Relaxin: a new cardiovascular hormone in humans? Comparative potency and mechanisms of action

INTRODUCTION: The focus of this MD thesis has been relaxin, a member of the insulin family, which is a protein composed of two disulphide linked chains of approximately 6000 Daltons. Relaxin has been traditionally recognised as a hormone of parturition, though more recently it has been postulated that relaxin may be involved in cardiovascular regulation. We used concentrations similar to those found in the plasma in physiological (non-pregnant, pregnancy) and pathophysiological (chronic heart failure) states. Firstly, we characterised the effects of relaxin in small human resistance arteries ex vivo using wire myography obtained from gluteal biopsies taken from patients with coronary heart disease (CHD) and normal left ventricular systolic function. We also studied the same effects in larger calibre arteries (internal mammary) and veins (saphenous) using standard organ bath techniques. The effect of relaxin in veins has not previously been described. Internal mammary arteries and saphenous veins were obtained from patients undergoing coronary artery bypass surgery. Small pulmonary arteries were obtained from patients undergoing thoracotomy for bronchial carcinoma. In addition, we wished to determine if a transcardiac or transpulmonary gradient of relaxin could be measured to suggest either pulmonary or cardiac secretion or clearance of the hormone. Relaxin secretion in heart failure has previously been described. Lastly, we wished to determine whether an increased relaxin plasma concentration in patients with chronic heart failure (CHF), is of prognostic importance. METHODS AND RESULTS i)comparative potency of relaxin compared to other vasodilators: Small resistance arteries were obtained from biopsies taken from patients with CHD. Each set of vessels was preconstricted with noradrenaline. Thereafter, cumulative concentration response (relaxation) curves (CRCs) were constructed with known vasodilators 25 atrial natriuretic peptide (ANP), epoprostenol, substance P and relaxin (n=8). Relaxin was found to be a more potent vasodilator than ANP and equipotent to epoprostenol. ii) mechanism of vasorelaxation: CRCs to relaxin (as above) were constructed to identify the importance of the endothelium – following the removal of the endothelium by the established method of intraluminal rubbing with a human hair. We found that relaxin is endothelium dependent. iii) interaction of relaxin with nitric oxide and other possible mechanisms of vasodilation and importance of ACE inhibitor treatment: We identified the importance of the effect of ACE inhibitor treatment on the action of relaxin in human resistance arteries. Relaxin’s vasodilatory action was significantly reduced in those patients on ACE inhibitors (n=28) compared with those patients not on ACE inhibitors (n=30). In patients treated with an ACE inhibitor, we found that manipulation of prostanoids is important. Indomethacin, (a cyclooxygenase inhibitor) (n=8) blocked relaxin’s vasodilatory action. Manipulation of the cAMP second messenger system, with milrinone, (a cAMP phosphodiesterase inhibitor) (n=6) is also important as relaxin’s vasodilatory action was enhanced. Manipulation of cyclic GMP second messenger system is also important. ODQ, (a guanylate cyclase inhibitor) (n=10) reduced relaxin’s action while zaprinast, (a cGMP phosphodiesterase inhibitor) (n=7) enhanced relaxin’s action. Manipulation of nitric oxide with L-NAME (n=8) and L-NOARG (n=10), nitric oxide synthase (NOS) inhibitors and EDHF with apamin and charybdotoxin (potassium channel blockers) (n=7) had a curious effect causing the opposite action to that expected, by enhancing relaxin’s vasodilatory action. In patients not treated with an ACE inhibitor, we found that manipulation of nitric oxide with L-NAME (n=8) and LNOARG (n=8), is important, as both reduced relaxin’s vasodilatory action. Manipulating the cGMP second messenger system with ODQ (n=8) greatly reduced relaxin’s action. but zaprinast (n=9) did not. Manipulation of EDHF with apamin and charybdotoxin (n=8) had no effect on relaxin’s action. Manipulation of prostanoids with indomethacin (n=10) reduced relaxin’s action but manipulation of cAMP with milrinone (n=8), had no effect. 26 iv)relaxin and small human pulmonary arteries: We determined, using wire myography, that relaxin is not a vasodilator of small pulmonary resistance arteries (n=5). v)relaxin and large calibre vessels: We determined, using the organ bath technique, that relaxin is not a vasodilator of larger calibre arteries i.e. internal mammary arteries removed from patients during coronary artery bypass surgery (n=5).Relaxin is not a venodilator studying saphenous veins removed from patients during coronary artery bypass surgery (n=5). vi)transmyocardial and transpulmonary gradient of relaxin: Plasma relaxin concentrations were measured using a validated assay. Samples were taken from patients undergoing CABG surgery, from the aorta, coronary sinus, pulmonary artery and pulmonary vein. We found that in 20 patients with normal left ventricular function that there was no transpulmonary gradient but there was a transcardiac gradient suggesting net cardiac extraction of relaxin. vii)prognostic value of relaxin in patients with chronic heart failure: Relaxin was compared with N-terminal pro brain natriuretic peptide to determine whether relaxin is of prognostic importance. Plasma concentrations of the hormones were measured in 87 patients admitted with CHF. These patients were followed up for a year during which time hospitalisations due to CHF and death were recorded. While NT-proBNP was found to be a powerful and independent predictor of outcome in these patients, relaxin was not. CONCLUSION. In addition to its established role in pregnancy, relaxin has many other actions. In particular, its antihypertensive, antithrombotic and vasodilatory properties suggest that relaxin may have a central role in cardiovascular regulation

Pedagogical Brief: CSR Consulting Project in an Online MBA

Research Brief: Corporate Partner Projects, Action Learning and Corporate Social Responsibility in the Online MBA Abstract Civic Engagement, Sustainability and Corporate Social Responsibility (CSR) are learning objectives for many MBA programs but implementing real world projects in an online environment takes careful consideration. This paper describes the process of creating and delivering a consulting project for a completely online MBA class from initial data gathering, to project outline and final results. We share what worked in this process and its success from the faculty, industry partner and student perspectives. The bottom line, don’t miss out on this type of opportunity even though it can involve a lot more work, the results are rewarding

Middle East in Crisis : a historical and documentary review

This book had its inception in a common teaching experience. Although it is now almost two years since we were first involved in the preparation of materials on the Middle East for a course in the problems of American democracy, world events continue to remind us of the critical importance of the Mediterranean area. Our students were aware of an increasing variety of proposals for the role the United States should play in easing the tensions in the Middle East, but they were relatively unfamiliar with the general history and geography of the area. Thus they were unable to evaluate these various proposals critically. As a result of this experience it was felt that there was a general need for a selection of materials designed to guide the citizen in formulating his own view of United States policy in this troubled zone. We then undertook a dual task: (1) the preparation of a descriptive essay which would meet the need of student and lay reader alike as a guide to the basic historical and geographical data of the Middle East; and (2) the provision of a source book of historical and recent documents which would constitute a framework for developing and testing foreign policy proposals

Middle East in Crisis: a historical and documentary review

This book had its inception in a common teaching experience. Although it is now almost two years since we were first involved in the preparation of materials on the Middle East for a course in the problems of American democracy, world events continue to remind us of the critical importance of the Mediterranean area. Our students were aware of an increasing variety of proposals for the role the United States should play in easing the tensions in the Middle East, but they were relatively unfamiliar with the general history and geography of the area. Thus they were unable to evaluate these various proposals critically. As a result of this experience it was felt that there was a general need for a selection of materials designed to guide the citizen in formulating his own view of United States policy in this troubled zone. We then undertook a dual task: (1) the preparation of a descriptive essay which would meet the need of student and lay reader alike as a guide to the basic historical and geographical data of the Middle East; and (2) the provision of a source book of historical and recent documents which would constitute a framework for developing and testing foreign policy proposals.https://surface.syr.edu/books/1001/thumbnail.jp

Opportunity for All: How the American Public Benefits From Internet Access at U.S. Libraries

Examines the use of free computer and Internet access in public libraries, by income level, age, race/ethnicity, and online activity. Explores libraries' role as a community resource for social media, education, employment, e-government, and other areas

Building Health Equity One Institution at a Time: The Research Infrastructure in Minority Institutions Project

Developing a well-trained workforce interested in, and prepared for, conducting health equity research is an important national priority. Scientists from Minority-Serving Institutions (MSIs) bring unique perspectives and experiences with racial, ethnic and social inequities in health and health status but often lack access to training and mentoring opportunities, which is crucial for increasing the diverse pool of investigators who are adequately prepared to conduct health disparities research and to compete for National Institutes of Health research funding. The focus of the California State University, Long Beach (CSULB) Research Infrastructure in Minority Institutions (RIMI) Project was to: (a) enhance CSULB’s infrastructure and research capacity, (b) conduct applied community health research on health conditions disproportionately affecting disadvantaged populations, and (c) support faculty to embark on careers in reducing health disparities. Faculty received training, mentorship, and release time support to participate in research-related activities. Select faculty also received funding to conduct a two-year health disparities research project. Within a relatively short period of time, the RIMI Project made important strides toward strengthening the research infrastructure at CSULB by enhancing faculty capacity, improving research utilization to address health disparities, and strengthening campus and community collaborations. MSIs are encouraged to apply for opportunities to build their institution’s research capacity. The lessons learned from this project may be used as a guide for other teaching institutions that have the goal to develop minority faculty researchers

Ergopeptine-Sensitive Calcium-Dependent Protein Phosphorylation System in the Brain

We studied a protein phosphorylation system that is regulated by the dopamine-mimetic ergot bromocriptine. Bromocriptine was found to inhibit selectively the endogenous phosphorylation of a threonine residue(s) in 50,000- and 60,000-dalton proteins in a synaptosome fraction. The bromocriptine-sensitive phosphorylation is stimulated by calcium and by calmodulin, and occurs predominantly in the brain. The inhibitory effect of bromocriptine was not mimicked by 3,4-dihydroxyphenylethylamine or by any of the neurotransmitters and related agents tested, but was mimicked, although less effectively, by other ergots that contain peptide moieties. In the hippocampus, the brain region with the highest content of the 50,000- and 60,000-dalton proteins, the ergopeptine-sensitive protein phosphorylation appears to be localized to interneurons or cell bodies whose axons synapse outside the hippocampus. The results raise the possibility that some of the bromocriptine- and ergopeptine-induced pharmacological effects in the CNS may be mediated by the inhibition of the calcium/calmodulin-dependent phosphorylation of these specific proteins.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65208/1/j.1471-4159.1984.tb02758.x.pd

Book Reviews

Book Review

An Assessment of the Oil Resource Base of the United States

A select panel of oil resource analysts, convened in August 1992 by the Bureau of Economic Geology, The University of Texas at Austin, and the National Institute for Petroleum and Energy Research (NIPER) at the request of the U.S. Department of Energy, concludes that the remaining, recoverable volume of crude oil in the United States ranges from 99 to 204 billion barrels, inclusive of 25 billion barrels of oil carried as proved reserves by the Energy Information Administration at the end of 1991. The range in estimates reflects different assumptions of price and technology (including the geological ability to apply that technology). The lower estimate assumes a stable oil price of $20 per barrel (1992 dollars) with existing technology. The higher estimate assumes a price of$27 per barrel (1992 dollars) but with advanced technology. The range in estimates of the remaining resource base recoverable under the given assumptions is equivalent to 35 to 75 years of continued U.S. crude oil production at the current annual rate of 2.7 billion barrels.Bureau of Economic Geolog