Theophylline-induced protection in myoglobinuric acute renal failure: further characterization.

We have reported previously that aminophylline has an ameliorating effect on the course and severity of glycerol-induced myoglobinuric acute renal failure in rats. Since aminophylline dissociates into theophylline in biological fluids and since theophylline is an adenosine receptor antagonist, we attributed the ameliorating effects to antagonism of the hemodynamic effects of endogenous adenosine. However, theophylline blocks tubuloglomerular feedback and produces natriuresis, and either of these effects might have accounted for the beneficial effects in acute renal failure. Therefore, this study was designed to further characterize the effects of theophylline in glycerol-induced acute renal failure in rats. Aminophylline had dose-dependent beneficial effects, as judged by the peak serum creatinine during the 3 days following induction of acute renal failure, by the number of animals with peak serum creatinine greater than 1 mg/dL, and by the mortality rate. Both furosemide and theophylline block tubuloglomerular feedback and produce natriuresis, but aminophylline had protective effects, whereas furosemide actually increased mortality, compared with aminophylline, following induction of myoglobinuric acute renal failure. Therefore, aminophylline's protective effects are independent of tubuloglomerular feedback and natriuresis. These results offer further support for the hypothesis that adenosine-induced hemodynamic changes play a pathogenic role in glycerol-induced acute renal failure in rats.

Arterial steroid receptors and their putative role in the mechanism of hypertension.

Data from clinical and experimental studies indicate that mechanism(s) for action of mineralocorticoids, other than renal, must be involved in the overall effect of mineralocorticoids on circulation--increased peripheral resistance and hypertension. We have postulated existence of such a mechanism in the arterial wall and have looked for the evidence for its presence. We have found high affinity, specific binders for mineralocorticoids, and glucocorticoids, with characteristics of steroid receptors, in the cytosol of rabbit aorta and femoral and carotid arteries. These binders possess physico-chemical properties of steroid receptors and, moreover, they translocate to cell nuclei (as steroid-receptor complexes) and bind to relatively specific "acceptor-sites" on nuclear chromatin. This provides evidence for the existence in the arterial wall of a molecular mechanism for a direct in situ action of mineralocorticoids and glucocorticoids. The mineralocorticoid receptors are not present in veins. We have also found that chronically elevated levels of 11-desoxycorticosterone (DOC) result in a marked increase in permeability of arterial smooth muscle cell membrane to sodium ions; this is in accord with findings of other investigators in the rat. This change presumably leads, through a chain of biochemical events, to increased arterial and arteriolar smooth muscle contractility, increased peripheral resistance and hypertension. Study is in progress to determine whether the effect of DOC on arterial smooth muscle cell-membrane permeability to electrolytes is elicited through the receptor-mediated mechanism for the in situ action of mineralocorticoids in the arterial wall. It is postulated that this mechanism is primarily responsible for "mineralocorticoid hypertension", but may well be instrumental also in pathogeneses of various other forms of hypertension, including "essential".

Evidence for the presence in arterial walls of intracellular-molecular mechanism for action of mineralocorticoids.

Data from clinical and experimental studies indicate that mechanism(s) for action of mineralocorticoids, other than renal, must be involved in the overall effect of mineralocorticoids on circulation--increased peripheral resistance and hypertension. We have postulated existence of such a mechanism in the arterial wall and have looked for the evidence for its presence. We have found high affinity, specific binders for mineralocorticoids, and glucocorticoids, with characteristics of steroid receptors, in the cytosol of rabbit aorta and femoral and carotid arteries. These binders possess physicochemical properties of steroid receptors and, moreover, they translocate to cell nuclei (as steroid-receptor complexes) and bind to relatively specific "acceptor-sites" on nuclear chromatin. This provides evidence for the existence of an intracellular-molecular mechanism for a direct in situ action of mineralocorticoids, and also glucocorticoids, in the arterial wall. We postulate that the demonstrated previously effect of mineralocorticoids on arterial smooth muscle cell-membrane permeability to electrolytes, leading presumably to increased peripheral resistance and hypertension, is elicited through the receptor-mediated mechanism for action of mineralocorticoids in the arterial wall.