Contractile effects of intracellularly administered angiotensin II are partially dependent on membrane receptors internalization in isolated rat aorta.

In the present study we used the isolated rat aorta as a model to characterize the modulation of contractile effects of extra- and intracellularly administered angiotensin II by dithiothreitol (DTT) and hyperosmotic sucrose. DTT inactivation of AT1 receptor as well as disruption of the clathrin-coated pits by hyperosmotic sucrose significantly inhibited the contraction induced by intracellularly administered AII. We suggest that these intracellular effects of angiotensin peptides are associated with AT1 receptor activation/internalization and may thus be part of the mechanism of angiotensin peptides direct contractile effects in the vascular smooth muscle.

Contractile effects of angiotensin peptides in rat aorta are differentially dependent on tyrosine kinase activity.

It has been suggested that tyrosine kinase activity participates in the regulation of signal transduction associated with angiotensin II (Ang II)-induced pharmaco-mechanical coupling in rat aortic smooth muscle. We further tested the effects of genistein, a tyrosine-kinase inhibitor, and its inactive analogue, daidzein, on angiotensin I (Ang I), angiotensin III (Ang III) and angiotensin IV (Ang IV) contractions, as compared with those on Ang II. Genistein partially inhibited Ang II- and Ang I-induced contractions. The genistein-induced inhibition was more evident on Ang III and especially important on Ang IV contractile effects. Thus, Ang IV- and Ang III-induced contractions seem to be more dependent on tyrosine kinase activity than those evoked by Ang II or Ang I. Daidzein did not significantly affect the contractile effects of any of angiotensin peptides tested. These results clearly suggest that the inhibition of the action of angiotensin peptides actions by genistein is mediated by inhibition of endogenous tyrosine kinase activity. Furthermore, our data show that the type and/or intensity of tyrosine kinase activity is differentially associated with the contractile effects of different angiotensin peptides in rat aorta. Nifedipine, a blocker of membrane L-type Ca2+ channels, strongly inhibited Ang IV-induced contractions. At the same time, it significantly inhibited Ang III contractile effects as compared with Ang II and Ang I contractions. Meanwhile, we observed a close relationship between calcium influx and tyrosine kinase phosphorylation activity under the stimulatory effects of angiotensin peptides. Furthermore, genistein did not significantly influence the phasic contractions induced by angiotensin peptides in Ca2+-free Krebs-Henseleit solution. Thus, it appears that Ca2+ influx, rather than the release of Ca2+ from IP3-sensitive stores, may play a major role in the contractile effects of angiotensin peptides in rat aorta via tyrosine kinase activation. One argument against a direct action of genistein on the Ca2+ channel itself is that it did not markedly affect the K+-induced contraction (depolarisation) in rat aorta. At the same time, a potential role for tyrosine kinase activity in the process of calcium entry is suggested. An elevation of intracellular calcium via tyrosine kinase-mediated processes may mediate the actions of G-protein coupled receptor agonists in smooth muscle, including angiotensin peptides.

Implications of imidazolines and imidazoline receptors role at the vascular level.

There are both post- and pre-synaptic vascular imidazoline (IM) binding sites. The importance of direct IM actions and that of peripheral imidazoline receptors (IRs) are shadowed by the central effects of IMs and by their interaction with alpha 2 adrenoceptors. Since the discovery of clonidine the many studies on IMs have been focused on their hypotensive effect, with rilmenidine and moxonidine as representative drugs. Formerly called IM preferring alpha 2 or IM/guanidium sites, the IRs (idazoxan-sensitive) are the plasmalemmal I1 (clonidine-sensitive) and the various I2 (one structure identified as MAO). I1 signaling includes activation of phosphatidylcholine-selective phospholipase C and inhibition of some ligand-gated channels. Inhibitory IRs on postganglionic sympathetic terminals, are not alpha 2, H3, I1 or I2. Some IMs directly affect CaL, while others inhibit K+ efflux. Clonidine-displacing substances including agmatine are endogenous ligands at IRs and alpha 2 and may participate in arterial pressure control. Beside few speculations, the roles of vascular IRs are largely unknown.

[Dipsogenic behavior]. / Comportamentul dipsogen.

Hydroelectrolytic homeostasis assumes balance between the intake and elimination of water and electrolyte, according to the necessities of the organism. The water intake is made mainly by fluid ingestion. The necessity to drink is a subjective sensation which is the expression of an objective situation, because it translates the homeostatic deviations. The ingestion of water is motivated (reparatory thirst), when it appears after hydric and electrolytic imbalances (ex. a decrease of the fluid volume, increase in the plasmatic osmolarity) or is manifested without an objective reason (unreparatory thirst).

[The effects of the intraventricular administration of captopril on water and ion metabolism in the rst]. / Efectele administrarii intracerebroventriculare de captopril asupra metabolismului apei si a unor ioni la sobolan.

The effects of the conversion enzyme on the hydroelectrolytic balance in adult rats, maintained in standard lab conditions have been followed. The administration protocol for the conversion inhibitor (captopril) produced a blocking of the transformation of angiotensin I in angiotensin II only at the level of the cerebral structures, during the whole period of the treatment (40 micrograms/kg x 3/24 hours). Following the intracerebroventricular (ICV) administration of captopril, the fluid ingestion decreased diuresis and urinary elimination of Na+ and Ca++ increased. The results plead for the existence of a cerebral renin-angiotensin system, which intervenes in the control of the hydroelectrolyte metabolism.

[The physio-pharmacological and pathological implications of the endothelins]. / Implicatii fizio-farmacologice si patologice ale endotelinelor.

The papers of Furchgott and Zawadzki have widely enlarged the research field concerning the dependence of the vascular smooth muscle reactivity upon the endothelium. Besides the relaxing factors produced by the endothelium, vasoconstrictor factors have been also emphasized. The endothelial cells are also able to synthesize endothelin-like vasoconstrictor peptides. There were described some types of endothelins. They all have common structural features but substitution of certain amino-acids leads to specific effects, and all of them keep the vasoconstrictor properties. The endothelins are normal constituents of a lot of tissues (brain, endothelial and tumor cells, the spinal nodes) and of the body fluids (plasma, urine, cerebrospinal fluid etc.). The endothelins accomplish their effects by the specific receptors located in the muscle and endothelial cell membrane (ET-A and, respectively, ET-B). The endothelins action in the cell is basically based on the cytosolic Ca2+ raise. The endothelins have numerous pathological implications, especially concerning the cardiovascular pathology.