We previously identified a 42 kDa Ins(1,3,4,5)P4 (InsP4) receptor protein (p42IP4) in brain membranes from several species. Here the cDNA sequence of p42IP4 was obtained by PCR using degenerate primers derived from peptide sequences of proteolytic fragments of the porcine protein and by subsequent screening of a pig brain cDNA library. The derived peptide sequence of 374 amino acids for porcine p42IP4 is 45 amino acids shorter at the C‐terminus than centaurin‐α from rat (84% homology) and has a calculated molecular mass of 43 kDa. From the InsP4 binding activity present in brain tissue homogenate about 25% is found in the cytosolic fraction and 75% associated with microsomes. Both activities are due to p42IP4 since (i) a peptide‐specific antiserum recognizing specifically p42IP4 labels the InsP4 receptor protein in membranes and in the cytosol, (ii) the antiserum immunoprecipitates both the membrane protein and the cytosolic protein of 42 kDa, (iii) the InsP4 binding activity released by high salt or by alkaline extraction from membranes is identified immunologically as the 42 kDa protein, and (iv) the affinity for InsP4 and specificity for various inositolphosphates are similar for the membrane‐associated and for the soluble p42IP4. The functional importance of p42IP4 is highlighted by the identical affinity for InsP4 and for phosphatidylinositol (3,4,5)P3 (Ki=1.6 and 0.9 nM, respectively). Thus, the InsP4 receptor, apparently a peripheral membrane protein, which exists also as a cytosolic protein can transfer the signals mediated by InsP4 or by PtdInsP3 between membranes and cytosolic compartment. © 1997 Federation of European Biochemical Societies

The 52 amino acid peptide hormone adrenomedullin (ADM) plays a major role in the development and regulation of the cardiovascular and lymphatic system and has therefore gained significant interest for clinical applications. Because adrenomedullin exhibits low metabolic stability, enhancement of the plasma half-life is essential for peptide-based drug design. Fluorescently labeled ADM analogues synthesized by Fmoc/t-Bu solid phase peptide synthesis were used to analyze their enzymatic degradation and specific fragmentation pattern in human blood plasma. The determination of important cleavage sites allowed the development of selectively modified peptides in a rational approach. By combination of palmitoylation, lactam-bridging, and Nα-methylation, ADM analogues protected from enzymatic cleavage in human blood were developed and revealed an explicitly elongated half-life of 5 days in comparison to the wild-type in vitro. This triple-modification did not alter the selectivity of the analogues at the AM1 receptor, highlighting their potential for therapeutic applications.

Study objective -The aim of the study was to assess the cardiovascular effects of human calcitonin gene related peptide (CGRP) in patients with congestive heart failure.Design -The effects of CGRP I1 (or p), 12.5 pgh-', given by intravenous infusion for 24 h to digitalised patients with congestive heart failure, were assessed by measurement of cardiac functional indices.Patients -Five patients (four female) were studied. Age was 73-82 years. Three were in New York Heart Association phase I11 and two in phase IV.Measurements and main results -The pre-ejection period to left ventricular ejection time ratio and the Q T distance adjusted for heart rate were lowered by 21% and 4% respectively. The left ventricular shortening index was raised by 43%. The arterial pressure and heart rate did not change consistently.Conclusion -Calcitonin gene related peptide improves myocardial contractility in patients with congestive heart failure. This is the first time this has been shown. vasodilatation, and hyp~tension.*-~ The stimulation of the heart rate and coronary vasodilatation presumably depend on the local release of CGRP from afferent nerve fibres in the heart induced by capsaicin and interaction with receptors linked to cyclic adenosine monophosphate The improved ventricular contractility of CGRP was suppressed in normal human subjects through blockade of adrenergic receptors, and may be driven by reflex sympathetic ~timulation.~ Here we show evidence of improved ventricular contractility with CGRP as recorded with non-invasive techiques in five digitalised patients with congestive heart failure. MethodsWe studied four female and one male patient aged 73 to 82 years with congestive heart failure, three in New York Heart Association phase I11 and two in phase IV. Four patients had coronary artery disease and the fifth had hypertrophic cardiomyopathy. Body weight was 44-66 kg, and height 147-158 cm. Informed consent about the experimental treatment with CGRP was obtained from all patients, and the study was approved by the appropriate ethics committee.The patients were treated with oral P-methyldigoxin (Lanitop, Boehringer, Mannheim, W Germany), 0.6 mg (0.77 nmol) per day for three days, followed by 0.3 mg (0.39 nmol) per day for four days (figure), after which they were given human CGRP I1 (or P) (Peninsula Laboratories, Belmont, CAY USA), 12.5 pgeh-' (3.3 nmol) by intravenous minipump infusion for 24 h.The systemic arterial pressure was monitored continuously by intra-arterial manometry. The duration of the pre-ejection period and the left ventricular ejection time were determined using electrocardiography, phonocardiography, and external carotid pulse tracings. l8 The corrected QT interval (QTJ was calculated by dividing QT by the square root of the preceding R-R interval. The left ventricular cavity was measured before and during the infusions with CGRP by M mode echocardiography at the end diastolic and the end systolic filling times." The left ventricular shortening index was calculated as the ratio between...

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Although isokinetic training is gaining in importance in prevention and rehabilitation, even for older patients, there is hardly any information available on the extent of cardiocirculatory stress. This study was aimed, therefore, at examining the cardiocirculatory reaction to various isokinetic forms of exercise in dependence on age. Sixty-four subjects between 22 and 60 years of age were assigned to four age groups and the maximum torque measured in concentric and eccentric exercises with various angle accelerations. Moreover, all subjects underwent 1-min concentric and eccentric endurance stress and an isometric test. The cardiocirculatory reaction as reflected in heart rate and blood pressure patterns was determined, as well as the plasma catecholamines adrenaline and noradrenaline measured. The eccentric maximum torque was significantly above the concentric maximum torque; there was a significant inverse relationship to age only in the concentric mode of exercise (r = -0.48; p < 0.01). The cardiocirculatory reaction in endurance stress and isometry, like the behavior of heart rate, blood pressure, and plasma catecholamines, was greatest in concentric exercise, although the maximum strength values were lower, followed by eccentric exercise and isometry. Exercise values such as those attained in maximum ergometric forms of exercise were not reached. It is concluded that no special precautionary measures are required in isokinetic forms of exercise.