Abstract: In his March 11 commentary, Franz Messerli1Messerli FH Implications of discontinuation of doxazosin arm in ALLHAT.Lancet. 2000; 355: 863-864Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar commented on the discontinuation of the doxazosin arm of ALLHAT. Doxazosin (an α1-adrenoceptor blocker) as monotherapy in patients with hypertension and at least one other coronary heart disease risk factor conferred less overall cardiovascular benefits than did treatment with chlorthalidone. The treatement with doxazosin was associated with a significantly higher percentage of development of congestive heart failure compared with chlorthalidone. Messerli suggested “that a yet unknown powerful risk factor associated with doxazosin therapy counteracts the beneficial effect”. We would like to propose candidates for such putative risk factors by considering possible consequences of blocking myocardial α1-adrenoceptors by doxazosin in addition to the vascular α1-adrenoceptors. We found that norepinephrine in myocardial strips from explanted failing human hearts elicited an inotropic effect through α1-adrenoceptors with a mean value of about 90% above basal in the presence of β-adrenoceptor blockade.2Skomedal T Borthne K Aass H et al.Comparison between α1-adrenoceptor mediated and β-adrenoceptor mediated inotropic components elicited by norepinephrine in failing human ventricular muscle.J Pharmacol Exp Therap. 1997; 280: 721-729PubMed Google Scholar The α1-adrenoceptors in failing human myocardium were located near the synaptic clefts indicating a functional role in vivo.3Skomedal T Dybvik T Osnes J-B et al.Location of myocardial α1- and β-adrenoceptors in relation to sympathetic nerve endings in failing human myocardium [suppl].Naunyn-Schmiedeberg's Arch Pharmacol. 1998; 358: R633Google Scholar In rabbit myocardium Hasenfuss and colleagues found that α1-adrenoceptor stimulation elicited an inotropic effect without decreasing the energetic economy in contrast to β-adrenoceptor stimulation.4Hasenfuss G Blanchard EM Holubarsch C et al.Influence of α- and β-receptor stimulation on myocardial energetics in rabbit myocardium [suppl].Circulation. 1989; 80: 153Google Scholar Thus, stimulation of myocardial α1-adrenoceptors can elicit a moderate and energetically favourable inotropic effect. This effect may serve to counteract development of heart failure. Treatment with an α1-adrenoceptor blocker may attenuate this low energy cost and supportive inotropic effect to an extent increasing the risk for developing heart failure in susceptible patients who are not concomitantly treated with a β-adrenoceptor blocker. We discovered that stimulation of myocardial α1-adrenoceptors activates a loop-diuretic sensitive Na/K/2Cl-cotransporter in the myocardium.5Andersen GO Enger M Thoresen GH et al.α1-Adrenergic activation of myocardial Na/K/2Cl-cotransport involving mitogen-activated protein kinase.Am J Physiol. 1998; 275: H641-H652PubMed Google Scholar This activation involved mechanisms unrelated to the inotropic effect. This cotransporter plays an important part in cell-volume regulation and maintenance of intracellular Cl− and other electrolytes essential for proper cellular functions. Blockade of myocardial α1-adrenoceptors may disturb this regulation and increase the risk of developing heart failure in susceptible patients. α1-adrenoceptor stimulation is known to increase myocardial protein synthesis and gene expression. The compensatory myocardial hypertrophy is deleterious in the long run, eventually contributing to development of heart failure. In this sense it would be expected that blockade of myocardial α1-adrenoceptors would be beneficial. But the findings of the doxazosin arm of ALLHAT indicate that a benefit from reduction of myocardial hypertrophy by α1-adrenoceptor blockade as monotherapy is counteracted by attenuation of α1-adrenoceptor mediated beneficial effects, some of which may be coupled to the myocardial α1-adenoceptors, as discussed above. We suggest that blockade of the myocardial α1-adrenoceptors may be one risk factor associated with doxazosin monotherapy in patients as those included in ALLHAT.