Reduced sodium intake normally blunts the systemic and renal vascular response to angiotensin II (AII) and potentiates the adrenal's. Our goal is to pursue preliminary evidence that this normal modulation is deranged substantially in about 50% of patients with essential hypertension: an identical abnormality involves the kidney and the adrenal in the same patient and could well be responsible for the hypertension. Our first goal is to examine the mechanisms underlying failure of modulation of renal and adrenal responsiveness to AII with shifts in sodium intake. Does acute sodium depletion restore the modulation of responsiveness? Does sodium depletion sustained by long-term treatment with diuretic restore to normal, disordered modulation of responsiveness? Are the abnormalities mediated by AII, and thus corrected by converting enzyme inhibition? Is correction specific for the converting enzyme inhibitor, or do other antihypertensive agents correct the abnomrality as blood pressure is controlled? Is the abnormality related to the angiotensin receptor, and thus identifiable in angiotensin receptors on platelets? Does potassium balance, known to modulate renal and adrenal responsiveness, participate? A second goal is to relate the abnormality in modulation to sodium homeostasis and to hypertension. Are the renal and adrenal abnormalities associated with deranged renal socium handling? Is there an association between the sodium sensitivity of the hypertension and the abnormalities in the adrenal and the kidney? Does correction of the modulation by converting enzyme inhibition modify renal sodium handling? Our third goal is to characterize further the patients who failed to modulate. Does the non-modulating group represent a true, discreet subgroup? Are the abnormalities in renal and adrenal responsiveness a reflection of lower baseline values? Is the blunted adrenal and renal vascular response related to other potentially relevant disorders including paradoxical agonist responses to saralasin, failure of suppression of renin release with saline, and abnormalities in sympathetic nervous system function? Successful completion of these studies will provide insight into the pathogenesis of essential hypertension in about 50% of the patients; it will explain sodium sensitivity and the action of diuretics, delineate the underlying renal and adrenal mechanisms, account for the unanticipated effectiveness of converting enzyme inhibition, and potentially provide a rational basis for antihypertensive therapy.
| Dluhy, R G; Smith, K; Taylor, T et al. (1989) Prolonged converting enzyme inhibition in non-modulating hypertension. Hypertension 13:371-7 |
| Canessa, M; Redgrave, J; Laski, C et al. (1989) Does sodium intake modify red cell Na+ transporters in normal and hypertensive subjects? Am J Hypertens 2:515-23 |
| Holtzman, E; Braley, L M; Menachery, A et al. (1989) Rate of activation of renin-angiotensin-aldosterone axis and sodium intake in rats. Am J Physiol 256:H1311-5 |
| Seely, E W; LeBoff, M S; Brown, E M et al. (1989) The calcium channel blocker diltiazem lowers serum parathyroid hormone levels in vivo and in vitro. J Clin Endocrinol Metab 68:1007-12 |
| Hollenberg, N K; Williams, G H (1988) Angiotensin and the renal circulation in hypertension. Circulation 77:I59-63 |
| Hollenberg, N K (1988) Control of renal perfusion and function in congestive heart failure. Am J Cardiol 62:72E-75E |
| Hollenberg, N K (1988) Angiotensin converting enzyme inhibition and the kidney. Curr Opin Cardiol 3:S19-29 |
