Does the Wall Stress Alone Stimulate the Natriuretic Peptide System?
To the Editor:
We read with great interest the article by Maeder et al1 published recently in Hypertension. We comment on this article by presenting some additional facts from the published literature, which may help in bringing about a new interpretation of the enormous amount of published clinical results on natriuretic peptides and open a new avenue of research. By the end of August 2010, a PubMed search produced >24 000 hits with “natriuretic peptide.” The high number of articles would suggest that there exist conflicting and confusing conclusions as to the role of natriuretic peptides in cardiology.
The concept that cardiac wall stress is the primary stimulus for the release of atrial natriuretic peptide (ANP; and also brain natriuretic peptide [BNP]) originates from the article by Lang et al2 in which a large and rapid intravascular volume load, produced experimentally, resulted in increased plasma levels of ANP in the laboratory rat, a species from dry and warm environments hardly ever experiencing such intravascular volume changes. The massive diuresis and natriuresis seen in rat after infusion of atrial extracts led to the conclusion that natriuretic peptides are hormones primarily regulating blood pressure. A high number of articles followed which verified that increased cardiac distension or pressure leads to increased plasma levels of ANP or BNP in different experimental studies and across a spectrum of cardiac diseases in humans.3
Parallel to pressure studies, it was shown by Baertschi et al4 that hypoxia was a direct and sufficient stimulus for the release of ANP from isolated perfused hearts of the rat and rabbit. These findings were corroborated in many studies with isolated cardiac myocytes and with isolated Langendorff-perfused animal hearts in the absence of any change in mechanical load.3 When the blood flow was surgically reduced to the area of the anterior ventricular wall of the heart of pigs resulting in hypoxia, the tissue content of BNP mRNA was increased several fold and, interestingly, hypoxia-response elements have been characterized from the promoter sequence of both the ANP and BNP genes.3
It appears that the measurement of natriuretic peptides, especially the BNP, has not met all of the expectations as a simple and useful tool in clinical cardiology. Confusing data have accumulated from the studies with critically ill patients in intensive care units,5 where patients most likely experience reduced tissue oxygenation.
Could it be possible that, in many cardiac diseases, there are hypoxic conditions in the heart tissue that play an independent factor regulating the synthesis of natriuretic peptides, thus confusing the interpretation of wall stress effect? It is noteworthy that, when in experimental animals with right ventricular hypertrophy, hypoxic conditions were replaced by normoxia, the ANP content fell to control levels despite persistent right ventricular hypertrophy.3
Sources of Funding
This work was funded by the Academy of Finland.
Maeder MT, Mariani JA, Kaye DM. Hemodynamic determinants of myocardial B-type natriuretic peptide release: relative contributions of systolic and diastolic wall stress. Hypertension. 2010; 56: 682–689.
Arjamaa O, Nikinmaa M. Natriuretic peptides in hormonal regulation of hypoxia responses [review]. Am J Physiol. 2009; 296: R257–R264.