Cardiorenal actions of neutral endopeptidase inhibition in experimental congestive heart failure

The present studies were designed to determine the action of neutral endopeptidase inhibition (NEP-I), an inhibitor of the degradation of atrial natriuretic factor (ANF), in congestive heart failure (CHF). Studies were conducted in two groups of anesthetized dogs with CHF induced by 8 days of rapid right ventricular pacing. Group 1 (n = 5) received a specific NEP-I (SQ 28,603) at two doses administered sequentially -30 mg/kg followed by a 60 mg/kg i.v. bolus. Group 2 (n = 5) received intravenous infusion of exogenous ANF (100 ng/kg/min) to achieve increases in plasma ANF concentration as observed in group 1. NEP-I resulted in a diuresis and natriuresis (p less than 0.05) with increases in the fractional excretion of sodium and fractional excretion of lithium, the latter a marker for proximal tubule sodium delivery. Such tubular actions occurred in the absence of increases in glomerular filtration rate or renal blood flow but were associated with significant increases in urinary ANF and urinary cyclic GMP. Plasma ANF increased after the 30 mg/kg NEP-I dose. In contrast, in group 2 with exogenous ANF and despite a marked increase in plasma ANF, no natriuresis was observed. Arterial pressure did not change in either group. These studies demonstrate for the first time in CHF that NEP-I may potentiate the natriuretic action of endogenous ANF by a mechanism that is independent of systemic or renal hemodynamics and does not parallel increases in plasma ANF. These studies support an important therapeutic role for NEP-I in CHF.     

Recent developments in noradrenergic neurotransmission and its relevance to the mechanism of action of certain antihypertensive agents

This report reviews a number of significant developments in the fields of noradrenergic transmission and adrenergic receptors which suggest that, in addition to the classical postsynaptic adrenoceptors, there are also presynaptic adrenoceptors that help modulate the release of norepinephrine (NE) from peripheral as well as central noradrenergic nerve endings during nerve stimulation. In particular, stimulation of presynaptic alpha-adrenoceptors reduces this release of transmitter and the reverse is observed after blockade of these receptors. Clearcut pharmacological differences exist between the postsynaptic alpha 1-adrenoceptors that mediate the responses of certain organs and the presynaptic alpha 2-adrenoceptors that modulate the NE release during nerve stimulation. Therefore, subclassification of alpha-adrenoceptors into alpha 1 and alpha 2 subtypes is warranted but must be considered to be independent of the anatomical location of these receptors. Some noradrenergic nerve endings have also been shown to possess beta-adrenergic receptors, the stimulation of which increases the quantity of transmitter released by nerve impulses. Physiologically, these receptors could be activated by circulating epinephrine (E) and be involved in essential hypertension. A third type of catecholamine receptor found at the noradrenergic nerve ending is the inhibitory dopamine (DA) receptor, which might be of significance in the development of new antihypertensive agents. Application of these new concepts of noradrenergic neurotransmission and the subclassification of alpha-adrenoceptors to the treatment of hypertension is presented. Clonidine, for example, appears to be a potent alpha 2-adrenoceptor agonist; the central receptor involved in its antihypertensive action is pharmacologically an alpha 2-type but located postsynaptically. Clonidine also induces activation of peripheral presynaptic alpha 2-adrenoceptors, which might contribute to its cardiovascular action. The antihypertensive effects of alpha-methyldopa are related to the formation of alpha-methylnorepinephrine, a preferential alpha 2-adrenoceptor agonist, which can stimulate peripheral presynaptic alpha 2-adrenoceptors leading to a decrease of NE release and a reduction in sympathetic tone. Prazosin is a new antihypertensive agent the mechanism of action of which involves a selective blockade of postsynaptic alpha 1-adrenoceptors. This drug does not antagonize several effects of clonidine that are mediated via alpha 2-adrenoceptors. The mechanisms presently considered to account for the antihypertensive activity of beta-adrenoceptor blocking agents are numerous. It is proposed that blockade of peripheral presynaptic facilitatory beta-adrenoceptors could be of significance in the antihypertensive action of these drugs.     

Left atrial strain in the assessment of diastolic function: providing new insights into primary myocardial dysfunction in Marfan syndrome

The International Journal of Cardiovascular Imaging - Previous studies using conventional echocardiographic measurements have reported subclinical left ventricular (LV) diastolic abnormalities in...     

Surgical treatment for hypertrophic obstructive cardiomyopathy

INTRODUCTION AND OBJECTIVES: Five percent of the patients with hypertrophic obstructive cardiomyopathy (HOCM) have symptoms unresponsive to medical treatment and are candidates for invasive therapy. The objective of this study was to analyze our results with surgical treatment of HOCM during the last 10 years. PATIENTS AND METHOD: Between July 1993 and January 2004 26 patients with HOCM refractory to drug therapy were operated on. An extended septal myectomy was performed, in combination with anterior mitral leaflet plication in 19 cases (73%) and with mitral valve replacement in 5 (19%). Evolution of the grade of dyspnea, left ventricle outflow tract gradient (LVOTG), mitral regurgitation, and systolic anterior motion after surgery was analyzed. RESULTS: Mean follow-up was 63 (37) months. After surgery, a significant reduction in LVOTG (from 96.5 to 19.5 mmHg; P<.001), grade of mitral regurgitation (from 2.54 to 0.69; P<.001) and systolic anterior motion (from 2.92 to 0.23; P<.001) was achieved, which led to improvement in functional class. Hospital mortality and need for pacemaker implantation due to complete heart block after surgery was 3.8% (n=1). There were no cases of iatrogenic ventricular septal defect or mitro-aortic valve injury. Actuarial survival at 5 years was 96% (4%). CONCLUSIONS: Surgery in patients with HOCM yields great clinical improvements with low morbidity and mortality. Simultaneous intervention for both myocardial and valvular components of the disease allows not only reduction in the LVOTG but also correction of mitral regurgitation and abolition of systolic anterior motion.     

Epidemiology of achondroplasia: A population‐based study in Europe

Achondroplasia is a rare genetic disorder resulting in short‐limb skeletal dysplasia. We present the largest European population‐based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. All cases of achondroplasia notified to 28 EUROCAT registries (1991–2015) were included in the study. Prevalence, birth outcomes, prenatal diagnosis, associated anomalies, and the impact of paternal and maternal age on de novo achondroplasia were presented. The study population consisted of 434 achondroplasia cases with a prevalence of 3.72 per 100,000 births (95%CIs: 3.14–4.39). There were 350 live births, 82 terminations of pregnancy after prenatal diagnosis, and two fetal deaths. The prenatal detection rate was significantly higher in recent years (71% in 2011–2015 vs. 36% in 1991–1995). Major associated congenital anomalies were present in 10% of cases. About 20% of cases were familial. After adjusting for maternal age, fathers >34 years had a significantly higher risk of having infants with de novo achondroplasia than younger fathers. Prevalence was stable over time, but regional differences were observed. All pregnancy outcomes were included in the prevalence estimate with 80.6% being live born. The study confirmed the increased risk for older fathers of having infants with de novo achondroplasia.     

Patient preferences for osteoporosis in Spain: a discrete choice experiment

Summary  

In Spain, various treatments are available to prevent osteoporotic fractures. A discrete choice experiment (DCE) was used to investigate the importance of different treatment aspects and its influence on patients’ preferences. All attributes included as type and place of drug administration as well as costs showed to be significant predictors of choice. Spanish osteoporosis patients have well-defined preferences and accept trade-offs among attributes.     

Regional distribution and pharmacological characterization of [125I]endothelin-1 binding sites in human fetal placental vessels

High-affinity binding sites for [125I]endothelin(ET)-1 have been detected in purified membrane preparations of the fetal arteries and veins of the chorionic plate and the stem villi vessels of the human term placenta. Regardless of the vessel type, the apparent dissociation constant was found to be in the picomolar range (26----45 pM), and the Bmax value close to 600 fmol/mg protein. In stem villi vessels, ET-1, ET-2, sarafotoxin S6b and vasocontractor intestinal peptide (VIC) were approximately equipotent in their competitive displacement of [125I]ET-1 binding. The endothelin precursors, human and porcine big-endothelin, recognized ET-1 sites with low affinity (nM range), a finding which reflects their low potency as recognized vasocontractant agents. Interestingly, [125I]ET-1 binding parameters and pharmacological profiles were identical in fetal veins and arteries of the chorionic plate. Similarly, a study carried out in rat aortic membranes, revealed the presence of high affinity [125I]ET-1 binding sites with pharmacological characteristics close to those of the human stem villi vessels. In all vessels investigated, the binding pattern of ET-3 against [125I]ET-1 was of a non-competitive nature. Thus, these results demonstrate the presence of specific [125I]ET-1 binding sites along the vascular tree of the fetal side of the placenta and would support evidence currently available, favouring the existence of distinct ET-1 and ET-3 receptors. Finally, ET-1 in the human placenta may play an important physiological role as regulator of vascular resistance and/or be implicated as a pathological factor in certain pregnancy-related diseases.