Immunosuppressant regimen based on sirolimus decreases aortic stiffness in renal transplant recipients in comparison to cyclosporine.

Whether or not a cyclosporine A (CsA)-free immunosuppressant regimen based on sirolimus (SRL) prevents aortic stiffening and improves central hemodynamics in renal recipients remains unknown. Forty-four patients (48 ± 2 years) enrolled in the CONCEPT trial were randomized at week 12 (W12) to continue CsA or switch to SRL, both associated with mycophenolate mofetil. Carotid systolic blood pressure (cSBP), pulse pressure (cPP), central pressure wave reflection (augmentation index, AIx) and carotid-to-femoral pulse-wave velocity (PWV: aortic stiffness) were blindly assessed at W12, W26 and W52 together with plasma endothelin-1 (ET-1), thiobarbituric acid-reactive substances (TBARS) and superoxide dismutase (SOD) and catalase erythrocyte activities. At W12, there was no difference between groups. At follow-up, PWV, cSBP, cPP and AIx were lower in the SRL group. The difference in PWV remained significant after adjustment for blood pressure and eGFR. In parallel, ET-1 decreased in the SRL group, while TBARS, SOD and catalase erythrocyte activities increased in both groups but to a lesser extent in the SRL group. Our results demonstrate that a CsA-free regimen based on SRL reduces aortic stiffness, plasma endothelin-1 and oxidative stress in renal recipients suggesting a protective effect on the arterial wall that may be translated into cardiovascular risk reduction.

To what extent is it possible to dissociate the anxiolytic and sedative/hypnotic properties of GABAA receptors modulators?

The relatively common view indicates a possible dissociation between the anxiolytic and sedative/hypnotic properties of benzodiazepines (BZs). Indeed, GABAA receptor (GABAAR) subtypes have specific cerebral distribution in distinct neural circuits. Thus, GABAAR subtype-selective drugs may be expected to perform distinct functions. However, standard behavioral test assays provide limited direction towards highlighting new action mechanisms of ligands targeting GABAARs. Automated behavioral tests, lack sensitivity as some behavioral characteristics or subtle behavioral changes of drug effects or that are not considered in the overall analysis (Ohl et al., 2001) and observation-based analyses are not always performed. In addition, despite the use of genetically engineered mice, any possible dissociation between the anxiolytic and sedative properties of BZs remains controversial. Moreover, the involvement the different subtypes of GABAAR subtypes in the anxious behavior and the mechanism of action of anxiolytic agents remains unclear since there has been little success in the pharmacological investigations so far. This raises the question of the involvement of the different subunits in anxiolytic-like and/or sedative effects; and the actual implication of these subunits, particularly, α-subunits in the modulation of sedation and/or anxiety-related disorders. This present review was prompted by several conflicting studies on the degree of involvement of these subunits in anxiolytic-like and/or sedative effects. To this end, we explored the GABAergic system, particularly, the role of different subunits containing synaptic GABAARs. We report herein the targeting gene encoding the different subunits and their contribution in anxiolytic-like and/or sedative actions, as well as, the mechanism underlying tolerance to BZs.

5-HT2C receptors in psychiatric disorders: A review.

5-HT2Rs have a different genomic organization from other 5-HT2Rs. 5HT2CR undergoes post-transcriptional pre-mRNA editing generating diversity among RNA transcripts. Selective post-transcriptional editing could be involved in the pathophysiology of psychiatric disorders through impairment in G-protein interactions. Moreover, it may influence the therapeutic response to agents such as atypical antipsychotic drugs. Additionally, 5-HT2CR exhibits alternative splicing. Central serotonergic and dopaminergic systems interact to modulate normal and abnormal behaviors. Thus, 5HT2CR plays a crucial role in psychiatric disorders. 5HT2CR could be a relevant pharmacological target in the treatment of neuropsychiatric disorders. The development of drugs that specifically target 5-HT2C receptors will allow for better understanding of their involvement in the pathophysiology of psychiatric disorders including schizophrenia, anxiety, and depression. Among therapeutic means currently available, most drugs used to treat highly morbid psychiatric diseases interact at least partly with 5-HT2CRs. Pharmacologically, 5HT2CRs, have the ability to generate differentially distinct response signal transduction pathways depending on the type of 5HT2CR agonist. Although this receptor property has been clearly demonstrated, in vitro, the eventual beneficial impact of this property opens new perspectives in the development of agonists that could activate signal transduction pathways leading to better therapeutic efficiency with fewer adverse effects.

Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure : role of nitric oxide, prostanoids, oxidant stress, and bradykinin.

BACKGROUND-Chronic heart failure (CHF) impairs the endothelium-dependent, flow-mediated dilation (FMD) of small arteries. However, whether chronic angiotensin-converting enzyme (ACE) inhibition affects the impairment of FMD in CHF is unknown. We investigated the effects of long-term ACE inhibition on the FMD of peripheral arteries in rats with CHF and the mechanism(s) involved. METHODS AND RESULTS-FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perindopril 2 mg. kg(-1). day(-1) for 10 weeks) rats with CHF (coronary artery ligation). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor N(W)-nitro-L-arginine, the cyclooxygenase inhibitor diclofenac, or the free radical scavenger N-2-mercaptopropionyl-glycine (MPG). Endothelial NO synthase mRNA expression was determined by reverse transcriptase polymerase chain reaction. In animals with hemodynamic and echographic signs of CHF, FMD was converted into vasoconstriction, and this was prevented by ACE inhibition. FMD of arteries from sham-operated or ACE inhibitor-treated CHF rats was abolished by N(W)-nitro-L-arginine. In untreated CHF rats, FMD was increased by diclofenac and MPG. In contrast, in arteries from ACE inhibitor-treated rats, neither diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevented the reduction of endothelial NO synthase mRNA by CHF. CONCLUSIONS-In CHF, ACE inhibition normalized NO-dependent dilatation and suppressed the production of vasoconstrictor prostanoid(s), resulting in improved FMD. The improvement of FMD might contribute to the beneficial effects of ACE inhibition during CHF.

Functional evidence for a role of vascular chymase in the production of angiotensin II in isolated human arteries.

BACKGROUND: In human arteries, angiotensin-converting enzyme (ACE) inhibitors incompletely block the production of angiotensin (Ang) II from Ang I. This ACE-independent production of Ang II appears to be caused by serine proteases, one of which presumably is chymase. However, several serine proteases may produce Ang II, and the exact role of chymase in the vascular production of Ang II has never been directly evaluated using selective chymase inhibitors. METHODS AND RESULTS: Rings of human mammary arteries were subjected to either Ang I or the chymase-selective substrate [pro,(11) D-Ala(12)] Ang I in the absence or the presence of the ACE inhibitor captopril, the serine protease inhibitor chymostatin, or the selective chymase inhibitor C41. Captopril only partially inhibited (by 33%) the response to Ang I. In the absence of captopril, C41 markedly reduced (by 44%) the response to Ang I, and this effect was identical to that of chymostatin. C41 also significantly reduced the response to Ang I in the presence of captopril, although this inhibitory effect was slightly less than that of captopril in combination with chymostatin. [Pro,(11)D-Ala(12)] Ang I induced potent contractions that were not affected by captopril but were abolished by chymostatin and markedly reduced by C41. In addition, we found that prior treatment of the patients with an ACE inhibitor did not affect the in vitro response to Ang I (in the absence or the presence of captopril) or to [Pro,(11)D-Ala(12)] Ang I. CONCLUSIONS: Our results reinforce the hypothesis that chymase is a major serine protease implicated in the ACE-independent production of Ang II in human arteries.

Hemodynamic stresses induce endothelial dysfunction and remodeling of pulmonary artery in experimental compensated heart failure.

BACKGROUND: We hypothesized that, in compensated heart failure (HF), hemodynamic perturbations and their consequences exist in pulmonary artery (PA) despite the absence of any perturbation in thoracic aorta (TA). METHODS AND RESULTS: The left coronary artery was ligated in 20 male Wistar rats with compensated HF. Four months after ligation, these rats were compared with 20 sham-operated control rats. Blood pressure, velocity, viscosity, luminal diameter, and wall tensile and shear stresses were determined in PA and TA. Arterial rings were mounted in a myograph for ex vivo study. Endothelial nitric oxide synthase (eNOS) mRNA expression was determined in lung and aorta. Sections of PA and TA were used for histomorphometric study. In PA from rats with compensated HF, (1) blood pressure and wall tensile stress increased, whereas blood velocity and wall shear stress decreased; (2) contractions to KCl were not altered, but maximal contraction to phenylephrine and EC(50) decreased; (3) endothelium-dependent relaxation to acetylcholine and basal NO activity were blunted, whereas endothelium-independent relaxation was preserved; (4) eNOS mRNA levels and eNOS transcription in lung nuclei decreased; and (5) medial cross-sectional area, thickness, smooth muscle cell number, elastin, and collagen contents increased. Conversely, no such changes were found in TA from rats with compensated HF. CONCLUSIONS: In compensated HF induced by small myocardial infarction, hemodynamics, vascular wall function, and structure are altered in PA but preserved in TA. These results indicate that the pulmonary vascular bed is an early target of regional circulatory alterations in HF.

Protective effects of preconditioning in cultured rat endothelial cells: effects on neutrophil adhesion and expression of ICAM-1 after anoxia and reoxygenation.

BACKGROUND: Preconditioning with brief periods of ischemia protects the coronary endothelium against acute and chronic reperfusion injury, but the mechanisms of this endothelial protection remain unknown. We hypothesized that preconditioning protects endothelial cells through a decreased production of endothelial adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), leading to a lesser adhesion of neutrophils to the endothelium. METHODS AND RESULTS: Cultured rat aortic endothelial cells were subjected to 6-hour anoxia followed by various durations of reoxygenation. Preconditioning was induced by 1-hour anoxia and 1-hour reoxygenation. ICAM-1 gene expression was measured by polymerase chain reaction, and the percentage of cells expressing ICAM-1 was assessed by confocal laser fluorescence microscopy. Anoxia/reoxygenation increased expression of ICAM-1, with a peak occurring after 6 hours of reoxygenation for mRNA and 9 hours for protein. Preconditioning prevented the increase in ICAM-1. Similar reductions were observed with the free radical scavenger N-2 mercaptopropionyl glycine (MPG). The inhibitory effect of preconditioning on ICAM-1 expression was abolished by an inhibitor of protein kinase C, an inhibitor of nitric oxide synthesis, and by MPG but was not affected by an adenosine receptor antagonist. Finally, both preconditioning and MPG partially prevented the increased adhesion of human neutrophils to reoxygenated endothelial cells. CONCLUSIONS: Preconditioning prevented reoxygenation-induced, free radical-mediated expression of ICAM-1 by a mechanism involving activation of protein kinase C and production of nitric oxide and free radicals, and this is associated with a lesser adhesion of neutrophils to endothelial cells. Such prevention of neutrophil adhesion may contribute to the protective effect of preconditioning against reperfusion-induced endothelial injury.

Selective endothelin-A versus combined endothelin-A/endothelin-B receptor blockade in rat chronic heart failure.

BACKGROUND: The relative efficacy of endothelin-A (ET(A)) receptor blockade versus combined ET(A)-ET(B) receptor blockade in chronic heart failure (CHF) is still largely unknown. METHODS AND RESULTS: We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ET(A) antagonist ABT-627 (5 mg x kg(-1) x d(-1)), the ET(B) antagonist A-192621 (30 mg x kg(-1) x d(-1)) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ET(A) blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ET(B) blockade). ET(A) and combined ET(A)-ET(B) blockade reduced systolic blood pressure to the same extent, whereas ET(B) blockade had no effect. In contrast, only combined ET(A)-ET(B) blockade significantly reduced heart rate. Both ET(A) and combined ET(A)-ET(B) blockade, but not ET(B) blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastolic and end-systolic volumes. However, all treatments (including ET(B) blockade) decreased LV collagen accumulation. CONCLUSIONS: The chronic blockade of both ET(A) and ET(B) receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ET(A) receptor blockade alone. However, only combined ET(A)-ET(B) receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ET(A) or mixed ET(A)-ET(B) antagonists in CHF remains to be determined.

Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure. Role of nitric oxide, prostanoids, and oxidant stress.

BACKGROUND: Flow-mediated dilatation (FMD) of the peripheral arteries may be impaired in chronic heart failure (CHF), and this could contribute to the increased peripheral resistance and exercise intolerance that occur with this disease. Physical exercise improves the FMD of large conduit arteries in CHF, but whether a similar impairment also occurs in smaller arteries is unknown. The mechanisms of the changes in FMD after CHF or exercise are also unknown. METHODS AND RESULTS: FMD was assessed in isolated, perfused, and preconstricted gracilis muscle arteries from sham-operated rats or CHF rats (coronary artery ligation) who were either sedentary or exercised (30-minute swimming period twice a day for 10 weeks, starting 7 days after ligation). In animals with hemodynamic and echographic signs of CHF, FMD was abolished and converted into vasoconstriction (percent change in diameter after 370 microL/min flow: sham, 42+/-5%; CHF, -4+/-3%; P<0.05). Exercise partially restored FMD (18+/-3%; P<0.05 versus CHF). In sham rats, FMD was abolished by the nitric oxide-synthase inhibitor Nomega-nitro-L-arginine (L-NA) but unaffected by the cyclooxygenase inhibitor diclofenac or the free radical scavenger N-(2-mercaptopropionyl)-glycine (MPG). In arteries from sedentary CHF rats, FMD was not modified by L-NA, but it was partially restored by diclofenac or MPG. In exercised CHF rats, FMD was abolished by L-NA and only moderately improved by diclofenac or MPG. Likewise, endothelial nitric oxide synthase mRNA expression (determined by reverse transcription polymerase chain reaction at the level of the gracilis muscle) was reduced by CHF, and this was prevented by exercise. CONCLUSIONS: CHF abolishes the FMD of small arteries by impairing the nitric oxide pathway, increasing oxidant stress, and releasing a prostanoid-contracting factor. Exercise partially restores FMD by increasing expression of endothelial nitric oxide synthase and preventing the production of vasoconstrictor prostanoids and free radicals. Such restoration of FMD might contribute to the increase in exercise capacity after physical exercise in CHF.

Increased survival after long-term treatment with mibefradil, a selective T-channel calcium antagonist, in heart failure.

OBJECTIVES: We sought to investigate the effects of mibefradil on survival, hemodynamic variables and cardiac remodeling in a rat model of chronic heart failure (HF) and to compare these effects with those of the angiotensin-converting enzyme (ACE) inhibitor cilazapril. BACKGROUND: The use of calcium channel blocking agents in chronic HF has been disappointing. Most studies have shown that these drugs have either no or even detrimental effects due in part to the negative inotropic effects they induce. Mibefradil is a calcium channel blocker that selectively blocks T channels and displays moderately negative inotropic properties only at high doses. Because T channels are upregulated in the hypertrophied heart and could mediate hypertrophic signals and increase arrhythmogenicity, blockade of these channels might be beneficial in chronic HF. METHODS: Rats were subjected to coronary artery ligation and 9 months of treatment with mibefradil (15 mg/kg body weight per day) or cilazapril (10 mg/kg per day) or no treatment. Survival and systolic blood pressure were assessed over the 9-month treatment period, after which cardiac hemodynamic variables and structure were determined. RESULTS: Mibefradil increased survival rate to the same extent as cilazapril (71% for mibefradil vs. 75% for cilazapril and 44% for no treatment). Mibefradil decreased systolic blood pressure, although to a lesser extent than cilazapril. Both treatments decreased left ventricular (LV) end-diastolic and central venous pressures, without any change in the first derivative of LV pressure over time or heart rate. Mibefradil decreased LV weight (although less than cilazapril) without affecting right ventricular weight. Finally, both drugs normalized LV collagen density. CONCLUSIONS: Mibefradil in a rat model improved survival to the same extent as an ACE inhibitor, without impairing LV function, and was associated with a reduction in LV weight and fibrosis. Thus, mibefradil might be beneficial in the treatment of chronic HF.

Targeting endothelial dysfunction in hypertensive subjects.

The endothelium is a favourite early target of cardiovascular risk factors and cardiovascular diseases like hypertension. This key role of the endothelium results from its capacity to respond to numerous autocrine and paracrine stimuli and to mechanical factors like shear stress but also from the pathophysiological consequences of endothelial dysfunction on vasomotor tone, arterial stiffness, arterial remodelling, and inflammation, all of which are factors that play a critical role in atherosclerosis and target-organ damage. In hypertension, endothelial dysfunction has been shown at the level of both resistance and conduit arteries and mainly results from an increase in nitric oxide (NO) degradation by interaction between NO and superoxide anions, while in experimental models of hypertension a decrease in NO production can also be observed. The fact that forearm endothelial dysfunction is a marker of future cardiovascular events in patients with hypertension stresses the importance of the clinical evaluation of endothelial function and of the evaluation of the effects of the different antihypertensive drug classes on this parameter. In this context, many studies have demonstrated that angiotensin-converting enzyme inhibitors, the perindopril-indapamide combination, and angiotensin II type I receptor (AT1) blockers improve endothelium-dependent vasodilatation partly independently of arterial pressure. Both their antioxidant effects and the stimulation of the release of NO are involved in their beneficial effects. For calcium antagonists, only the recent drugs have been shown to improve endothelial function with a simultaneous improvement in several markers of oxidative stress. Finally, beta-blockers classically do not affect endothelial function. Only nebivolol, a beta-blocker with NO donor properties, has been shown to improve endothelial function, but this effect results from the increase in NO and not from the beta-blocking properties of the drug.

[Role of vascular calcium-activated potassium channels in the regulation of human peripheral conduit artery diameter]. / Rô1e des canaux potassiques calcium-dépendants dans la régulation du diamètre basal des artères de conductance périphériques humaines.

The role of an endothelium-derived hyperpolarizing factor (EDHF), acting through the opening of vascular calcium-activated potassium (K(Ca)) channels, in the regulation of the basal diameter of human peripheral conduit arteries has never been investigated in vivo. We measured in 7 healthy subjects the effect of the local infusion of an inhibitor of K(Ca) channels, tetraethylammonium chloride (TEA, 9 micromol/min, 8 min), on radial artery diameter (echotracking) and flow (Doppler). Endothelium-independent dilatation was assessed before and after TEA using sodium nitroprusside (SNP: 5, 10 and 15 nmol/min, 3 min each). TEA induced a decrease in radial artery diameter (2.65 +/- 0.09 to 2.52 +/- 0.09 mm: p < 0.05) and flow (9.4 +/- 1.2 to 7.4 +/- 1.1 ml/min; p < 0.01) without modification in the radial artery dilatation in response to SNP (NS). The decrease in radial artery diameter was still significant even when the decrease in flow was taken as covariate into analysis (p < 0.05). These results demonstrate the role of vascular K(Ca) channels in the regulation of basal peripheral conduit artery diameter and arteriolar tone in human strongly suggesting the involvement of an EDHF a these two levels.

Ischaemic preconditioning is not mediated by oxygen derived free radicals in rats.

OBJECTIVE: Although several studies have shown that ischaemic preconditioning greatly limits myocardial infarct size in the rat, the mechanisms of the beneficial effect of preconditioning in this species are not known. Experiments in dogs and rabbits have suggested that this effect could be related in part to the production of oxygen derived free radicals, as free radical scavengers partially prevent the limitation of infarct size induced by preconditioning. This study was designed to assess the contribution of oxygen derived free radicals in the infarct size limiting effects of preconditioning in rats, using the cell diffusible free radical scavenger N-2-mercaptopropionyl glycine (MPG). METHODS: Open chest rats underwent 20 minutes of coronary occlusion followed by one hour of reperfusion. Preconditioning was elicited by three cycles of five minutes ischaemia and five minutes reperfusion. MPG (20 mg.kg-1) was infused for 60 minutes starting 30 minutes before preconditioning. Control hearts (with or without MPG) were treated identically but without ischaemic preconditioning. Area at risk and infarct size were determined by India ink injection and triphenyltetrazolium chloride stain, with computerised analysis of enlarged sections after colour video acquisition. RESULTS: During preconditioning, reperfusion after the first episode of ischaemia was associated with a high occurrence of severe ventricular arrhythmias, and this was reduced by MPG. Preconditioning, however, reduced arrhythmias and mortality during subsequent episodes of ischaemia and reperfusion. In the absence of MPG, preconditioning greatly limited infarct size (from (mean (SEM)) 59.8(3.9)% to 1.2(0.6)% of the area at risk; p < 0.01). MPG alone did not affect infarct size (60.5(6.1)%), and did not modify the infarct size limiting effect of preconditioning (infarct size: preconditioning 1.2(0.6)%; preconditioning + MPG 2.9(1.2)%. CONCLUSIONS: Preconditioning greatly reduced infarct size, and this was not affected by MPG. These experiments suggest that production of oxygen derived free radicals does not contribute to preconditioning in the rat heart.

Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure.

BACKGROUND: Left ventricular (LV) dilation, which is a predictor of survival in humans with chronic heart failure (CHF), is limited by a mixed endothelin ETA-ETB antagonist. Whether selective ETA receptor blockade influences LV dilation is unknown. We determined, in a rat model of CHF, the effects of the ETA receptor blocker LU 135,252 on LV remodeling. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and treated for ten weeks with placebo or LU 135,252 (LU), at a dose of 10 or 30 mg kg-1 day-1. Systolic blood pressure and heart rate (plethysmography) were determined in conscious animals before and after four and ten weeks of treatment. At these time points, cardiac output and LV dimensions were measured in anesthetized rats by transthoracic echocardiography. LV hemodynamics were determined in anesthetized rats after ten weeks. Pressor responses to ET-1 (1 nmol/kg, i.v.) and sarafotoxin S6c (0.3 ng/kg, i.v.) were measured, to assess the efficacy of ET receptor antagonism and the lack of blockade of ETB receptor blockade, respectively. The pressor response to ET-1 was significantly reduced by LU (% change in systolic blood pressure: sham: 9 +/- 1; CHF: 5 +/- 1; CHF LU: 0 +/- 3 and -4 +/- 2% for the low and high dose, respectively). LU did not affect the response to sarafotoxin (CHF: -37 +/- 3; CHF LU: -29 +/- 3 and -28 +/- 2% for the low and high dose, respectively). Both doses of LU decreased systolic blood pressure, but only the high dose of LU reduced heart rate. Furthermore, LU restored cardiac output dose-dependently throughout the study. Both doses of LU limited LV dilatation and deterioration of LV fractional shortening to the same extent. After ten weeks, LU normalized LV end-diastolic- and central venous pressures, but did not affect LV dP/dtmax or dP/dtmin. LU did not prevent the development of cardiac hypertrophy, but reduced LV collagen density. CONCLUSIONS: In this rat model, the selective ETA receptor blocker LU, at the dose of 30 mg kg-1 day-1, reduced blood pressure and heart rate, limited progressive left ventricular remodeling and improved cardiac hemodynamics and function. These effects of LU might have important clinical relevance in the treatment of heart failure.

Production and metabolism of serotonin (5-HT) by the human adrenal cortex: paracrine stimulation of aldosterone secretion by 5-HT.

In the human adrenal cortex, serotonin (5-HT) is contained in mast-like cells, and we have shown that 5-HT stimulates aldosterone secretion, suggesting that 5-HT may control glomerulosa cells through a paracrine mechanism. Concurrently, the presence of 5-hydroxyindolacetic acid in human adrenocortical extracts indicates that 5-HT may be metabolized after local release by mast cells. The aim of the present study was to investigate in vitro the production and metabolism of 5-HT by the human adrenal cortex. Perifused adrenal slices released spontaneously detectable amounts of 5-HT (0.74 +/- 0.38 fmol/mg wet tissue.min). The mast cell-depleting drug compound 48/80 induced a burst of 5-HT secretion followed by a gradual increase in aldosterone production. Administration of the specific 5-HT(4) receptor antagonist GR 113808 (10(-6) M) did not affect compound 48/80-induced 5-HT release but abolished the stimulatory effect of compound 48/80 on aldosterone secretion, indicating that 5-HT released locally is responsible for a paracrine control of steroidogenesis. Incubation of cells from the human adrenal cortex with 5-HT (10(-5) M) provoked the formation of the 5-HT metabolite 5-hydroxytryptophol. The type A monoamine oxidase (MAO) inhibitor clorgyline (10(-6) M) suppressed the metabolism of 5-HT into 5-hydroxytryptophol. Immunocytochemical staining of cultured cells revealed the presence of a subpopulation of MAO-A-positive cells. Double labeling with an antiserum against chromogranin A showed that MAO-A was actually contained in chromaffin cells. Similarly, immunohistochemical staining of adrenal slices showed that MAO-A was expressed in chromaffin cells located both in the medulla and in intracortical rays. In conclusion, the present study shows that, in the human adrenal cortex, 5-HT, released by mast-cells, may stimulate aldosterone secretion in a paracrine manner. Our data also indicate that 5-HT is metabolized by MAO-A located in intracortical chromaffin cells.

Role of basal and stimulated release of nitric oxide in the regulation of radial artery caliber in humans.

Although it is well established that nitric oxide contributes to the regulation of resistance arterial tone in humans, its role at the level of large arteries is less clear. Therefore, we assessed in healthy volunteers the effect of local administration of the inhibitor of nitric oxide synthesis NG-monomethyl-L-arginine (L-NMMA) on basal radial artery diameter (transcutaneous A-mode echotracking) and radial blood flow (Doppler) as well as on the radial response to acetylcholine and the nitric oxide donor sodium nitroprusside. A catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of L-NMMA (2, 4 and 8 mumol/min for 5 minutes, n = 11), acetylcholine (3, 30, 300 and 900 nmol/min for 3 minutes, n = 8), and nitroprusside (2.5, 5, 10, and 20 nmol/min for 3 minutes, n = 6). None of the treatments affected arterial blood pressure or heart rate. L-NMMA dose-dependently decreased radial blood flow (from 31 +/- 6 to 17 +/- 3 10(-3) L/min after 8 mumol/min, P < .01) but did not affect radial artery diameter (from 2.93 +/- 0.11 to 2.90 +/- 0.14 mm). Acetylcholine dose-dependently increased radial blood flow (154 +/- 43% after 900 nmol/min) and radial artery diameter (16 +/- 4%), and both effects were markedly reduced after L-NMMA (increase in radial blood flow and radial artery diameter: 22 +/- 20% and 3 +/- 2%, respectively; both P < .01 versus controls). Nitroprusside also dose-dependently increased radial artery diameter (14 +/- 4% after 20 nmol/min) but only moderately affected radial blood flow (47 +/- 21%).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of nitric oxide in the regulation of the mechanical properties of peripheral conduit arteries in humans.

Whether nitric oxide (NO) contributes to the regulation of the mechanical properties of large arteries in humans is not known. We measured the effect of local administration of the inhibitor of NO synthesis N(G)-monomethyl-L-arginine (L-NMMA; 1 and 4 micromol x L[-1] x min[-1] for 5 minutes) and acetylcholine (3 and 30 nmol x L[-1] x min[-1] for 3 minutes) on radial artery diameter and wall thickness in 11 healthy volunteers using an echo-tracking system coupled to a measurement of radial blood flow (Doppler) and arterial pressure. At the highest dose, L-NMMA reduced radial blood flow but surprisingly decreased incremental elastic modulus (from 1.36+/-0.22 to 1.00+/-0.22 kPa x 10[3]; P<.05) and increased arterial compliance (from 3.20+/-0.46 to 4.07+/-0.45 m2 x kPa x 10(-8), P<.05), without affecting radial artery internal diameter, wall thickness or midwall stress, thus reflecting a decrease in vascular tone. Acetylcholine decreased incremental elastic modulus (from 1.27+/-0.08 to 0.88+/-0.07 kPa x 10[3]; P<.05) and increased arterial diameter, radial blood flow, and compliance (from 2.82+/-0.16 to 5.30+/-0.62m2 x kPa x 10[-8]; P<.05). These results demonstrate in vivo that NO is involved in the regulation of the mechanical properties of large arteries in humans. However, the effects of L-NMMA, ie, a decrease in arterial wall rigidity and an increase in arterial compliance, which occur in the absence of any changes in blood pressure or arterial geometry, suggest that inhibition of NO synthesis is associated in humans with a paradoxical isometric smooth muscle relaxation. This effect could be due to the development of compensatory vasodilating mechanisms after NO synthesis inhibition.

Systemic and regional hemodynamic effects of zabicipril in healthy volunteers.

The effects of two oral doses of zabicipril, a new angiotensin converting enzyme inhibitor, on systemic (arterial pressure, heart rate, and cardiac output) hemodynamic parameters and regional (brachial, carotid and femoral arteries' diameters and flows) hemodynamic parameters and on biologic (plasma-converting enzyme and renin activities, catecholamines, and atrial natriuretic factor) parameters were noninvasively investigated and compared with those of a placebo in a double-blind crossover study performed in six healthy male volunteers. Although it did not affect the systemic hemodynamic parameters, zabicipril induced a strong peripheral vasodilation, significantly reducing brachial, carotid, and femoral resistances and increasing the corresponding blood flows from 3 or 4 1/2 hours to 9 hours. This vasodilation affected only the arterioles, not the large arteries, and resulted in a redistribution of cardiac output toward the three regional vascular beds. Zabicipril induced an early, potent, and long-lasting converting enzyme inhibition. Furthermore, zabicipril did not affect plasma catecholamines and atrial natriuretic factor.

Theophylline kinetics and ventilatory flow in bronchial asthma and chronic airflow obstruction: influence of erythromycin.

The kinetics and the effects on the ventilatory function peak expiratory flow rate (PEFR) of a single 600-mg oral dose of theophylline were investigated in 46 adult patients with bronchial asthma (BA) and in 16 adult patients with chronic airflow obstruction (CAO). In the former, theophylline induced an early and potent bronchodilatation (60% rise in PEFR), the kinetics of which correlated with plasma concentration. Theophylline was also effective in patients with CAO, but the magnitude of its bronchodilator effect was less than in those with BA: this was despite plasma concentrations of much the same order. In adult patients with BA (but not with CAO) theophylline plasma levels and bioavailability are higher after simultaneous erythromycin dosing.

Fixed-dose combination of perindopril with indapamide in spontaneously hypertensive rats: haemodynamic, biological and structural effects.

OBJECTIVE: The present study was designed to test the effects of chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor (perindopril) and of the diuretic indapamide in spontaneously hypertensive rats (SHR). METHODS: Adult SHR were treated with placebo or increasing doses of the combination of the drugs (0.3, 1 and 3 mg/kg per day; ratio of doses 0.32). In a separate set of experiments, the effects of the drugs combined (1 mg/kg per day) was compared with those induced by each drug alone. RESULTS: The drug combination dose-dependently decreased systolic blood pressure and its hypotensive effect was more marked than those induced by each treatment administered alone (untreated 208 +/- 5 mmHg, indapamide 185 +/- 5 mmHg, perindopril 150 +/- 3 and the combination 123 +/- 7 mmHg). A 12-week treatment with the drug combination (1 mg/kg per day) was not accompanied by any change in diuresis or urinary excretion of Na or K. The same treatment decreased cardiac hypertrophy and collagen. At the vascular level, the drug combination decreased aortic, carotid and femoral media cross-sectional areas, as well as aortic and carotid collagen density. This latter effect was accompanied by a significant increase in carotid artery compliance assessed in vivo at constant pressure. Finally, in isolated aortae, chronic combined drug treatment was associated with an increased basal release of nitric oxide and a decrease in the hypertension-induced endothelium-dependent contractions in response to acetylcholine. CONCLUSION: These experiments suggest that chronic combined treatment with low doses of an angiotensin converting enzyme inhibitor and a diuretic such as indapamide may be of value in the treatment of hypertension.