Chronic imipramine administration alters the activity and phosphorylation state of tyrosine hydroxylase in dopaminergic regions of rat brain.

In the present study the influence of imipramine, a tricyclic antidepressant, on the expression and function of tyrosine hydroxylase (TH) in dopaminergic rat brain regions was examined. Chronic administration of imipramine (18 days) decreased levels of TH enzyme activity in ventral tegmental area (VTA) and substantia nigra (SN), dopaminergic cell body regions, as well as in caudate-putamen (CP), nucleus accumbens (ACB), prefrontal cortex (PFC), and olfactory tubercle (OT), dopaminergic terminal fields. These effects were dependent on chronic drug treatment, as imipramine administration for 1 or 7 days did not significantly influence levels of TH activity in either SN or VTA. In contrast to drug regulation of enzyme activity, chronic imipramine treatment did not decrease levels of TH immunoreactivity in any of the dopaminergic cell body or terminal field regions studied, although levels of TH immunoreactivity were decreased in locus coeruleus (LC) as previously reported. However, imipramine treatment increased levels of TH back phosphorylation in VTA, suggesting that the antidepressant-induced decrease in levels of TH activity is a result of decreased phosphorylation of the enzyme. These results demonstrate that imipramine treatment regulates levels of TH enzyme activity in dopaminergic brain regions, and may account for some of the previously observed effects of these drugs on dopaminergic function. Finally, imipramine regulation of TH enzyme activity in VTA and immunoreactivity in LC was observed in Sprague Dawley, but not Wistar rats, demonstrating that different rat strains exhibit different biochemical responses to antidepressant treatment.

Why is nisoldipine a specific agent in ischemic left ventricular dysfunction?

Nisoldipine is a dihydropyridine calcium entry blocker that inhibits contraction of vascular smooth muscle with a potency that is 2-3 times greater than its impact on myocardial contractility. In isolated human coronary arteries, tonic contractions induced by serotonin are inhibited by nisoldipine with a potency 10 times greater than that in internal mammary arteries and 1,000 times greater than that in electrically driven myocardium. In contrast, nifedipine had little effect and verapamil and diltiazem had none. In this article an hypothesis is reviewed that relates vascular smooth muscle selectivity to membrane potential sensitivity. Nisoldipine's effect on calcium channel binding and blocking is enhanced by the degree of depolarization of the cell membrane. Verapamil and diltiazem are not membrane-potential sensitive. Vascular smooth muscle cells are more depolarized than myocardial cells, and human coronary arteries have a particularly small membrane potential. Thus, the potency of nisoldipine in these organs parallels the degree of membrane depolarization. This may then suggest ischemia selectivity, since membrane depolarization occurs in ischemic tissue. Nisoldipine might therefore have a potent negative inotropic effect and an enhanced vasodilator action in ischemic myocardium, yet leave normoxic regions functionally intact. Some experimental evidence is discussed.

Influence of nifedipine on experimental arteriosclerosis.

The nonhemodynamic actions of nifedipine and some other calcium antagonists are reviewed with regard to their relevance to the vasculoprotective and antiarteriosclerotic action of calcium antagonists. Nifedipine, and in order of declining potency, verapamil and diltiazem were shown to inhibit vascular myocyte proliferation and migration. Also, the incorporation of cholesteryl esters into macrophages or myocytes was inhibited by dihydropyridines and verapamil but not by diltiazem. The cholesterol and calcium contents were found to be lowered in the aortae of hypercholesterinemic rabbits treated chronically with dihydropyridine calcium antagonists. Replacement of damaged vascular endothelium and internal elastic lamina was seen in hypertensive Dahl-S rats after 6 weeks of antihypertensive treatment with nifedipine. In addition to their blood-pressure lowering action, these nonhemodynamic effects might be involved in the prevention and reversal of hypertensive vascular disease and neuropathologic symptoms observed after the treatment of hypertensive rats with nifedipine or other dihydropyridine calcium antagonists, since these therapeutic effects were also seen after blood-pressure neutral doses.

The anxiogenic beta-carboline FG-7142 increases in vivo and in vitro tyrosine hydroxylation in the prefrontal cortex.

Systemic administration of the anxiogenic beta-carboline FG-7142, a benzodiazepine inverse agonist, results in a regionally selective increase in dopamine (DA) utilization in the anteromedial prefrontal cortex (PFC). We have examined both in vivo and in vitro tyrosine hydroxylation in the PFC and other mesotelencephalic DA system terminal fields in order to determine if FG-7142 effects changes in DA synthesis, and to determine if the beta-carboline biochemically activates certain DA neurons through an action occurring at the cell body level (impulse-dependent regulation) or at the terminal field level (presynaptic regulation). FG-7142 increased in vivo tyrosine hydroxylation in the PFC and in the ventral tegmental area, midbrain source of the DA innervation of the PFC; no changes were observed in mesolimbic or nigrostriatal regions. The beta-carboline also increased in vitro tyrosine hydroxylation in the PFC, but decreased tyrosine hydroxylation in striatal slices. The effects of FG-7142 were blocked by the benzodiazepine antagonist RO 15-1788. Another beta-carboline inverse agonist, methyl-beta-carboline-3-carboline-3-carboxylate, also increased in vitro tyrosine hydroxylation in the PFC. GABA exerted opposite effects to those of the beta-carbolines, decreasing in vitro tyrosine hydroxylation in the PFC and increasing DA synthesis in the CP. These data indicate that the benzodiazepine inverse agonists increase both in vivo and in vitro tyrosine hydroxylation in the PFC, and that the beta-carboline may act to increase DA synthesis at both the terminal field and the cell body level.

Modulation by chronic nifedipine of plasma atrial natriuretic peptide, cell Na+ transport and plasma volume in rats with renal hypertension.

The influence of a 6-week treatment of female Wistar rats with one-kidney, one clip (1-K, 1 C) renal hypertension, with the calcium antagonist nifedipine on plasma volume, red cell Na+ handling and plasma atrial natriuretic peptide immunoreactivity (ANP-IR) was studied. Measurements were performed at 2 and 6 weeks after surgery. In 1-K, 1 C rats plasma volume was increased and red cell Na+ pump activity was reduced only after 2 weeks. Blood pressure, heart weights and plasma ANP were massively increased after both 2 and 6 weeks. 1-K, 1 C-rats treated with nifedipine had normal plasma volume, plasma ANP, and red cell Na+ pump activity in comparison with sham-operated rats. Increases in blood pressure and heart weights were attenuated. It is concluded that 1-K, 1 C hypertension in the rat is associated with cardiomegaly, rise in plasma ANP, initial hypervolemia and depression of the membrane Na+ pump. Nifedipine prevents the occurrence of hypervolemia and secondary phenomena such as rises in plasma ANP and cardiomegaly. This may play an important contributory role in the prevention of pathological sequelae.