Hemin and L-arginine regulation of blood pressure in spontaneous hypertensive rats.

Perturbation in heme metabolism is known to affect the level and activity of hemoproteins, including cytochrome P450-dependent arachidonic acid metabolism. The latter has been associated with elevation in blood pressure seen in spontaneously hypertensive rats. The effect of heme arginate and its components, arginine and heme, on cytochrome P450 levels and blood pressure in spontaneously hypertensive rats were studied. Administration of heme arginate or heme alone at doses of 9 to 30 mg/kg body wt/day for 4 days resulted in a marked decrease of blood pressure in spontaneously hypertensive rats, whereas blood pressure in rats receiving the vehicle control was not affected. Similarly, L-arginine, but not D-arginine, in a dose-dependent manner decreased blood pressure in spontaneously hypertensive rats. The maximal change in blood pressure was achieved at 100 mg/kg body wt of arginine and was associated with a significant increase in heme oxygenase activity. A higher concentration (500 mg/kg) did not cause an additional decrease in blood pressure but further increased heme oxygenase activity. The arginine-induced heme oxygenase activity was suppressed by Sn-protoporphyrin. Administration of heme to spontaneously hypertensive rats resulted in an accumulation of heme oxygenase mRNA, which was accompanied by an increase in enzyme activity. The increase in heme oxygenase activity was also prevented by Sn-protoporphyrin. It is postulated that heme treatment resulted in an increase in heme oxygenase mRNA, which consequently led to a diminution of cellular heme and depletion of hemoproteins, such as the cytochrome P450 arachidonate metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular response to exercise and autonomic control mechanisms in end-stage renal disease.

Left ventricular (LV) function during rest and during exercise was evaluated in patients with end-stage renal disease (ESRD) in whom other causes of LV dysfunction were eliminated through rigid selection criteria. Autonomic function was also assessed in these patients with Valsalva's maneuver and plasma catecholamine determinations. Echocardiography and radionuclide ventriculography in the group with ESRD revealed no abnormalities of LV wall motion or ejection fraction. During graded exercise, patients with ESRD achieved 85% of age-predicted heart rate, and no differences in exercise tolerance or LV function were observed. Valsalva's response was abnormal in patients with ESRD, and post exercise the norepinephrine level was markedly increased (12.5 +/- 1.43 vs 8.28 +/- 0.82 nmol/L). Our results fail to indicate an independent adverse effect of ESRD on LV function.

Pharmacologic toxicity of cimetidine on hepatic and renal drug metabolism.

We studied the effect of cimetidine on liver and kidney heme metabolism and on the activity of the cytochrome P-450 drug metabolizing enzyme system. Results show that the induction of a heme biosynthetic enzyme and the activities of two drug metabolizing enzymes are impaired when cimetidine is given in combination with phenobarbital (PB). When rats were given four 33 mg doses of cimetidine IP per day for 2 days and sacrificed, we found no significant effect on kidney or liver delta-aminolevulinic acid (ALA) synthase activity. Heme oxygenase and cytochrome P-450 levels were also unchanged in these tissues. In contrast, when we measured activities of certain liver drug metabolizing enzymes, it was found that cimetidine significantly inhibited aniline hydroxylase and aminopyrine-N-demethylase by 43% and 65%, respectively. The observed changes in the activities of these drug metabolizing enzymes led us to study cimetidine in combination with other drugs. When the porphyric inducing agent allylisoprophyacetamide (AIA) was administered alone, we found a 326% increase in hepatic ALA synthase activity at 16 hours. Cimetidine given together with AIA increases hepatic ALA synthase 291 and 300% at 16 and 20 hour intervals respectively. Cytochrome P-450 levels in AIA treated rats with or without cimetidine were decreased to 52-65% of control values without a significant change in heme oxygenase levels. When PB was given alone, we found an increase in hepatic ALA synthase activity by 223 and 400% at 16 and 20 hour intervals, respectively. Cimetidine in combination with PB at the same time intervals showed a slightly diminished increase of hepatic ALA synthase activity by 146 and 238%, respectively. When PB was given alone, hepatic cytochrome P-450 was increased 96% at 16 hours, whereas when combined with cimetidine a similar increase of hepatic cytochrome P-450 was observed. In conclusion cimetidine does not significantly alter the action of the porphyric agents PB and ALA on cytochrome P-450; however, combined administration of PB plus cimetidine does impair the induction of ALA synthase. Additionally, cimetidine markedly decreased the drug metabolizing enzymes aniline hydroxylase and aminopyrine-N-demethylase in vivo, and subsequently may interfere with the endogenous metabolism of other drugs.

Inhibition of erythropoiesis in chronic renal failure: the role of parathyroid hormone.

Sera from 20 anemic patients with chronic renal failure (CFR) were studied for their effect on bone marrow in vitro erythroid colony formation (CFUE) and the observations correlated with parathyroid hormone (PTH) and ionized calcium levels in the patients' sera. Results demonstrated that 17 out of 20 patients' sera significantly inhibited in vitro erythropoiesis by 47% to 97%. No significant elevation in ionized calcium was found in 16 of the patients tested. Furthermore, assay of PTH levels in these patients revealed that 9 out of 20 had elevated levels of PTH. No correlation was found between PTH serum levels and the degree of in vitro inhibition of erythropoiesis (CFUE) by the patients' sera. Addition of up to 2,000 pg/mL (far above the patients' levels) of exogenous N-terminal or C-terminal PTH with in vitro bone marrow cultures resulted in no inhibitory effect on CFUE. It is concluded that the circulating inhibitor of erythropoiesis which has been shown to exist in the sera of this particular group of patients with CRF, is not PTH.

Hearing impairment associated with chronic renal failure.

The auditory sensitivity of 67 patients with chronic end-stage renal failure was assessed. In order to determine the incidence of hearing loss and to describe the impairment and possible contributing factors, one group of 39 patients was assessed prior to treatment by hemodialysis. Twelve of these subjects were then followed for 1 year as they are treated by hemodialysis. The remaining 27 patients, not treated by hemodialysis, were also retested in one year. A second group of 28 patients who ad been receiving hemodialysis over periods of 1 1/2, 3, and 6 years was also evaluated. A high incidence of high-frequency impairment was obtained which could not be attributed to age, noise exposure, ototoxicity, or hereditary. An association between this high-frequency impairment and both the renal disease and its treatment was suggested. Clinically significant sensorineural hearing loss did not appear associated with non-genetic kidney disease.

Presence of creatine phosphokinase brain band in the serum of chronic renal disease patients.

The almost universal presence of the isoenzyme creatine phosphokinase brain band (CPK-BB) in the sera of patients with chronic renal insufficiency and serum creatinine above 4.5 mg/dl is noted. It is absent in patients with severe acute renal failure and in transplanted patients with normal renal function. The source of the enzyme may be nerve tissue and may represent neuronal cell damage in uremics over a period of time.