Abstract The oligoamine RE 1492C ( N , N ′, N ″ ‐4‐phenylbutyl‐1,3,5‐benzene‐trimethanamine‐ N , N ′, N ″ ‐triethylcarbamate) inhibited the electrically provoked leucocyte adhesion to the endothelium of rat mesenteric venoles. An oral dose of 60 mg/kg gave a significant inhibition of 65–78%. This is comparable to effects seen after i.v. administration of iloprost or PGE 1 , respectively. In the same dosage the NO‐donor RE 2047 (3‐methyl‐ N ‐nitroso‐sydnone‐5‐imine) produced an inhibition of 21–27%.
We examined the effects of the optical isomers of D 600 on cardiovascular parameters and on arrhythmias caused by aconitine infusion and ligation of left coronary artery in urethane-anesthetized rats. (-)-D 600 decreased blood pressure and LV dP/dtmax with respective Ed30% of 0.045 and 0.018 mg/kg i.v.; increased PQ duration with an ED20% of 0.045 mg/kg i.v.: and caused AV-block with an ED50 of 0.07 mg/kg i.v., thereby showing a potency 20--50 times that of (+)-D 600 and about twice that of the racemate. (+)-D 600 in the effective dose range additionally widened QRS complex (ED20%, 2.44 mg/kg i.v.) and increased arrhythmogenic aconitine dose (ED75% 4.97 mg/kg i.v.) with a potency about equal to quinidine. In contrast to the (-)-isomer and the racemate of D 600 and to (+/-)-verapamil, (+)-D 600, at a dose slightly below AV block-generating ED50 of 2.15 mg/kg i.v., significantly attenuated ventricular arrhythmias following left coronary artery ligation with a potency similar to 4.64 mg/kg i.v. quinidine but inferior to 4.64 mg/kg i.v. lidocaine. It is concluded that the optical isomers of D 600 exert stereospecific actions in vivo with respect to Ca2+-antagonistic potency. While (-)-D 600 in the effective dose range shows cardiovascular actions indicative of pure Ca2+-antagonistic properties, and activity of the racemate resides in the Ca2+-antagonistic properties of the (-)-isomer, cardiovascular effects of (+)-D 600 and its effectiveness against ventricular arrhythmias are indicative of parallel Ca2+-antagonistic and membrane-stabilizing properties.
A series of prostacyclin analogues were synthesized and investigated for influence on blood pressure in rats, in vivo inhibition of platelet aggregation in rats, and in vitro inhibition of platelet aggregation in human platelet-rich plasma. The common feature of the analogues described is a replacement of C1-C4 of prostacyclin by a carboxyphenylene residue. The following structure-activity relationships were obtained. Only the meta-carboxyphenylene derivatives yield substantial prostacyclin activity. The 2,3,4-trinor-1,5-inter-m-phenylene prostacyclin analogues in contrast to the natural prototype are reasonably stable against hydrolysis of the enolether bond. The corresponding 2,3,4-trinor-1,5-inter-m-phenylene analogues of carbaprostacyclin have a somewhat lower specific activity but are superior in stability at acid pH values. With regard to the stereoisomerism at the delta 5 double bond, the Z-isomers of the oxa-cyclic prostacyclin series and the E-isomers of the carba-cyclic prostacyclin series are substantially more active than their counterparts. As with natural prostacyclin, the OH group at C15 has to be present in S-configuration. The "wrong" isomers do not inhibit prostacyclin-dependent effects. Resistance against 15-hydroxyprostaglandin dehydrogenase is achieved by substitutions at or near C15. Optimum specific activity combined with resistance against all known prostaglandin-activating enzymes is observed in prostacyclin and carbaprostacyclin analogues, in which the terminal n-pentyl residue is replaced by cyclohexyl. Duration of action, i.e. lowering of blood pressure in anaesthesized rats and inhibition of platelet aggregation in anaesthesized rats, was investigated with selected analogues in order to check the consequences of chemical and metabolic stabilization.(ABSTRACT TRUNCATED AT 250 WORDS)
Iloprost (ILO) and ZK 96 480 (96 480) are stable prostacyclin (PGI2) analogues with platelet aggregation-inhibiting and hypotensive activities equal or superior to PGI2 which in contrast to PGI2 show longlasting pharmacological effects also after oral application. PGI2 as well as ILO and 96 480 with i.v. infusion at equihypotensive doses in rats after coronary artery ligation reduce ventricular ectopic beats, markedly reduce or abolish the periods of ventricular tachycardia and entirely prevent ventricular fibrilloflutter. Even nonhypotensive doses of the prostanoids attenuate postligation arrhythmias. Catecholamine depletion by reserpine pretreatment also markedly reduced the incidence of arrhythmias. As PGI2 and ILO have previously been shown by others to preserve noradrenaline content of sympathetic nerve terminals in ischemic myocardium, prevention of excessive catecholamine loss from hypoxically compromised sympathetic nerve terminals might be involved in the antiarrhythmic action of PGI2, ILO and 96 480.
In the hamster cheek pouch, microvascular effects of iloprost at a nonhypotensive dose include vasodilatation at the level of arterioles and venules without changes in microvascular permeability, increased number of perfused capillaries/cm2, prevention of microvascular spasm and capillary ischemia as caused by LTD4, and inhibition of histamine- and 5-HT-induced venular leakage of FITC-dextrane. As regards the effects on basal vessel tone, capillary density, and prevention of LTD4 effects, PGE1 had similar effects as also shown by others in the human cutaneous microcirculation. However, PGE1 did not prevent the microvascular leakage caused by histamine. The Ca2+-antagonist nifedipine, apart from arteriolar vasodilatation, neither increased venular diameter and capillary perfusion nor prevented the effects of LTD4 and histamine. The microvascular actions of iloprost by improvement of tissue perfusion and prevention of mediator-induced tissue edema and vasospasm could contribute to the beneficial effects observed in ischemic diseases.
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