No description available.

No description available.

In order to determine whether the recovery from damage of central noradrenergic fibers could be modified by an opioid specific action of morphine, animals treated with the neurotoxin, 6-hydroxydopa (6-OHDOPA), were co-treated with morphine sulfate (3.33 mg/kg i.p.). After a period of 6 weeks it was found that morphine treatment in the 6-OHDOPA-group was associated with a recovery of norepinephrine (NE) levels in the cerebellum, and a 2-fold elevation of NE in the pons-medulla, when compared to the group treated with 6-OHDOPA alone. Histofluorometrically, the noradrenergic fiber number corresponded to changes in NE content. These actions of morphine were antagonized by the opioid receptor antagonist, naloxone. These findings indicate that morphine, by a specific opioid action, is able to enhance the recovery of damaged noradrenergic fibers in the brain.

Experiments were conducted in anesthetized rats to determine the effect of unilateral carotid artery occlusion on the reflex bradycardia caused by elevated arterial pressure (AP) and on clonidine's ability to potentiate that bradycardia. AP was recorded by catheterizing the carotid (CA-cath) or the iliac (IA-cath) artery. Elevated AP was obtained by rapid intravenous injection of methoxamine. Rats with CA-cath had higher APs and heart rates (HRs) than rats with IA-cath. The maximum increase in AP and reflex decrease in HR caused by methoxamine did not differ between sites of recording. Clonidine markedly increased the reflex bradycardia in rats with IA-cath. The reflex decrease in HR caused by methoxamine was not potentiated by clonidine in rats with either CA-cath or IA-cath with the CA clamped or following chemical denervation of the carotid sinus area with phenol. It is concluded that while unilateral carotid artery occlusion does not alter the reflex response to elevations in AP, it significantly interferes with clonidine's ability to potentiate baroreceptor responses.

The role of chemical interactions in the genesis of induced embryotoxicity in humans and in experimental animals is a point of current concern and interest. This review summarizes the current knowledge in this field and demonstrates that, under appropriate conditions, the observed results of chemical interactions can be explained, in part, through an understanding of the underlying pharmacokinetic and pharmacodynamic parameters. These define the concentration of the 'primary' teratogen at its receptor site in cells and tissues that are particularly sensitive to its embryotoxic action. The interacting 'secondary' or 'coteratogen' is viewed as an agent that is capable of altering these parameters in a way that is correlated with an observed alteration in the embryotoxic response. A series of recent experiments (diazouracil: 5-fluouracil; hydroxyurea: 5-bromodeoxyuridine; caffeine: 5-bromodeoxyuridine; caffeine: phenytoin) are reported which demonstrate both the validity and the limitations of such an approach and attempt to interpret observations, which are primarily empirical in nature, in pharmacologic terms.

No description available.

No description available.

The radioactive microsphere technique was used to determine the contribution of acute changes in systemic hemodynamic variables to the lowering of blood pressure caused by substance P in rats anesthetized with urethane. Infusion of 0.74 nmol/kg/min of substance P caused a decrease of blood pressure, cardiac output, stroke volume and blood flow to most tissues. Total and regional vascular resistances were not affected. Heart rate was increased. These results suggest that the lowering of blood pressure caused by substance P occurs as a result of the decreased stroke volume and cardiac output. The most likely explanation for the decreased stroke volume is a decreased venous return. Several studies have shown that substance P has a direct effect to dilate peripheral arteries. Since substance P dilates arteries, one would expect a decrease of peripheral vascular resistance. The results of this study suggest, however, that counter-regulatory processes, elicited in response to the vasodilatation and direct effects of substance P on sympathetic ganglia to increase the sympathetic nervous system activity, offset the direct effect of substance P on arteries that would otherwise cause a decrease of peripheral vascular resistance.

Human mast cell tryptase (EC 3.4.21.59) is a trypsin-like serine protease that is stored in and released from mast cell granules. This enzyme has been expressed in Pichia pastoris via homologous recombination of the cDNA coding for the mature active tryptase with the addition of a KEX 2 processing site into the Pichia genome. Cells producing recombinant human tryptase I (rHT) were selected by screening with antibodies. Induction with methanol resulted in the secretion of rHT into the Pichia growth medium; tryptase activity was stabilized by the addition of heparin to the culture medium. Increasing levels of enzyme were detected in the medium for up to 3 days. Fully active enzyme was purified from the culture medium with a 100% yield of activity via a simple two-step procedure, with hydrophobic interaction chromatography followed by affinity chromatography on immobilized heparin. Bands of 33 (faint), 34.2, 35.9 and 50 kDa (diffuse) were observed on SDS/PAGE. These multiple forms were due to differences in post-translational glycosylation of asparagine residues, because enzymic deglycosylation resulted in only one band at 33 kDa. A single symmetrical peak with an estimated size of 197 kDa was obtained on gel filtration. Kinetic analyses in comparison with native human lung mast cell tryptase (HLT) yielded similar K(m) values, but the k(cat) of rHT was more than twice that of HLT.

Ozone decreased the trypsin, chymotrypsin, and elastase inhibitory activities of human α1-proteinase inhibitor (α1-PI) both in plasma and in solutions of the pure inhibitor. The total loss of porcine elastase inhibitory activity required 18 mol of ozone/mol of pure α1-PI and approximately 850 mol of ozone/mol of α1-PI in plasma. A corresponding loss of the ability to inhibit human leukocyte elastase was observed. Inactivated α1-PI contains four residues of methionine sulfoxide, in addition to oxidized tyrosine and tryptophan. Electrophoretic analysis demonstrated that the ozone-inactivated α1-PI did not form normal complexes with serine proteinases. These findings suggest that the inhalation of ozone could inactivate α1-PI on the airspace side of the lung to create a localized α1-PI deficiency, which might contribute to the development of emphysema.