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

RC Internal medicine;QP Physiology

Fisher, Carol, Jane ; McMurray, J.J.

University:University of Glasgow

Department:Institute of Cardiovascular and Medical Sciences

关键词: relaxin, vasodilation, cardiovascular regulation, coronary artery disease, chronic heart failure;   

Others  :  http://theses.gla.ac.uk/752/1/2009fishermd.pdf.pdf

来源: University of Glasgow

【 摘 要 】

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 approximately6000 Daltons. Relaxin has been traditionally recognised as a hormone ofparturition, though more recently it has been postulated that relaxin may beinvolved in cardiovascular regulation. We used concentrations similar to thosefound in the plasma in physiological (non-pregnant, pregnancy) andpathophysiological (chronic heart failure) states. Firstly, we characterised theeffects of relaxin in small human resistance arteries ex vivo using wire myographyobtained from gluteal biopsies taken from patients with coronary heart disease(CHD) and normal left ventricular systolic function. We also studied the sameeffects in larger calibre arteries (internal mammary) and veins (saphenous) usingstandard organ bath techniques. The effect of relaxin in veins has not previouslybeen described. Internal mammary arteries and saphenous veins were obtainedfrom patients undergoing coronary artery bypass surgery. Small pulmonary arterieswere obtained from patients undergoing thoracotomy for bronchial carcinoma. Inaddition, we wished to determine if a transcardiac or transpulmonary gradient ofrelaxin could be measured to suggest either pulmonary or cardiac secretion orclearance of the hormone. Relaxin secretion in heart failure has previously beendescribed. Lastly, we wished to determine whether an increased relaxin plasmaconcentration in patients with chronic heart failure (CHF), is of prognosticimportance.METHODS AND RESULTSi)comparative potency of relaxin compared to other vasodilators: Small resistancearteries were obtained from biopsies taken from patients with CHD. Each set ofvessels was preconstricted with noradrenaline. Thereafter, cumulative concentrationresponse (relaxation) curves (CRCs) were constructed with known vasodilators25atrial natriuretic peptide (ANP), epoprostenol, substance P and relaxin (n=8).Relaxin was found to be a more potent vasodilator than ANP and equipotent toepoprostenol.ii) mechanism of vasorelaxation: CRCs to relaxin (as above) were constructed toidentify the importance of the endothelium – following the removal of theendothelium 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 ofvasodilation and importance of ACE inhibitor treatment: We identified theimportance of the effect of ACE inhibitor treatment on the action of relaxin inhuman resistance arteries. Relaxin’s vasodilatory action was significantly reducedin those patients on ACE inhibitors (n=28) compared with those patients not onACE inhibitors (n=30). In patients treated with an ACE inhibitor, we found thatmanipulation of prostanoids is important. Indomethacin, (a cyclooxygenaseinhibitor) (n=8) blocked relaxin’s vasodilatory action. Manipulation of the cAMPsecond messenger system, with milrinone, (a cAMP phosphodiesterase inhibitor)(n=6) is also important as relaxin’s vasodilatory action was enhanced. Manipulationof cyclic GMP second messenger system is also important. ODQ, (a guanylatecyclase inhibitor) (n=10) reduced relaxin’s action while zaprinast, (a cGMPphosphodiesterase inhibitor) (n=7) enhanced relaxin’s action. Manipulation ofnitric oxide with L-NAME (n=8) and L-NOARG (n=10), nitric oxide synthase(NOS) inhibitors and EDHF with apamin and charybdotoxin (potassium channelblockers) (n=7) had a curious effect causing the opposite action to that expected, byenhancing relaxin’s vasodilatory action. In patients not treated with an ACEinhibitor, 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 reducedrelaxin’s action. but zaprinast (n=9) did not. Manipulation of EDHF with apaminand charybdotoxin (n=8) had no effect on relaxin’s action. Manipulation ofprostanoids with indomethacin (n=10) reduced relaxin’s action but manipulation ofcAMP with milrinone (n=8), had no effect.26iv)relaxin and small human pulmonary arteries: We determined, using wiremyography, 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 mammaryarteries removed from patients during coronary artery bypass surgery (n=5).Relaxinis not a venodilator studying saphenous veins removed from patients duringcoronary artery bypass surgery (n=5).vi)transmyocardial and transpulmonary gradient of relaxin: Plasma relaxinconcentrations were measured using a validated assay. Samples were taken frompatients undergoing CABG surgery, from the aorta, coronary sinus, pulmonaryartery and pulmonary vein. We found that in 20 patients with normal leftventricular function that there was no transpulmonary gradient but there was atranscardiac gradient suggesting net cardiac extraction of relaxin.vii)prognostic value of relaxin in patients with chronic heart failure: Relaxin wascompared with N-terminal pro brain natriuretic peptide to determine whetherrelaxin is of prognostic importance. Plasma concentrations of the hormones weremeasured in 87 patients admitted with CHF. These patients were followed up for ayear during which time hospitalisations due to CHF and death were recorded.While NT-proBNP was found to be a powerful and independent predictor ofoutcome in these patients, relaxin was not.CONCLUSION.In addition to its established role in pregnancy, relaxin has many other actions. Inparticular, its antihypertensive, antithrombotic and vasodilatory properties suggestthat relaxin may have a central role in cardiovascular regulation.