Mechanisms of Histamine-Induced Coronary Vasodilatation: H ₁-Receptor-Mediated Release of Endothelium-Derived Nitric Oxide

Abstract

Although the content of histamine in myocardial tissue is high, its contribution to the regulation of coronary blood flow has not been clearly defined. The aim of the present study was to investigate whether or not nitric oxide (NO), an important modulator of coronary vascular tone, is involved in histamine-induced coronary vasomotion and to characterize which histaminergic receptor subtype mediates this process. Isolated, constant-flow-perfused guinea pig hearts were challenged with histamine, the H₁-receptor agonist pyridyleth-ylamine (PYR) and the H₂-receptor agonist dimaprit (DIM). Apart from coronary perfusion pressure (CPP), left ventricular pressure (LVP) and the development of contractile force (dp/dt), the release of NO and cyclic GMP (cGMP) were continuously measured. Histamine and DIM induced concentration dependently a coronary vasodilatation with an almost 50% decrease in CPP paralleled by an enhancement of LVP and dp/dt by more than 80%. PYR selectively reduced CPP by 47% without affecting LVP and dp/dt. Histamine-and PYR-induced coronary vasodilatation were paralleled by a more-than-twofold increase in basal cGMP release from isolated hearts, whereas DIM exerted no effects on cGMP release. Oxyhemoglobin (4 µ M), an effective scavenger of NO, shifted the concentration-response curve for histamine- and PYR-induced changes in CPP significantly to the right and in parallel inhibited the increase in cGMP release. Histamine and PYR rapidly (within 2 s) decreased CPP, while the onset of DIM-induced coronary vasodilatation followed changes in LVP with a lag period of 10 s. Histamine increased basal NO release concentration dependently by a maximum of 351 ± 21 pmol/min. Amounts of NO released were within the vasodilatory effective range of exogenously applied NO. These data suggest that the rapid onset of histamine-induced coronary vasodilatation is mediated via the activation of H₁ receptors with the subsequent release of endothelium-derived NO followed by a long-lasting and profound component which is due to the H₂-receptor-mediated increase in LVP. Amounts of NO released upon stimulation of endothelial H₁ receptors are sufficient to fully account for the increase in cGMP and the observed coronary vasodilatation.