X线造影剂对肺阻力动脉张力的影响

目的 观察并比较临床上常用的四类Ｘ线造影剂对肺阻力动脉张力的影响。方法 取内径为０．３－０．６毫米的大鼠肺小动脉,通过自动血管Ｍｙｏｇｒａｐｈ仪连续地记录血管条张力,观察１０、２０、４０、８０、１５０或２００ｍｇＩ／ｍｌ等浓度的四种不同类型Ｘ线造影剂（泛影葡胺、低渗显影葡胺、优维显、伊索显）及甘露醇渗管压对溶液对肺阻力动态张力的影响。结果 所有四种造影剂均引起肺阻力动脉血管条的双相性张力改变,包括     

Role for intrarenal adenosine in the renal hemodynamic response to contrast media

The intrarenal injection of contrast media results in a transient fall in renal blood flow (RBF) and a decrease in glomerular filtration rate (GFR). These effects are enhanced by dietary sodium restriction and attenuated by sodium loading. A similar sodium-dependent response of RBF and GFR occurs with the intrarenal injection of adenosine. In view of these similarities, we sought to determine whether endogenous adenosine is involved in the renal hemodynamic response to contrast media. The intrarenal injection of contrast media (meglumine-Na diatrizoate, 76%) in six sodium-depleted, anesthetized dogs resulted in a 17% +/- 4% decrease in RBF and a 31% +/- 5% decrease in GFR. The infusion of the adenosine receptor antagonist, theophylline (5 mumol/min), reduced the decrease in RBF to 6% +/- 2% and in GFR to 12% +/- 3% of control values. During the intrarenal infusion of dipyridamole (24 micrograms/kg/min), a potentiator of adenosine through its action to inhibit the cellular uptake of nucleosides, the hemodynamic response to contrast media was greater; RBF fell 25% +/- 4% and GFR fell 44% +/- 7%. In addition, the urinary excretion of endogenous adenosine increased after the injection of contrast media (388 +/- 79 vs. 830 +/- 231 nmol/min). In summary, the contrast media-induced fall in RBF and GFR was attenuated by theophylline and augmented by dipyridamole, and the administration of contrast media resulted in an increase in the excretion of endogenous adenosine. These results support the hypothesis that endogenous adenosine is involved in the renal hemodynamic response to contrast media.     

Progress in the pursuit of therapeutic adenosine receptor antagonists

Ever since the discovery of the hypotensive and bradycardiac effects of adenosine, adenosine receptors continue to represent promising drug targets. First, this is due to the fact that the receptors are expressed in a large variety of tissues. In particular, the actions of adenosine (or methylxanthine antagonists) in the central nervous system, in the circulation, on immune cells, and on other tissues can be beneficial in certain disorders. Second, there exists a large number of ligands, which have been generated by introducing several modifications in the structure of the lead compounds (adenosine and methylxanthine), some of them highly specific. Four adenosine receptor subtypes (A1, A2A, A2B, and A3) have been cloned and pharmacologically characterized, all of which are G protein-coupled receptors. Adenosine receptors can be distinguished according to their preferred mechanism of signal transduction: A1 and A3 receptors interact with pertussis toxin-sensitive G proteins of the Gi and Go family; the canonical signaling mechanism of the A2A and of the A2B receptors is stimulation of adenylyl cyclase via Gs proteins. In addition to the coupling to adenylyl cyclase, all four subtypes may positively couple to phospholipase C via different G protein subunits. The development of new ligands, in particular, potent and selective antagonists, for all subtypes of adenosine receptors has so far been directed by traditional medicinal chemistry. The availability of genetic information promises to facilitate understanding of the drug-receptor interaction leading to the rational design of a potentially therapeutically important class of drugs. Moreover, molecular modeling may further rationalize observed interactions between the receptors and their ligands. In this review, we will summarize the most relevant progress in developing new therapeutic adenosine receptor antagonists.     

Selective blockade of angiotensin responses in the rabbit isolated vas deferens by angiotensin receptor antagonists

We examined the effect of two angiotensin receptor antagonists on neuromodulatory and prostaglandin-producing effects of angiotensin II in the rabbit isolated vas deferens because prior studies have established that angiotensins selectively influence the two neural events, one being adrenergic and the other nonadrenergic. Angiotensin II increased adrenergic neurotransmission and prostaglandin E synthesis in a concentration-dependent manner while depressing nonadrenergic neurotransmission. The [1-Sarcosine, 8-Alanine]-angiotensin II preferentially antagonized adrenergic neuromodulatory effects of angiotensin II. In contrast, the nonadrenergic neuromodulatory and prostaglandin E-releasing effects of angiotensin II were suppressed by [1-Sarcosine, 8-Alanine]-angiotensin II to a lesser extent. The nonpeptide angiotensin receptor antagonist, Dupont 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2(1)-(1-H-tetrazol-5-yl) biphenyl-4-yl)methyl] imidazole, potassium salt, exhibited the opposite selectivity. It eliminated the depression of nonadrenergic neurotransmission without significantly altering the potentiation of adrenergic neurotransmission caused by angiotensin II. The angiotensin-induced stimulation of prostaglandin E synthesis was also eliminated by this antagonist. These data suggest that angiotensin effects in the vas deferens are mediated by at least two types of angiotensin receptors.     

Effects of histamine H2 receptor agonists and antagonists on the isolated guinea pig gallbladder

Histamine H2 receptor-mediated responses were examined on cholecystokinin-octapeptide (CCK-8)-precontracted guinea pig gallbladder in vitro, testing histamine and a series of specific histamine H2 receptor agonists and antagonists. Among the antagonists tested, zolantidine and compound SKF 92857 were previously shown to antagonize H2 receptor-mediated responses in the heart, but not in the stomach. Histamine, in the presence of the H2 receptor antagonist mepyramine (10 microM), and the H2 receptor agonists dimaprit, impromidine and amthamine, inhibited CCK-8 (3 nM)-induced contractions in a concentration-dependent fashion, with the following rank orders of potency: impromidine > amthamine > histamine > dimaprit (pD2 values were 6.73 +/- 0.04, 5.44 +/- 0.07, 4.64 +/- 0.04 and 3.71 +/- 0.05, respectively). The maximal relaxation produced by dimaprit was significantly lower than that produced by histamine, as well as by impromidine and amthamine, which behaved as full agonists. All the H2 receptor antagonists examined were able to inhibit amthamine-induced relaxation. Famotidine (pA2 = 7.09 +/- 0.26), zolantidine (pA2 = 6.54 +/- 0.11), compound SKF 92857 (pA2 = 6.58 +/- 0.13) and aminopotentidine (pA2 = 6.86 +/- 0.06) competitively antagonised the amthamine-induced effect, while iodoaminopotentidine produced surmountable antagonism only at low concentrations (1 microM, pA2 = 6.83 +/- 0.21). Finally, the slowly-dissociable antagonist loxtidine caused a non-parallel displacement to the right of the concentration--response curve to amthamine (pKB = 7.55 +/- 0.24), with a significant depression of the maximal response to the agonist, even at the lowest effective concentration (0.3 microM). In conclusion, histamine H2 receptors in guinea pig gallbladder resemble those of the heart, as regards their sensitivity to zolantidine and compound SKF 92857, which, by contrast, were unable to antagonize histamine effects at gastric H2 receptors in different experimental models.     

Effects of chronic norepinephrine administration on sympathetic neurotransmission in the isolated perfused rat kidney

The effects of chronic NE administration (100 micrograms/kg/hr s.c., 6 days) on the stimulus-induced overflow of neurotransmitter from the isolated perfused rat kidney were examined. This treatment increased renal NE content and increased the absolute stimulus-induced overflow of NE. The increase in absolute overflow was not simply the result of the increase in renal NE content as fractional overflow was also increased slightly (20%). Alpha adrenoceptor blockade with phentolamine eliminated the NE treatment-induced difference in fractional overflow. However, the dose-response curves to phentolamine and the alpha-2 adrenoceptor agonist UK 14,304 on stimulus-induced overflow from the kidney were not significantly different after NE treatment. Chronic EPI treatment (same dose) produced an 80% increase in fractional stimulus-induced overflow of neurotransmitter but the dose-response curve to UK 14,304 was shifted only slight to the right (3-fold) of the control curve. No influence of prejunctional beta adrenoceptors on stimulus-induced overflow was observed in either the control of the NE-treated group. In conclusion, the data regarding fractional overflow and the effects of the phentolamine suggest that NE treatment produces minimal change whereas EPI treatment produces marked decreases in the influence in prejunctional alpha adrenoceptors. However, although the data with UK 14,304 after NE treatment support this conclusion, the failure of EPI treatment to alter the dose-response curve to UK 14,304 does not. The apparent contradiction of the results with the alpha adrenoceptor agonist in the EPI-treated group as well as the large differences between the effects of NE vs. EPI treatment on stimulus-induced overflow and prejunctional alpha adrenoceptor function cannot be explained at this time.     

Caffeine and theophylline as adenosine receptor antagonists in humans

Substantial in vitro and animal data suggest that methylxanthines, such as caffeine and theophylline, act as adenosine receptor antagonists. To test this hypothesis in humans, we first determined if theophylline would antagonize the effects of adenosine. Intravenous administration of adenosine, 80 micrograms/kg/min, increased heart rate 28 +/- 6 bpm, systolic blood pressure 19 +/- 5 mm Hg and minute ventilation 6.1 +/- 2.2 liters/min. All these changes were significantly attenuated during theophylline administration (17 +/- 3 bpm and 1 +/- 2 mm Hg and 1.6 +/- 0.6 liters/min, respectively, P less than .05), at a dose (10 mg/kg over 1 hr, followed by 1.8 micrograms/kg/min i.v.) that produced plasma theophylline levels of 17 +/- 2 micrograms/ml (94 microM). We then determined if chronic caffeine consumption resulted in upregulation of platelet adenosine receptors in eight normal volunteers. After 7 days of caffeine abstinence, the adenosine analog 5'-N-ethylcarboxamidoadenosine produced a dose-dependent inhibition of thrombin-induced aggregation (EC50 = 69 nM). Subjects then were given caffeine, 250 mg p.o. 3 times a day for 7 days. Actual caffeine withdrawal, that is, virtual disappearance of caffeine in plasma, was apparent 60 hr after the last dose of caffeine. Caffeine withdrawal produced a significant shift to the left of 5'-N-ethylcarboxamidoadenosine inhibition of aggregation (EC50 = 49 nM, P less than .01), implying sensitization and/or upregulation of adenosine receptors as seen after chronic exposure to an antagonist. These results suggest that methylxanthines act as adenosine receptor antagonists in humans.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sonographic detection of kidney infarctions using ultrasound contrast media

Contrast-enhanced CT is currently the gold standard for the diagnosis of kidney infarction. Particularly in patients with renal insufficiency, however, the use of iodine contrast media is limited. Sonographic examination using ultrasound contrast media may be an alternative for these patients. CASE REPORTS: We examined three patients with suspected ischaemic kidney infarction with ultrasound contrast media. Scanning was performed with low mechanical index, and SonoVue was used as by contrast-enhancing agent. In all three patients, kidney infarctions were clearly shown. In two patients, the lesions were confirmed by contrast-enhanced CT, in one no CT was performed because of impaired renal function. CONCLUSION: Kidney infarctions can reliably be detected by contrast-enhanced ultrasound using SonoVue as contrast agent. This is particularly valuable in patients with renal impaired renal function and other contraindications against iodine contrast media.     

Antinociceptive effects of novel A2B adenosine receptor antagonists

Caffeine, an adenosine A1, A2A, and A2B receptor antagonist, is frequently used as an adjuvant analgesic in combination with nonsteroidal anti-inflammatory drugs or opioids. In this study, we have examined the effects of novel specific adenosine receptor antagonists in an acute animal model of nociception. Several A2B-selective compounds showed antinociceptive effects in the hot-plate test. In contrast, A1- and A2A-selective compounds did not alter pain thresholds, and an A3 adenosine receptor antagonist produced thermal hyperalgesia. Evaluation of psychostimulant effects of these compounds in the open field showed only small effects of some antagonists at high doses. Coadministration of low, subeffective doses of A2B-selective antagonists with a low dose of morphine enhanced the efficacy of morphine. Our results indicate that analgesic effects of caffeine are mediated, at least in part, by A2B adenosine receptors.     

Effects of spinal cholecystokinin receptor antagonists on morphine antinociception in a model of visceral pain in the rat

The objective of the present study was to determine the effects of spinal cholecystokinin (CCK) receptor antagonists on morphine antinociception in a model of visceral nociception, colorectal distension, in rats with chronic colonic inflammation and vehicle-treated controls. Three to five days after intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS), an enhanced visceromotor response to all pressures of colorectal distension (10-80 mm Hg) was evident. The ED(50) of intrathecal morphine (0.93 microgram) in vehicle-treated rats produced significantly greater antinociception in TNBS-treated rats. Intrathecal proglumide, a nonselective CCK receptor antagonist, dose dependently enhanced the antinociceptive effect of morphine in vehicle-treated rats, but not in TNBS-treated rats. Similarly, L-365, 260, a specific CCK(B) receptor antagonist, dose dependently increased morphine's antinociceptive effects in vehicle-treated rats but had no effect in rats with TNBS-induced colonic inflammation. L-364,718, a specific CCK(A) receptor antagonist, had no effect on morphine antinociception in either vehicle-treated or TNBS-treated rats. These data indicate that CCK, acting at the CCK(B) receptor, is involved in modulating morphine antinociception following a noxious visceral stimulus. However, CCK receptor antagonists no longer enhance morphine antinociception after instillation of intracolonic TNBS, suggesting that visceral inflammation may lead to a reduction in spinal CCK release.     

Effects of putative thromboxane receptor agonists and antagonists on rat small intestinal ion transport

Effects of a thromboxane mimic, U46619, on electrolyte transport were examined in vitro using stripped segments of rat ileal mucosa mounted in Ussing chambers. Addition of U46619 to the serosal bathing solution elicited a transient increase in short-circuit current (Isc) and decrease in transepithelial conductance (Gt). The increase in Isc was accompanied by a transient increase in Cl- secretion and decrease in Na+ absorption. In the steady-state, Isc was not increased whereas Gt remained decreased and Na+ and Cl- absorption were inhibited. Removal of Cl- or pretreatment with serosal and mucosal indomethacin (1 microM) or the thromboxane receptor antagonist, SK&F 88046, added to the serosal bathing solution, inhibited the increase in Isc stimulated by U46619 (apparent KB approximately 8 nM). The effects of U46619 on both Isc and Gt are qualitatively similar to those resulting from stimulation with leukotriene D4. However, the changes in Isc with leukotriene D4 (10 microM) are antagonized by SK&F 88046 only at high concentrations (1-10 microM). In addition, the secretagogues prostaglandin F2 alpha, lys-bradykinin, serotonin and histamine, produce qualitatively similar changes in Isc to those seen with U46619 without altering Gt. With the exception of prostaglandin F2 alpha, the effects of these secretagogues are not inhibited by SK&F 88046 (10 microM). These results indicate that U46619 acts at a thromboxane receptor to stimulate intestinal Cl- secretion and inhibit Na+ and Cl- absorption. These changes are inhibited selectively by the thromboxane receptor antagonist, SK&F 88046.     

Modulation of the rat hippocampal dinucleotide receptor by adenosine receptor activation

Diadenosine pentaphosphate (Ap(5)A) and ATP stimulate an intracellular free calcium concentration ([Ca(2+)](I)) increase in rat hippocampal synaptosomes via different receptors as demonstrated by the lack of cross-desensitization between Ap(5)A and ATP responses. The ATP response was inhibited by P2 receptor antagonists and not by the dinucleotide receptor antagonist, diinosine pentaphosphate (Ip(5)I). In contrast, the Ap(5)A response was inhibited by Ip(5)I but not by P2 receptor antagonists. Studies in single hippocampal synaptic terminals showed that 31% of them responded to Ap(5)A by a [Ca(2+)](i) increase. Adenosine receptors (A(1), A(2A), and A(3)) were also present in isolated terminals as demonstrated by immunohistochemistry. The activation of A(1) or A(2A) receptors by specific agonists changed the sigmoid concentration-response curve for Ap(5)A (EC(50) = 33.5 +/- 4.5 microM) into biphasic curves. When the high-affinity adenosine receptors A(1) or A(2A) were activated, the Ap(5)A dose-response curves showed a high-affinity component with EC(50) values of 41.1 +/- 1.9 pM and 99.9 +/- 10.2 nM, respectively. The low-affinity component showed EC(50) values of 17.1 +/- 0.8 and 21.6 +/- 1.4 microM for A(1) and A(2A) receptor activation, respectively. However, the adenosine A(3) receptor activation induced a right shift of the dinucleotide concentration-response curve, showing an EC(50) value of 331.4 +/- 54.6 microM. In addition, in the presence of the A(2A) agonist, the Ap(5)A calcium influx responses were increased up to 300% of the control values. These results clearly demonstrate that the activation of presynaptic adenosine receptors is able to modulate the dinucleotide response in hippocampal nerve terminals.     

Role of receptor reserve in the inhibition of alpha-1 adrenoceptor-mediated pressor responses by calcium antagonists in the pithed rat

The effect of the calcium channel antagonists nifedipine and FR 34235 on the vasopressor response to alpha-1 adrenoceptor stimulation in the pithed normotensive rat was investigated. The maximal pressor response elicited by the full alpha-1 adrenoceptor agonist SK&F l-89748 was slightly but significantly reduced by 1-mg/kg doses of nifedipine (21 +/- 2%) and FR 34235 (34 +/- 4%). In comparison, the maximal pressor response to alpha-1 adrenoceptor stimulation by the partial alpha-1 agonist SK&F 88444 was markedly inhibited by nifedipine (51 +/- 1%) and FR 34235 (65 +/- 3%). Partial inactivation of the postsynaptic alpha-1 adrenoceptors with phenoxybenzamine (0.1 mg/kg) resulted in a maximal increase in diastolic pressure to alpha-1 adrenoceptor activation by SK&F l-89748 less than that induced by SK&F 88444. After phenoxybenzamine treatment, nifedipine and FR 34235 produced even greater reductions in the maximal vasopressor response to alpha-1 adrenoceptor stimulation by SK&F l-89748 (77 +/- 8 and 85 +/- 1%, respectively). Moreover, an inverse linear correlation (r = 1.00) was observed between the sensitivity of the maximal vasopressor response to nifedipine and FR 34235 and the magnitude of the maximal pressor response. The data suggest that the sensitivity of the alpha-1 adrenoceptor-mediated pressor response to inhibition by calcium antagonists in the pithed rat is inversely related to the magnitude of the pressor response, and they are consistent with the notion that the presence of "spare" alpha-1 adrenoceptors may determine the sensitivity of the pressor response to calcium antagonists.     

Effects of endothelin receptor antagonist on cyclosporine-induced vasoconstriction in isolated rat renal arterioles.

Recent evidence suggests that the potent constrictor peptide, endothelin (ET) has a mediating role in cyclosporine A (CsA)-related renal vasoconstriction. However, the nature of the CsA-ET interaction and effect on the renal vasculature is uncertain. The purpose of the present study was twofold: (a) to determine if CsA exposure caused direct local release of ET from the endothelium of the renal microvasculature and (b) to determine if locally generated ET has paracrine effects on the underlying vascular smooth muscle to induce vasoconstriction. Experiments were performed in isolated rat renal arterioles. First it was determined that both afferent arteriole (AA) and efferent arteriole (EA) exhibited concentration-dependent decreases in lumen diameter to increasing molar concentrations of CsA. The AA was more sensitive to the vasoconstrictive effects of CsA than the EA. Next, the blocking effect of a recently synthesized putative ETA receptor antagonist was verified in both the AA and EA, where it was found that the cyclic peptide cyclo D-Asp-L-Pro-D-Val-L-Leu-D-Trp totally inhibited the vasoconstriction observed with ET addition. Finally, the role of locally stimulated ET in CsA-induced vasoconstriction was tested by determining the effect of the ETA receptor antagonist on CsA-induced AA and EA constriction. In the AA the vasoconstrictor effect of 10(-11) M CsA was completely blocked by the ETA receptor antagonist. However, in contrast to AA, 10(-11) M CsA in EA in the presence of the ETA receptor antagonist decreased EA lumen diameter by a mean of 41% from baseline (4.80 +/- 0.75 microns vs 7.80 +/- 0.84 microns, P < 0.05). This change in lumen diameter was similar to that induced by CsA alone. These data suggest that CsA directly constricts renal microvessels. This effect is mediated by ET in the AA but not the EA.     

On the ability of endogenous adenosine to regulate purine nucleoside receptor binding of antagonists in smooth muscle membranes

Adenosine, acting at A1 and A2 purine nucleoside receptors, regulates the physiology of many tissues. Myometrial smooth muscle from pregnant guinea pigs, which is contracted by the actions of adenosine, possesses an A1 receptor whose agonist affinity is regulated by guanine nucleotides. In addition to its expected effect on the affinity of the A1 receptor for agonist, the addition of guanine nucleotide also dramatically increases antagonist binding by as much as 62%. This action of guanine nucleotides on adenosine A1 receptors is common to many smooth muscle preparations and suggests the possibility that GTP-binding proteins might alter the conformation of the adenosine receptor in such a way that receptors not previously able to bind ligands are recruited by the guanine nucleotide. Such an action of guanine nucleotides would alter our general view of the interaction of antagonists with GTP-binding protein coupled receptors, as well as bear significantly on the interpretation of experimental data designed to characterize purinergic receptors. Thus, we have investigated the actions of guanosine-5'-O-[3-thiotriphosphate] on A1 adenosine receptor binding in membranes prepared from pregnant guinea pig myometrium containing 61% right-side-out vesicles. We show that guanosine-5'-O-[3-thiotriphosphate] lowers the affinity of adenosine A1 receptors for agonist in vesicles leading to increased competition of antagonist radioligand for receptor. We suggest that the endogenous adenosine we measure originates from breakdown of significant amounts of adenine nucleotides present in membranes vesicles. Furthermore, we demonstrate that opening membrane vesicles to remove trapped adenosine yields maximal antagonist radioligand binding without subsequent effects of guanosine-5'-O-[3-thiotriphosphate]. We conclude that the presence of endogenous adenosine, unavailable to the actions of adenosine deaminase, is responsible for the effect of guanine nucleotides to increase antagonist binding to adenosine A1 receptors.     

Experimental glomerulonephritis in the isolated perfused rat kidney.

The development of immune deposits on the subepithelial surface of the glomerular capillary wall was studied in isolated rat kidneys perfused at controlled perfusion pressure, pH, temperature, and flow rates with recirculating oxygenated perfusate containing bovine serum albumin (BSA) in buffer and sheep antibody to rat proximal tubular epithelial cell brush border antigen (Fx1A). Control kidney were perfused with equal concentrations of non-antibody immunoglobulin (Ig)G. Renal function was monitored by measuring inulin clearance, sodium reabsorption, and urine flow as well as BSA excretion and fractional clearance. Perfused kidneys were studied by light, immunofluorescence, and electron microscopy. All kidneys perfused with anti-Fx1A developed diffuse, finely granular deposits of IgG along the glomerular capillary wall by immunofluorescence. Electron microscopy revealed these deposits to be localized exclusively in the subepithelial space and slit pores. Similar deposits were produced in a nonrecirculating perfusion system, thereby excluding the formation of immune complexes in the perfusate caused by renal release of tubular antigen. Control kidneys perfused with nonantibody IgG did not develop glomerular immune deposits. Renal function and BSA excretion were the same in experimental and control kidneys. Glomerular deposits in antibody perfused kidneys were indistinguishable from deposits in rats injected with anti-Fx1A or immunized with Fx1A to produce autologous immune complex nephropathy. These studies demonstrate that subepithelial immune deposits can be produced in the isolated rat kidney by perfusion with specific antibody to Fx1A in the absence of circulating immune complexes. In this model deposits result from in situ complex formation rather than circulating immune complex deposition.     

Binding of 125I-insulin to the isolated glomeruli of rat kidney.

To investigate a possible action of insulin on the glomerulus, the binding 125I-insulin to the isolated glomeruli prepared from rat kidney was examined. When incubated at 22 degrees C, 125I-insulin binding proceeded with time and reached a steady state at 45 min at which time nonspecific binding was less than 25% of total binding. A small fraction of 125I-insulin was degraded during incubation. This binding was specific to insulin in that it was inhibited by unlabeled porcine and beef insulins and to a lesser extent by porcine proinsulin and desalanine-desasparagine insulin, but not by glucagon, parathyroid hormone, vasopressin, calcitonin, and angiotensin II. Increasing concentrations of nonlabeled insulin displaced 125I-insulin binding in a dose-dependent fashion. Scatchard plot of the data was curvilinear consistent with either two classes of receptors with different affinities or a single class of receptors that demonstrate negative cooperativity. The addition of excess nonlabeled insulin to the glomeruli preincubated with 125I-insulin resulted in a rapid dissociation of approximately or equal to 70% of bound 125I-insulin. Insulin decreased the increments in glomerular cyclic AMP levels by epinephrine and by prostaglandin E2, but not those by histamine. These data showed the presence of specific insulin receptors in the glomeruli, and that insulin action may be, at least in part, through modulation of glomerular cyclic AMP concentrations. Such action of insulin may underlie the alteration in glomerular ultrafiltration and the glomerular ultrafiltration and the development of glomerular lesions in diabetes mellitus, a disease in which insulin deficiency or the tissue resistance to insulin exists.