The data suggest that cocaine increases the endothelin-1 release in vitro and in vivo. The cocaine-induced vasoconstriction/vasospasm may therefore be facilitated by the release of endothelin-1. Cocaine appears to be an exogenous stimulator at endothelial sigma-receptors. The endogenous ligands of this antiopioid system may prove to play a role in vasospastic angina, acute myocardial infarction, and sudden cardiac death.

Inoculation of the right hind paw with Mycobacterium butyricum rapidly led to swelling and inflammation. The afflicted limb showed an enhanced sensitivity to noxious pressure (hyperalgesia) and a reduced sensitivity to noxious heat 24 h following treatment. Both naloxone and MR 2266 (which has greater activity at kappa-opioid receptors) further increased the sensitivity to pressure (that is, potentiated the hyperalgesia) but did not affect the response to heat. They did not affect the response of the uninflamed paw. At 1 week, only MR 2266 was effective. At both 24 h and 1 week, the inflamed paw showed pronounced supersensitivity to the antinociceptive action of morphine against noxious pressure. At both 24 h and (to a greater extent) 1 week, a rise in levels of immunoreactive (ir)-dynorphin (DYN) was seen in the ipsilateral dorsal horn of the lumbar spinal cord. There was no alteration in the contralateral dorsal horn or in either ventral horn. Furthermore, levels of ir-met-enkephalin (ME) and ir-leu-enkephalin (LE) were unaffected. There was no difference in the density of mu-, delta- or kappa-binding sites in any part of the lumbar cord, at either 24 h or 1 week, between ipsilateral and contralateral tissue. By 3 and 5 weeks postinoculation, the symptoms had spread to the contralateral hind limb and ir-DYN was elevated in the contralateral dorsal horn and the ipsilateral ventral horn. At 5 weeks, levels of ir-ME and ir-LE also were increased in the ipsilateral and contralateral dorsal horns, but not in the contralateral ventral horn. Furthermore, levels of ir-DYN were increased in the cervico-thoracic spinal cord, and rats displayed adrenal hypertrophy and a rise in plasma levels of ir-beta-endorphin (beta-EP). These data indicate: (1) Peripheral inflammation localized to a single limb selectively modifies levels of ir-DYN in ipsilateral dorsal horn. The effect is specific to DYN as compared to ME and LE. The density of mu-, delta-, or kappa-receptors in the lumbar spinal cord is unmodified. (2) The altered response to opioid agonists and antagonists shown by rats with an inflamed limb may be selective to the injured tissue. (3) Alterations in opioid systems associated with unilateral hind limb inflammation may not be exclusively chronic in nature: they appear very rapidly (within 24 h) of the induction of pain. With time, the contralateral limb becomes affected and, eventually, the effects resemble those seen with generalized polyarthritis.

No abstract

Factors influencing brain uptake of benzodiazepine derivatives were evaluated in adult Sprague Dawley rats (n = 8-10 per drug). Animals received single intraperitoneal doses of alprazolam, triazolam, lorazepam, flunitrazepam, diazepam, midazolam, desmethyldiazepam, or clobazam. Concentrations of each drug (and metabolites) in whole brain and serum 1 h after dosage were determined by gas chromatography. Serum free fraction was measured by equilibrium dialysis. In vitro binding affinity (apparent Ki) of each compound was estimated based on displacement of tritiated flunitrazepam in washed membrane preparations from rat cerebral cortex. Lipid solubility of each benzodiazepine was estimated using the reverse-phase liquid chromatographic (HPLC) retention index at physiologic pH. There was no significant relation between brain:total serum concentration ratio and either HPLC retention (r = 0.18) or binding Ki (r = -0.34). Correction of uptake ratios for free as opposed to total serum concentration yielded a highly significant correlation with HPLC retention (r = 0.78, P less than 0.005). However, even the corrected ratio was not correlated with binding Ki (r = -0.22). Thus a benzodiazepine's capacity to diffuse from systemic blood into brain tissue is much more closely associated with the physicochemical property of lipid solubility than with specific affinity. Unbound rather than total serum or plasma concentration most accurately reflects the quantity of drug available for diffusion.

The role of the atrial natriuretic factor and of the main counteracting sodium‐retaining principle, the renin‐aldosterone system, in acute volume regulation of cirrhosis of the liver has been investigated. Central volume stimulation was achieved in 21 patients with cirrhosis, 11 without and 10 with ascites, and 25 healthy controls by 1‐hr head‐out water immersion. Immersion prompted a highly significant (p<0.001) increase of atrial natriuretic factor plasma concentrations in cirrhotic patients without ascites from 8.5 ± 1.3 fmoles per ml to 16.5 ± 2.6 fmoles per ml, comparable to the stimulation in control subjects (6.0 ± 0.6 fmoles per ml to 13.6 ± 2.6 fmoles per ml). In cirrhotic patients with ascites, atrial natriuretic factor increase (from 7.7 ± 1.3 fmoles per ml to 11.4 ± 2.3 fmoles per ml) was blunted (p<0.05). Plasma renin activity and plasma aldosterone concentration were elevated in cirrhotic patients, especially in the presence of ascites. Following immersion, plasma renin activity and plasma aldosterone concentration were reduced similarly in all groups. Water immersion induced a more pronounced natriuresis and diuresis in control subjects than in cirrhotic patients. Neither atrial natriuretic factor nor plasma renin activity nor plasma aldosterone concentration alone correlated to sodium excretion. However, atrial natriuretic factor to plasma aldosterone concentration ratios were closely correlated to basal and stimulated natriuresis in cirrhotic patients, particularly in those with ascites. These data suggest that atrial natriuretic factor and the renin‐aldosterone system influence volume regulation in patients with cirrhosis.

In vitro lipophilicity of a series of benzodiazepines was evaluated by octanol: buffer partition ratio at physiological pH, and by retention time on a reverse-phase high-pressure liquid chromatographic (HPLC) system with a neutral-pH mobile phase. Both approaches ranked diazepam as highly lipophilic, but overall the two indices were poorly correlated (r = 0.23). For seven of the benzodiazepines, the in vivo volume of distribution (Vd) was determined in pharmacokinetic studies. After correlation for individual values of protein binding, Vd for unbound drug was significantly correlated with octanol: buffer partition ratio (r = 0.74), and to a greater extent with HPLC retention (r = 0.81). Thus, lipid solubility at least partly determines the extent of benzodiazepine distribution in vivo, which in turn is a major determinant of the duration of clinical action after single doses.

In an anaesthetized dog model, serum kinetics and CSF entry were determined after i.v. administration of the following 8 drugs: salicylic acid (as acetylsalicylic acid), antipyrine, acetaminophen (paracetamol), lidocaine (lignocaine), trimipramine, amitriptyline, haloperidol, and imipramine. Kinetic variables were evaluated in relation to in-vitro lipophilicity, measured by the reverse-phase high-pressure liquid chromatographic (HPLC) retention index. After correction for individual values of serum binding (determined as the CSF: serum ratio at equilibrium), in-vivo volume of distribution was highly correlated with HPLC retention (r = 0.92). Conversely, the time of peak CSF concentration and the CSF entry half-life were negatively correlated with HPLC retention (r = -0.83 and -0.63, respectively). Thus lipophilicity is a physiochemical property which has an influence on the peripheral distribution of drugs as well as their rate of entry into CSF.

This paper describes a highly specific and sensitive radioimmunoassay for a-human atrial natriuretic factor (a-hANF), the C-terminal 28-amino-acid residue portion of human prepro-ANF in human plasma. A novel extraction and prepurification procedure allowed for detection of levels of immunoreactive-a-hANF as low as 0.5 fmol/ml. In normotensive subjects, levels in the range l-23 fmol/ml (mean = 8.9 fmol/ml) were found. Combined gel permeation and HPLC analysis demonstrated that this ir-a-hANF was comprised virtually exclusively of authentic 28-residue a-hANF. No evidence for occurrence of larger precursor forms in human plasma was acquired. A heterogenous group of hypertensive patients displayed considerably higher levels (mean = 62.2 fmol/ml), of interest in view of the hypotensive properties of ANF.