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The net contribution of endothelin type A (E[T.sub.A]) and type B (E[T.sub.B]) receptors in blood pressure regulation in humans and experimental animals, including the conscious mouse, remains undefined. Thus we assessed the role of E[T.sub.A] and E[T.sub.B] receptors in the control of basal blood pressure and also the role of ETA receptors in maintaining the hypertensive effects of systemic E[T.sub.B] blockade in telemetry-instrumented mice. Mean arterial pressure (MAP) and heart rate were recorded continuously from the carotid artery and daily (24 h) values determined. At baseline, MAP ranged from 99 [+ or -] 1 to 101 [+ or -] 1 mmHg and heart rate ranged between 547 [+ or -] 15 and 567 [+ or -] 19 beats/min (n = 6). Daily oral administration of the E[T.sub.B] selective antagonist A-192621 [10 mg/kg twice daily] increased MAP to 108 [+ or -] 1 and 112 [+ or -] 2 mmHg on days 1 and 5, respectively. Subsequent coadministration of the ETA selective antagonist atrasentan (5 mg/kg twice daily) in conjunction with A-192621 (10 mg/kg twice daily) decreased MAP to baseline values on day 6 (99 [+ or -] 2 mmHg) and to below baseline on day 8 (89 [+ or -] 3 mmHg). In a separate group of mice (n = 6) in which the treatment was reversed, systemic blockade of E[T.sub.B] receptors produced no hypertension in animals pretreated with atrasentan, underscoring the importance of ETA receptors to maintain the hypertension produced by E[T.sub.B] blockade. In a third group of mice (n = 10), E[T.sub.A] blockade alone (atrasentan; 5 mg/kg twice daily) produced an immediate and sustained decrease in MAP to values below baseline (baseline values = 101 [+ or -] 2 to 103 [+ or -] 2 mmHg; atrasentan decreased pressure to 95 [+ or -] 2 mmHg). Thus these data suggest that ETA and E[T.sub.B] receptors play a physiologically relevant role in the regulation of basal blood pressure in normal, conscious mice. Furthermore, systemic ETa receptor blockade produces sustained hypertension in conscious telemetry-instrumented mice that is absent in mice pretreated with an ETA antagonist, suggesting that ETA receptors maintain the hypertension produced by E[T.sub.B] blockade. atrasentan; A-192621; endothelin; mouse; vasculature

The role of endothelin-B (E[T.sub.B]) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hypertension produced by E[T.sub.B] blockade and the role of E[T.sub.A] receptors in mediating this response. Mean arterial pressure (MAP) and heart rate (HR) were measured 24 h/day for 24 days under control conditions and during administration of the [E.sub.TB]-selective antagonist A-192621 (0.1, 1.0, and 10 mg/kg bid, 4 days/dose) followed by coadministration of the [ET.sub.A] antagonist atrasentan (5 mg/kg bid) + A-192621 (10 mg/kg bid) for another 4 days. High-dose [ET.sub.B] blockade increased MAP from 79 [+ or -] 3 (control) to 87 [+ or -] 3 and 89 [+ or -] 3 mmHg on the first and fourth day, respectively; HR was unchanged, and plasma ET-1 concentration increased from 2.1 [+ or -] 0.3 pg/ml (control) to 7.24 [+ or -] 0.99 and 11.03 [+ or -] 2.37 pg/ml. Atrasentan + A-192621 (10 mg/kg) decreased MAP from hypertensive levels (89 [+ or -] 3) to 75 [+ or -] 2 and 71 [+ or -] 4 mmHg on the first and fourth day, respectively; plasma ET-1 and HR increased to 26.64 [+ or -] 3.72 and 28.65 [+ or -] 2.89 pg/ml and 113 [+ or -] 5 (control) to 132 [+ or -] 5 and 133 [+ or -] 7 beats/min. Thus systemic E[T.sub.B] blockade produces a sustained hypertension in conscious nonhuman primates, which is mediated by E[T.sub.A] receptors. These data suggest an importance clearance function for E[T.sub.B] receptors, one that influences arterial pressure homeostasis indirectly by reducing plasma ET-1 levels and minimizing E[T.sub.A] activation. endothelium-derived factors; blood pressure; endothelin receptor blockade

Amino acid release studies revealed a significantly high production of arachidonic acid (AA) in human pericardial smooth muscle cells (HPSMC) exposed to endothelin-1 (ET-1). Similar results were observed in cell cultures containing the calcium (Ca2+) ionophore A-23187 at 2 mumolars and extracellular Ca2+. Removal of the Ca2+ source markedly reduced ET-1-evoked AA release. Exposure of cells to inhibitors of protein kinase C reduced ET-1-evoked AA release by 70%, whereas inhibitors of phospholipase A2 potentiated the effects of ET-1. These results suggest that ET-1-evoked AA release in HPSMC could be promoted by phospholipase A2.

Analysis of the long-term cardiovascular and renal actions of endothelin in dogs preadministered with a converting-enzyme inhibitor (CEI) or angiotensin II (ANG II) replacement shows that long-term increases in circulating endothelin increase arterial pressure, but are independent of the renin-angiotensin system (RAS). Long-term increases in endothelin are also associated with decreases in renal blood flow and glomerular filtration rate.

Characterization of endothelin receptors in human pericardium smooth muscle cells (HPSMC) and evaluation of the potency of antagonists on ET-evoked signal transduction and DNA synthesis reveal that ET-1 binding is inhibited by a nonselective antagonist or a combination of E(TA)- and E(TB)-selective ligands. The activation of phosphatidylinositol hydrolysis and arachidonic acid release by ET-1 is dose- and time-dependent, reaching a plateau within 20-40 min, while ET-1-stimulation of DNA synthesis is dose-dependent, reaching prominent levels after 24 h. The ET-1 effects on signal transduction are blocked by 1 muM BQ-123.

Studies on time course of glomerular filtration (GFR) onset in spontaneously diabetes-prone (BB/DP) rats reveal that the process occurs even after 14 days in BB/DP rats maintained at mildly hyperglycemic levels with continuous insulin infusion. The atrial natriuretic peptide (ANP) levels do not increase at this stage and the infusion of an ANP receptor antagonist does not suppress the increased GFR triggered by insulin-dependent diabetes mellitus.

The role of the endothelin receptor ET-A in mediating the renal hemodynamic response to endothelin-1 (ET-1) was examined. ET-A is one of two ET receptor types and is believed to mediate the potent vasoconstrictor effects of ET-1. The study protocol involved the observation of the effects of BQ-123, a selective ET-A antagonist, on the renal hemodynamics during intravenous infusion of ET-1 in the rat. The results suggest a role for ET-A in the maintenance of renal vascular resistance and arterial pressure. However, ET-A does not mediate ET-1 renal vasoconstrictor events.

Reinhart, Glenn A., Lee C. Preusser, Terry J. Opgenorth, Craig D. Wegner, and Bryan F. Cox. Endothelin and [ET.sub.A] receptors in long-term arterial pressure homeostasis in conscious nonhuman primates. Am J Physiol Regulatory Integrative Comp Physioi 279: R1701-R1706, 2000.--This study was designed to quantify the long-term contribution of endogenous endothelin-1 (ET-1) and [ET.sub.A] receptors to the regulation of arterial pressure under normal conditions in nonhuman primates. Therefore, mean arterial pressure (MAP) and heart rate were measured 24 h/day with the use of telemetry techniques in conscious cynomolgus monkeys under control conditions, during administration of an [ET.sub.A] selective receptor antagonist (ABT-627; 5 mg/kg, 2 times a day by mouth, 4 days), and a 6-day posttreatment period. Systemic [ET.sub.A] blockade reduced MAP (24 h) from 89 [+ or -] 3 to 82 [+ or -] 2 and 79 [+ or -] 2 mmHg on days 1 and 4, respectively. Subsequently, MAP remained suppressed for 3 days posttreatment. Heart rate increased from 111 [+ or -] 5 to 122 [+ or -] 4 and 128 [+ or -] 6 beats/min on days 1 and 4 of ABT-627, respectively, and remained above control for 3 days posttreatment. Plasma ET-1 concentration increased from 1.0 [+ or -] 0.3 to 1.9 [+ or -] 0.4 pg/ml in response to ABT-627 (day 4) but decreased to control values 4 days posttreatment. These data demonstrate a physiologically important role for endogenous ET-1 and [ET.sub.A] receptors in the long-term regulation of arterial pressure and plasma ET-1 levels in the conscious non-human primate. endothelium-derived factors; endothelin-receptor blockade