Coronary hypertonia and angina

Coronary hypertonia was observed in a patient with unstable angina. It was possible on one occasion to reproduce the clinical picture, electrocardiographic changes, lactate production and coronary hypertonia by means of atrial pacing. He had a normal left coronary arteriogram when the diffuse spasm was relieved by nitroglycerin. Therefore hypertonia (or spasm) of the left coronary artery was believed to be the cause of his variant angina with subendocardial ischemia.     

Mechanism of melatonin action

Melatonin transduces the effect of photoperiod on the neuroendocrine system. Synthesis of melatonin in the pineal gland is well described, but the location of its target(s) and the mechanism of its action are little known. In attempt to localize melatonin target(s), the presence of high affinity binding sites in rat brain was determined. Such sites were detected in discrete brain areas, including the hypothalamus and anterior pituitary. Subcellular analysis indicated these binding sites were on plasma membranes, which suggests that melatonin modulates cell functions through intracellular second messengers. The effects of melatonin on second messengers were studied using the neonatal anterior pituitary, in which melatonin is known to inhibit the LHRH-induced release of LH. Studies on the effects of melatonin on second messenger indicated [corrected] that melatonin inhibits accumulation of cAMP and cGMP as well as synthesis of diacylglycerol and release of arachidonic acid. Time-course analysis indicates that inhibition by melatonin of the LHRH-induced release of LH increases following long preincubation. Since the effect of melatonin on LHRH-induced release of LH is prevented by dibutyryl cAMP, we conclude that melatonin might act by inhibiting production of cAMP.     

Mechanism of prolactin action

Most experimental information regarding the mechanism of action of prolactin in its diverse array of target tissues has been discovered using mammary tissues. Evidence has recently been presented that suggests that prolactin may be "internalized" into its target cells and have intracellular actions. Accordingly, it has been reported that prolactin stimulates RNA synthesis in isolated nuclei from mammary tissues; and by immunoflorescent studies, prolactin has been located within its target cells. It has been further suggested from additional experimental studies that the primary action of prolactin may involve its initial interaction with fixed plasma membrane receptor sites. Subsequent actions of prolactin may involve the following: a) an increased intracellular concentration of potassium and a reduced level of sodium, b) an increased level of cGMP and a reduced level of cAMP, c) an enhanced rate of prostaglandin biosyntheesis mediated by a stimulation of phospholipase A2 activity, and d) a stimulation of polyamine synthesis. It has also been shown that the actions of prolactin require calcium ions in the extracellular environment. Laboratory studies have thus indicated that the actions of prolactin may be carried out by a number of processes; but a single, primary action of this hormone that accounts for all of its actions has not yet been proven.     

Mechanism of action of cytochalasin B on actin

Substoichiometric cytochalasin B (CB) inhibits both the rate of actin polymerization and the interaction of actin filaments in solution. The polymerization rate is reduced by inhibition of actin monomer addition to the "barbed" end of the filaments where monomers normally add more rapidly. 2 microM CB reduces the polymerization rate by up to 90%, but has little effect on the rate of monomer addition at the slow ("pointed") end of the filaments and no effect on the rate of filament annealing. Under most ionic conditions tested, 2 microM CB reduces the steady state high shear viscosity by 10-20% and increases the steady state monomer concentration by a factor of 2.5 or less. In addition to the effects on the polymerization process, 2 microM CB strongly reduces the low shear viscosity of actin filaments alone and actin filaments cross-linked by a variety of macromolecules. This may be due to inhibition of actin filament-filament interactions which normally contribute to network formation. Since the inhibition of monomer addition and of actin filament network formation have approximately the same CB concentration dependence, a common CB binding site, probably the barbed end of the filament, may be responsible for both effects.     

Mechanism of action of salsolinol on tyrosine hydroxylase

Tyrosine hydroxylase (TH) is the first and rate-limiting enzyme in dopamine synthesis. Dopamine regulates TH as an end-product inhibitor through its binding to a high and low affinity site, the former being abolished by Ser40 phosphorylation only, and the latter able to bind and dissociate according to intracellular dopamine levels. Here, we have investigated TH inhibition by a dopamine metabolite found in dopaminergic brain regions, salsolinol (SAL). SAL is known to decrease dopamine in the nigrostriatal pathway and mediobasal hypothalamus, and to also decrease plasma catecholamines in rat stress models, however a target and mechanism for the effects of SAL have not been found. We found that SAL inhibits TH activity in the nanomolar range in vitro, by binding to both the high and low affinity dopamine binding sites. SAL produces the same level of inhibition as dopamine when TH is non-phosphorylated. However, it produces 3.7-fold greater inhibition of Ser40-phosphorylated TH compared to dopamine by competing more strongly with tetrahydrobiopterin, the cofactor of this enzymatic reaction. SAL’s potent inhibition of phosphorylated TH would prevent TH from being fully activated to synthesise dopamine.