Metabolic and hemodynamic effects of moxonidine in the Zucker diabetic fatty rat model of type 2 diabetes.

We studied the effect of moxonidine, an imidazoline ligand, on metabolic and hemodynamic parameters in Zucker diabetic fatty rats, a model of type 2 diabetes. In one group (metabolic group), 8-week-old rats were started on a diet containing either moxonidine (3 or 10 mg x kg(-1) x day(-1)) or vehicle for 4 weeks. Body weight and food intake were monitored daily, plasma insulin and glucose were monitored weekly, and an oral glucose tolerance test (OGTT) was performed at study's end. In another group of rats (hemodynamic group), radio frequency transmitters were implanted 1 week before starting the diet, and mean blood pressure, heart rate, and motor activity were continuously monitored at baseline and for 4 weeks after beginning drug exposure. Moxonidine (10 mg x kg(-1) x day(-1)) significantly decreased elevated glucose levels and prevented the decrease in plasma insulin noted in vehicle-treated or pair-fed groups. Moxonidine also decreased fasting glucose (3 and 10 mg x kg(-1) x day(-1)) and prevented the decrease in fasting insulin (10 mg x kg(-1) x day(-1)) compared with vehicle. Fasting glucose at 10 mg x kg(-1) x day(-1) was equivalent to lean littermates. Both doses significantly increased glucose disposal and the insulin secretory response during the OGTT. Moxonidine lowered daily mean arterial pressure compared with both baseline values and vehicle and decreased daily heart rates. Motor activity was unaffected, except for an increase in the 10 mg x kg(-1) x day(-1) group during low activity periods. Moxonidine did not significantly affect body weight, fluid intake, or urine volume, but the 10 mg x kg(-1) x day(-1) dose reduced urinary protein excretion compared with vehicle-treated animals. These results demonstrate that, in an animal model of type 2 diabetes, the antihypertensive agent moxonidine induces a beneficial effect on abnormal glucose metabolism and renal protein excretion at doses that are effective in lowering arterial blood pressures and heart rate.

Recurrent urethral obstruction secondary to idiopathic renal hematuria in a puppy.

A seven-month-old, neutered male Catahoula leopard dog cross was presented for recurrent urethral obstruction and intermittent hematuria. After exploratory laparotomy and ventral cystotomy, unilateral idiopathic renal hematuria was diagnosed based on gross observation of hematuria from the left ureteral catheter. The hematuria resolved after nephrectomy of the left kidney. The histopathological diagnosis was multifocal, acute congestion and intratubular hemorrhage. Although idiopathic renal hematuria has been described previously, this puppy was unique because the hematuria caused recurrent, complete urethral obstruction.

Differential effects of stress-induced adrenal function on components of the herpes simplex virus-specific memory cytotoxic T-lymphocyte response.

We have previously demonstrated in a murine model system that psychological stress, applied in the form of physical restraint, suppresses both the activation of splenic-derived, herpes simplex virus (HSV)-specific memory cytotoxic T-lymphocytes (CTLm) to the lytic phenotype and the production of cytokines associated with CTL activation and function. In the studies described herein, we investigated the hypothesis that an adrenal-dependent event is responsible, either in whole or in part, for these observations. While adrenalectomy was shown to abrogate stress-induced suppression of both HSV-specific CTLm activation and the production of IL-6 and IFN-gamma, the reduction in splenic cellularity associated with restraint stress remained, In addition, a role for adrenal function in the regulation of splenic cellularity and IFN-gamma production in non-stressed mice was observed. Together, these results indicate that both adrenal-dependent and adrenal-independent events, operative under both baseline and stress conditions, mediate control of the memory component of the cellular immune response to HSV infection. Overall, these studies provide insight into the mechanisms by which psychological stress modulates immune responsiveness to viral pathogens.

Structural evolution and pharmacology of a novel series of triacid angiotensin II receptor antagonists.

cis-4-(4-Phenoxy)-1-[1-oxo-2(R)-[4-[(2-sulfobenzoyl)amino)-1H- imidazol-1-yl]octyl]-L-proline derivatives represent a novel class of potent nonpeptide angiotensin II (Ang II) receptor antagonists. These compounds evolved from directed structure-activity relationship (SAR) studies on a lead identified by random screening. Further SAR studies revealed that acidic modification of the 4-phenoxy ring system produced a series of triacid derivatives possessing oral activity in pithed rats. The most potent compound, cis-4-[4-(phosphonomethyl)phenoxy]-1-[1-oxo-2(R)-[4-[(2-sulfobenzoyl+ ++) amino]-1H-imidazol-1-yl]octyl]-L-proline (1e), inhibited the pressor response to exogenously administered Ang II for periods up to 8 h following oral dosing. The antihypertensive activity of 1e was evaluated in the Lasix-pretreated conscious spontaneously hypertensive rat (SHR) where it produced a dose-dependent fall in blood pressure following oral dosing lasting > 12 h. Antagonists such as 1e may serve as useful therapeutic agents for the treatment of hypertension as well as for studying the role of Ang II in various disease states.

Dissociation between the detection and perception of motion in Alzheimer's disease.

To better understand the damage to the motion pathway that occurs in senile dementia of the Alzheimer type (SDAT), we developed a system to assess separately the conscious perception and unconscious detection of motion in patients with SDAT. Motion perception thresholds were significantly elevated in SDAT (n = 9) compared with controls (n = 12), but motion detection thresholds were normal. This dissociation between the perception and detection of motion in early SDAT parallels histologic evidence of a disconnection between primary and association visual cortices. This disconnection may underlie the severe visual perception deficits seen in SDAT.

Refractive changes induced by electrocautery of the rabbit anterior lens capsule.

The pathologic basis for presbyopia is classically attributed to lenticular sclerosis or atrophy of the ciliary muscle, but recent work suggests that thickening and loss of elasticity of the anterior lens capsule play an important role. As no practical means for attenuating or reversing the aging process of lens protein has been identified, alteration of the lens capsule eventually might prove to be a desirable alternative to spectacle correction in presbyopic individuals. This paper describes changes in the refractive properties of the lens resulting from alteration of the anterior lens capsule by application of focal cautery, using both an in vitro, in situ and an in vivo rabbit model. In vitro thermal treatment (electrocautery) of the capsule significantly increased the anterior curvature of the lens by an average of +2.95 diopters. Histologic examination of the treated lenses showed thinning of the capsule in the treated areas, as well as focal vacuolar degeneration in the lens substance beneath the lesions. In vivo thermal treatment of eyes induced a significant shift toward myopia, compared with control eyes. The accommodative range increased post-treatment relative to the controls, but the effect diminished over time, stabilizing near baseline at two to three weeks after treatment. Histologic examination showed localized changes but no signs of diffuse cataract formation. We conclude that the anterior capsule may play a significant role in the refractive power and accommodative changes in the crystalline lens.(ABSTRACT TRUNCATED AT 250 WORDS)

Chiral recognition of pinacidil and its 3-pyridyl isomer by canine cardiac and smooth muscle: antagonism by sulfonylureas.

Pinacidil, a potassium channel opener (PCO), relaxes vascular smooth muscle by increasing potassium ion membrane conductance, thereby causing membrane hyperpolarization. PCOs also act on cardiac muscle to decrease action potential duration (APD) selectively. To examine the enantiomeric selectivity of pinacidil, the stereoisomers of pinacidil (a 4-pyridylcyanoguanidine) and its 3-pyridyl isomer (LY222675) were synthesized and studied in canine Purkinje fibers and cephalic veins. The (-)-enantiomers of both pinacidil and LY222675 were more potent in relaxing phenylephrine-contracted cephalic veins and decreasing APD than were their corresponding (+)-enantiomers. The EC50 values for (-)-pinacidil and (-)-LY222675 in relaxing cephalic veins were 0.44 and 0.09 microM, respectively. In decreasing APD, the EC50 values were 3.2 microM for (-)-pinacidil and 0.43 microM for (-)-LY222675. The eudismic ratio was greater for the 3-pyridyl isomer than for pinacidil in both cardiac (71 vs. 22) and vascular (53 vs. 17) tissues. (-)-LY222675 and (-)-pinacidil (0.1-30 microM) also increased 86Rb efflux from cephalic veins to a greater extent than did their respective optical antipodes. The antidiabetic sulfonylurea, glyburide (1-30 microM), shifted the vascular concentration-response curve of (-)-pinacidil to the right by a similar extent at each inhibitor concentration. Glipizide also antagonized the response to (-)-pinacidil, but was about 1/10 as potent with a maximal shift occurring at 10 and 30 microM. Glyburide antagonized the vascular relaxant effects of 0.3 microM (-)-LY222675 (EC50, 2.3 microM) and reversed the decrease in APD caused by 3 microM (-)-LY222675 (EC50, 1.9 microM). Nitroprusside did not alter 86Rb efflux, and vascular relaxation induced by sodium nitroprusside was unaffected by sulfonylureas. Thus, the enantiomers of the 3-pyridyl isomer of pinacidil demonstrate enhanced stereospecificity in both canine cardiac and vascular tissues compared to the enantiomers of pinacidil. However, the relative selectivity of pinacidil and its 3-pyridyl isomer for cardiac and vascular smooth muscle remains unaltered. Sulfonylureas antagonize the more potent enantiomers in both tissues, supporting the involvement of an ATP-sensitive potassium channel in the action of PCOs; however, antagonism in canine vascular smooth muscle by sulfonylureas does not resemble classical competitive antagonism.

Losartan, a nonpeptide angiotensin II (Ang II) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteries.

Angiotensin-converting enzyme inhibitors have been shown to inhibit intimal thickening following balloon catheterization of rat carotid arteries. To assess the role of the renin-angiotensin pathway and the angiotensin type-I (AT1) receptor in this effect, the nonpeptide Ang II antagonist losartan (DuP 753) or vehicle was infused continuously i.v. in rats from two days before to two weeks after balloon injury to the left common carotid artery; drug effects upon intimal thickening were examined histologically. Losartan produced a dose-dependent reduction in cross-sectional area of intimal lesions determined two weeks post balloon injury. At 5 mg/kg/day a nonsignificant 23% reduction of intimal area was observed. At the higher dose of 15 mg/kg/day, losartan produced a 48% reduction in intimal area (P less than 0.05) compared to the vehicle-infused group. The cellular density of the neointima was not affected by losartan, indicating a probable effect of the drug upon migration and/or proliferation of smooth muscle cells. In separate groups of non-ballooned rats, losartan infusions of 5 and 15 mg/kg/day produced significant rightward shifts (averaging 6.4- and 55-fold, respectively) in curves relating increases in blood pressure to intravenous Ang II in pithed rats determined between 2 and 16 days following initiation of losartan infusion. Mean arterial blood pressure (determined under alpha-chloralose anesthesia) was reduced following continuous losartan infusion for 6 days from 128 +/- 8 mm Hg (vehicle) to 105 +/- 8 mm Hg at 5 mg/kg/day (P less than 0.05), and 106 +/- 4 mm Hg at 15 mg/kg/day (P less than 0.05). Thus, losartan attenuated the vascular response to balloon catheter injury, and this effect was associated with functional block of vascular AT1 receptors. The results support a role for Ang II, acting via AT1 receptors, in myointimal thickening subsequent to balloon injury of rat carotid arteries.

How Do Temperature and Salinity Affect Relative Rates of Growth, Morphological Differentiation, and Time to Metamorphic Competence in Larvae of the Marine Gastropod Crepidula plana?

The influence of environmental conditions on rates of larval growth has been documented many times for various marine mollusks. But the factors that influence rates of morphological and physiological differentiation, particularly the rate at which larvae within a population become competent to metamorphose, remain obscure. In four experiments, we reared larvae of the gastropod Crepidula plana at 29°C, 25°C, and 20°C at 30 ppt salinity, and in two other experiments, in salinities between 4-30 ppt at 25°C. Rates of shell growth and morphological differentiation, and rates of becoming competent within populations were recorded. Larvae were considered to be competent to metamorphose if they could be stimulated to metamorphose by exposure to a high concentration of KCl (20 mM above ambient). Larvae consistently became competent faster at higher temperatures, but in only one of four experiments did temperature also consistently increase the rates of growth and morphological differentiation. Larvae took longer to become competent when reared at lower salinities, but the effects were poorly predicted by the influence of salinity on rates of growth and morphological differentiation. Competent larvae could also not be recognized by shell length; many individuals were competent at shell lengths of 600-800 µm, while many other individuals were still not competent at sizes exceeding 1000 µm. At 29°C, many individuals became competent at smaller sizes than those reared at lower temperatures. Presence of gill filaments or shell brims also did not correlate with individual metamorphic competence. The data suggest that growth rate, rate of morphological differentiation, and time required for larvae of C. plana to become competent can be uncoupled markedly by shifts in rearing conditions.

LY249933: a cardioselective 1,4-dihydropyridine with positive inotropic activity.

Compound LY249933 and its component diastereomers, (RR) and (SR), were studied for their vascular and cardiac effects in vitro and in vivo. In guinea pig cardiac ventricular membranes, LY249933, (RR), and (SR) potently displaced bound [3H]nitrendipine (Kd values = 2-6 nM). In isolated guinea pig right ventricular strips, LY249933 produced a small but significant increase in contraction, whereas (RR) substantially increased (-log EC50 (M) = 4.6 +/- 0.8) and (SR) decreased contraction (-log EC50 (M) = 4.1 +/- 0.8). In isolated canine cephalic vein, contracted with 80 mM KCl, an increase in contraction was produced by (RR), whereas relaxation was produced by LY249933 (-log EC50 (M) = 5.9 +/- 0.9) and (SR) (-log EC50 (M) = 6.0 +/- 0.7). At 20 mM KCl, (RR) increased, (SR) decreased, but LY249933 did not alter contraction. In anesthetized dogs, LY249933 (200 micrograms/kg/min, i.v.) increased dP/dt60, decreased heart rate, but did not change vascular resistance or rate pressure product. At the same dose, (RR) and (SR) both tended to increase dP/dt60 nonsignificantly, whereas (RR) increased and (SR) decreased vascular resistance. Both (RR) and (SR) tended to decrease heart rate nonsignificantly, whereas (RR) did not change and (SR) decreased rate pressure product. Thus, LY249933 produced potentially beneficial cardiovascular changes resulting from the combined actions of its (RR) and (SR) diastereomers that are postulated to be calcium agonist and antagonist, respectively.