Some reactions of 1,4-dihydropyridines with organic azides. Synthesis of 2,7-diazabicyclo[4.1.0]hept-3-enes with analgesic and antiprotozoal activity.

The 1,3-dipolar cycloaddition reaction of 1,4-dihydropyridines, 2, with organic azides, 3, afford 2,7-diazabicyclo[4.1.0]hept-3-enes, 4, which exhibit significant analgesic and antiprotozoal activities. The most active analgesics, 4a and 4c, were more potent than aspirin or dextropropoxyphene. Diazabicyclo[4.1.0]hept-3-enes 4a-e exert potent antiprotozoal activity, inhibiting growth of Trichomonas vaginalis at concentrations of less than 10 micrograms/mL of medium. The broad spectrum pharmacological screen also revealed moderate hypoglycemic (4a), antiinflammatory (4c), antidepressant (4d and 4e) and antihistaminic (4f) activities.

NaCl-induced hypertensive rat model of non-insulin-dependent diabetes: role of sympathetic modulation.

Systemic hypertension is common in individuals with non-insulin-dependent diabetes (NIDD) and, in this population, markedly increases the risk for cardiovascular complications. The aims of this study were to develop a rat model of combined NaCl-induced hypertension and NIDD, and to determine the contribution of the sympathetic nervous system to the development of the manifest hypertension. Two-day old male Wistar-Kyoto rats were injected with either streptozotocin (90 mg/kg, ip; NIDD) or vehicle (citrate buffer; control). At 4 weeks of age, the animals underwent either a right nephrectomy or a sham operation. Animals in each group were further subdivided, with one group maintained on normal (0.72 %) NaCl diet whereas the other was placed on a high (8%)-NaCl diet. At 6 months of age, diabetes was confirmed by glucose tolerance testing. Hemodynamic parameters were measured in the freely moving animal (ia) before and after the administration of prazosin (peripheral alpha1-adrenergic antagonist, iv) or clonidine (central alpha2-adrenergic agonist). The NIDD rat displayed a higher (P < .05) blood glucose concentration than the nondiabetic control rat during the glucose tolerance test. Elevated dietary NaCl significantly increased mean arterial pressure (MAP) in the uninephrectomized, but not the sham-operated groups. Acute administration of prazosin resulted in a significantly greater reduction in MAP of both hypertensive groups than of their normotensive counterparts. Moreover, clonidine caused a significant reduction in MAP of the hypertensive control rat but not in the normotensive controls. By contrast, both the hypertensive NIDD and the normotensive NIDD rats showed a similar reduction in MAP in response to clonidine administration. The data suggest that the combination of uninephrectomy and dietary NaCl excess confers hypertension on the NIDD rat. Moreover, enhancement of the sympathetic pathway plays an important role in the regulation of arterial pressure in the hypertensive NIDD rat.

Renal function in the noninsulin-dependent diabetic rat: effects of unilateral nephrectomy.

A new model of noninsulin-dependent diabetic (NIDD) is described which exhibits more prominent defects in renal function than does the standard neonatal NIDD model. To produce this model, 2-day-old neonatal male Wistar Kyoto (WKY) rats were injected intraperitoneally with streptozotocin (90 mg/kg; NIDD), while their corresponding nondiabetic controls were administered vehicle (citrate buffer, pH: 4.5; control). At 3 weeks of age, the animals were weaned, and 1 week later, under ether anesthesia, the animals underwent a right nephrectomy or a sham operation. Diabetes was confirmed by intraperitoneal administration of a glucose load (2g/kg), which resulted in significantly higher blood glucose concentration in the NIDD, compared to the nondiabetic rats. Surgical reduction of renal mass had no effect on the glycemic response to a glucose tolerance test in either group. Intravenous administration of an isotonic saline load resulted in a similar pattern of enhanced sodium and fluid excretion in the two-kidney sham-operated nondiabetic and NIDD rats. These responses were significantly higher than those observed in their counterparts with one remaining kidney. Yet, the natriuretic and diuretic responses to the saline load were significantly lower in the nephrectomized NIDD, compared to the nephrectomized nondiabetic rats. The glomerular filtration rate was similar in the sham-operated (two kidneys) NIDD and nondiabetic rats. In contrast, both the basal and saline-stimulated glomerular filtration rate were lower in the nephrectomized NIDD rats compared to the nephrectomized nondiabetic group. Mean arterial pressure was similar between the two nephrectomized groups, thereby ruling out a significant contribution from the pressure-diuresis-natriuresis mechanism to the reduction in sodium and fluid excretion in the nephrectomized NIDD rats. Thus, unilateral nephrectomy is an effective method of accelerating the manifestation of NIDD-related renal alterations. The mild, but progressive, nature of diabetes in this model should facilitate the investigation of temporal changes in renal function in NIDDM.

Effects of inorganic fluoride on renal excretion of fluid and sodium in diabetic rats.

The hypothesis that the diabetic rat is more susceptible to the adverse renal effects (i.e., urine concentrating defect) of inorganic fluoride was tested by comparing fluid and sodium excretion rates in nondiabetic and diabetic rats before and after fluoride administration. Male Fischer 344 rats were injected with either vehicle (0.1 M citrate buffer, i.v.) or streptozotocin (55 mg/kg body weight). Renal excretions of fluid and sodium were determined in conscious animals following administration (i.v.) of a saline volume load containing or lacking inorganic fluoride (0.2 mg/ml). To examine the effect of fluoride without the contribution of a saline load, renal excretions of fluid and sodium were determined following a gradual, graded elevation in plasma fluoride concentration. The natriuretic and diuretic responses to an isotonic saline load were similar between the groups prior to and after fluoride administration. Graded elevations in the fluoride concentration of plasma mediated a slight increase in fluid and sodium excretion in the control rat while the treatment protocol led to a reduction in fluid excretion and an increase in the sodium excretion in the diabetic rat. As a result, the ratio of sodium/fluid excretion following fluoride administration was significantly higher in the diabetic compared to the control rat. These results suggest a differential effect of inorganic fluoride on the renal excretion of sodium and fluid between the nondiabetic and diabetic rat.

Renal adenosine A3 receptors in the rat: assessment of functional role.

The functional roles of adenosine A3 receptors in the rat kidney were assessed for the first time with respect to A1 receptor-mediated responses. Utilizing a chronically instrumented conscious rat preparation, we tested renal excretory responses to acute administration of the A3 receptor antagonists 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1 ,4-(+)-dihydropridine-3,5-dicarboxylate (MRS-1191) and 9-chloro-2-(2-furyl)-5-phenylacetylamino-[1,2,4]-triazolo[1,5-c]qu inazoline (MRS-1220) with reference to the effects of the A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The intravenous administration of DPCPX resulted in significant increases in fluid and sodium excretions without affecting glomerular filtration rate (GFR). This suggests that DPCPX-induced diuretic and natriuretic responses are related to decreased tubular reabsorption. However, neither MRS-1191 nor MRS-1220 alone affected fluid or sodium excretions, or GFR, indicating lack of an effect of either compound on renal function. On the other hand, the co-administration of MRS-1220 with DPCPX abolished both the diuretic and natriuretic responses to DPCPX, being suggestive of antagonism between these two compounds. MRS-1191, however, did not affect the DPCPX-induced fluid and sodium excretions. Neither the A1 nor the A3 receptor antagonists altered potassium excretion individually or in combination. The data suggest that while adenosine A1 receptors are involved in the regulation of renal fluid and sodium transport, A3 receptors do not appear to have a major role in regulation of renal excretory function under baseline physiological conditions.

Renal excretory responses of taurine-depleted rats to hypotonic and hypertonic saline infusion.

Male Wistar-Kyoto rats were given either tap water (control) or 3% beta-alanine (taurine-depleted) for three weeks. To prepare for the kidney function studies, the animals were then implanted with femoral vessels and bladder catheters. Two days after surgery, each rat was given an intravenous infusion of saline at the rate of 50 microliter/min and urine samples were collected at specific time intervals. An isotonic saline solution (0.9% NaCl) was infused for determination of baseline parameters and was followed by the infusion of a hypotonic saline solution (0.45% NaCl). Two days later, the infusion protocol was repeated in the same animals; however, a hypertonic saline solution (1.8% NaCl) was substituted for the hypotonic saline solution. Renal excretion of fluid and sodium increased in the control, but not taurine-depleted, rats during the hypotonic saline infusion. Interestingly, diuretic and natriuretic responses were similar between the groups during hypertonic saline infusion. The results suggest that taurine-depletion in rats affects renal excretory responses to a hypotonic, but not a hypertonic, saline solution.