ways. In this hypothetical proposal by Markewitz and Kohan [34], it is suggested that the development of excessive responsiveness to the peptide may arise from either an increased number of receptor or a decreased intrarenal degradation of ET-1. It is unclear if the kidney secretes ET1 into the circulation in chronic renal disease. Equally unclear is whether ET-1 is a cause of hypertension or if its high levels in ESRD represent endothelial injury induced by hypertension (see text). Paradoxically, the contribution of ET-1 to ESRD hypertension might include reversal of its effects on inner medullary collecting duct (IMCD) to inhibit sodium and water reabsorption. This could result from an alteraltion in receptor number or sensitivity induced by the chronic disease state effect on the IMCD. S-70 Martinez-Maldonado: Pathophysiology of hypertension in ESRD of ESRD. This peptide is frequently high in ESRD patients and bears little correlation to the level of blood pressure. ABNORMAL CHANNELS Arteries of rats with hypertension exhibit an enhanced K1 efflux. A distinct K1 channel type in vascular smooth muscle cell membranes has been identified that is the pathway for the increased K1 current when these cells are exposed to high pressure [38]. This is considered “a universal finding” of hypertension [39]. Recent studies support that the ion channel represents a Ca21-sensitive K1 channel (KCa channel) that opens as a result of sudden stretch of arterial smooth muscle [40]. Opening of these channels would favor a loss of K1 from the cell, hyperpolarization that would reduce voltage-dependent calcium influx and relaxation of vascular muscle. Hypertension increases the expression of KCa channels, which increases the density of channel pathways, permitting compensatory K1 efflux. The effect of hypertension on the Ca21-sensitive K1 channel persists in arteries removed from their hypertensive environment [41]. Moreover, pharmacological normalization of hypertension in genetically hypertensive rats reduces the KCa current in arterial myocytes within two weeks [42]. Studies to determine the role of Ca21-sensitive K1 channels in the hypertension of ESRD or anephric patients would be of great interest. It is evident that in individuals who develop hypertension, these channels curtail, but do not prevent hypertension. Blockade of the channels in vitro causes intense vasoconstriction in hypertensive but not in normotensive arteries, suggesting that their principal role is to prevent excessive rises in blood pressure in the chronic phase of hypertension [43]. It is therefore possible that hypertensive subjects have abnormal channels or abnormal signaling pathways through the channels. In ESRD, substances that are non-dialyzable or whose release depends on volume expansion might be responsible for blocking the channels and either worsening hypertension or making it resistant to therapy. 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