Pancreatic Atrophy in Rats Produced by the Cholecystokinin-A Receptor Antagonist Devazepide

According to recent reports, the powerful and selective cholecystokinin (CCK)-A receptor antagonist devazepide (also referred to as L-364,718 or MK-329) is without effect on the weight of the pancreas. This has been interpreted to mean that basal and meal-stimulated endogenous CCK does not play a major role in the normal maintenance of the pancreas. In the present study we show that continuous subcutaneous infusion of devazepide effectively and dose-dependently reduced the weight of the pancreas both in normal rats and in hyperCCKemic rats (because of pancreaticobiliary diversion). The maximum reduction of the pancreatic weight was 40%. Maximum or near-maximum effects were seen with a dose of 200 ng/kg/h. The DNA content of the pancreas was also reduced. The reduction in weight and DNA content of the pancreas was maximal after 10 days. Provided that devazepide acts solely by inhibiting CCK-A receptors, we can conclude that endogenous CCK plays an important role in both normal and stimulated growth of the rat pancreas.     

Release of Interleukin-1 Receptor Antagonist by Combining a Leukocyte Adsorption Carrier With Ulinastatin

Both granulocyte/monocyte adsorptive apheresis (GMA) and ulinastatin, a serine protease inhibitor, are reported to be effective in patients with ulcerative colitis; however, combination therapy with GMA and ulinastatin has not been attempted. Investigating the effect of ulinastatin on GMA is required for combination therapy since the inhibition of serine protease suppresses the reaction of GMA. To clarify the effects of ulinastatin on GMA, we investigated whether granulocyte adsorption to cellulose acetate beads (carriers for GMA) and interleukin-1 receptor antagonist (IL-1ra) release were inhibited by ulinastatin. Peripheral blood containing ulinastatin, a different serine protease inhibitor (gabexate mesilate), or signal-transduction inhibitors was incubated with cellulose acetate beads in vitro, and the ratios of adsorbed granulocytes and IL-1ra release were measured. Granulocyte adsorption and IL-1ra release were significantly suppressed with increasing gabexate mesilate concentrations; however, the adsorption was not significantly inhibited by ulinastatin. Furthermore, IL-1ra release was augmented by the addition of a high dose of ulinastatin or PD98059 as compared to a low dose. The activation levels of extracellular signal-regulated protein kinase may regulate IL-1ra release induced by the carrier, because both ulinastatin and PD98059 inhibit extracellular signal-regulated protein kinase. High concentrations of ulinastatin increased IL-1ra release without inhibiting granulocyte adsorption to cellulose acetate beads. This result warrants clinical trials of a combination of ulinastatin and GMA for the treatment of ulcerative colitis.     

Conivaptan: A Dual Receptor Vasopressin V1a/V2 Antagonist

Several fluid retentive states such as heart failure, cirrhosis of the liver, and syndrome of inappropriate antidiuretic hormone secretion are associated with inappropriate elevation in plasma levels of arginine vasopressin (AVP), a neuropeptide that is secreted by the hypothalamus and plays a critical role in the regulation of serum osmolality and in circulatory homeostasis. The actions of AVP are mediated by three receptor subtypes V_1a, V₂, and V_1b. The V_1a receptor regulates vasodilation and cellular hypertrophy while the V₂ receptor regulates free water excretion. The V_1b receptor regulates adrenocorticotropin hormone release. Conivaptan is a nonpeptide dual V_1a/V₂ AVP receptor antagonist. It binds with high affinity, competitively, and reversibly to the V_1a/V₂ receptor subtypes; its antagonistic effect is concentration dependent. It inhibits CYP3A4 liver enzyme and elevates plasma levels of other drugs metabolized by this enzyme. It is approved only for short-term intravenous use. Infusion site reaction is the most common reason for discontinuation of the drug. In animals conivaptan increased urine volume and free water clearance. In heart failure models it improved hemodynamic parameters and free water excretion. Conivaptan has been shown to correct hyponatremia in euvolemic or hypervolemic patients. Its efficacy and safety for short-term use have led to the Food and Drug Administration (FDA) approval of its intravenous form for the correction of hyponatremia in euvolemic and hypervolemic states. Despite its ability to block the action of AVP on V_1a receptors, no demonstrable benefit from this action was noted in patients with chronic compensated heart failure and it is not approved for this indication. Consideration should be given to further evaluation of its potential benefits in patients with acute decompensated heart failure.     

Cytokinins: Development of a Potent Antagonist

A systematic search has resulted in the synthesis of a class of cytokinin antimetabolites. The development and biological properties of the anticytokinins are discussed in terms of one member of the class, 3- methyl - 7 - (3 - methylbutylamino)pyrazolo[4,3 - d]- pyrimidine.     

Methylation of Cytosine Residues in DNA Controlled by a Drug Resistance Factor

The proportion of 5-methylcytosine (5MeCyt) and 6-methylaminopurine (N⁶-methyladenine, 6MeAde) in bacteriophage P22 DNA was analyzed as a function of the host-specificity the phage carried. In the DNA of P22 grown in strains harboring the modifying drug-resistance-transfer-factor N-3, the 5MeCyt content was at least twice that after growth in strains lacking the factor. In contrast, the 6MeAde level of P22 DNA was unaffected by the presence or absence of the factor. The 6MeAde and 5MeCyt levels were unaffected by factors 222 and N-1, which do not modify phage DNA.     

Nonvirion Antigens Produced by Herpes Simplex Viruses 1 and 2

Of nine herpes simplex virus 1 strains (from lip, mouth, throat, cornea, or brain) only five produced enough nonvirion antigen (i.e., not a structural component of the virus) to be detected by complement fixation with specially prepared, virion-absorbed, type-1 guinea pig antisera, while the remaining four strains produced only enough of the same antigen to induce specific antibody in hyperimmunized guinea pigs. While the type 1 virion antiserum used reacted equally well by complement fixation with the type 1 and type 2 strains, the type 1 nonvirion antisera failed to react with nonvirion antigens produced by three type-2 (genital) strains. However, type 2 nonvirion antiserum reacted equally well with the three type 2 and four type 1 nonvirion antigens that were tested. It appears, therefore, that while herpes simplex virus 1 codes only for type 1 nonvirion antigen, herpes simplex 2 codes not only for an immunologically distinct type 2 nonvirion antigen but also for enough type 1 nonvirion antigen to stimulate antibody production for it.Herpes simplex 2 nonvirion antigen exhibited the same properties as type 1, i.e., its activity was lost on storage at 4 degrees for 15 days, it was sedimented by centrifugation at 33,360 x g for 1 hr, and the maximum concentration was found at 3 hr in guinea pig kidney culture cells, but at 24 hr in HEp 2 and rabbit kidney culture cells. Sera from patients with genital lesions caused by herpes simplex virus 2, as well as from randomly selected adults, failed to react with either type 2 or type 1 nonvirion antigens. Accordingly, the basic information is now available to permit the use of these nonvirion antigens to determine the possible role of the herpes simplex viruses in certain human cancers.     

Early Afterdepolarizations Produced by d,1-Sotalol and Clofilium

EAD Formation by Class III Drugs. Introduction: The roles for L-type calcium current and Na-Ca exchange in early afterdepolarizations (EADs) attending d, l-sotalol and clofilium were examined in canine Purkinje fibers and in enzymatically dispersed myocytes from canine subepicardium. Methods and Results: Spontaneous EADs were compared to EAD formation potentiated by stimulation of Na-Ca exchange and facilitation of I_Ca-L (Bay K8644). Bay K8644 (10^-8 M) and stimulation of Na-Ca exchange potentiated bradycardia-dependent EADs. Stimulation of Na-Ca exchange in Pnrkinje fibers pretreated with d, l-sotalol (10^-5 M) and clofilium (10^-7 M) induced EADs at takeoff potentials negative (-63 ± 4 and -62 ± 4 mV, respectively) to EADs potentiated by Bay K8644 (10^-8 M) (-33 ± 2 and -34 ± 2 mV, respectively, P < 0.05), or EADs induced by Bay K8644 alone (10^-6 M) (-31 ± 5 mV). In myocytes, Bay K8644 (10^-8 M) potentiated EADs in d, l-sotalol- (10^-6 to 10^-4M) or clofilium-treated (10^-9 to 10^-7 M) cells at reduced potentials (-10 ± 3 and -10 ± 4 mV, respectively) compared to EADs elicited by clofilium or d, l-sotalol alone (-25 ± 3 and -24 ± 3 mV, respectively), or stimulation of Na-Ca exchange in the presence of d, l-sotalol or clofilium (-26 ± 4 and -26 ± 4 mV, respectively). Spontaneous EADs or EADs elicited by stimulation of Na-Ca exchange coincident with drug treatment were suppressed by increasing Ca_o²⁺ but were not suppressed by nifedipine (10^-7 M). Conclusion: EADs elicited by d, l-sotalol and clolllium in canine Purkinje tissue and epicardial myocytes are dependent upon Na-Ca excbange rather than I_Ca-L“window current.”     

Development of Monocrotaline-Induced Pulmonary Hypertension Is Attenuated by a Serotonin Receptor Antagonist

The significance of serotonin in the pathogenesis of monocrotaline-induced pulmonary hypertension (MCT-PH) in rats, plasma serotonin concentrations, and the effect of a serotonin receptor antagonist administration in association with the number of proliferative cells were investigated. The thickness of the media of the small pulmonary arteries and the weight ratio of the RV to that of LV + S (RV/[LV + S] weight ratio) were used as indices of the severity of PH. Plasma serotonin concentrations were measured by high-performance liquid chromatography. Histopathologic analysis of the lung tissue was performed by hematoxylin-eosin and elastin van Gieson staining. Immunohistopathologic staining for proliferating cell nuclear antigen (PCNA) was performed to identify proliferative cells. The severity of PH as determined by the medial thickness of the small pulmonary arteries and RV/(LV + S) weight ratio in rats with MCT-PH was significantly reduced after treatment with MCI-9042 (p < 0.01 and p < 0.05, respectively). The serotonin concentration was significantly greater in MCT-PH rats than in normal control rats (p < 0.05). The scores for histopathologic changes, such as thickening of the alveolar walls and interstitial inflammatory cell infiltration in MCT-PH rats, were significantly reduced after treatment with MCI-9042 (p < 0.05 and p < 0.01, respectively). The number of PCNA-positive cells was significantly greater in MCT-PH rats than in normal control rats (p < 0.0001) and was reduced after treatment with MCI-9042 (p < 0.0001). Treatment with MCI-9042 significantly inhibited the development of MCT-PH along with a decrease in the number of PCNA-positive cells, suggesting a pivotal role of serotonin in the development of PH induced by MCT. Accepted for publication: 10 November 1999     

血管紧张素Ⅱ1型受体拮抗剂与醛固酮受体拮抗剂对逆转高血压大鼠心肌重塑的作用

在受体水平阻断肾素—血管紧张素系统 ,比较血管紧张素Ⅱ 1型受体拮抗剂与醛固酮受体拮抗剂对逆转高血压心肌重塑的作用 ,来探讨高血压性心肌重塑的可能机理。为此 ,制作二肾一夹型高血压大鼠模型形成心肌肥厚及纤维化 ,然后分成高血压对照组、缬沙坦组 [10 μg (kg·d) ]和螺内酯组 [4 0mg (kg·d) ]。分别观察给药前、给药后 4周和 12周血浆及心肌血管紧张素Ⅱ和醛固酮含量、左心室重量指数、心肌胶原含量、心肌胶原容积分数及Ⅰ、Ⅲ型胶原的病理特征。结果发现 ,与高血压对照组比较 ,缬沙坦组左心室重量指数、心肌胶原含量和心肌胶原容积分数显著下降 (P <0 .0 5 ) ,以降低Ⅰ型胶原沉积为主 ;螺内酯组左心室重量指数、心肌胶原含量和心肌胶原容积分数亦有所下降 (P <0 .0 5 ) ,以降低Ⅲ型胶原沉积为主 ,但作用不如缬沙坦。结果提示 ,左心室肥厚发展过程与心肌纤维化存在异时性。血管紧张素Ⅱ和醛固酮在心肌重塑过程中起关键作用 ,血管紧张素Ⅱ 1型受体可能主要介导Ⅰ型胶原的沉积 ,而醛固酮受体可能主要介导Ⅲ型胶原的沉积。     

Both a Calcium Antagonist and ACE Inhibitor Reverse Hypertrophy in Hypertension But a Calcium Antagonist also Depresses Contractility

The aim of this study was to compare the effects of a calcium antagonist, nicardipine SR, with an angiotensin-converting enzyme (ACE) inhibitor, alacepril, on the regression of left ventricular hypertrophy (LVH) and function. Twenty patients with LVH, aged 42–73 years, were treated with nicardipine SR or alacepril. Ten patients were treated with nicardipine SR (40–80 mg) for 21 months, and the other 10 patients were treated with alacepril (25–100 mg) for 18 months. All patients underwent echocardiography to assess left ventricular structure and function before and after the treatment. After nicardipine SR or alacepril treatment, blood pressure was decreased significantly from 176.0 ± 13.9/97.0 ± 5.3 mmHg to 140.0 ± 14.0/77.4 ± 7.2 mmHg and from 168.2 ± 22.3/99.0 ± 5.5 mmHg to 138.4 ± 12.5/85.2 ± 9.7 mmHg, respectively (both p < 0.01), whereas heart rate did not change (73.8 ± 14.6 beats/min vs. 69.9 ± 13.5 beats/min and 71.6 ± 9.7 vs. 65.8 ± 8.1 beats/min, respectively). The left ventricular mass index decreased significantly from 133.2 ± 11.7 g/m2 to 114.4 ± 15.7 g/m2 with nicardipine SR and from 137.1 ± 14.8 g/m2 to 99.3 ± 23.0 g/m2 with alacepril (both p < 0.01). The fractional shortening, peak shortening rate, and peak lengthening rate all improved significantly after each treatment. The end-systolic wall stress/left ventricular end-systolic volume index, as an index of left ventricular contractility, was decreased significantly after treatment with nicardipine SR but was not changed after treatment with alacepril. In conclusion, both nicardipine SR and alacepril similarly reduced LVH and improved left ventricular systolic and diastolic function. However, alacepril did not alter left ventricular contractility, whereas nicardi-pine SR decreased left ventricular contractility.