6-iodoamiloride and Hypertension

Anatagonists to angiotensin, catecholamines, aldosterone, and vasopressin have long been used to help determine agonist roles in hypertension. We here call attention to a possible extension of this approach to detect, evaluate, and treat vascular sodium transport defects in hypertension. Two basic types of transport defects have been identified in the blood vessels of hypertensive animals, increased sodium permeability and decreased sodium pump activity. Intravenous injection of 6-iodo-amiloride, a sodium channel blocker and vasodilator, produces an immediate and sustained decrease in blood pressure in two genetic models of hypertension characterized by increased permeability of the vascular smooth muscle cell membrane to sodium (Okamoto spontaneously hypertensive rat, Dahl salt sensitive rat), whereas it produces only a transient fall in arterial pressure in two renal models of hypertension having normal sodium permeability in vascular smooth muscle cells (reduced renal mass-saline rat, one-kidney, one clip rat). Canrenone, a metabolic product of spironolactone which can compete with oubain for binding to Na+,K+-ATPase at the digitalis receptor site, decreases blood pressure in a low renin, volume expanded model of hypertension which has been shown to have depressed sodium pump activity in arteries and increased sodium pump inhibitor in plasma (reduced renal mass-saline rat) but has no effect on blood pressure in a genetic model of hypertension which has been shown to have increased sodium pump activity secondary to increased sodium permeability (spontaneously hypertensive rat). Thus, a sodium channel blocker and a competitor to ouabain binding can detect and determine the functional significance of sodium transport defects in the blood vessels of intact hypertensive animals. Studies in red and white blood cells suggest that similar defects may exist in the blood vessels of hypertensive humans. Thus, this approach, probing for vascular transport defects in the intact animal, may ultimately also be useful in the clinical setting.

Topics: Amiloride; Animals; Biological Transport, Active; Canrenone; Humans; Hypertension; Ion Channels; Ouabain; Sodium; Sodium-Potassium-Exchanging ATPase; Vascular Diseases

6-Iodoamiloride, an analogue of the sodium channel blocker amiloride, is a vasodilator-depressor, diuretic-natriuretic, and antikaliuretic agent. In these experiments we intravenously infused 6-iodamiloride (0.38 mg/100 g body weight) over a 10- to 11-minute period into rats with reduced renal mass-saline hypertension or one-kidney, one clip hypertension. The infusion produced a prompt but transient fall in blood pressure. These findings are in contrast to those in spontaneously hypertensive rats (SHR), in which the same infusion of 6-iodoamiloride produced a prompt, pronounced, and sustained fall in blood pressure. Studies from a number of laboratories suggest that vascular smooth muscle cells from the SHR have increased permeability to sodium whereas vascular smooth muscle cells from the other two models do not. Thus, 6-iodoamiloride may have potential both as a diagnostic probe and a therapeutic agent for hypertension characterized by increased vascular smooth muscle cell permeability to sodium.

Topics: Amiloride; Animals; Blood Pressure; Diuresis; Hypertension; Hypertension, Renovascular; Infusions, Intravenous; Male; Natriuresis; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The current study tested the hypothesis that NaCl-sensitive hypertension may result from increased membrane sodium channel activity. The effect of 6-iodoamiloride, and analog of the sodium channel blocker amiloride, on mean arterial pressure (MAP) was examined in conscious, freely moving NaCl-sensitive spontaneously hypertensive rats (SHR-S) fed high (8%) or normal (1%) NaCl diets. SHR-S and age-matched NaCl-resistant SHR (SHR-R) and normotensive Wistar-Kyoto (WKY) control rats were studied at 9 weeks of age after 2 weeks on either high (8%) NaCl or control (1%) NaCl diets. 6-iodoamiloride was infused intravenously in doses of 0.38 or 0.76 mg/100 g body weight, and MAP and heart rate (HR) were monitored from a femoral arterial cannula for 2 hours. The 8% NaCl diet caused a significant elevation in MAP in SHR-S but not in SHR-R or WKY. Administration of 6-iodoamiloride (both doses) produced a significant, sustained decrease in MAP in both SHR-S and SHR-R. Maximal depressor responses to high dose 6-iodoamiloride were significantly enhanced in SHR-S fed 8% NaCl (31.2 +/- 3.7 mm Hg) compared to SHR-S fed 1% NaCl (14.8 +/- 2.4 mm Hg) or SHR-R fed either 8% or 1% NaCl diets (15.6 +/- 4.2 and 10.2 +/- 3.0 mm Hg, respectively). In contrast, feeding an 8% NaCl diet had no significant effect on the depressor responses to 6-iodoamiloride in either SHR-R or WKY rats. In WKY, these doses of 6-iodoamiloride had no significant effect on MAP in either diet group. 6-iodoamiloride had no significant effect on heart rate in any group. These results support the hypothesis that the exacerbation of hypertension in SHR-S fed a high NaCl diet may result from increased membrane sodium channel activity.

Topics: Amiloride; Animals; Blood Pressure; Depression, Chemical; Heart Rate; Hypertension; Ion Channels; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium; Sodium Chloride

6-Iodo-amiloride, an analogue of the sodium channel blocker amiloride, was infused intravenously for 10 min in anaesthetized Okamoto spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats in doses ranging from 0.08 to 0.38 mg/100 g body weight. Systemic arterial blood pressure and urine flow were measured for 120 min. In SHR, 6-iodo-amiloride produced a prompt, sustained, dose-dependent decrease in pressure. The lower doses were associated with increased urine flow and sodium excretion, while higher doses were not. Paradoxically, in WKY all doses produced a small dose-independent sustained increase in pressure and were associated with diuresis and natriuresis. 6-Iodo-amiloride had no effect on cardiac output, dP/dt or heart rate in isolated working hearts from SHR or WKY. However, addition of 6-iodo-amiloride to physiological salt solution bathing an isolated Wistar rat tail artery produced hyperpolarization of impaled vascular smooth muscle cells. These studies show that 6-iodo-amiloride is a vasodilatory antihypertensive agent in SHR, and that this can be associated with natriuresis and diuresis.

Topics: Amiloride; Animals; Blood Pressure; Diuresis; Dose-Response Relationship, Drug; Hemodynamics; Hypertension; Ion Channels; Male; Natriuresis; Rats; Rats, Inbred SHR; Rats, Inbred Strains; Rats, Inbred WKY; Sodium