting duct. ANF apparently activates membrane-bound guanylate cyclase in this segment.     

Atrial natriuretic factor reduces cyclic adenosine monophosphate content of human fibroblasts by enhancing phosphodiesterase activity

Radioligand binding studies disclosed one class of high affinity atrial natriuretic factor (ANF) receptors on human fibroblast membranes (Kd = 66 pM; maximum number of binding sites [Bmax] = 7,000 sites/cell). ANF increased cellular cyclic guanosine monophosphate (cGMP) content and suppressed isoproterenol- and PGE1-elevated, but not basal, cAMP content. Pertussis toxin pretreatment, which maximally ADP-ribosylated Gi, the guanine nucleotide-binding protein that couples inhibitory receptors to adenylate cyclase and blocks receptor-mediated inhibition of adenylate cyclase, did not interfere with ANF suppression of isoproterenol- or PGE1-elevated cellular cAMP content. Preliminary incubation of fibroblasts with 8-bromo cGMP or phosphodiesterase inhibitors, including 3-isobutyl-1-methylxanthine, Ro 20-1724, and cilostamide, however, prevented the ANF suppression of cAMP. MB 22948, an inhibitor that is partially selective for cGMP phosphodiesterase, did not block the effect of ANF. We conclude that in these cells, unlike other systems, ANF reduces cAMP content by activating a phosphodiesterase rather than by inhibiting adenylate cyclase.     

Pharmacological characterization of rat renal medulla dopamine-sensitive cyclic adenosine monophosphate generating system

The dopamine (DA) DA-1 and DA-2 receptors coupled to 3'-5'-cyclic adenosine monophosphate (cAMP) generating system were characterized in membrane particles of the rat kidney medulla. In confirmation of reports using central and other peripheral tissues, activation of DA-1 receptors with DA, apomorphine or SKF 82526 induced accumulation of cAMP. This effect was blocked by the DA-1 receptors antagonist SCH 23390 and by the other DA-2 receptor antagonists fluphenazine and haloperidol. DA-2 receptor responses coupled negatively to the cAMP generating system were obtained by incubating renal medulla membrane particles with DA or SKF 82526 together with SCH 23390. DA-2 receptor responses were also elicited with the receptor agonists quinpirole and bromocriptine in the absence of SCH 23390. These inhibitory effects on cAMP generation were abolished by the DA-2 receptor antagonist l-sulpiride. Our findings suggest that rat renal medulla contains DA DA-1 and DA-2 receptors similar to those found in brain and in other peripheral tissues. The physiological significance of these receptors, if any, should be established in future studies.     

Angiotensin II stimulates early proximal bicarbonate absorption in the rat by decreasing cyclic adenosine monophosphate.

These studies explored the hypothesis that angiotensin II increases bicarbonate absorption in the proximal convoluted tubule (PCT) by decreasing intracellular cAMP. In vivo microperfusion was performed in rat PCT with measurements of bicarbonate absorption and of tubular fluid cAMP delivery, as a reflection of intracellular cAMP. Intravenous angiotensin II potently increased S1 PCT bicarbonate absorption (348 +/- 11 to 588 +/- 8 peq/min.min, P less than 0.001) and decreased tubular fluid cAMP (18 +/- 2 to 12 +/- 2 fmol/mm.min, P less than 0.05). Parathyroid hormone had the expected opposite effects, which were additive to those of angiotensin II. Over a wide range of hormonal activities, there was an excellent inverse relationship between hormonally modulated bicarbonate absorption and cAMP delivery. Pertussis toxin pretreatment significantly attenuated (by 35-45%) the angiotensin-induced increase in bicarbonate absorption and decrease in cAMP delivery, indicating Gi-protein intermediation. Luminal dibutyryl cAMP abolished the transport response to angiotensin II. In conclusion, these in vivo results suggest angiotensin II stimulates bicarbonate absorption in the S1 PCT by a G1-mediated depression in intracellular cAMP.     

Plasma 1,25(OH)2D3 response to parathyroid hormone, cyclic adenosine monophosphate, and phosphorus depletion in the spontaneously hypertensive rat

Spontaneously hypertensive rats (SHR) have several abnormalities of calcium metabolism compared with normotensive control Wistar-Kyoto (WKY) rats. Previously the vitamin D metabolite 1,25-dihydroxycholecalciferol (1,25[OH]2D3) was found to be inappropriately low in SHR in view of their ionized hypocalcemia and hyperparathyroidism. We examined the responses of plasma 1,25(OH)2D3 to several known stimuli. Baseline plasma 1,25(OH)2D3 levels tended to be lower in SHR than WKY rats (51.5 +/- 4.3 vs. 82.3 +/- 14.1 pg/ml, P = 0.06). Infusion of a pharmacologic dose of parathyroid hormone (8 U/hr over a period of 17 hours) resulted in a plasma 1,25(OH)2D3 level of 504 +/- 77 pg/ml in SHR vs. 1016 +/- 211 pg/ml in WKY rats (P less than 0.03). Cyclic adenosine monophosphate infusion (1 mumol/hr/100 gm over a period of 17 hours) in thyroparathyroidectomized animals resulted in a 1,25(OH)2D3 level of 121 +/- 24 pg/ml in SHR vs. 557 +/- 26 pg/ml in WKY rats (P less than 0.01). After dietary phosphorus depletion for 3 weeks, SHR also had lower 1,25(OH)2D3 levels than WKY rats (83 +/- 13 vs. 300 +/- 42 pg/ml, P less than 0.001) even though a comparable degree of hypophosphatemia was achieved. Thus, the response of plasma 1,25(OH)2D3 levels to several known stimuli is submaximal in SHR as compared with WKY rats, suggesting defective synthesis or enhanced metabolic clearance of this hormone.     

靶肌肉注射环磷酸腺苷对周围神经再生的作用

目的:观察靶肌肉注射外源性环磷酸腺苷对大鼠坐骨神经再生的治疗作用。方法:实验于2004-10/2005-03在华中科技大学同济医学院协和医院骨科实验室完成。选择健康雄性Wistar大鼠48只,制备大鼠左侧坐骨神经挤压伤模型。实验动物随机数字表法分为3组,每组16只,高剂量组:腓肠肌内注射0.2mL环磷酸腺苷1mg。低剂量组:腓肠肌内注射注射0.2mL环磷酸腺苷0.1mg。对照组:腓肠肌内注射0.2mL生理盐水。术后每日给药1次,共4周。术后4,8周时检测左侧小腿三头肌湿质量。术后8周时检测坐骨神经运动神经传导速度、小腿三头肌复合肌肉动作电位波幅、潜伏期及形态学观察神经再生情况。结果:纳入动物48只,均进入结果分析。①术后4,8周时高剂量组和低剂量组大鼠左小腿三头肌湿质量显著高于对照组[术后4周分别为(1.70±0.58),(1.26±0.71),(0.91±0.24)g;术后8周分别为(2.26±0.62),(1.65±0.16),(1.24±0.37)g],且高剂量组明显高于低剂量组,差异有显著性意义(P<0.01)。②术后8周高剂量组和低剂量组坐骨神经运动神经传导速度、小腿三头肌复合肌肉动作电位波幅、潜伏期及有髓神经纤维计数、髓鞘厚度、轴突直径均高于对照组[运动神经传导速度分别为(33.54±2.65),(26.96±4.12),(19.83±2.74)m/s;复合肌肉动作电位波幅分别为(2.435±1.257),(1.867±0.566),(1.218±0.647)mV;复合肌肉动作电位潜伏期分别为(2.946±0.658),(4.537±0.932),(5.825±1.043)ms;有髓神经纤维计数分别为(1693±201),(1357±185),(876±124)个;髓鞘厚度分别为(1.149±0.138),(0.924±0.086),(0.633±0.105)μm;轴突直径分别为(1.045±0.150),(0.794±0.095),(0.512±0.138)μm],且高剂量组显著高于低剂量组,差异有显著性意义(P<0.01)。结论:靶肌肉注射环磷酸腺苷可促进周围神再生,高剂量环磷酸腺苷对神经再生具有更好的促进作用。     

Virus-induced alterations in cyclic adenosine monophosphate generation in hamster islets of Langerhans.

Inoculation of golden Syrian hamsters with Venezuelan encephalitis (VE) virus results in a sustained diminution in glucose-stimulated insulin release that is correctable by cyclic (c) AMP analogs and phosphodiesterase inhibitors. This suggested the importance of directly measuring cAMP content in VE-infected and control islets in response to insulin secretagogues. The basal cAMP content of VE-infected islets (0.14 +/- 0.02 pmol/micrograms islet DNA) was approximately half that of control islets (0.27 +/- 0.02 pmol/micrograms islet DNA) (P less than 0.05). In the presence of 10 microM glucagon (and 3 mM glucose), the rate of cAMP generation in VE-infected islets was only half that of control islets. With 10 mM alpha-ketoisocaproic acid, the rates of cAMP generation were indistinguishable between control and experimental groups. In response to 20 mM glucose and 3-isobutyl-1-methylxanthine (IBMX) (a phosphodiesterase inhibitor), cAMP generation in VE-infected islets was 81% (NS) of the control rate. When a more specific phosphodiesterase inhibitor, RO 20-1724, was used with 20 mM glucose, cAMP generation in the infected islets was only 44% (P less than 0.001) of the control value. Insulin secretion over the perifusion period paralleled the cAMP levels. In the presence of 10 mM alpha-ketoisocaproic acid, there was no difference in insulin secretion between VE-infected and control islets, while there was a statistically significant (P less than 0.05) difference with 10 microM glucagon or 20 mM glucose (in 1 mM RO 20-1724). These data point to a defect in the cAMP generation system of VE-infected islets, although additional factors involved in insulin secretion may also be impaired by the virus.     

Arginine vasopressin and cyclic adenosine monophosphate during acute sodium loading in chronic glomerulonephritis

The relationship of arginine vasopressin (AVP) in plasma to cyclic adenosine 3' 5'-monophosphate (cAMP), sodium excretion in urine, and arterial blood pressure were determined during intravenous infusion of hypertonic sodium chloride solution (500 ml of 50 g/l) in 10 normotensive control subjects and in 11 normotensive and 10 hypertensive patients with chronic glomerulonephritis and relatively well preserved kidney function. The concentration of AVP in plasma increased 2-4 fold, osmolality in serum increased 12-16 mosmol/kg, and urinary excretion of cAMP increased 20-40% during sodium loading to the same extent in all three groups. Sodium and water excretion were higher during the sodium loading in the hypertensive patients, but not in the normotensive patients when compared to the control subjects. Neither AVP nor changes in AVP correlated significantly with changes in cAMP excretion, sodium excretion or blood pressure. In the control subjects the level of parathyroid hormone in serum was unchanged during the sodium chloride infusion. Water loading without sodium loading in eight of the control subjects caused a decrease in the excretion of cAMP. In conclusion, the increase in cAMP excretion in urine during the sodium loading might be explained by an AVP-induced stimulation of renal cAMP production. The study does not suggest that AVP plays a role in the increased sodium excretion during sodium loading or in the development of hypertension or chronic glomerulonephritis.