Bronchodilating effect of dopexamine efficacy and safety when used with theophylline

Concern has been expressed about the usefulness of dopexamine, a beta2 adreno-ceptor agonist used clinically in low cardiac output states, as an anti-asthma drug. So experiments of the present study were designed to shed light on the effect of dopexamine on airway smooth muscles of isolated sensitized and non sensitized guinea pigs. The mechanism of its bronchodilating action was also investigated. As beta agonists are commonly used in conjunction with theophylline in the treatment of asthma, so interaction between these drugs on isolated guinea pig tracheal preparations was also carried out. Lastly the occurrence of any interaction [during this combined therapy on arterial blood pressure, ECG, glucose and potassium content of the blood in experimental dogs was also detected. In-vitro results demonstrated that dopexamine [0.2- 0.8 micro g/ml], in cumulative doses, induced a dose dependent fall in basal tone reaching maximum at 0.8 micro g/ ml which closely approached the isopren-aline effect [1 micro g/ml]. An antispasmodic effect of dopexamine [0.2- 0.8 micro g/ml] on histamineinduced contractions of tracheal strips isolated from sensitized and non sensitized guinea pigs was also detected in this work. Insignificant differences were found between the relaxant effect of dopexamine on both preparations. Also dopexamine, in a single dose or in cumulative doses, exhibited a spasmolytic action of slow onset. Within 10 minutes, the mean percent reduction of either hista-mine- or acetyl choline-induced contractions caused by dopexamine [0.4 micro g/ml] was29 +/- 2.01 and 25.4 +/- 1.61 respectively. In the present study, as expected, pro-pranolol blocked the relaxant effect of dopexamine. In contrast addition of N-nitro-L-arginine methyl ester [L-NAME], a nitric oxide synthase inhibitor or indomethacin, a cyclooxygenase inhibitor, didn't change the effect of dopexamine on histamine-induced contractions. This suggests that nitric oxide and prostanoids do not play a role in dopexamine mediated relaxation of guinea pigs trachea. In addition the ATP-sensitive K+channel blocker glibenclamide didn't modify the action of dopexamine on histamine tone, indicating that the ATP-sensitive K+channels are not involved in regulating dopexamine induced relaxation. The participation of Ca2 +/- activated K+ channels [maxi-K] in the relaxation of dopexamine was also tested in the present study. Inhibition of these channels by tetraethylammonium [TEA] reduced dopexamine induced relaxation. This indicates that the maxi-K+channel blocker TEA either blocked dopexamine-induced opening of these channels or it activated the voltage-gated Ca[2]+ channels as a result of closure of the K+ channels. Accordingly the intracellular Ca2+ rises which in turn leads to contraction thus reducing dopexamine-induced relaxation. The last mechanism was confirmed in this study when nifedipine, added to TEA, preserved dopexamine-induced relaxation i.e. closure of Ca2+ channels prevented the influx of Ca2+ and this accounted for the preserved relaxant effect of dopexamine. Accordingly opening of maxi-K+ channels do not seem to play a role in dopexamine-induced relaxation. We propose that dopexamine may produce relaxation by acting on other types of K+ channels or by another mechanism of action. Dopexamine-theophylline combination, in this study, showed synergistic interactions between both drugs. Regarding the effect of this combined regimen on the isolated guinea pig tracheal preparations, it was found that the antispasmodic effect of theophylline, on both sensitized and non sensitized preparations, was much increased when dopexamine was coinjected. Assessement of the spasmolytic action of this combined therapy revealed also that within ten minutes the mean percent reduction of histamine tone caused by theophylline, when injected alone or combined with dopexamine, was 30 +/- 2.66 and 68.2 +/- 5.01 respectively, whereas it produced 28 +/- 2.03% and 58.4 +/- 5.24% relaxation of acetyl choline-induced contractions respectively In addition the inhibitory effect of cumulative doses of dopexamine, in this work, was greater against histamine-induced contractions of tracheal strips isolated from theophylline pretreated guinea pigs than against those isolated from normal non treated animals; thus the curve was shifted to the left. As regards the cardiovascular and biochemical studies of theophylline-dopexamine combination, it was found that theophylline alone, in this work, had no significant effect on any of the parameters measured apart from increased heart rate by 4 +/- 1.01%. When dopexamine was then infused, the heart rate showed a significant dose dependent increase. A slight increase of blood pressure was only noticed when small doses of dopexamine were infused, however significant rise of plasma glucose and fall in serum potassium were noticed after infusion of high doses of the drug. In conclusion, this study recognized a new value of dopexamine, namely being a bronchodilator. This suggests a future role of the drug in the management of asthmatic cardiac patients or at least in relieving bronchial obstruction following low cardiac output states. However this suggestion needs further clinical investigations. In addition, combined therapy of dopexamine with theophylline would be of benefit to the asthmatic by offering synergistic bronchodilatation as has been shown by in vitro experiments. However a reduction of dopexamine doses or frequent monitory of serum potassium are suggested when these drugs are used together

inotropic drug dopexamine: pharmacodynamic and effect of its interaction with digoxin on blood pressure, electrocardiogram recordings, blood glucose, serum electrolytes content and acute toxicity in experimental animals

Since co-administration of inotropic drugs is frequent in the management of acute heart failure, a possible interaction between these drugs may occur. So, in this study the interaction between dopexarnine and digoxin on arterial blood pressure, ECG pattern. glucose and electrolytes level in the blood of experimental dogs was investigated. The effect of dopexamine alone and Its site of action on these parameters was firstly carried out On blood pressure of anaesthetized dogs, 10 minutes intravenous infusion of dopexarnine [1, 2 and 4 micro g/kg/mini caused a biphasic action: initial vasodilatation and subsequent vasoconstriction. With the aid of selective dopaminerglc receptor antagonists. haloperidol and bulbocapnine, the Initial vasodilatation was shown to be mediated by stimulation of DA2 and DA1 respectively. Prior blockade of uptake l with cocaine prevented the subsequent vasoconstriction suggesting that this effect is mediated by uptakel blockade thus potentiating the effect of endogenous noradrenaline. This explanation was furtherty confirmed when dopexamine administration attenuated the hypertensive effect of tyramine. By contrast, large doses of dopexamine [8 and 16 1micro g/kg/min]. in this work, produced fall in blood pressure which was proved to be mainly due to beta 2 adrenargic agonistic activity. In the present study, prevention of reflex compensation by ganglion block-ads and airopine almost prevented dopexarnine-Induced tachycardia. This demonstrates that the positive chronotropic action of dopexarnine is due to baroreceptor activation which occurs secondary to the drop of blood pressure. Also, we have shown in this work that the tachycardia mediated by dopexamine was reduced after cocaine administration. This suggests that the chronotropic response of the drug may be also due to its blocking effect on neuronal uptake I, thus providing larger concentration of the neurotransmitter to act at the betal adrenoceptors. As regards the effect of dopexamine on glucose and electrolytes level in the blood of dogs, it was found in the present study, that large doses of the drug only produced significant drop of serum potassium and rise of plasma glucose levels in experimental dogs. Dopexamine-digitalis combination, in this work, didn't produce significant changes in the effects of dopexamine on arterial blood pressure, ECG, blood glucose and serum electrolytes content of dogs. Significant potentiation of either dopexamine or digoxin-induced hypokalaemia as well as prolongation of PR interval were noticed by co-administration of digoxin with 16 micro g/kg/min of dopexamine only. In the acute toxicity test, administration of 180 and 720 micro g/kg of dopexamine with digoxin to mice shifted the intraperitoreal median lethal dose [LD50] of digoxin from 5.8 mg/kg to 6.6 and 5.2 mg/kg respectively. In conclusion, the present study has shown that no significant interaction between digoxin and dopexamine on blood pressure, ECG, blood glucose and serum electrolytes content of dogs was observed. However coadministration of digoxin with the large dose of clopexamine accentuated digoxin-Induced hypokalaemia. So patients receiving this combined therapy may require monitoring of their potassium level since hypokalaemia may increase the risk of digoxin intoxication

Some pharmacodynamic aspects of ropivacaine on the cardiovascular system

In a previous work, it was demonstrated that ropivacaine, an aminoamide local anaesthetic, possessed a negative inotropic activity on isolated rabbit heart. It also elicited vasopressor effect on arterial blood pressure of anaesthetized cats. Bradycardia occurred only with high doses of the drug. The present study was designed to clarify the mechanism by which ropivacaine affect cardiac contractility, blood pressure, heart rate and vascular reactivity. The bradycardia and the vasopressor effect of ropivacaine was proved in spinal cat preparations to be the result of a peripheral action of the drug. This hypertensive response was furtherly proved to be mediated via activation of alpha adrenergic receptors and blocking beta2 adrenoceptors.-The negative inotropic action of ropivacaine was found to be probably the result of a beta adrenergic blocking effect and a direct action of the drug. Furthermore, different doses of ropivacaine [1.5-12 micro g/ml] elicited well-pronounced potentiation of the height of norepinephrine-induced concentrations of spiral aortic strips isolated from normal rabbits. This enhancement could be attributed to its alpha adrenergic agonistic effect. Concerning the isolated rat hind limb, it was found in the present investigation that ropivacaine produced dose dependent minor reduction in vascular outflow, which may be due to the increased peripheral resistance produced by the drug. In this study, it was concluded that the vasopressor effect of ropivacaine seems to be mediated via alpha adrenoceptor agonistic and beta adrenergic blocking activities while the negative inotropic effect of the drug may be due to a direct action on the heart and a beta-adrenergic receptor blockade of the myocardial tissue