Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists.

Angiotensin II (AngII) regulates cerebral circulation and binds with a similar affinity to AT and AT receptors. Biased AT agonists, such as TRV027, which are able to selectively activate β-arrestin while blocking the G pathway, appear promising as new therapeutics. New pharmacological tools are needed to further explore the impact of biased AT agonists on cells or tissues, such as the cerebral vessels.

PBPK modeling: What is the role of CYP3A4 expression in the gastrointestinal tract to accurately predict first-pass metabolism?

Gastrointestinal first-pass metabolism plays an important role in bioavailability and in drug-drug interactions. Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool to integrate these processes mechanistically. However, a correct bottom-up prediction of GI first-pass metabolism is challenging and depends on various model parameters like the level of enzyme expression and the basolateral intestinal mucosa permeability (P).

The AT/AT Receptor Equilibrium Is a Cornerstone of the Regulation of the Renin Angiotensin System beyond the Cardiovascular System.

The AT receptor has mainly been associated with the pathological effects of the renin-angiotensin system (RAS) (e.g., hypertension, heart and kidney diseases), and constitutes a major therapeutic target.

Basic Life Support Knowledge among Junior Medical and Dental Students, Communication Channels, and the COVID-19 Pandemic.

Background and objective: The prognosis of cardiac arrest victims strongly depends on the prompt provision of Basic Life Support (BLS) maneuvers. Medical students should therefore be proficient in this area, but many lack essential BLS knowledge. The goal of this prospective, closed web-based study was to determine whether a short intervention designed to motivate first-year medical students to follow a blended BLS course could lead to a significant improvement in BLS knowledge in the following year.

Clinical and Organizational Impacts of Medical Ordering Settings on Patient Pathway and Community Pharmacy Dispensing Process: The Prospective ORDHOSPIVILLE Study.

During the dispensing process of medical orders (MOs), community pharmacists (CPs) can manage drug-related problems (DRPs) by performing pharmacist interventions (PIs). There is little evidence that the PI rate is higher with MOs from hospitals (MOHs) than ambulatory (MOAs) settings, and their impact on the patient and community pharmacy is unknown. The primary objective of this study was to compare the MOH and MOA PI rates.

Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes.

The physiological and pathophysiological relevance of the angiotensin II type 1 (AT) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin-angiotensin system and the AT receptor are the targets of several classes of therapeutics (such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, ARBs) used as first-line treatments in cardiovascular diseases. The importance of AT in the regulation of the cerebrovascular system is also acknowledged.

S-nitrosoglutathione inhibits cerebrovascular angiotensin II-dependent and -independent AT receptor responses: A possible role of S-nitrosation.

Background And Purpose: Angiotensin II (AngII) and NO regulate the cerebral circulation. AngII AT receptors exert ligand-dependent and ligand-independent (myogenic tone [MT]) vasoconstriction of cerebral vessels. NO induces post-translational modifications of proteins such as S-nitrosation (redox modification of cysteine residues).

Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor.

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands.

No answer to the lack of specificity: mouse monoclonal antibody targeting the angiotensin II type 1 receptor AT fails to recognize its target.

Numerous antibodies targeting G protein-coupled receptors (GPCRs) have been described as non-specific among the polyclonal antibodies against angiotensin II type 1 receptor (AT). We have tested the newly developed AT receptor mouse monoclonal antibody for its specificity. Human embryonic kidney (HEK293) cells, which do not endogenously express AT receptor, were transfected in order to overexpress a fluorescently labeled enhanced green fluorescent protein (EGFP)-tagged human AT receptor.

In vivo and in silico evaluation of a new nitric oxide donor, S,S'-dinitrosobucillamine.

Purpose: In a previous work, we have synthetized a new dinitrosothiol, i.e. S,S'-dinitrosobucillamine BUC(NO) combining S-nitroso-N-acetylpenicillamine (SNAP) and S-nitroso-N-acetylcysteine (NACNO) in its structure.

In Situ Microparticles Loaded with S-Nitrosoglutathione Protect from Stroke.

Treatment of stroke, especially during the first hours or days, is still lacking. S-nitrosoglutathione (GSNO), a cerebroprotective agent with short life time, may help if administered early with a sustain delivery while avoiding intensive reduction in blood pressure. We developed in situ forming implants (biocompatible biodegradable copolymer) and microparticles (same polymer and solvent emulsified with an external oily phase) of GSNO to lengthen its effects and allow cerebroprotection after a single subcutaneous administration to Wistar rats.

Impact of short-term treatment with telmisartan on cerebral arterial remodeling in SHR.

Background And Purpose: Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR.

Are in situ formulations the keys for the therapeutic future of S-nitrosothiols?

S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylpenicillamine (SNAP) were formulated into in situ forming implants (ISI) and microparticles (ISM) using PLGA and either N-methyl-2-pyrrolidone (NMP) or triacetin. Physicochemical characterization was carried out, including the study of matrix structure and degradation. A strong correlation between drug hydrophobicity and the in vitro release profiles was observed: whatever the formulation, GSNO and SNAP were completely released after ca.

Differential effects of short-term treatment with two AT1 receptor blockers on diameter of pial arterioles in SHR.

Chronic treatment with angiotensin receptor blockers is largely accepted for protecting cerebral circulation during hypertension, but beneficial effects of short-term treatments are questionable, as highlighted by the recent SCAST trial. We compared the impact of 10 days treatment with candesartan (as SCAST) versus telmisartan (previously described to reverse arteriolar remodeling, chronic treatment) on pial arterioles of spontaneously hypertensive rats (SHR). We explored whether PPAR-gamma agonist activity or AT(1) receptor blockade are involved in their differential effects.

Formulation, characterization and pharmacokinetic studies of coenzyme Q₁₀ PUFA's nanoemulsions.

Coenzyme Q(10) (CoQ(10)) is an insoluble antioxidant molecule with great biological value but exhibit poor bioavailability. To improve the bioavailability of CoQ(10), we have proposed to formulate a nanoemulsion consisting of salmon oil, salmon lecithin, CoQ(10) and water. A commercial oily mixture, based on soybean oil and CoQ(10), was used for comparison, as well as a second oily mixture, composed of salmon lecithin, salmon oil and CoQ(10).

High salt intake abolishes AT(2)-mediated vasodilation of pial arterioles in rats.

Background: Angiotensin II (Ang II) induces constriction (AT(1)) and dilation (AT(2) receptors) of cerebral arterioles. High sodium intake induces changes in receptors expression and loss of AT(2)-mediated vasodilation in extracerebral vessels. We investigated whether high salt modifies the AT(2)-mediated response of cerebral arterioles.

Effects of suboptimal doses of the AT1 receptor blocker, telmisartan, with the angiotensin-converting enzyme inhibitor, ramipril, on cerebral arterioles in spontaneously hypertensive rat.

Objective: Antihypertensive treatment with standard clinical doses of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) reverses cerebral arteriolar remodeling, thus restoring dilatation and the lower limit of cerebral blood flow (CBF) autoregulation (LL CBF AR). In humans, a combination of standard clinical doses of the two drugs does not produce greater protection against stroke than that obtained with single-drug treatments and increases the risk of side-effects. We hypothesized that a combination of suboptimal doses of the ARB, telmisartan (TEL) and of the ACEI, ramipril (RAM), could be a well tolerated and effective treatment of hypertension-induced remodeling of cerebral arterioles.

Comparative effects of the angiotensin II receptor blocker, telmisartan, and the angiotensin-converting enzyme inhibitor, ramipril, on cerebrovascular structure in spontaneously hypertensive rats.

Objective: Antihypertensive treatment with angiotensin-converting enzyme inhibitors (ACEIs) reverses cerebral arteriolar remodeling, thus restoring dilatation and hence the lower limit of cerebral blood flow (CBF) autoregulation (LLCBF). The objective of this study was to determine whether angiotensin II receptor AT1 blockers (ARBs) produce the same effect.

Design: We examined the effects of treatment with an ARB [telmisartan (TEL), 1.

Captopril improves cerebrovascular structure and function in old hypertensive rats.

We examined the effects of an angiotensin-converting enzyme inhibitor (ACEI), captopril, on cerebral arterioles in young and old spontaneously hypertensive rats (SHR). Animals were anesthetized with sodium pentobarbitone (60 mg kg(-1) day(-1)). We measured cerebral blood flow (CBF, arbitrary units) and cerebral arteriolar internal diameter (ID, mum) prior to and during stepwise hypotension (SH) in 6- (WKY-6) and 15-month-old (WKY-15) Wistar Kyoto rats and in age-matched SHR that were untreated (SHR-6 and SHR-15) or treated for 3 months with captopril (SHR-6C, 105+/-2 mg kg(-1) day(-1) and SHR-15C, 94+/-1 mg kg(-1) day(-1)).

Visual p300 effects beyond symptoms in concussed college athletes.

In order to assess whether cerebral anomalies may be observed in the absence of clinical symptoms, the current study compared the effects of concussions on attentional capacities (reaction times, accuracy) and Event-Related Potentials (ERPs) in concussed athletes with (n = 10) or without (n = 10) symptoms as well as in athletes who never had a concussion (n = 10). The P300 response was recorded from 28 electrodes during a modified visual oddball paradigm. Participants were instructed to press a key upon the appearance of the frequent stimuli as well as when a rare nontarget stimulus followed the frequent one.

Impact of treatment with melatonin on cerebral circulation in old rats.

Melatonin deprival in young rats induces alterations in cerebral arteriolar wall similar to those observed during aging: atrophy and a decrease in distensibility. In this study, we examined the effects of melatonin treatment on cerebral arteriolar structure and distensibility and on the lower limit of cerebral blood flow autoregulation (LLCBF) in old rats. We measured cerebral blood flow (arbitrary unit, laser Doppler, open skull preparation) prior to and during stepwise hypotension (SH) in adult (12/13 months) and old (24/25 months) IcoWI and WAG/Rij male rats.