Alain G. Dupont

Involvement of insulin-regulated aminopeptidase in the effects of the renin-angiotensin fragment angiotensin IV: a review.

For decades, angiotensin (Ang) II was considered as the end product and the only bioactive peptide of the renin–angiotensin system (RAS). However, later studies revealed biological activity for other Ang fragments. Amongst those, Ang IV has drawn a lot of attention since it exerts a wide range of central and peripheral effects including the ability to enhance learning and memory recall, anticonvulsant and anti-epileptogenic properties, protection against cerebral ischemia, activity at the vascular level and an involvement in atherogenesis. Some of these effects are AT1 receptor dependent but others most likely result from the binding of Ang IV to insulin-regulated aminopeptidase (IRAP) although the exact mechanism(s) of action that mediate the Ang IV-induced effects following this binding are until now not fully known. Nevertheless, three hypotheses have been put forward: since Ang IV is an inhibitor of the catalytic activity of IRAP, its in vivo effects might result from a build-up of IRAP’s neuropeptide substrates. Second, IRAP is co-localized with the glucose transporter GLUT4 in several tissue types and therefore, Ang IV might interact with the uptake of glucose. A final and more intriguing hypothesis ascribes a receptor function to IRAP and hence an agonist role to Ang IV. Taken together, it is clear that further work is required to clarify the mechanism of action of Ang IV. On the other hand, a wide range of studies have made it clear that IRAP might become an important target for drug development against different pathologies such as Alzheimer’s disease, epilepsy and ischemia.

Effect of carvedilol on ambulatory blood pressure, renal hemodynamics, and cardiac function in essential hypertension.

Summary: A randomized, double‐blind, placebo‐controlled study was set up to study the effects of acute and chronic administration of carvedilol, a vasodilatory &bgr;‐blocker in essential hypertension. Acute administration of a single dose of 50 mg of carvedilol reduced systolic and diastolic blood pressure, without inducing reflex tachycardia. Renal blood flow was preserved: accordingly renal vascular resistance was significantly reduced. A significant reduction of glomerular filtration rate and filtration fraction was observed. Plasma renin activity (PRA) and plasma aldosterone were not changed. Chronic carvedilol treatment produced a significant fall in systolic and diastolic office and ambulatory blood pressure, heart rate, cardiac output, PRA and plasma aldosterone. Blood pressure variability was not changed. Renal blood flow, glomerular filtration rate and filtration fraction also remained unchanged; renal vascular resistance decreased significantly. It is concluded that carvedilol possesses definite antihypertensive and renal vasodilating properties, both acutely and after chronic treatment.

Effect of Medication Reconciliation at Hospital Admission on Medication Discrepancies During Hospitalization and at Discharge for Geriatric Patients

Background: Medication discrepancies have the potential to cause harm. Medication reconciliation by clinical pharmacists aims to prevent discrepancies and other drug-related problems. Objective: To determine how often discrepancies in the physician-acquired medication history result in discrepancies during hospitalization and at discharge. Secondary objectives were to determine the influence of clinical pharmacists’ interventions on discrepancies and to investigate possible patient-related determinants for experiencing discrepancies. Methods: This was a retrospective, single-center, cohort study of patients who were admitted to the acute geriatric department of a Belgian university hospital and followed up by clinical pharmacists between September 2009 and April 2010. Patients were limited to those 65 years or older who were taking 1 or more prescription drug. Medication reconciliation at admission, during hospitalization, and at discharge was conducted by an independent pharmacist who gathered information via chart reviews. Results: The reconciliation process at admission identified 681 discrepancies in 199 patients. Approximately 81.9% (163) of patients had at least 1 discrepancy in the physician-acquired medication history. The clinical pharmacists performed 386 interventions, which were accepted in 279 cases (72.3%). A quarter of the medication history discrepancies (165; 24.2%) resulted in discrepancies during hospitalization, mostly because the intervention was not accepted. At discharge, 278 medication history discrepancies (40.8%) resulted in discrepancies in the discharge letter, accounting for 50.2% of all 554 discrepancies identified in the discharge letters. The likelihood for experiencing discrepancies at admission increased by 47% for every additional drug listed in the medication history. Conclusions: Discrepancies in the physician-acquired medication history at admission do not always correlate with discrepancies during hospitalization because of clinical pharmacists’ interventions; however, discrepancies at admission may be associated with at least half of the discrepancies at discharge. Clinical pharmacist–conducted medication reconciliation can reduce these discrepancies, provided the erroneous information in the physician-acquired medication history is corrected and each intentional change in the medication plan is well documented during hospitalization and at discharge.

Brain angiotensin peptides regulate sympathetic tone and blood pressure

Brain angiotensin II (Ang II) induces tonic sympathoexcitatory effects through AT1 receptor stimulation of glutamatergic neurons and sympathoinhibitory effects via GABAergic neurons in the rostral ventrolateral medulla, the brainstem ‘pressor area’. NADPH-derived superoxide production and reactive oxygen species signalling is critical in these actions, and AT2 receptors in the rostral ventrolateral medulla appear to mediate opposing effects on sympathetic outflow. In the hypothalamic paraventricular nucleus, Ang II has AT1 receptor-mediated sympathoexcitatory effects and enhances nitric oxide formation, which in turn inhibits the Ang II effects through a GABAergic mechanism. Ang II also decreases the tonic sympathoinhibitory effect of gamma amino butyric acid within the paraventricular nucleus. Angiotensin III and Angiotensin IV increase blood pressure via brain AT1 receptor stimulation. Angiotensin (1-7) influences cardiovascular function through a specific Mas-receptor. This review examines the evidence that brain angiotensin peptides, glutamate, gamma amino butyric acid and nitric oxide interact within the rostral ventrolateral medulla and paraventricular nucleus to control sympathetic tone and blood pressure.

Brain and peripheral angiotensin II type 1 receptors mediate renal vasoconstrictor and blood pressure responses to angiotensin IV in the rat

Objectives Angiotensin (Ang) IV was reported to increase renal cortical blood flow (CBF) via putative angiotensin IV receptor (AT4) stimulation but reduce total renal blood flow (RBF) via angiotensin II type 1 (AT1) receptors. We investigated the effect of Ang IV on simultaneously measured mean arterial pressure (MAP), RBF, and CBF. The possible involvement of AT1 or AT4 receptors, the possible natriuretic effect, and responses to central administration were also explored. Methods and results Intravenous injections of Ang IV dose dependently increased MAP and decreased CBF and RBF; these effects were abolished by AT1 receptor blockade. These reductions in CBF and RBF highly correlated as did renal vascular responses to Ang II and fenoldopam. Ang IV did not induce renal vasodilation even following AT1 receptor blockade. Intrarenal Ang IV infusion reduced CBF and RBF but had no natriuretic effect. Central Ang IV administration induced an AT1-mediated immediate increase in MAP and renal vascular resistance and a secondary increase in RBF. AT4 selective ligands, LVV-hemorphin-7 and AT4-16 (intravenous, intrarenal or intracerebroventricular), had no effects on MAP, RBF or urinary sodium excretion. Additional in-vitro experiments indicated that the majority of the Ang IV-sensitive aminopeptidase activity in kidney membranes is attributed to aminopeptidase-N. Conclusion Insulin-regulated aminopeptidase (IRAP)/AT4 receptors are involved in neither the regulation of RBF or CBF nor in the handling of renal sodium. Ang IV increases MAP and induces renal vasoconstriction via stimulation of brain and peripheral AT1 receptors and may be involved in the regulation of renal blood flow and blood pressure.

Discrepancies in Medication Information for the Primary Care Physician and the Geriatric Patient at Discharge

BACKGROUND: Medication discrepancies in discharge medication lists can lead to medication errors and adverse drug events following discharge. OBJECTIVE: To determine the incidence and type of discrepancies between the discharge letter for the primary care physician and the patient discharge medication list as well as identify possible patient-related determinants for experiencing discrepancies. METHODS: A retrospective, single-center, cohort study of patients discharged from the acute geriatric department of a Belgian university hospital between September 2009 and April 2010 was performed. Medications listed in the discharge letter for the primary care physician were compared with those in the patient discharge medication list. Based on the clinical pharmacist–acquired medication list at hospital admission and the medications administered during hospitalization, we determined for every discrepancy whether the medication listed in the discharge letter or the patient discharge medication list was correct. RESULTS: One hundred eighty-nine discharged patients (mean [SD] age 83.9 [5.7] years, 64.0% female) were included in the study. Almost half of these patients (90; 47.6%) had 1 or more discrepancies in medication information at discharge. The discharge letters were often more complete and accurate than the patient discharge medication lists. The most common discrepancies were omission of a brand name in the patient discharge medication list and omission of a drug in the discharge letter. Increasing numbers of drugs in the discharge medication list (OR 1.19; 95% CI 1.07 to 1.32; p = 0.001) and discharge letter (OR 1.18; 95% CI 1.07 to 1.32; p = 0.001) were associated with a higher risk for discrepancies. CONCLUSIONS: Discrepancies between the patient discharge medication list and the medication information in the discharge letter for the primary care physician occur frequently. This may be an important source of medication errors, as confusion and uncertainty about the correct discharge medications can originate from these discrepancies. Increasing numbers of drugs involve a higher risk for discrepancies. Medication reconciliation between both lists is warranted to avoid medication errors.

Pressor and Renal Hemodynamic Effects of the Novel Angiotensin A Peptide Are Angiotensin II Type 1A Receptor Dependent

Recently, a new derivative of angiotensin (Ang) II, called “Ang A,” has been discovered to be present in plasma of healthy humans and, in increased concentrations, in end-stage renal failure patients. The objectives of the study were to investigate the blood pressure and renal hemodynamic responses to Ang A in normotensive and hypertensive rats and in genetically modified mice and the binding properties of Ang A to Ang II type 1 (AT1) or Ang II type 2 (AT2) receptors. Intravenous and intrarenal administration of Ang A induced dose-dependent pressor and renal vasoconstrictor responses in normotensive rats, which were blocked by the AT1 receptor antagonist candesartan but were not altered by the AT2 receptor ligands PD123319, CGP42112A, or compound 21. Similar responses were observed after intravenous administration in spontaneously hypertensive rats. Deletion of AT1a receptors in mice almost completely abolished the pressor and renal vasoconstrictor responses to Ang A, indicating that its effects are mediated via AT1a receptors. Ang A was less potent than Ang II in vivo. The in vitro study demonstrated that Ang A is a full agonist for AT1 receptors, with similar affinity for AT1 and AT2 receptors as Ang II. Overall, the responses to Ang A and Ang II were similar. Ang A has no physiological role to modulate the pressor and renal hemodynamic effects of Ang II.

Influence of the dopamine receptor agonists fenoldopam and quinpirole in the rat superior mesenteric vascular bed

1 The effect of local administration of the dopamine2 (DA2)‐receptor agonist quinpirole and of the DA1‐receptor agonist fenoldopam was studied in the in situ, constant flow autoperfused, superior mesenteric vascular bed of the rat. 2 Local infusion of quinpirole (30 μg kg−1 min−1 for 5 min) had no effect on baseline perfusion pressure; it reduced the pressor responses to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial sympathetic nerves to 45.6 ± 2.1% of its original value but did not modify similar pressor responses produced by locally administered noradrenaline. 3 The inhibitory effect of quinpirole was antagonized by the selective DA2‐receptor antagonist domperidone (10 μg kg−1) but not by the selective DA1‐receptor antagonist SCH 23390 (50 μg kg−1). 4 Local infusion of fenoldopam (30 μg kg−1 min−1 for 5 min) reduced baseline perfusion pressure to 89.9 ± 1.9%, increased the pressor response to electrical stimulation (4 Hz, 1 ms, supramaximal voltage) of the periarterial nerves to 134.7 ± 14.0%, but reduced the pressor response to locally administered noradrenaline to 37.2 ± 8.2%. Similar pressor responses induced by the selective α1‐adrenoceptor agonist phenylephrine were also reduced by fenoldopam (to 38.4 ± 6.4%), but responses to locally administered angiotensin II were not modified. 5 Pretreatment with SCH 23390 (50 μg kg−1) antagonized the effect of fenoldopam on baseline perfusion pressure, but had no influence on the effect of fenoldopam on responses to electrical stimulation or to noradrenaline. 6 Pretreatment with the selective α2‐adrenoceptor antagonist rauwolscine (100 μg kg−1) had no effect on the reduction in baseline perfusion pressure induced by fenoldopam nor on its inhibitory effect on the response to noradrenaline, but it antagonized the stimulatory effect of fenoldopam on the response to electrical stimulation. 7 The results show that quinpirole inhibits neurogenic vasoconstriction in the rat superior mesenteric vascular bed through stimulation of presynaptic DA2‐receptors while fenoldopam stimulates postsynaptic vasodilatory DA1‐receptors. In addition, our results suggest that the inhibitory effect of fenoldopam on the vasoconstrictor response to noradrenaline may be due to an antagonistic action at postsynaptic α1‐adrenoceptors, while its potentiating effect on neurogenic vasoconstriction is due to blockade of presynaptic α2‐adrenoceptors.

Angiotensin II Type 2 Receptor–Mediated and Nitric Oxide–Dependent Renal Vasodilator Response to Compound 21 Unmasked by Angiotensin-Converting Enzyme Inhibition in Spontaneously Hypertensive Rats In Vivo

Angiotensin II type 2 receptor (AT2R)–mediated vasodilation has been demonstrated in different vascular beds in vitro and in perfused organs. In vivo studies, however, consistently failed to disclose renal vasodilator responses to compound 21, a selective AT2R agonist, even after angiotensin II type 1 receptor blockade. Here, we investigated in vivo whether angiotensin-converting enzyme inhibition, reducing endogenous angiotensin II levels, could unmask the effects of selective AT2R stimulation on blood pressure and renal hemodynamics in normotensive and hypertensive rats. After pretreatment with the angiotensin-converting enzyme inhibitor captopril, intravenous administration of compound 21 did not affect blood pressure and induced dose-dependent renal vasodilator responses in spontaneously hypertensive but not in normotensive rats. The D1 receptor agonist fenoldopam, used as positive control, reduced blood pressure and renal vascular resistance in both strains. The AT2R antagonist PD123319 and the nitric oxide synthase inhibitor L-NMMA (NG-monomethyl-L-arginine acetate) abolished the renal vasodilator response to compound 21 without affecting responses to fenoldopam. The cyclooxygenase inhibitor indomethacin partially inhibited the renal vascular response to compound 21, whereas the bradykinin B2 receptor antagonist icatibant was without effect. Angiotensin-converting enzyme inhibition unmasked a renal vasodilator response to selective AT2R stimulation in vivo, mediated by nitric oxide and partially by prostaglandins. AT2R may have a pathophysiological role to modulate renal hemodynamic effects of angiotensin II in the hypertensive state.

Identification of a D1 dopamine receptor, not linked to adenylate cyclase, on lactotroph cells

1 We studied the lactotroph cells of the rat by both in vivo and in vitro pharmacological techniques for the presence of D1‐receptors. Both approaches revealed the presence of a D2‐receptor, stimulated by quinpirole (resulting in an inhibition of prolactin secretion) and blocked by domperidone. 2 Administration of fenoldopam, the most selective D1‐receptor agonist currently available, resulted in a dose‐dependent decrease of prolactin secretion in vivo (after pretreatment with α‐methyl‐p‐tyrosine) and in vitro (cultured pituitary cells). This increase was dose‐dependently blocked by the selective D1‐receptor antagonist, SCH 23390, and although the effect of fenoldopam was less than that obtained by D2‐receptor stimulation, these data suggest that a D1‐receptor also controls prolactin secretion. 3 In order to detect the location of these dopamine receptors, autoradiographic studies were performed by use of [3H]‐SCH 23390 and [3H]‐spiperone as markers for D1 and D2‐receptors, respectively. Specific binding sites for [3H]‐SCH 23390 were demonstrated. Fenoldopam dose‐dependently reduced [3H]‐SCH 23390 binding, but had no effect on [3H]‐spiperone binding. Immunocytochemical labelling of prolactin cells after incubation with [3H]‐SCH 23390 revealed that the granulae and hence, D1 binding sites were present on the lactotroph cells. 4 Radioligand binding studies performed on membranes from anterior pituitary cells revealed the presence of the D2‐receptor (54 fmol mg−1 protein) with a Kd of 0.58 nm for [3H]‐spiperone, but failed to detect D1 ‐receptors. 5 Finally, we studied the effect of dopamine and of fenoldopam on the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) content of anterior pituitary cells. Although cyclic AMP increased upon prostacyclin administration, indicating an intact adenylate cyclase system, fenoldopam failed to increase the cyclic AMP production. 6 It is tempting to speculate that fenoldopam reduces prolactin secretion through interaction with a non‐cyclase‐linked D1‐receptor on the lactotroph cells.