Altered vascular responses in experimental congestive heart failure

University dissertation from Cellbiology 1, EB-bloc, University Hospital, 221 85 Lund, Sweden

Abstract: Congestive heart failure is accompanied with increased circulatory levels of several vasoregulatory neurotransmitters and hormones which affect the outcome of this disease. In this thesis the blood levels of several vasoactive peptides in humans with congestive heart failure and their effects on the vasculature by the use of an animal model of heart failure were studied. Patients with congestive heart failure had increased levels of noradrenaline (NA), adrenaline (A), neuropeptide Y, atrial natriuretic peptide (ANP) and antidiuretic hormone. The increased levels of ANP and NA correlated to the survival time in patients with congestive hart failure. Increased levels of NA and A were also found in the animal heart failure model. The passive elastic and active contractile capacity of small mesenteric arteries were attenuated in heart failure animals. Ca2+-mediated and KCl -induced contractions were attenuated in heart failure vessels, an effect due to alterations of a-adrenoceptors. The contractile responses of isolated vessel segments to agonists of the sympathetic nervous system were altered, especially the a2- adrenergic receptor, which mediated an attenuated response in several vascular beds, both in vivo and in vitro, in heart failure animals. The sympathetic co-transmitter neuropeptide Y (NPY) enhanced the response to NA in human omental arteries via the Y1 receptor and this receptor was involved in the modulation of the response to endothelin (ET) -1, U46619 and 5-HT in heart failure vessels. NPY-induced potentiation of ET seem to be mediated by a receptor different from the NPY Y1 type. Endothelin was found to be less potent in large conductance arteries in heart failure while the reverse was noted in small mesenteric arteries. The response mediated through the smooth muscle endothelin B receptor was altered since inhibition of this receptor in endothelium-denuded arteries induced a leftward shift of the concentration-response curve in heart failure but not in control animals. The dilatory response to calcitonin gene-related peptide was attenuated in several arterial beds in heart failure rats. It is concluded that the animal model is suitable for studying the effects of neurotransmitters in heart failure and correlates with findings in humans. Further, several receptor alterations are induced which might influence the outcome of this condition.

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