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Articles in PresS, published online ahead of print August 29, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00606.2002
Submitted on July 25, 2002
Accepted on August 19, 2002
1 Physiology, Water and Salt Research Centre, University of Aarhus, Aarhus, Denmark; Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada
2 Clinical Pathology, St Paul's Hospital, University of British Columbia, Vancouver, BC, Canada
3 Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, Colorado, USA
4 Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada
5 Physiology, Water and Salt Research Centre, University of Aarhus, Aarhus, Denmark
6 Cardiology, University of Colorado Health Sciences Centre, Denver, Colorado, USA
* To whom correspondence should be addressed. E-mail: laher{at}interchange.ubc.ca.
Hypertrophic cardiac myopathy (HCM) is the leading cause of mortality in young athletes. Abnormalities in small intramural coronary arteries are observed at autopsy in such patients. The walls of these intramural vessels, especially in the ventricular septum, are thickened and the lumen frequently appears narrowed. Whether these morphological characteristics have functional correlates is unknown. We studied coronary myogenic tone in a transgenic mouse model of HCM that has mutations in the cardiac (alpha) myosin heavy chain gene. The transgenic mouse has a cardiac phenotype that resembles those occurring in humans. We examined the possible vascular contributions to the pathology of HCM. Septal arteries from 3 and 11- month old wild type (WT) and transgenic (HCM) mice were studied on a pressure myograph. The myogenic response to increased intravascular pressure in older animals was significantly reduced [maximal constriction: 32
4% (HCM) and 464% (WT), p<0.05]. After inhibition of endothelin receptors with bosentan, both WT and HCM mice had similar increases in myogenic constriction. The sensitivity to exogenous endothelin was significantly reduced in HCM mice, suggesting that the reduced myogenic constriction in HCM was due to reduced receptor sensitivity. In conclusion, we show for the first time that 1) myogenic tone in the coronary septal artery of the mouse is regulated by a basal release of endothelin, and 2) pressure induced myogenic activation is attenuated in HCM, possibly consequent to a reduction in endothelin sensitivity. The associated reduction in coronary vasodilatory reserve may increase susceptibility to ischemia and arrhythmias.
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