腺苷A1受体激动剂2-氯化腺苷抑制异丙肾上腺素诱导大鼠心肌肥厚的作用及机制

目的通过观察腺苷A1受体激动剂2-氯化腺苷(2-CADO)对异丙肾上腺素所致大鼠心肌肥厚的抑制作用及能量代谢的改变,探讨腺苷A1受体激动剂对肥厚心肌能量代谢的调节作用及其可能的作用机制。方法大剂量异丙肾上腺素皮下注射建立大鼠心肌肥厚模型。SD大鼠40只,雌雄不限,分为空白对照组、肥厚模型组、2-CADO组[2-氯化腺苷0.6 mg/(kg.d)腹腔注射]、普萘洛尔组[28 mg/(kg.d)普萘洛尔灌胃],每组10只。造模完毕第2天给药,连续8周。检测大鼠全心质量指数(HMI)、左心质量指数(LVMI);取左心室组织进行Masson染色,观察细胞横径(TDM)改变;碱水解法进行羟脯氨酸(Hyp)含量测定;紫外分光光度法检测心肌组织乳酸(LA)和游离脂肪酸(FFA)含量;激光共聚焦显微镜定量检测线粒体膜电位(MMP)。结果与空白对照组相比,肥厚模型组HMI、LVMI显著上升,心肌组织形态发生肥厚样改变;Hyp、LA和FFA含量显著升高,MMP下降了44%。与肥厚模型组相比,2-CADO组HMI、LVMI下降,TDM明显降低,Hyp、LA和FFA含量显著降低,MMP上升了50%。结论 2-CADO可以抑制异丙肾上腺素导致的心肌肥厚,其机制可能与改善肥厚心肌的能量代谢有关。     

Changes of cyclic AMP concentration to isoproterenol after abrupt cessation of propranolol in rats

Because the mechanism of adverse reactions to abrupt cessation of propranolol in patients with coronary heart disease was an enigma, we studied the effect of cessation of propranolol on beta-adrenergic receptor reactivity to catecholamine stimulation. The cyclic AMP concentrations in plasma and left ventricular muscle after the administration of isoproterenol (5 mg/Kg) were measured in rats before, during, 2 days after, and 4 days after of the administration of propranolol (5 mg/Kg). Two days after withdrawal from propranolol, the cyclic AMP concentrations in plasma and left ventricular muscle were significantly increased (p less than 0.005, p less than 0.01). Four days after withdrawal from propranolol, the cyclic AMP concentration in plasma was significantly increased (p less than 0.001). On the other hand, that of left ventricular muscle showed a tendency to have higher value, although, this was statistically not significant. From these results, this study suports that there is a hypersensitivity to adrenergic stimultion after abrupt cessation of long-term propranolol treatment. The explanation of propranolol withdrawal phenomenon most likely lies in lthe nature of beta adrenergic receptors that become activated during long-term blockade.     

Effects of cardiotoxic doses of adrenergic amines on myocardial cyclic AMP.

The role of beta-adrenergic activation in the cardiotoxicity of adrenergic amines was assessed by measuring rat myocardial cyclic AMP at various times after subcutaneous injection of necrosis-inducing amounts of isoproterenol, phenylephrine or epinephrine in the presence and in the absence of the phosphodiesterase inhibitor aminophylline. The β-adrenergic agonist isoproterenol (5.25 mg/kg) increased myocardial cyclic AMP at 1 h to 147% of control and in the presence of aminophylline (75 mg/kg) to 261% of control as compared to 146% for aminophylline alone. Propranolol (6.25 mg/kg) blocked isoproterenol-induced increases in cyclic AMP. Neither the α-adrenergic agonist phenylephrine (15 mg/kg) nor epinephrine (4 mg/kg), which has both α- and β-adrenergic properties, increased myocardial cyclic AMP above control levels even in the presence of aminophylline. With α-adrenergic blockade by tolazoline (15 mg/kg) or phenoxybenzamine (2 mg/kg), combined administration of epinephrine and aminophylline caused an increase of the myocardial cyclic AMP content to 163% and 173%, respectively, of that of control rats. These results suggest that in the intact rat, cyclic AMP-mediated myocardial stimulation is an important factor in the cardiotoxicity of isoproterenol but not of phenylephrine, while the beta-adrenergic component of epinephrine cardiotoxicity is unmasked only in the presence of α-adrenergic blockade.     

曲美他嗪对异丙肾上腺素所致大鼠心肌肥厚的影响

目的探讨曲美他嗪（TMZ）对异丙肾上腺素（ISO）致大鼠心肌肥厚的影响及可能的作用机制。方法30只Sprague-Ddwley（SD）大鼠,随机分为3组。正常对照组、ISO组、TMZ组,每组10只。通过大剂量注射ISO制成心肌肥厚模型,以TMZ干预,观察心肌组织病理学变化和心肌细胞超微结构改变,计算心脏质量/体质量（HW/BW）,测定心肌三磷酸腺苷（ATP）、丙二醛（MDA）、超氧化物歧化酶（SOD）和血清乳酸脱氢酶（LDH）、肌酸激酶（CK）含量。结果TMZ组与ISO组比较,HW/BW、LDH、CK、SOD和ATP有显著差异（P<0.05）,而与正常对照组比较无显著差异。TMZ组心肌组织病理损伤程度及细胞超微结构改变程度,较ISO组明显减轻,而接近正常对照组。结论TMZ可拮抗ISO所致的大鼠心肌肥厚,其机制可能与改善心肌能量代谢、提高组织对缺氧的耐受力、消除氧自由基等有关。     

The mechanism of the control of renin release by beta-adrenergic receptors

Recent reports suggest that prostaglandins play an important role in the beta-adrenergic receptor mechanism of renin release. However, the site of the action of prostaglandins has not yet been clarified. Superfusion of rabbit renal cortical slices was used to evaluate the beta-adrenergic receptor mechanism of renin release. Renin release was stimulated by isoproterenol, prostaglandin E2, and dibutyryl cyclic AMP. Renin release stimulated by isoproterenol was inhibited by propranolol, whereas renin release stimulated by prostaglandin E2 was not inhibited by propranolol. Isoproterenol stimulated prostaglandin E2 release as well as renin release, and indomethacin inhibited these effects of isoproterenol. Propranolol inhibited prostaglandin E2 release stimulated by isoproterenol. On the other hand, indomethacin did not affect renin release stimulated by prostaglandin E2 release. Dibutyryl cyclic AMP did not stimulate prostaglandin E2 release. Indomethacin did not affect renin release stimulated by dibutyryl cyclic AMP, however, it suppressed prostaglandin E2 release during the superfusion with dibutyryl cyclic AMP. Finally, isoproterenol and prostaglandin E2 stimulated cyclic AMP release. These data suggest that prostaglandins play an important role in the beta-adrenergic receptor mechanism of renin release and the site of the action of prostaglandins is between the beta-adrenergic receptor and cyclic AMP.     

Effects of beta-adrenoceptor-related agents on hypoxic pulmonary vasoconstriction and relation with cyclic AMP and prostaglandins]

Effects of a beta-agonist (isoproterenol) and beta-antagonists (propranolol and pindolol) on hypoxic pulmonary vasoconstriction (HPV) and on changes in some chemical mediators were compared between HPV-responsive lobes and non-responsive lobes in which HPV was induced by aspirin DL-lysine (ASA groups). Hypoxic ventilation (4 min) was repeated in 56 of isolated, blood-perfused dog lung lobes. Each drug was administrated in a bolus dose of 0.2 mg in the intermittent period between hypoxia. In HPV-responsive lobes, the first hypoxia increased pulmonary vascular resistance by 33% or more in all groups. Both isoproterenol and pindolol inhibited the elicitation of HPV completely, but propranolol induced almost the same degree of HPV as control. In ASA groups, HPV was completely inhibited by isoproterenol, but was not influenced by propranolol. However, pindolol's inhibitory effect on HPV was less than that in HPV-responsive lobes. Isoproterenol significantly increased cyclic AMP from 17.0 to 76.7 pmol/ml in HPV-responsive lobes (n = 7). Pindolol increased prostaglandin E2 from 87.0 to 1015.4 pg/ml in HPV-responsive lobes (n = 7), and from 93.4 to 361.3 pg/ml when ASA was treated. Propranolol did not show the different results from the control group whether ASA was present or not. The different mechanisms among beta-adrenoceptor-related agents in HPV and pulmonary circulation were investigated.     

Cyclic AMP in myocytes isolated from hypertrophied rat hearts.

Impaired inotropic responsiveness to isoproterenol stimulation has been reported in the hypertrophied hearts of spontaneously hypertensive rats and renal hypertensive rats. This study was carried out in order to investigate the possibility that a defect in cyclic AMP production by cardiac myocytes is responsible for the impaired inotropic responsiveness of these hearts. Basal and isoproterenol stimulated cyclic AMP levels were measured in ventricular myocytes isolated from hypertrophied rat hearts. Cyclic AMP accumulation was also measured in the presence of isobutyl-methyl-xanthine, a phosphodiesterase inhibitor, and the results were compared to the appropriate controls. In the spontaneously hypertensive rat, no changes were detected in the basal or isoproterenol stimulated cyclic AMP formation. This suggests that the biochemical alterations leading to a diminished inotropic response in this model of cardiac hypertrophy involve abnormalities in mechanisms other than cyclic AMP production. In the renal hypertensive rat, basal and isoproterenol stimulated cyclic AMP levels were significantly depressed as compared to controls. This suggests that abnormalities in the signal transduction mechanism and formation of cyclic AMP are, at least in part, responsible for the impaired inotropic responsiveness seen in this model. These results confirm that cardiac hypertrophy is a heterogeneous process. Reduced inotropic responsiveness to isoproterenol stimulation in the hypertrophied hearts of the SHR and the RHR, both models of pressure overload hypertrophy, involve different biochemical alterations. Results of this study suggest that the physiologic response of cardiac hypertrophy may not be as important as the underlying cause of hypertrophic stimuli in determining the pathophysiological consequences.     

Demonstration of the role of stimulation of purinergic receptors in the electrophysiologic effect of adenylic compounds in man

In order to study the mechanism of action of AMP on the AV node conduction, 10 patients with re-entrant tachycardia including the AV node in the circuit (SVT) were studied. The mean age was 32.8 +/- 11.1. Tachycardia was induced by programmed atrial stimulation. Electrophysiological studies were made in all the cases. Intravenous injection of AMP suppressed SVT in all the patients in the first part of the study. The mean doses was 0.095 +/- 0.037 mg/Kg., and the mean time was 15.2 +/- 2.6 sec. In the second part (after 0.04 mg/Kg. IV atropine) the induced SVT was suppressed with a mean doses of 0.122 +/- 0.45 mg/Kg of AMP (P = NSD) in a mean time of 16.2 +/- 2.2 sec. (p = NSD). In the last part of this study the intravenous injection of aminophylline (4 mg/Kg) avoided the suppression of induced SV T in 8/10 patients. In to patients the AMP doses was 0.250 mg/Kg., and in the other 0.075 mg/Kg. Our studies demonstrated that the mechanism of action of AMP is by means of agonistic stimulation of purinergic receptors in the AV node.     

Effect of captopril on isoproterenol-induced myocardial ornithine decarboxylase activity.

Polyamines are thought to play an essential role in cellular hypertrophy and proliferation. Ornithine decarboxylase (ODC) catalyzes the first and probably the rate-limiting step in biosynthesis of polyamines. In this study, we evaluated the pathophysiological role of the renin-angiotensin system in isoproterenol-induced cardiac hypertrophy, using myocardial ODC activity as an indicator of cardiac hypertrophy. Isoproterenol caused an eight-fold increase of myocardial ODC activity in normotensive Wistar rats within 4 h after injection. Captopril suppressed the induction of ODC by isoproterenol to two-thirds of the control level. These results indicate that the renin-angiotensin system may participate in the induction of myocardial hypertrophy by isoproterenol.     

Development of cardiac adenylate cyclase hypersensitivity to isoproterenol in the chronic action of propranolol on rats

The chronic treatment of rats with the beta-adrenergic antagonist propranolol causes a double increase in the amount of beta-adrenergic receptors in the cardiac membranes. The purpose of the paper is to investigate the effect of propranolol on the activity and regulatory properties of rat heart adenylate cyclase. Propranolol injections to rats for 3 weeks (10-20 mg/l kg bw) did not influence the enzyme basal activity but caused a rise of a degree of myocardial adenylate cyclase activation by isoproterenol and glucagon.     

alpha-Adrenergic reduction of cyclic adenosine monophosphate concentrations in rat myocardium.

We determined the effect of alpha-adrenergic receptor stimulation on cyclic adenosine monophosphate (cyclic AMP) concentrations in isolated myocytes derived from adult rat hearts and in isolated perfused rat hearts. Activation of alpha-adrenergic receptors with either phenylephrine (10(-8) M to 10(-6) M) or epinephrine (10(-8) M to 10(-6) M) plus propranolol (10(-6) M) resulted in a reduction in cyclic AMP levels in isolated myocytes. The action of phenylephrine was antagonized by phentolamine (10(-6) M). Phenylephrine (10(-5)M attenuated cyclic AMP generation in response to isoproterenol (10(-8) M and 10(-5) M). However, this effect of phenylephrine was not antagonized by phentolamine. Elevation of cyclic AMP concentrations produced by glucagon and by theophylline in isolated myocytes was attenuated by phenylephrine and by epinephrine plus propranolol and the attenuation was antagonized by phentolamine. In isolated perfused rat hearts epinephrine (10(-6) M), when given with propranolol, diminished the rate of development of tension and also reduced tissue levels of cyclic AMP. Epinephrine alone, as well as isoproterenol, increased contractility and myocardial cyclic AMP concentrations as expected. These results indicate that catecholamines may increase or decrease cyclic AMP levels in rat myocardium, depending on the intensity of stimulation of receptor types. Increases are mediated by beta-adrenergic receptors, whereas decreases appear to by mediated by alpha-adrenergic receptors.     

Concentration of myocardial cyclic AMP and ventricular fibrillation induced by aminophylline.

The concentration of myocardial cyclic AMP was measured in 9 dogs by radioimmunoassay after the administration of aminophylline. Fourteen dogs served as control. The concentration of cyclic AMP in the left ventricle was the highest and the lowest value was obtained in the right atrium in the control dogs. Ventricular fibrillations were induced immediately after the injection of 30 mg/Kg aminophylline in 3 dogs out of 9. The concentration of the left ventricular cyclic AMP in 6 dogs which tolerated aminophylline was significantly elevated compared with that of the control dogs (p less than 0.05). The left ventricular cyclic AMP in 3 dogs with ventricular fibrillation was significantly higher compared with that in the aminophylline tolerated dogs with non-fibrillating hearts (p less than 0.01). These results showed that the concentration of cyclic AMP was elevated in the fibrillating heart.     

The effects of dilazep and SG 75 on cyclic nucleotides in the coronary artery

We examined the effects of new long acting coronary vasodilators (dilazep and SG 75) on cyclic nucleotides in the coronary artery and the myocardium at the maximum coronary blood flow. The cyclic AMP concentrations in the anterior descending coronary artery after the injection of saline (control), SG 75 (0.2 mg/Kg), and dilazep (0.1 mg/Kg) were 229 +/- 20 pmole/Gm, 249 +/- 21 pmole/Gm, and 320 +/- 21 pmol/Gm, respectively. A significant increase above control values was found in the dilazep treated group (p less than 0.02). The cyclic GMP concentrations in the coronary artery after the injection of saline, SG 75, and dilazep were 35.6 +/- 4.4 pmole/Gm, 40.4 +/- 3.3 pmole/Gm, 35.3 +/- 3.2 pmole/Gm, respectively. There were no significant differences between them. The cyclic AMP and cyclic GMP concentrations in the left ventricular muscle did not significantly increase after the administration of dilazep and SG 75. Our findings showed that the mechanism of coronary vasodilating action of dilazep might be associated with an increased cyclic AMP in the coronary artery.     

Interaction between cyclic adenosine monophosphate and cyclic gunaosine monophosphate in guinea pig ventricular myocardium.

The purpose of this study was to examine the mechanisms underlying adrenergic-cholinergic antagonism in ventricular myocardium. Myocardial contractility, cyclic adenosine monophosphate (AMP) levels, and cyclic guanosine monophosphate (GMP) levels were measure in isolated guinea pig ventricles after treatment with various inotropic agents given alone and simultaneously with acetylcholine. Acetylcholine alone markedly elevated cyclic GMP levels but did not substantially change myocardial contractility. However, the same concentration of acetylcholine significantly attenuated the inotropic effect of isoproterenol and histamine, two drugs that may act by increasing myocardial levels of cyclic AMP. The decrease in the inotropic response to isoproterenol did not appear to be due to a decrease in the generation of cyclic AMP, because cyclic AMP levels were similar in hearts receiving isoproterenol alone and those receiving isoproterenol with acetylcholine. Dibutyryl cyclic GMP also antagonized the intropic action of isoproterenol. Acetylcholine did not alter the inotropic effects of ouabain, an agent that increases myocardial contractility without changing cyclic AMP levels. These results suggest that cyclic GMP mediates the antiadrenergic effects of acetylcholine by specifically antagonizing the inotropic actions of cyclic AMP.     

High-energy phosphate contents of subepicardium and subendocardium in the rat treated with isoproterenol and some other drugs

High-energy phosphate content of the myocardium was reduced after subcutaneous injection of isoproterenol in rats. ATP was significantly decreased 24 h after the administration of isoproterenol 0.25 mg/kg, while creatine phosphate (CP) remained unchanged until the doses more than 1 mg/kg were used. In doses higher than 2.5 mg/kg, CP as well as ATP was markedly declined, becoming 50% of the control at 25 mg/kg. Pretreatment with propranolol prevented the reduction of high-energy phosphate content by isoproterenol. In rat hearts without isoproterenol, the content of inorganic phosphate (Pi) and lactate was significantly higher in subendocardium than in subepicardium, while CP was significantly lower in subendocardium and there was no appreciable difference in ATP. In isoproterenol-treated hearts, the difference of the phosphate content became much more prominent. When used in rats without isoproterenol, propranolol tended to increase high-energy phosphate content in subendocardium, and the difference of Pi and CP between the two layers became significantly smaller. Itramin tosylate rather decreased the CP content in subendocardium and the difference became more marked. Phenylephrine did not produce any change in the phosphate content of the two layers. It was considered that besides a relative myocardial hypoxia, characteristic exhaustion of high-energy phosphate compounds due to betareceptor stimulation may be involved in the isoproterenol-induced disturbances in rat myocardial metabolism. The physiologically existing anaerobic metabolism in subendocardium seemed to be difficult to improve with drugs affecting coronary hemodynamics. The effectiveness of propranolol may be based on the reduction in heart rate and contractility resulting from beta-receptor blockade.     

Nipradilol, a new β-adrenergic blocker, reduces left ventricular remodeling following myocardial infarction in spontaneously hypertensive rats

Summary Left ventricular (LV) cavity dilation (remodeling) following myocardial infarction (MI) is a risk factor for morbidity and mortality. This study was undertaken to determine whether nipradilol, a new -adrenergic blocker with vasodilating action, reduces LV remodeling after MI produced by coronary ligation in spontaneously hypertensive rats. The effects on LV remodeling of the following drugs, which were administered orally for 4 weeks, were evaluated by assessing LV end-diastolic volume index (LVEDVI): (1) vehicle, (2) nipradilol, 10mg/kg per day, (3) propranolol, 50mg/kg per day, and (4) captopril, 30mg/kg per day. Since LVEDVI depends on infarct size, the effects of the drugs on LVEDVI were compared between rats with a similar infarct size, i.e., moderate, 20%–40%; and large, 40%–60%, on the basis of the histological determination of infarct size. The nipradilol-treated and captopriltreated rats had significantly smaller LVEDVI than did the vehicle-treated rats with both moderate and large infarction (large infarct: 2.48 ± 0.12ml/kg for the vehicle group, 1.69 ± 0.10ml/kg for the nipradilol group,P < 0.01, and 1.79 ± 0.14ml/kg for the captopril group,P < 0.01). In contrast, LVEDVI in the propranololtreated rats was significantly greater than that in the vehicle-treated rats with a moderate infarct (2.09 ± 0.09ml/kg for the vehicle group versus 2.44 ± 0.10ml/kg for the propranolol group,P < 0.05). The results indicate that nipradilol and captopril reduce LV remodeling after MI, whereas propranolol promotes it.     

Comparison of cardiac lesions induced in rats by isoproterenol and by repeated stress of restraint and water immersion with special reference to etiology of cardiomyopathy

Cardiac lesions induced in rats by isoproterenol, a potent beta-agonist, and by repeated stress of restraint and water immersion, in which sensitization of beta-adrenergic receptors would be expected to be induced, were investigated morphologically and following facts were revealed. 1) Cardiac lesions induced by isoproterenol, characteristic findings of which were myocardial hypertrophy, myocardial degeneration and myocardial necrosis replaced by interstitial fibrosis, were more analogous to cardiomyopathy than myocardial infarction or cardiac hypertrophy. 2) Cardiac lesions induced by repeated stress of restraint and water immersion, characteristic findings of which were myocardial hypertrophy, myocardial degeneration and myocardial necrosis replaced by interstitial fibrosis, were similar to those induced by isoproterenol. These results suggest that the endogenously induced dominant beta-adrenergic stimulating action during stress may play an important role in the pathogenesis of cardiomyopathy, the specific etiology of which is not yet known.     

The inability of isoproterenol or propranolol to alter the lateral dimensions of experimentally induced myocardial infarcts

Summary The relationship between the blood flow pattern immediately following coronary artery occlusion and the resulting infarct 24 hours later was studied in dogs treated with isoproterenol (0.5 g/kg/min for 2 hours) or with propranolol (2mg/kg every 6 hours). The coronary artery of a closed chest dog was perfused via a special cannula with arterial blood. A 2-mm diameter plastic bead was introduced into the perfusate to embolize a coronary branch. One minute after occlusion, radiolabelled microspheres were injected into the perfusate. The dogs were then allowed to recover. 24 hours later the dogs were reanesthetized and their hearts removed. The hearts were sliced into 4 mm thick sections and the microsphere distribution was visualized by autoradiography of the tissue. Superimposition of developed autoradiographs and tracings of the infarct pattern of stained sections allowed direct comparison of the blood flow pattern immediately after occlusion to the eventual pattern of infarction. In all 8 control dogs, all 6 isoproterenol dogs and all 12 propranolol dogs the lateral borders of blood flow and infarction were superimposable indicating no lateral change in infarct size resulting from treatment. In the control group there was a subepicardial region of the ischemic zone which did not infarct (15.2±2.3% of the ischemic zone). Though isoproterenol did not significantly change the size of this zone, propranolol increased it to 35.9±6,5% (p<0.005) indicating vertical but not lateral salvage.Supported by Grant HL-20648 from NIH: HLBI and a Grant-in-aid from the American Heart Association and with funds contributed in part by the Northwest Ohio Chapter, Inc.     

Effects of phospholipase inhibitors and calcium antagonists on the changes in myocardial phospholipids induced by isoproterenol

Summary To investigate the change in myocardial phospholipids after the administration of isoproterenol and its prevention by pretreatment with phospholipase inhibitors and calcium antagonists, we determined the phospholipid species in the heart of female Wistar rats. Isoproterenol (40 mg/kg) was administered 24 h before excising the heart, and chlorpromazine, mepacrine (phospholipase inhibitors), nifedipine, verapamil (calcium antagonists) and propranolol (-adrenoceptor blocker) were injected intraperitoneally 30 min prior to isoproterenol administration. The phospholipid species were quantified using silica gel precoated thin-layer rods and the hydrogen flame ionization method. Isoproterenol induced significant increases in heart/body weight ratio, myocardial protein/heart weight ratio and lysophosphatidylcholine (LPC), and significant decreases in myocardial total phosphorus, creatine kinase (CK) activity, phosphatidylethanolamine and phosphatidylcholine (PC). The significant decrease in PC and increase in LPC indicated the degradation of myocardial phospholipids. Pretreatment with nifedipine (30 mg/kg), verapamil (50 mg/kg) or propranolol (20 mg/kg) completely prevented the occurrence of myocardial injury through the preservation of myocardial phospholipid composition, total phosphorus, CK activity and heart/body and protein/heart weight ratios. On the other hand, chlorpromazine (30 mg/kg) and mepacrine (50 mg/kg) partially prevented myocardial damage through the preservation of myocardial phospholipid composition, total phosphorus and CK activity. Results suggest that not only calcium influx but also phospholipase activation plays an important role in the development of myocardial injury induced by isoproterenol.     

Catecholamine-dependent cyclic adenosine monophosphate and renin in the dog kidney.

Lithium inhibits the catecholamine-dependent cyclic adenosine monophosphate (AMP) generation in the kidney but not the hemodynamic effects of beta-adrenergic stimulation. Therefore, the possible role of catecholamine-dependent cyclic AMP in the release of renin was investigated in lithium-treated dogs both in vivo and vitro. Lithium therapy had no measurable effect on the increase in plasma renin activity induced by an injection of isoproterenol (2.6 plus and minus 1.2 (SE) ng/hour in control dogs vs. 3.0 plus and minus 1.2 ng/hour in lithium-treated dogs, P greater than 0.05). However, lithium inhibited the isoproterenol-induced increase in urinary excretion of cyclic AMP in vivo (791 plus and minus 199 pmoles/min in control dogs vs. 123 plus and minus 129 pmoles/min in lithium-treated dogs, P less than 0.05) and the increase in cyclic AMP concentration in renal tissue in vitro (4.50 plus and minus 0.15 pmoles/ng wet tissue in control dogs vs. 0.34 plus and minus 0.26 pmoles/mg in lithium-treated dogs, P less than 0.01). The finding that, in the lithium-treated dogs, isoproternol increased plasma renin activity but not cyclic AMP generation in the kidney suggests that the increase in plasma renin activity observed after an injection of isoproterenol is probably not mediated through the beta-adrenergic stimulus-dependent cyclic AMP system in the kidney.