Preclinical enantioselective pharmacology of (R)- and (S)- ketorolac.

Many of the nonsteroidal anti-inflammatory drugs (NSAIDs) are marketed as racemic mixtures, composed of (R)- and (S)- enantiomers. Racemic NSAIDs are potent cyclooxygenase (COX) inhibitors only through the action of the (S)- enantiomers, as the (R)- enantiomers do not exhibit COX inhibition. However, the (R)- enantiomer of ketoprofen exhibits potent analgesic activity and minimal ulcerogenic potential.

Differences in beta 3-adrenergic receptor cardiovascular regulation in conscious primates, rats and dogs.

The goal of our study was to compare the effects of two beta 3-adrenergic receptor agonists, i.e., BRL37344 (BRL) and CL316243 (CL), in conscious dogs, rats and nonhuman primates, instrumented with aortic and atrial catheters, ascending aortic flow probes and left ventricular (LV) pressure gauges.

Depolarization-induced 86Rb+ efflux in CHO cells expressing a recombinant potassium channel.

Cells expressing a recombinant human voltage-activated potassium channel (K-channel), Kv1.5, have been used in a functional assay that measures depolarization-stimulated 86Rb+ efflux as an indicator of K-channel function. Neither untransfected nor vector-transfected cells display measurable 86Rb+ efflux under depolarizing conditions.

Identification and characterization of angiotensin II receptors in rat epididymal adipocyte membranes.

To better understand the role of the mitogenic vasoactive peptide angiotensin II (AII) in growth and differentiation, we have investigated the existence of membrane receptors for this peptide in rat adipocytes. Following isolation of epididymal fat cells, membrane protein was removed and incubated with varying concentrations of 125I-AII with or without submicromolar concentrations of unlabeled AII. Binding of AII was highly specific, rapid, and reversible.

Transforming growth factor alpha and atrial natriuretic peptide in white adipose tissue depots in rats.

To detect the presence in adipose tissue of peptides known to affect tissue growth and to investigate potential regional differences, epididymal and perirenal adipose tissue depots from male Sprague-Dawley rats were separated into adipocyte and stroma-vascular fractions by collagenase digestion, sequential centrifugation and filtration. Identity and integrity of the fractions were demonstrated by light and electron microscopy, while dose-response curves for angiotensin-converting enzyme (ACE) were performed, revealing maintained functional capacity of the stroma-vascular fraction. ACE, atrial natriuretic peptide (ANP), and transforming growth factor-alpha (TGF-alpha) concentrations were significantly greater in epididymal than perirenal stroma-vascular tissue.

Relationship of cardiac hemodynamic and biochemical adaptations to mortality during long-term aortic constriction.

To determine the biochemical and hemodynamic responses to aortic ligation, and to assess the survival rate after the induction of hypertension, 90 normotensive rats were subjected to surgical constriction of the abdominal aorta. Mortality, left ventricular hemodynamics, myocardial biochemical assays, and plasma renin assays were determined 1 week, 1 month, 3 months, or 1 year later. Mortality was greatest between 1 week and 3 months after aortic ligation, during which plasma renin activity was significantly elevated.

Characterization of serotonin receptors in isolated rat intramyocardial coronary artery.

The purpose of the present study was to characterize the receptor subtypes that mediate serotonin (5-HT)-induced contraction in isolated rat intramyocardial coronary artery. In coronary artery with and without endothelium, only 5-HT and alpha-methylserotonin maleate (5-HT2 agonist) elicited equipotent concentration-dependent contractions. The EC50 values for 5-HT and alpha-methylserotonin maleate in endothelium-intact arteries were 4.

Effect of experimental obesity and subsequent weight reduction upon circulating atrial natriuretic peptide.

The effect of obesity and weight reduction upon circulating concentrations of atrial natriuretic peptide was assessed in an experimental model of the disease. Obese rats weighing in excess of 750 g were compared with formerly obese animals subjected to a 15-week period of caloric restriction resulting in a 40% reduction in body weight. Mean adipocyte size was significantly reduced with weight loss, as was estimated body fat.

Cardiovascular effects of intermittent drinking: assessment of a novel animal model of human alcoholism.

The development of a novel model of human alcoholism has involved the presentation of a 30% alcohol solution to Sprague-Dawley rats via a syringe-feeding needle apparatus. With twice daily intermittent drinking, rats consumed an equivalent of 7-8 g/kg body weight of alcohol, which represented 25% of total daily caloric intake. Alcohol was absorbed rapidly, as significant circulating concentrations were observed within 15 min of gavage, eventually peaking at approximately 200 mg% 1 h later.

Endothelium-dependent basilar and aortic vascular responses in normotensive and coarctation hypertensive rats.

The responsiveness of acetylcholine (ACh), nitroglycerin (NG) and norepinephrine (NE) (aorta only) in both basilar arteries (BA) and thoracic aortic (TA) rings from coarctation hypertensive rats (CHR) were studied and compared to their sham-operated normotensive control rats (SNR). The effects of these agents were also evaluated in TA or BA with and without endothelium from naive normotensive rats (NNR). Blood pressure (BP) and plasma renin activity (PRA) of CHR were significantly higher than their time-matched SNR.

Skin metabolism and transdermal absorption of viprostol, a synthetic PGE2 analog, in the rat: effect of vehicle.

The effects of three formulations on the transdermal absorption and antihypertensive activity of 14C-viprostol were investigated in the spontaneously hypertensive rat. Single doses of 14C-viprostol were administered topically to rats in three formulations: silicone oil, petrolatum base, and triethyl citrate (TEC). Mean arterial blood pressure (MABP) and blood concentrations of radioactivity were measured over 24 h.

Effect of gamma-aminobutyric acid (GABA) on vasodilation in resistance-sized arteries isolated from the monkey, rabbit, and rat.

The effect of gamma-aminobutyric acid (GABA) and papaverine on cerebral arteries of rat, rabbit, and monkey and the small mesenteric arteries of the rat were studied in vitro with a microvessel apparatus. GABA (1 x 10(-7) to 1 x 10(-3) M) did not affect the basal tension of arteries of rats at rest. In PGF2 alpha-contracted monkey basilar artery and middle cerebral artery and rat basilar artery, cumulative addition of GABA (1 x 10(-7) to 1 x 10(-3) M) did not produce any relaxation.

Effect of varying concentrations of linoleic acid on alpha-adrenoceptor responses in spontaneously hypertensive rats.

The effect of increased intake of linoleic acid on the alpha-adrenergic system was assessed by safflower oil supplementation to spontaneously hypertensive rats. Linoleic acid-enriched intake at 5%, 15% and 30% by weight of total food intake for 12 wk was associated with a reduction in resting arterial blood pressure, while heart rate and heart to body weight ratios were similar to control group values. A dose-response analysis to norepinephrine bitartrate administered intravenously indicated a significant reduction in the vascular reactivity to this alpha-adrenergic agonist in all groups given linoleic acid.

Relaxant actions of viprostol and prostaglandin E2 on tracheal muscle and their effects on calcium influx.

The relaxant effect of viprostol was studied in monkey and guinea-pig tracheal muscle rings in vitro and compared to that of prostaglandin E2 (PGE2), isoproterenol (ISO) and verapamil (guinea-pig trachea only). Viprostol, PGE2, ISO and verapamil produced a concentration-dependent relaxation of carbachol-contracted tracheal preparations. The rank order of potency in monkey trachea was viprostol = ISO greater than PGE2, while in guinea-pig treachea it was ISO greater than viprostol greater than PGE2 greater than verapamil.

Studies on the effects of viprostol in isolated small blood vessels and thoracic aorta of the rat.

1. The effects of viprostol, prostaglandin E2 (PGE2) and nitroglycerin were studied in basilar artery, small mesenteric artery and the vein parallel to it as well as thoracic aorta of the rat. 2.

Development of an animal model for investigating disparate myocardial effects of obesity and hypertension.

An experimental model for investigating the disparate effects of obesity and hypertension on the heart was developed by ligation of the aorta of male Sprague-Dawley rats made obese through ad libitum feeding. Experimental obesity was associated with an increased body fat and cardiac muscle mass, yet a normotensive systemic arterial pressure. Aortic ligation produced an elevated mean arterial pressure and resting heart rate, whereas body weight was similar to that of normotensive lean control rats.

Antilipolytic activity of viprostol, a transdermally active antihypertensive PGE2 analog.

Viprostol, a novel prostaglandin E2 congener, was assessed for in vitro antilipolytic activity in the spontaneously obese rat. In isolated epididymal adipocytes, viprostol exhibited a dose-dependent inhibition of catecholamine-stimulated lipolysis at concentrations ranging from 10 microM to 1 mM, but was ineffective at lower concentrations. Additionally, viprostol exhibited approximately 50% of the antilipolytic activity of naturally-occurring PGE1 and PGE2 at similar concentrations, but was as potent as PGF2 alpha.

Antiarrhythmic agents inhibit the in vitro formation of thromboxane (TX) in platelets from spontaneously hypertensive rats (SHR).

The occurrence of early life threatening arrhythmias in the ischemic myocardium has been associated with local generation of thromboxane (TX). Antiarrhythmic agents are typically classified according to the fundamental mechanism involved in restoring normal rhythm but identifying those agents also capable of suppressing TX formation offers a means of improving the rationale of antiarrhythmic therapy. Accordingly, representative antiarrhythmic agents from classes I-IV were evaluated in the present study for their ability to suppress TX formation from intact rat platelets, in vitro.

Assessment of animal models for investigating the cardiovascular adaptations to obesity.

Several animal models of obesity have been reviewed with respect to the cardiovascular adaptations to this disorder. While some cardiovascular data are available for each model reviewed, the spontaneously obese rat has been most extensively characterized. Biochemical adaptations of the myocardium to experimental obesity have been reported, but this area has not been investigated extensively.

Mechanism of action of a new prostaglandin antihypertensive, viprostol [CL 115 347; (dl)-15-deoxy-16-hydroxy-16(alpha/beta)-vinyl-prostaglandin E2 methyl ester]: (I). Vasodilation.

Viprostol [(dl)-15-deoxy-16-hydroxy-16(alpha/beta)-vinyl-prostaglandin E2 methyl ester; CL 115 347], injected directly into coronary, renal, mesenteric, femoral and carotid arteries of the anaesthetized beagle dogs at doses which did not lower the systemic arterial blood pressure, increased blood flow of the vascular beds being studied. Viprostol was as potent as I-prostaglandin E2 (I-PGE2) in the renal bed, but less potent in the other vascular beds. Viprostol was as potent as I-PGE2 in relaxing smooth muscle of the perfused isolated central ear artery of the rabbit.

Mechanism of action of a new prostaglandin antihypertensive, viprostol [CL 115 347; (dl)-15-deoxy-16-hydroxy-16(alpha/beta)-vinyl-prostaglandin E2 methyl ester]: (II). Effects on the adrenergic nervous system.

Viprostol [(dl)-15-deoxy-16-hydroxy-16(alpha/beta)-vinyl-prostaglandin E2 methyl ester; CL 115 347] is a new orally and transdermally active antihypertensive agent that exerts its major antihypertensive action by vasodilation. The present studies were conducted to examine its effects on the adrenergic nervous system. In cats, viprostol did not inhibit renal sympathetic nerve discharge (RSND) monitored at the postganglionic region, indicating that nerve transmission or conduction was not blocked at the ganglion or the pre- or postganglionic fibres.

Hemodynamics of obesity: influence of pattern of adipose tissue cellularity.

Direct quantitation of blood flow with radioactive microspheres in conscious spontaneously obese rats indicated that the development of obesity was associated with an elevated cardiac output and stroke volume, a normotensive blood pressure, and a reduced total peripheral resistance when directly comparing obese rats with their lean counterparts. Obesity was also associated with increased blood flow and decreased regional vascular resistance in a variety of vascular beds, whereas cardiac index and total peripheral resistance per unit of body weight were similar between groups. When corrected for tissue weight, unique alterations in flow and resistance were observed in the adipose tissue.

Myocardial adaptations to dietary sucrose in spontaneously hypertensive rats.

The effects of dietary sucrose upon specific myocardial and hemodynamic parameters were examined in spontaneously hypertensive rats (SHR). Following a 6 wk program, SHR consuming a supplement of 10% sucrose in the drinking water exhibited increased heart weight, heart mass, left ventricular free wall thickness and increased resting heart rate when compared to the hypertensive control group. Total caloric intake was similar between groups.