CLONIDINE AND ST-91 MAY ACTIVATE IMIDAZOLINE BINDING-SITES IN THE HEART TO RELEASE ATRIAL-NATRIURETIC-PEPTIDE

It is well established that the antihypertensive drug clonidine acts t hrough specific imidazoline receptors in the brain and kidney to incre ase diuresis, natriuresis, acid kaliuresis. We have previously shown t hat the effects of clonidine are associated with elevated plasma atria l natriuretic peptide (ANP). Similar to clonidine, ST-91, a clonidine analogue that does not cross the blood-brain barrier, evokes renal res ponses that are also associated with elevated plasma ANP. The mechanis ms of ANP increase elicited by these imidazoline drugs are unclear. Si nce ANP is primarily released from the cardiac atria, we investigated the direct effect of the imidazoline drugs on ANP release by incubatin g left and right atrial sections with 10(-6) mom ST-91 in the presence and absence of efaroxan, a selective imidazoline I-1 receptor antagon ist, for 30 minutes at 37 degrees C. ST-91 significantly stimulated AN P release, and the effect was inhibited by 10(-6) mol/L efaroxan. Furt her studies using heart perfusion with the imidazoline drugs with and without antagonists over 30 minutes revealed that both clonidine and S T-91 gradually stimulated ANP release. Also, perfusion with these comp ounds resulted in a gradual decrease in heart rate, but bradycardia wa s significant only with clonidine. The effects of ST-91 were inhibited by 10(-6) mol/L efaroxan and to a lesser extent by 10(-6) mol/L yohim bine, implying that the actions of ST-91 were mainly mediated by I-1 r eceptors. On the other hand, the actions of clonidine were inhibited b y 10(-5) mol/L efaroxan and by 10(-6) mol/L yohimbine, an alpha(2)-adr enoceptor antagonist, which may suggest that the actions of clonidine were preferentially mediated by alpha(2)-adrenoceptors in the heart. T hese results indicate that the peripheral actions of clonidine are pro bably mediated by alpha(2) and imidazoline receptors and may involve d irect stimulation of ANP release by the cardiac atria-an effect that m ay account for the increase in plasma ANP levels and diuresis and natr iuresis observed in vivo after administration of clonidine and its ana logues.