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

Fisher, Carol, Jane (2009) Relaxin: a new cardiovascular hormone in humans? Comparative potency and mechanisms of action. MD thesis, University of Glasgow.

Abstract

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
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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.
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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.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Keywords: relaxin, vasodilation, cardiovascular regulation, coronary artery disease, chronic heart failure
• Subjects: R Medicine > RC Internal medicine; Q Science > QP Physiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: McMurray, Prof. J.J.
• Date of Award: 2009
• Depositing User: Dr Carol Fisher
• Unique ID: glathesis:2009-752
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 29 Jun 2009
• Last Modified: 10 Dec 2012 13:25
• URI: https://theses.gla.ac.uk/id/eprint/752