Verapamil reverses PTH- or CRF-induced abnormal fatty acid oxidation in muscle

Chronic renal failure (CRF) is associated with impaired long chain fatty acids (LCFA) oxidation by skeletal muscle mitochondria. This is due to reduced activity of carnitine palmitoyl transferase (CPT). These derangements were attributed to the secondary hyperparathyroidism of CRF, since prior parathyroidectomy in CRF rats reversed these abnormalities and PTH administration to normal rats reproduced them. It was proposed that these effects of PTH are mediated by its ionophoric property leading to increased entry of calcium into skeletal muscle. A calcium channel blocker may, therefore, correct these derangements. The present study examined the effects of verapamil on LCFA oxidation, CPT activity by skeletal muscle mitochondria, and 45Ca uptake by skeletal muscle obtained from CRF rats and normal animals treated with PTH with and without verapamil. Both four days of PTH administration and 21 days of CRF produced significant (P < 0.01) reduction in LCFA oxidation and CPT activity of skeletal muscle mitochondria, and significant (P < 0.01) increment in 45Ca uptake by skeletal muscle. Simultaneous treatment with verapamil corrected all these derangements. Administration of verapamil alone to normal rats did not cause a significant change in any of these parameters. The data are consistent with the proposition that the alterations in LCFA in CRF or after PTH treatment are related to the ionophoric action of the hormone and could be reversed by a calcium channel blocker

Effects of verapamil on the abnormalities in fatty acid oxidation of myocardium

The oxidation of long (LCFA) and short chain fatty acids (SCFA) by myocardial mitochondria is impaired in CRF due to reduced activity of carnitine palmitoyl transferase (CPT) and of enzymes in the β-oxidation sequence in mitochondrial matrix. It was proposed that PTH, through its ability to augment entry of calcium into cells, enhances calcium uptake by the myocardium leading to calcium accumulation which in turn affects mitochondrial function. A calcium channel blocker may therefore correct these derangements. The present study examined the effects of verapamil on LCFA and SCFA oxidation and on CPT activity of myocardial mitochondria and on 45Ca uptake by, and clacium content of, myocardium obtained from CRF rats and rats treated with PTH, with and without administration of verapamil. Both four days of PTH administration and 21 days of CRF produced significant (P < 0.01) reduction in the oxidation of LCFA and SCFA by and of CPT activity of myocardial mitochondria and a significant increase in 45Ca uptake by, and content of, the myocardium. Simultaneous administration of verapamil reversed all these derangements. Administration of verapamil alone to normal rats for 4 or 21 days did not cause significant changes in these parameters. The results of our studies are consistent with the notion that the alterations in myocardial oxidation of LCFA and SCFA in CRF or after PTH treatment are related to PTH-induced calcium accumulation in the heart, and could be reversed by a calcium channel blocker. The data could provide a rational therapeutic approach for the management of uremic myocardiopathy

Impaired activity of alpha-ketoglutarate dehydrogenase of heart mitochondria in chronic renal failure: Role of secondary hyperparathyroidism

Chronic renal failure (CRF) is associated with impaired oxidation of α-ketoglutarate (α-KG) by heart mitochondria, and previous data indicated that this derangement is due to the state of secondary hyperparathyroidism of CRF. A reduction in the utilization of α-KG by heart mitochondria implies that the activity of mitochondrial α-ketoglutarate dehydrogenase (α-KGDH) is impaired; however, direct evidence for such an abnormality is not available. We examined the V(max) and the K(m) of α-KGHD of heart mitochondria obtained from normal rats, CRF animals and normocalcemic parathyroidectomized (PTX) CRF rats. Our data showed that CRF has no effect on the K(m) of α-KGDH for α-KG. However, V(max) of the enzyme was significantly (p < 0.01) reduced and this abnormality was prevented by PTX of CRF rats. Our results provide the evidence that the impaired utilization of α-KG by myocardial mitochondria of CRF rats is due to reduced V(max) of α-KGDH and that both derangements are mediated by excess PTH or a metabolic consequence of the secondary hyperparathyroidism of CRF