Effects of adrenoceptor agonists and antagonists on cardiovascular functional parameters in rats.

The effects of intravenous administration of adrenoceptor agonists and antagonists on electrocardiographic or blood pressure (BP) functional parameters were assessed in urethane-anesthetized rats. The responses of cardiovascular functional parameters produced by these drugs included: (1) isoproterenol decreased the duration of a whole BP cycle (Wd), duration of the diastolic wave (Dd), peak amplitude of the systolic wave (SYa), amplitude of the diastolic notch (DNa), amplitude of the diastolic wave (DWa), pulse pressure (dp) and mean arterial pressure (mp) but increased the heart rate (HR) accompanied by prolonged R-R (RR) or P-P interval (PP) (2) propranolol decreased SYa, DNa, dp, mp, HR, the amplitude of the P wave (Pa) and amplitude of the S wave (Sa) but increased the duration of the QRS wave, P-R interval, duration of the R wave (Rd) and duration of the P wave (Pd); (3) adrenaline decreased HR (accompanied by prolonged RR and PP), Rd, Pa and amplitude of the T wave (Ta) but increased Pd, Wd, Dd, DNA, the time interval between aortic valve opening and closure (Dw), dp, mp, amplitude of the Q wave and amplitude of the R wave (Ra); (4) noradrenaline decreased HR (accompanied by prolonged RR and PP) and Pa but increased Wd, Pd, SYa, DNa, Dw, dp, mp, Ra and Ta; (5) phenylephrine decreased HR (accompanied by prolonged RR and PP) and Pa but increased Wd, Dd, DNa, mp and Ra; (6) phentolamine decreased SYa, DNa, DWa, Dw, dp and mp. This study illustrates the utility of the automated electrocardiogram (ECG) and BP analysis system for investigation of adrenoceptor agonists and antagonists. The use of this methodology not only reproduced most of cardiovascular functional parameter effects produced by these drugs using the conventional methodology but also realizes some new information about the drug-induced ECG or BP waveform effects.     

Interaction of some atypical antidepressants and adrenoceptor antagonists with imipramine: a behavioural study with isoprenaline-induced drinking

The systemic administration of isoprenaline to rats produced a dose-dependent increase in drinking which was antagonized by propranolol. While oral administration of the antidepressant, imipramine, alone had no significant effect on this response, the increase was significantly inhibited by administration of imipramine together with each of the following drugs over a period of 4 days: bupropion (21.0 mg/kg/day, p.o.), a selective inhibitor of the uptake of dopamine and nomifensine (10.6 mg/kg/day, p.o.), a relatively selective dopamine and a blocker of the uptake of noradrenaline. Similarly, the combination of the selective alpha 1-adrenoceptor antagonist, prazosin (2.37 mg/kg/day, p.o.); the selective alpha 2-adrenoceptor antagonist, yohimbine (2.38 mg/kg/day, p.o.) or the non-selective alpha-adrenoceptor blocker, phentolamine (4.65 mg/kg/day, p.o.) with imipramine caused a significant inhibition of the isoprenaline-induced drinking. It is concluded that fast desensitization of central beta-adrenoceptors in the rat can be produced after the oral subacute simultaneous administration of imipramine with alpha-adrenoceptor antagonists or atypical antidepressants, such as nomifensine or bupropion.     

The potential antidiabetic activity of some alpha-2 adrenoceptor antagonists.

The effect of alpha-2 adrenoceptor antagonists, yohimbine and efaroxan, on the plasma glucose and insulin levels was studied in non-diabetic control, type-I (insulin-dependent) and type-II (non-insulin-dependent) diabetic rats. Pretreatment with either yohimbine or efaroxan potentiated glucose-induced insulin release in non-diabetic control rats and produced an improvement of the oral glucose tolerance and potentiated glucose-induced insulin release in type-II but not in type-I diabetic rats. Treatment with either yohimbine or efaroxan reduced the plasma glucose level and increased the plasma insulin level of non-diabetic control and type-II diabetic rats but not of type-I diabetic rats. Effects of efaroxan were more marked. Pretreatment of non-diabetic control and type-II diabetic rats with either yohimbine or efaroxan inhibited clonidine-induced hyperglycaemia and suppressed or reversed clonidine-induced hypoinsulinaemia. Also, pretreatment of these animals with either yohimbine or efaroxan enhanced the hypoglycaemic and insulinotropic effects of glibenclamide. The combination of glibenclamide and efaroxan led to a synergistic increase in insulin secretion, while that of glibenclamide and yohimbine led to an additive increase. The hyperglycaemic effect of diazoxide in non-diabetic control and type-II diabetic rats was inhibited by pretreatment with either yohimbine or efaroxan. The hypoinsulinaemic effect of diazoxide in these animals was antagonized and reversed by pretreatment with yohimbine and efaroxan, respectively. In type-I diabetic rats, there was no change in the plasma glucose and insulin levels induced by the treatment of animals with each of clonidine or diazoxide alone or in combination with either yohimbine or efaroxan. Glibenclamide produced a slight decrease in the plasma glucose level of type-I diabetic rats, at the end of the 120 min period of investigation but there was no change in the plasma insulin level. Pretreatment of these animals with either yohimbine or efaroxan produced no change in glibenclamide effects. Additionally, bath application of efaroxan or glibenclamide inhibited the relaxant effects of different concentrations of diazoxide on the isolated norepinephrine-contracted aortic strips, while the application of yohimbine produced insignificant changes. The combination of glibenclamide and efaroxan led to complete inhibition of the relaxant effects of different concentrations of diazoxide, while that of glibenclamide and yohimbine did not produce such an effect. It is concluded that yohimbine, via blockade of postsynaptic alpha-2 adrenoceptors, and efaroxan, via blockade of postsynaptic alpha-2 adrenoceptors and adenosine triphosphate-sensitive potassium channels in the pancreatic beta-cell membrane, produce insulinotropic and subsequent hypoglycaemic effects.     

Effects of adrenoceptor agonists and antagonists on sulfobromophthalein disposition in mice

The effects of alpha 2-adrenoceptor agonists on sulfobromophthalein (BSP) disposition in mice were studied. It was found that agents with both central and peripheral activities (clonidine, guanabenz, B-HT 920 and methyldopa) as well as peripherally acting alpha 2-adrenoceptor agonists (para amino-clonidine and St 91) inhibited sulfobromophthalein disposition in the mouse, and also caused substantial hypothermia. The effects of these agonists were inhibited by yohimbine, a specific alpha 2-antagonist, except for those of para amino-clonidine where only partial reversal was achieved. The effects of clonidine on BSP disposition were also reversed by piperoxan but not by the alpha 1-adrenoceptor antagonists, prazosin and phenoxybenzamine, nor by the beta-blocker, propranolol. These results suggest that, in mice, peripheral alpha 2-adrenoceptors are involved in the effects of the alpha-agonists on BSP disposition.     

Effects of adrenoceptor agonists and antagonists on morphine-induced Straub tail in mice

Straub-tail behavior was induced by subcutaneous injection of different doses (10-60 mg/kg) of morphine to mice. The maximum response was obtained with 20-40 mg/kg of the drug. The response induced by morphine (40 mg/kg) was decreased by intraperitoneal administration of different doses of clonidine (0.05-0.1 mg/kg). Pretreatment of animals with yohimbine (1-4 mg/kg i.p.) reversed the inhibitory action of clonidine. Yohimbine did not elicit any response by itself. Administration of prazosin (0.25, 0.5, and 1 mg/kg) reduced the morphine response. The combination of prazosin with yohimbine (1 mg/kg), but not with clonidine (0.05 mg/kg), caused a potentiated inhibition of the morphine effect. Phenylephrine (2-6 mg/kg i.p.) did not elicit any effect by itself and also did not alter the response induced by morphine or morphine plus clonidine. Dobutamine (2.5-10 mg/kg i.p.), atenolol (2.5-10 mg/kg i.p.), salbutamol (2.5-10 mg/kg i.p.), and propranolol (2.5-10 mg/kg i.p.) did not alter morphine-induced Straub-tail behavior in mice. In conclusion, activation of alpha2-adrenergic pathways contributes to morphine-induced Straub tail, while alpha1- and beta2-adrenergic may not be involved in this phenomenon.     

In vivo release by histamine agonists and antagonists of endogenous catecholamines in the cat hypothalamus

Summary The posterior hypothalamus of anaesthetized cats was superfused through a push-pull cannula with histamine agonists and antagonists and the release of endogenous catecholamines was determined in the superfusate. Hypothalamic superfusion with histamine, 2-methylhistamine (H₁-agonist), dimaprit (H₂-agonist) or metiamide (H₂-antagonist) enhanced the release of the catecholamines dopamine, noradrenaline and adrenaline. The releasing effects of these substances depended on the presence of calcium ions. Superfusion with 2-pyridylethylamine (H₁-agonist) was virtually ineffective, while superfusion with 2-thiazolethylamine (H₁-agonist) enhanced the rate of release of noradrenaline and adrenaline without influencing the release of dopamine. Superfusion with mepyramine (H₁-antagonist) inhibited the release of noradrenaline and adrenaline without affecting the release of dopamine. Hypothalamic superfusion with a concentration of procaine which was equi-anaesthetic to that of mepyramine was ineffective. Ranitidine (H₂-antagonist) did not alter the rates of release of the catecholamines. The releasing effect of histamine was inhibited on hypothalamic superfusion with mepyramine and ranitidine. Ranitidine also inhibited the releasing effects of dimaprit and 2-methylhistamine thus indicating that the releasing action of the latter compound was mainly due to stimulation of H₂-receptors. These data suggest that blockade of H₁-receptors of the posterior hypothalamus reduces the release of noradrenaline and adrenaline, while stimulation of H₁-receptors seems to increase the rates of release of these two catecholamines. Stimulation of H₂-receptors enhances the release of all three catecholamines. Thus, dopaminergic neurones of the hypothalamus seem to possess H₂-receptors, while noradrenergic and adrenergic neurones possess H₁- and H₂-receptors.This work was supported by the Deutsche Forschungsgemeinschaft     

Biphasic effects of morphine on cardiovascular system of the cat

Morphine has been reported to both lower blood pressure (BP) and cause excitation in some species. These are seemingly contradictory effects. In this series of experiments, the actions of morphine on BP, heart rate (HR) and pupillary diameter were re-examined in sedated, paralyzed cats under 2 ranges of dosage and 3 types of sedative. Small doses (1--2 mg/kg) lowered BP and HR while larger doses (8--12 mg/kg) increased both BP and HR. The effect of morphine on pupillary diameter, however, was not biphasic in that increasing doses proportionally increased pupillary diameter. In adrenalectomized cats smaller doses of morphine decreased, but larger doses no longer increased, BP and HR as it has in the non-adrenalectomized animals. Morphine also no longer produced mydriasis in the adrenalectomized cats. The results suggest that, in the cat, morphine can have a biphasic effect and that the adrenals may play a role in the excitatory phase.     

Actions of some cholinergic antagonists on fast-twitch and slow-twitch skeletal muscle of the cat

1. The anticholinergic drug N-ethyl-2-pyrrolidylmethylcyclopentylphenyl glycollate (PMCG) has been studied for its effects on the contraction of fast-twitch (flexor hallucis longus, FHL) and slow-twitch (soleus) muscles in the cat.2. In both muscles lower doses (0.25 to 10 mg intra-arterially) potentiated and higher doses (10 mg and above) depressed twitches produced by indirect stimulation. Similar effects were obtained in directly stimulated muscles.3. The effects of the drug on muscles stimulated repetitively were dependent on both dose and frequency of stimulation. Doses which potentiated twitches also potentiated low frequency tetani (5-30 Hz for soleus; 10-50 Hz for FHL). There was a depression and non-maintenance of higher frequency tetani (80 Hz and above for soleus; 150 Hz and above for FHL).4. Both atropine and caramiphen had similar dose dependent potentiating and depressant actions. Hyoscine acted similarly in some cats; in others it had only a depressant action.5. It is suggested that the potentiating actions of PMCG, caramiphen, atropine and hyoscine are due to a direct musculotropic action. The depressant actions resulting from higher doses are due, in part, to a curare-like action and in part to a direct action on the muscle fibres.     

Catechol-substituted phenoxypropanolamines: adrenoceptor activity in the anaesthetized cat.

1 The pharmacological actions of racemic noradrenaline, adrenaline, isoprenaline and N-t-butylnoradrenaline have been compared with those of their corresponding derivatives containing an oxymethylene (OXY) link between the ring and ethanolamine side chain. 2 The compounds were tested in the anaesthetized cat for their ability to produce positive chronotropic effects, bronchodilator actions, changes in perfusion pressure in the perfused hind limb and decreases in soleus muscle contractions. 3 All the OXY-derivatives were potent beta-adrenoceptor agonists. The inclusion of the oxymethylene link promotes selectivity for beta1-as opposed to beta2-adrenoceptor activity. 4 In comparison with the parent compounds, the OXY-derivatives of adrenaline and noradrenaline had very weak alpha-adrenoceptor stimulant effects.     

Sympathomimetic effects of amezinium on the cardiovascular system and plasma catecholamines in man

Summary Thirty one in-patients suffering from depression were treated orally with clomipramine (Cl) at various dosage, for 28 days, after a “wash-out” period of three days. In 17 patients receiving 75 mg per day of Cl, steady state plasma levels of Cl were reached at Day 14, and steady state plasma levels of its active metabolite, desmethylclomipramine (DMCl), were reached at Day 21. In contrast, in 7 other patients receiving a dosage increasing to 150 mg per day at Day 7, mean plasma levels of Cl and DMCl continued to rise during the entire treatment period. At the steady state, a correlation was found between Cl dosage expressed as mg kg body weight and the plasma concentration of Cl and DMCl. Factors such as tobacco and alcohol consumption seem to modify the Cl/DMCl ratio. A comparison of clinical response with plasma levels of Cl, DMCl and Cl + DMCl showed a significant negative linear correlation.     

The effect of acetylsalicylic acid on the response of the cardiovascular system to catecholamines

In vitro studies using the rabbit ear artery were carried out to examine possible interactions between acetylsalicylic acid, normetanephrine and deoxycorticosterone acetate. Acetylsalicylic acid and normetanephrine alone siginificantly potentiated the response of the rabbit ear artery to noradrenaline by 1.9 ± 0.1 and 2.0 ± 0.2 respectively. Prior treatment of arteries with either normetanephrine or deoxycorticosterone acetate reduced this effect of acetylsalicylic acid; prior treatment of arteries with acetylsalicylic acid reduced the effect of normetanephrine in potentiating noradrenaline.In vivo studies using dogs showed that acetylsalicylic acid potentiated the effects of isoprenaline on cardiac output.It was concluded that acetylsalicylic acid potentiates the effects of catecholamines in vivo and in vitro possibly by inhibiting uptake₂.     

Neuromuscular blocking and ganglion blocking activities of some acetylcholine antagonists in the cat

The potencies of tubocurarine, gallamine, pancuronium, benzoquinonium, hexamethonium and mecamylamine in blocking neuromuscular transmission in the soleus muscle, and in blocking contractions of the nictitating membrane evoked by preganglionic sympathetic stimulation have been compared in cats under chloralose anaesthesia. On a molar basis, pancuronium was about 8 times and benzoquinonium about 2·5 times more potent than tubocurarine in blocking the soleus muscle; gallamine was less than half as potent, mecamylamine about 128 times and hexamethonium about 380 times less potent. In blocking the superior cervical ganglion, mecamylamine was about 17 times more, tubocurarine was about 5 times more and pancuronium about twice as potent as hexamethonium. Benzoquinonium was about half as potent as hexamethonium, and gallamine about 5 times less potent. The results emphasize that the shorter distance between charged centres, as in hexamethonium, reduces affinity for muscle receptors but does not necessarily enhance affinity for ganglion receptors, and from the point of view of deductions concerning the configuration of the ganglionic receptor, the ganglion blocking potencies of some neuromuscular blocking drugs should be taken into account.     

Mutal suppression of cardiovascular effects of some beta-adrenoreceptor agonists in the cat

Observations were made of the effects of adrenaline, isoprenaline and orciprenaline on the blood pressure, heart rate and configuration of the ECG in cats. The effects of single injections of these amines in producing a rise in heart rate and a fall in blood pressure were reduced during the intravenous infusion of any one of them: the pressor response to injected adrenaline was enhanced during an infusion. Combinations of these amines did not produce changes in the configuration of the ECG. These experiments were motivated by allegations of acute toxic effects on the cardiovascular system of large doses, or of combinations, of sympathomimetic bronchodilators in asthma. No evidence of deleterious effects of interactions was obtained.     

Effects of menadione on the cardiovascular system

Cardiotoxic mechanisms induced by anthracyclines are not clearly determined. A possible hypothesis is free radical formation and cell damage due to the quinone part of the molecule. We have studied the effect of menadione on myocardial structure and function. The effect on the red blood cells has been also determined. Groups of rats were treated orally with increasing doses (5 mg/kg/d, increased to 20 mg/kg/d and 40 mg/kg/d in the 3rd and 5th w, respectively). Duration of treatment was 6 w. ECG and blood pressure changes and blood cell count, including Heinz-Ehrlich bodies and reticulocytes, hemoglobin and hematocrit, were determined before and after treatment weekly and every 2 w, respectively. At the end of the experiment, the hearts of 2 rats/group were processed for electron microscopy. Heart, spleen and liver weights were determined. Heart, spleen, liver and kidney were subjected to histopathological examinations. Menadione treatment did not affect growth. No significant ECG changes were obtained; only significant changes of wave amplitude were observed. Menadione caused no relevant hematological changes but there were some blood pressure alterations. Morphological changes in myocardial tissue were observed including a small disorganization of myofibrils and mitochondria crystolisis. Z-lines appear forming zigzags. There were differences in organ weights. This study showed the damage induced by menadione was less than injury induced by anthracyclines.