Impairment of renal urinary excretion in neonatal, but not in adult capsaicin-pretreated rats.

The effect of saline and/or water load on diuresis, natriuresis and kaliuresis in control and in neonatal or adult capsaicin-pretreated awake rats has been assessed. Urine was collected by means of metabolic cages or intra-abdominally from a previously catheterized ureter. Neonatal but not adult capsaicin-pretreated animals exhibited a remarkable reduction in volume of urine output and in electrolytes excretion. This effect was more evident following saline as compared to water load. Similar results were also obtained when urine was directly collected from the ureters, suggesting that pharmacological ablation, at neonatal stage, of a subset of capsaicin-sensitive sensory nerves could impair the excretory kidney function.

Effect of capsaicin neonatal treatment on the salt intake of the adult rat.

The present study investigated the involvement of capsaicin-sensitive sensory neurons on salt intake control in the rat, following capsaicin neonatal treatment. Capsaicin did not affect salt appetite induced by intramuscular injection of deoxycorticosterone enantate, or by intracranial injection of renin. Moreover, it did not alter salt preference of rats given access to a variety of NaCl concentrations, or the need-free salt intake of multidepleted male rats. On the other hand, in response to furosemide-induced sodium depletion, the salt intake of capsaicin-treated rats was lower than that of controls. However, furosemide-induced Na+ excretion of capsaicin-treated rats proved to be lower than that of controls, thus suggesting that difference in salt intake might be secondary to lower sensitivity of capsaicin-treated rats to the natriuretic action of furosemide. Salt intake is known to be influenced by sensory information from the oral cavity, from the liver and from the intravascular compartment. The absence of effect of capsaicin neonatal treatment suggests that sensory fibers relevant to salt intake control may not be capsaicin sensitive. On the other hand, our findings indicate that capsaicin treatment alters the renal response to furosemide and stimulate further studies on the effects of capsaicin on renal function.

Pharmacodynamic profile of isbufylline, a new antibronchospastic xanthine devoid of central excitatory actions.

1,3-Dimethyl-7-isobutylxanthine (isbufylline, TE/06; CAS 90162-60-0) is a newly synthetized xanthine derivative. This compound exhibits remarkable antibronchospastic properties both in in vitro and in vivo (after oral or intravenous administration) experimental models. Isbufylline is significantly more effective than theophylline in antagonizing bronchospasms elicited by spasmogens (capsaicin, arachidonic acid, PAF and antigen) which mainly act by a local release of biologically active substances proposed to be involved in the pathogenesis of asthma. Isbufylline, unlike theophylline, possesses little or no CNS excitatory properties. This reduced neuroexcitatory action is probably related to the poor affinity of isbufylline, as compared to theophylline, to A1 purinoceptor. Indeed, isbufylline is ineffective in antagonizing 2Cl-adenosine-induced EEG synchronization. In normotensive and hypertensive rats oral administration of isbufylline resulted in small and transient positive chronotropic and hypotensive response, markedly lower than those elicited by theophylline or enprofylline. Finally isbufylline exhibits phosphodiesterase inhibitory properties, although at concentration 50-100 times higher than those exerting spasmolytic effects in isolated bronchial tissues. As a whole the pharmacodynamic profile of isbufylline is promising and, in the clinical setting, this compound might exert enhanced antiasthma effects coupled to a low incidence of central and cardiovascular adverse effects.

Resolution and pharmacological properties of the enantiomers of the potent alpha-adrenoceptor antagonist 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine.

Resolution of the optical isomers of the alpha-adrenoceptor antagonist IP-66 (1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl)piperazine) and its intermediate IP-30 (1-[2-hydroxy-2-(3'-pyridyl)ethyl]-4- (2'-methoxy-phenyl)piperazine have been carried out. Optical purity was assayed by high-pressure liquid chromatography. The antagonistic potencies of racemic mixtures and stereoisomers toward phenylephrine- and norepinephrine-induced contraction in isolated rat aortic strips have been compared. (+)-IP-66 and (+)-IP-30 were resp. 363 and 170 times more potent than respective (-) isomers in eliciting competitive alpha 1-adrenoceptor blockade. Similarly IP-66 (+) or (+/-) were extremely more effective than the (-) isomer in antagonizing norepinephrine-induced pressor responses in pithed rat.

In vitro comparison of pre- and postsynaptic effects of dihydroergotoxine mesylate and 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl) piperazine (IP-66).

The effects caused on the intestine mesenteric artery preparation by 1-[2-ethoxy-2-(3'-pyridyl)ethyl]-4-(2'-methoxy-phenyl) piperazine (IP-66), a compound having a prevailing alpha-blocking action, and by dihydroergotoxine mesylate (DHEM) were compared in normal conditions and in propranolol-induced beta-receptors block. The two drugs behaved in a completely different way both on vasoconstrictor response (delta p) and on noradrenaline (norepinephrine, NA) outflow induced by electrical stimulation of periarterial nerves. In fact IP-66 inhibited delta p much more than DHEM did but, unlike the latter, it increased NA outflow only at the lowest concentration (8.7 X 10(-9) mol/l) whereas it reduced it at the highest one (2.9 X 10(-7) mol/l). Moreover the effect of IP-6--but not that of DHEM--on NA outflow was completely abolished by propranolol. The hypothesis is put forward that IP-66 may show a strong antagonism towards postsynaptic alpha-receptors and a slight agonism towards presynaptic beta-receptors.

The rat mesenteric artery-intestinal loop preparation. Noradrenaline outflow and vascular responses to nerve stimulation and drugs.

A new preparation, intestine-mesenteric blood vessels of the rat, was tested for simultaneous measure of noradrenaline (NA) overflow and vasoconstrictor response (delta p) induced by electric stimulations. Control experiments showed that this preparation could be used within a wide range of frequencies and repeatedly stimulated without any important decrease of response. The effects of phenoxybenzamine, dihydroergotoxine mesylate, imipramine and pargyline were investigated. All the drugs inhibited delta p and, except for dihydroergotoxine mesylate, increased NA outflow. The results were discussed in the light of the present knowledge. It is concluded that this preparation can be profitably used to study drug effects at pre- and post-synaptic level.

Lack of hypotensive and brain catecholamine depleting effects by erythro- and threo-alpha-methyl DOPS.

An investigation was carried out to ascertain whether erythro- and threo-alpha-methyl-dihydroxy-phenyl-serine were able of depleting cerebral and peripheral norepinephrine (NE) through their metabolization to alpha-mNE. The results show that the alpha-methyl-aminoacids were decarboxylated only at the periphery and that the threo-form caused depletion in cardiac NE. In any case, both isomers were unable to cross the blood-brain barrier leaving the cerebral NE unaffected. Consequently the use of alpha-mDOPS as alternative tool to alpha-mDOPA in the therapy for hypertension seems unlikely to occur. The results also provide evidence for differences in the pharmacokinetics of the two isomers.

The effect of two inhibitors of histidine decarboxylase on gastric secretion in the rat.

The effects of the hydrazino-analogue of histidine (HH) and DL-gamma-N(1,2,3,4-tetrahydroisoquinolyl)-alpha-hydrazino-butyric acid (AIS 48), two inhibitors of histidine decarboxylase, and atropine on gastric secretion stimulated by histamine and pentagastrin were studied in the perfused rat stomach. The results confirm that the mechanism of action of the physiological polypeptide is mediated, and that the inhibition of histidine decarboxylase can be useful means to control gastric secretion.