ET _B Receptor Blockade Potentiates the Pressor Response to Big Endothelin-1 But Not Big Endothelin-2 in the Anesthetized Rabbit

Abstract

Abstract-The precursor of endothelin-1, big endothelin-1, is considered to be a more reliable marker of systemic production of vasoactive peptide. However, it is largely unclear whether ET B receptor-dependent clearance and endothelium-derived relaxing factors affect the precursor in a similar manner to mature ET-1. These ET B -dependent modulations of big ET-1 and big ET-2 pressor properties were therefore studied in the anesthetized rabbit. When injected into the left cardiac ventricle, ET-1 and ET-2 (0.01 to 1 nmol/kg) each induced biphasic responses (a depressor followed by a pressor response), whereas big ET-1 and big ET-2 (0.1 to 3 nmol/kg) caused only protracted pressor responses. The highest dose of big ET-1 caused significantly greater responses than ET-1, ET-2, or big ET-2. A selective ET A receptor antagonist, BQ-123 (1 mg/kg), markedly reduced pressor responses to all 4 peptides, whereas blockade of ET B receptors with BQ-788 (0.25 mg/kg) sharply potentiated the responses to ET-1, ET-2, and big ET-1, but not to big ET-2. Indomethacin (10 mg/kg) sharply potentiated the pressor response to ET-1 (1 nmol/kg), but not big ET-1, at all time points. In control animals, ET-1, but not big ET-1, also triggered an indomethacin-sensitive increase in circulating prostacyclin. Finally, systemically administered big ET-1, but not big ET-2, induced a phosphoramidon-sensitive increase in plasma IR-ET. Our results suggest a significant limiting role of ET B receptors on pressor responses to big ET-1. In contrast, the same receptor entities do not modulate the hemodynamic properties of the ET-2 precursor, given that, unlike big ET-1, it is poorly converted in the pulmonary or systemic circulation in anesthetized rabbits. Key Words: endothelin Ⅲ endothelium-derived relaxing factor Ⅲ endothelin-converting enzyme Ⅲ prostacyclin Ⅲ chromatography Ⅲ receptors T he potent vasoconstrictor peptide endothelin-1 (ET-1), and its isomers ET-2 and ET-3 are formed through proteolytic cleavage of their immediate precursors, big ET-1, big ET-2, and big ET-3, by phosphoramidon-sensitive endothelin-converting enzymes (ECEs). 1 ECEs display pronounced activity in vivo, such that big ET-1, which shows very low affinity for endothelin ET receptors, is as potent as its active metabolite ET-1 as a hypertensive agent on an equimolar basis. 2 As big ET-1 plasma levels in the human, rabbit, and rat are higher than those of its active metabolite, studies have suggested that the precursor might be the actual factor released from endothelial cells. 3 Interestingly, big ET-1 plasma levels have been shown to correlate closely with severity of chronic heart failure in patients and to constitute a good prognostic marker of kidney function and survival. 4 When administered intravascularly, big ET-1 induces only a monophasic pressor response, whereas its active metabolite, ET-1, induces a characteristic transient depressor effect, due to vasodilation, before onset of its pressor effect. 1,2 This discrepancy in hemodynamic effects of exogenous ET-1 and bi...

Endothelin-1 (1-31) Is an Intermediate in the Production of Endothelin-1 After Big Endothelin-1 Administration In Vivo

“…In contrast, the ET B antagonist BQ-788 (0.25 mg/kg) potentiated the increases in MAP afforded by big ET-1 (as reported previously) 15 and ET-1 (1-31) (Figure 3).…”

“…We had shown previously in this same animal model that big ET-1 was converted in the circulation to ET-1 via a phosphoramidon-sensitive process, 15 suggesting that the precursor was inactive per se. Nakano et al 2 reported the existence of ET-1 (1-31), and Hayasaki-Kajiwara et al 4 suggested that this particular intermediate could generate ET-1 via an ECE/NEP process in human cultured bronchial smooth muscle cells.…”

“…Noteworthy, we had demonstrated previously 15 that intracardiac administration of big ET-1 generates a phosphoramidonsensitive increase in plasma ET-1 concentration.…”

“…Experiments were performed in ketamine/xylazine-anesthetized and ventilated (5 mL air/kg; 45 strokes/min; model 683; Harvard Apparatus) New Zealand White rabbits of either sex (1.25 to 1.75 kg) as reported previously. 15,16 Briefly, a catheter (PE-90) was placed into the left ventricle via the right carotid artery for administration of the various agents and for blood sampling. Mean arterial blood pressure (MAP) and heart rate (HR) were constantly monitored via a heparinized cannula in the left femoral artery with a blood pressure analyzer (BPA-200A; Micro-Med).…”

“…15,16 In addition, we investigated whether the pressor properties of ET-1 (1-31), similar to big ET-1, 15 require a conversion into the mature peptide ET-1. We have also explored the putative contribution of NEP and ECE in that phenomenon in vivo.…”