Biomedical subjects
Publications and source records attributed to S Guarini.
Intravenously injected cholecystokinin octapeptide (CCK-8) (5-20/micrograms/kg) and caerulein (1.25-10/micrograms/kg) caused a prompt, dose-dependent and sustained improvement in blood pressure, pulse amplitude and survival in rats subjected to otherwise invariably fatal hemorrhagic shock.
To gain direct insight into the mechanism of sodium deoxycholate (DOC)-induced enhancement of gastroenteral heparin absorption in rats, we performed light and electron microscopic examination of the mucosa of the small intestine of animals treated orally with DOC, heparin or DOC plus heparin. The sole morphological change observed after DOC and DOC plus heparin administration was a marked reduction in the length and distribution of glycocalyx filaments on the microvilli of epithelial cells. The morphological picture had reverted to normal after 24 h, when the promotion of enteral heparin absorption by DOC is greatly reduced. Thus, we suggest that DOC may promote the enteral absorption of heparin in rats by affecting some as yet unidentified barrier mechanism requiring glycocalyx integrity.
Phentolamine (Phe) prevents the induction by epinephrine (E: 1800 nmol/kg, i.v.) of lung edema (LE) in urethane-anesthetized and bivagotomized rats in a dose-related manner (from 246 to 3933 nmol/kg, i.v.). Since Phe blocks and E activates both alpha 1- and alpha 2-adrenoceptors, the evidence does not allow us to link LE to selective (alpha 1 or alpha 2) or non-selective (alpha 1 + alpha 2) alpha-adrenoceptor activation. Accordingly, we tried to find out whether: phenylephrine (PE), a selective alpha 1-adrenoceptor agonist, and B-HT 920, a selective alpha 2-adrenoceptor agonist, would cause LE; prazosin (Praz), a selective alpha 1-adrenoceptor antagonist, and yohimbine (Yoh), a selective alpha 2-adrenoceptor antagonist, would protect rats against LE caused by E or PE. We found that: 1) PE (from 736 to 5892 nmol/kg, i.v.), but not B-HT 920 (from 190 to 12200 nmol/kg, i.v.), caused LE, while both drugs increased arterial blood pressure; 2) Praz prevented induction of LE, whether by E (1800 nmol/kg, i.v.) or by PE (5892 nmol/kg, i.v.), in a dose-related manner (from 15 to 119 nmol/kg, i.v.). In contrast, Yoh was ineffective at doses up to 7675 nmol/kg, i.v. We conclude, therefore, that E-induced LE in urethane-anesthetized and bivagotomized rats strictly depends on alpha 1-adrenoceptor activation. The outcome of E-induced LE is usually rat death, the incidence of which depends on the dose. Since alpha 1-adrenoceptor agonists rank in the same order of potency for the induction of death as for that of LE, and since Phe and Praz protect from death at LE-preventing doses, there seems to be some link between LE and death, even though protection against death is obtained with doses of antagonists lower than those abolishing induction of LE. Finally, alpha 1-agonists cause maximum arterial hypertension at all doses used, irrespective of induction of LE and of protective pretreatment against LE.
In order to elucidate the pathogenesis of epinephrine (E)-induced lung edema (LE) as well as the mechanism of protection afforded by alpha-adrenoceptor blockade in urethane-anesthetized and bivagotomized rats, we investigated the influence of phentolamine (Phe) and prazosin (Praz) on arterial hypertension and LE provoked by continuous intravenous infusion of E and on blood pressure changes in left (LHV) and right (RHV) heart ventricles caused by a bolus injection of E at a LE-producing dose (1800 nmol/kg). Our results show that neither LE nor death are related to E-induced hypertension and also that LE-induction is accompanied by significant increases in LHV (telediastolic and systolic) as well as in RHV (systolic) pressures, of which the LHV telediastolic and the RHV systolic pressure increases are prevented by Phe and Praz at a dose capable of counteracting E-induced LE. The significance of this finding is briefly discussed.
Sodium deoxycholate (DOC), selected as a promoter of gastrointestinal absorption of heparin, was administered orally to rats, followed, at increasing intervals, by heparin. Maximal plasma clearing activity (PC) was obtained with a 60-min interval, though PC was still elicited after 24 h, suggesting that DOC acts on the gastrointestinal mucosa. Inhibition of blood coagulation was also observed after oral heparin. The suggestion that DOC increases heparin absorption is supported by increased plasma levels of heparin. No signs of several gastrointestinal damage were seen.
Aqueous heparin sodium solution dispersed in olive oil administered esophageally to fed rats induced blood plasma clearing activity, inhibition of blood coagulation and increased plasma heparin level. Plasma clearing activity was dependent on heparin dose (125 to 1000 mg/Kg). No plasma clearing activity being observed in pylorus- or coledoch-ligated rats, while heparin absorption reappeared after ox or rat bile administration, we conclude that olive oil favours enteral absorption of heparin by increasing bile function.
Heparin sodium, dissolved in water, causes plasma clearing activity (PC) and appreciable heparinemia (HE) when directly delivered into the duodenum, the jejunum, the ileum or the large intestine of rats, as well as when administered through an esophageal tube to distal duodenum-ligated animals. However, choledochus occlusion significantly decreases both PC and HE produced by intraesophageal heparin application. It is suggested that, in rats, bile flow participates in intestinal heparin absorption.
In male rats, clonidine in a dose range of 1-3000 micrograms/kg i.p. antagonized the stretching-yawning syndrome induced by the intraventricular injection of ACTH-(1-24) (3 micrograms/rat) dose-dependently. On the other hand, the effect of clonidine on ACTH-induced penile erections was potentiation at low doses (5 and 10 micrograms/kg) and inhibition at the highest doses (1000 and 3000 micrograms/kg), the intermediate doses (50 and 100 micrograms/kg) being without effect. There was no relationship between these behavioral effects and the effect on arterial blood pressure.
Selected non-ionic surfactants of the polyoxyethylene ether series as well as selected bile acids elicit plasma clearing activity (PC) after oral heparin administration by action on the gastro-intestinal mucosa. Evidence obtained indicates that certain structural characteristics are needed for promoting heparin absorption, since this effect is observed with some but not all non-ionic detergents (cetyl and stearyl ethers but not lauryl) and bile components (deoxycholic, chenodeoxycholic and cholic acids, but not ursodeoxycholic or dehydrocholic acids or lecithin). It is suggested that a specific mechanism of action is involved.
A series of quaternary ammonium salts of 3-alkylaminoderivatives of 1,2,4-benzothiadiazine-1,1-dioxide were prepared and tested for cardiovascular activity. Almost all the substances tested proved to have some measure of depressant activity on arterial pressure and the most interesting compounds in this respect were (XII), (XIII), (XV) and (XIX) for which hypotensive values between 60 and 70% with respect to the base level were recorded. Compound (XV) also caused increase in the differential pressure and decrease of cardiac frequency. The later however was increased by some other compounds [(XII), (XVIII)]. The structure-activity relationships are discussed taking into account also the activity of the parent tertiary amines.
In rats bled to invariably fatal haemorrhagic shock (mean arterial pressure = 18-24 mmHg), the prompt and sustained improvement of cardiovascular function, obtained with the i.v. injection of cholecystokinin octapeptide (CCK-8, 20 g/kg) is associated with a massive increase in the volume of residual circulating blood (0.69 +/- 0.12 ml/100 g b.w. in saline-treated rats; 1.61 +/- 0.09 ml/100 g b.w. in CCK-8-treated rats). The number of red cells/mm3 and the % Hb content is the same in CCK-8-treated and in control rats. So, in a condition of severe haemorrhage, otherwise incompatible with survival, the i.v. injection of CCK-8 not only induces an impressive increase in arterial pressure and in circulating blood volume, but also greatly improves tissue oxygenation.
In anesthetized rats, step-wise bleeding to a severe condition of hemorrhagic shock causes a decrease in arterial and venous pH and in venous PO2 and SO2 and an increase in arterial PO2 and in venous PCO2 and lactic acid. The intravenous bolus injection of ACTH-(1-24) (160 micrograms/kg)--which causes a rapid and sustained reversal of the shock condition--produces a gradual and almost complete recovery (within 60 min) of venous PO2, PCO2 and SO2; on the other hand, the normalization of blood pH and lactate is preceded by a further worsening during the first minutes after treatment. On the whole, these data are compatible with the ACTH-(1-24)-induced mobilization of the residual blood--which is pooled in poorly oxygenated tissues--and with the improved circulatory and respiratory functions.
In haemorrhage-shocked rats, the recovery of mean arterial pressure (MAP), pulse pressure (PP) and respiratory rate (RR), as well as the improvement of survival rate, induced by the i.v. administration of centrally acting cholinergic drugs (physostigmine, oxotremorine) are not affected by morphine at the dose of 2.5 mg/kg i.v., and only partially (MAP, PP, survival rate) or not at all (RR) prevented by a dose of morphine of 5 mg/kg i.v. These results indicate that the anti-shock effect of cholinergic drugs is largely independent of the opioid tone, this possibly being of practical relevance.
An extremely severe hypovolemic shock was produced in urethane-anesthetized rats by massive bleeding. In such preterminal conditions (mean arterial pressure = 19-25 mmHg; pulse pressure = 10-18 mmHg; death of all saline-treated animals in 26.16 +/- 3.18 min) the i.v. injection of protirelin tartrate (TRH-T) within 5 min after shock induction promptly and dose-dependently improved arterial pressure, pulse pressure and respiration, the dose of 4 mg/kg ensuring survival for 402.01 +/- 39.45 min without the need for the restoration of blood volume. The injection of TRH-T 20 min after shock induction, on the other hand, was ineffective. The concurrent administration of morphine (2.5 mg/kg i.v.) partially antagonized the effect of TRH-T; however, if the dose of the peptide was increased, its effect was restored. The effect of TRH-T in haemorrhagic shock was associated with a significant increase in the volume of residual circulating blood. The present data (i) confirm that TRH-T improves cardiovascular function and greatly prolongs survival in an otherwise irreversible model of haemorrhagic shock; (ii) show that this effect is associated with mobilization of residual blood and that respiratory function is greatly improved as well; (iii) indicate that the anti-shock effect of TRH-T is partially antagonized by morphine in a surmountable way. Finally, on the basis of our results, it appears that TRH-T has to be given rapidly after shock induction to be effective.
In a rat model of extremely severe hemorrhagic shock, invariably leading to death within 30 min, the i.v. bolus injection of ACTH-(1-24) at the dose of 160 micrograms/kg produced a dramatic and sustained reversal of the shock condition, with normalization of mean arterial pressure, pulse pressure and respiratory rate, and with survival of all rats at the end of the observation period (2 h). Such effect was neither prevented nor reduced by the bilateral anesthetization of carotid bodies, suggesting that chemoreceptors of these structures are of no relevance in the complex mechanism of the ACTH-induced reversal of hemorrhagic shock.