Effects of neuropeptides on the sumatriptan-disturbed circulation in the optic nerve head of rabbits.

The purpose of this work was to study 'in vivo' the vascular responses of retinal vessels of New Zealand white rabbits to substance P (SP), neurokinin A (NKA), neurokinin B (NKB), senktide, capsaicin (CAPS), and calcitonin gene related peptide (CGRP) before and after selective antagonist administration. We examined the effects of these neuropeptides on the normal circulation in the optic nerve head of the rabbit. Drugs were injected via pars plana through a micropipette system. Ten minutes before perivascular injection of 10 nmol/l sumatriptan (to contract the vessel), a selective antagonist or its solvent was administered. Then, cumulative injection of the agonist was performed. The other eye was used as control. Direct measurement of retinal arteriole diameters was performed using digital angiography. The quantification of the relaxing effect is expressed as percentage related to the precontracted vascular diameter. Microinjection of SP (NK1 receptor agonist) up to 10 nmol/l induced a dose-dependent arteriolar dilating effect [E(max) (mean +/- SEM) 21.3 +/- 2.3%]. After the perivascular preinjection of 1 nmol/l L-668,169 or 1 nmol/l L-733,060 (NK1 receptor antagonists), the SP dose-response curve was shifted to the right. The same results were obtained with NKA (NK2 receptor agonist) which induced the most potent effect of all neuropeptides (E(max) 53.3+/-2.5%). The NK2 receptor antagonists L-659,877 and GR 159897 (1 nmol/l) strongly inhibited this arteriolar vasodilation. As for CGRP, doses up to 10 nmol/l induced a marked vasodilation (E(max) 41.1+/-0.4%) which decreased after microinjection of the selective antagonist CGRP8-37. The NK3 receptor agonists (senktide and NKB) showed a minor vasodilating effect (E(max) 5.1+/-1.2 and 8.0+/-0.9%, respectively). On the contrary, CAPS showed a marked dose-dependent vasodilating effect (E(max) 43.2+/-2.9%), antagonized by the tachykinin receptor antagonists and CGRP8-37. These results suggest, for the first time, the presence of NK1, NK2, and CGRP receptors on the retinal arteriolar wall of the rabbit.

Cyclosporin effect on rat aorta alpha(1)-adrenoceptors and their transduction mechanisms.

A possible explanation for cyclosporin-induced arterial hypertension may be its action on the adrenergic system. In spite of the controversial results reported in literature, it seems that cyclosporin changes the vascular response to noradrenaline. Therefore, after observation that two cyclosporin doses increase rat blood pressure and vascular reactivity in response to noradrenaline, the aim of this work was to study the cellular mechanisms beside the cyclosporin-induced changes in response to noradrenaline. Therefore, the cyclosporin influence on alpha(1)-adrenoceptors as well as on their transduction mechanism in smooth muscle cells was studied. Through Scatchard analysis of specific [(3)H]-prazosin binding, the alpha(1)-adrenoceptor number and related affinity were studied, before and after cyclosporin exposure. The cyclosporin influence on alpha1-adrenoceptor transduction mechanisms was also evaluated by the quantification of intracellular free calcium contents [Ca2+]i and inositol phosphate (InsP) turnover. All in vitro experiments were performed in rat aortic smooth muscle cells in culture. Results showed that both cyclosporin concentrations (10(-6) and 10(-7) M) changed alpha1-adrenoceptor number but only 10(-7) M cyclosporin increased its affinity for [(3)H]-prazosin. Compared with control cells, only 10(-7) M cyclosporin increased InsP levels. Stimulation by noradrenaline increased InsP in 10(-7) M cyclosporin-treated cells but decreased InsP in the presence of 10(-6) M cyclosporin. Both cyclosporin concentrations increased [Ca2+]i in basal conditions and after noradrenaline stimulation. The results suggest that after noradrenaline stimulation cyclosporin increases [Ca2+]i, probably through different mechanisms, depending on the cyclosporin concentration used. However, 10(-7) M cyclosporin increases alpha1-adrenoceptor affinity and their related transduction mechanisms. The higher cyclosporin concentration (10(-6) M) seems to induce downregulation of alpha1-adrenoceptors, probably by activation of protein kinase C.

Cardiovascular effects of cyclosporin treatment in an experimental model.

OBJECTIVE: This work aims to study the cardiovascular and renal effects of cyclosporin treatment. This purpose was achieved by using an animal model treated with cyclosporin in doses equivalent to the Cmin and Cmax values from human pharmacokinetics. METHODS: Wistar rats, weighing between 300 and 400 g, were treated with cyclosporin (Sandimmune Neoral) for 7 weeks. The cyclosporin was diluted in orange juice and administered in two doses: 5 and 30 mg/kg/day. The control group received only orange juice. Blood pressure was evaluated by the tail-cuff method and an ECG was also performed. Besides blood cyclosporin levels, CPK, LDH, SGPT, SGOT, sodium, potassium and creatinine in serum and protein in urine, as well as plasma lipids (triglycerides, total and HDL cholesterol), were measured. RESULTS: Both doses of cyclosporin increased blood pressure but only 30 mg/kg/day induced tachycardia. Changes in electrocardiographic profile were also observed: an increase in QTc as well as an increase in T wave amplitude. Thus, the group treated with 30 mg/kg/day of cyclosporin showed an ischemic heart disease electrocardiographic profile which was reinforced by increased CPK, SGPT and SGOT but with no changes in LDH values. None of the cyclosporin-treated rats presented cardiac hypertrophy. Despite the increase in plasma lipids there was little or no increase in body weight, which was most evident in the group that received 30 mg/kg/day of cyclosporin. No alterations were observed in serum Na+, K+ or creatinine values or in urine protein levels. CONCLUSIONS: Our results showed that the cardiovascular effects of cyclosporin in Wistar rats are characterized by arterial hypertension, ischemic heart disease and tachycardia, but not cardiac hypertrophy. However, when these changes occur, kidney function seems to be normal. These facts suggest that cyclosporin-induced cardiovascular changes, particularly hypertension, are prior to renal damage. Moreover, our cyclosporin-induced hypertension model could be useful to study drugs that could treat or prevent these changes.

Influence of Concurrent Heroin and Cocaine Abuse on the Adrenergic and Serotonergic Systems in Mana.

Drugs of abuse interfere with the adrenergic activity at the periphery and the study of their effects In Vivo at this level may contribute to understand the central mechanisms of action. Free and sulfoconjugated catecholamines and serotonin (5-hydroxytryptamine, 5-HT) were measured by high-performance liquid chromatography with electrochemical detection (HPLC-ECD); plasma dopamine (DA)-b-hydroxylase (DBH) activity was determined by a HPLC technique. When compared with healthy subjects (n = 49), the results in drug addicts (n = 48) revealed: a) Significant increases in plasma DA (free and sulfoconjugated), epinephrine (Epi)- and norepinephrine (NE)-sulfate levels; b) no significant differences in the levels of plasma free NE or Epi, serum and platelet 5-HT. Concerning DBH activity, there was a tendency for an increase. In conclusion, since catecholamines are rapidly inactivated during blood circulation, the measurement of their sulfates may better reflect catecholamine turnover. The differences found may be interpreted as a reflection of the activation of adrenergic neurotransmission, principally as a consequence of catecholamine uptake blockade by cocaine. Finally, in our conditions the abuse of cocaine plus heroin does not significantly interfere with 5-HT uptake by platelets.