In hypothyroid rat myocardium, the low-ouabain-sensitivity Na,K-ATPase activity had a KI = 10(-4) M and accounted for approximately 95% of the enzyme activity, while the high-ouabain-sensitivity activity contributed approximately 5% to the total activity, with a KI = 3 x 10(-7) M. mRNA alpha 1 was 7.2- and 5.5-fold more abundant than mRNA alpha 2 and mRNA beta, respectively, in hypothyroid ventricles while mRNA alpha 3 was undetectable. Administration of T3 increased total Na,K-ATPase activity 1.6-fold; the low-ouabain-sensitivity activity increased 1.5-fold while high-ouabain-sensitivity activity was stimulated 3.2-fold. T3 increased the number of high-affinity ouabain-binding sites 2.9-fold with no change in Kd (approximately 2 x 10(-7) M). The abundances of mRNA alpha 1, mRNA alpha 2, and mRNA beta (per unit RNA) following T3 treatment increased 3.6-, 10.6-, and 12.7-fold, respectively. The larger increments in subunit mRNA abundances than in Na,K-ATPase activity suggests the involvement of translational and/or post-translational regulatory steps in Na,K-ATPase biogenesis in response to T3. It is concluded that T3 enhances myocardial Na,K-ATPase subunit mRNA abundances and Na,K-ATPase activity, and that the expression of the high- and low-ouabain-sensitivity activities are probably a reflection of the abundances of the alpha 2 and alpha 1 isoforms, respectively. The physiological role played by the beta subunit remains uncertain.

The effects of thyroid hormone on Na,K-ATPase alpha-subunit mRNA (mRNA alpha) content and Na,K-ATPase activity were measured in renal cortex, heart, and cerebrum of hypothyroid rats 24 and 72 h after injection of diluent or T3. Use of a cDNA probe complementary to rat brain mRNA alpha in Northern blot analysis revealed a single 26-27 S band in RNA isolated from these three tissues regardless of thyroid status. Tissue mRNA alpha content was estimated by dot blot analysis of whole cell extracts and isolated total RNA. Injection of T3 augmented mRNA alpha content by 2.1- to 2.5-fold in kidney cortex and myocardium at 24 h. After three daily injections of T3, the increases in mRNA alpha were evident despite a global increase in RNA content associated with hypertrophy of these target tissues. Furthermore, the increases in abundance of mRNA alpha after 72 h of T3 treatment correlated with enhancement of Na,K-ATPase activity. In contrast, both mRNA alpha and enzyme activity were invariant in the cerebrum. These data suggest that T3-induced augmentation of Na,K-ATPase activity is mediated, at least in part, by increased mRNA alpha content in target tissues.

Both type 1 and type 2 diabetic patients have an increased incidence of ischemic heart disease and congestive heart failure. Cardiovascular disease accounts for up to 80% of the excess mortality in patients with type 2 diabetes. The burden of cardiovascular disease is especially pronounced in diabetic women. Factors that underlie diabetic heart disease include multiple vessel coronary artery disease, long-standing hypertension, metabolic derangements such as hyperglycemia and dyslipidemia, microvascular disease, and autonomic neuropathy. There is also increased sudden death associated with diabetes, which is due, in part, to the underlying autonomic neuropathy. This article reviews diabetic cardiac disease, with an emphasis on type 2 diabetes.

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A peptide with high intrinsic activity for specifically stimulating the secretion of immunoreactive growth hormone (GH; somatotropin) has been characterized and reproduced by total synthesis. This peptide, human pancreatic growth hormone-releasing factor, 44-amino-acid form (hpGRF1-44-NH2), was isolated from a tumor localized in the pancreas of a patient with acromegaly. We report here the effect of this growth hormone-releasing factor (GRF) on GH release and the GH mRNA levels in monolayer cultures of rat pituitary. The cytoplasmic dot hybridization technique was used to examine the effect of GRF on GH mRNA levels. Incubation of rat pituitary cultures with GRF for 72 hr resulted in a 2-to 2.5-fold increase in GH mRNA levels, and the maximal levels of stimulation were achieved at GRF concentrations as low as 1 fM. GRF did not stimulate prolactin release, nor did it affect specific prolactin mRNA levels in the pituitary cultures. We conclude that GRF is a potent and specific GH secretagogue that also affects specifically GH mRNA levels in normal pituitary cells.The hypothalamus fulfills a dual function in the regulation of growth hormone (GH; somatotropin) release. An inhibitory factor, somatostatin, has been characterized since 1972, whereas the stimulatory factor [growth hormone-releasing factor (GRF) or somatocrinin] has eluded investigators until recently. In order to circumvent the problem of low abundance of GRF in the hypothalamus, extrahypothalamic sources of GRF production were sought. A solid tumor of the pancreas obtained at surgery from a patient who had produced the clinical syndrome of acromegaly was used to isolate and characterize the primary structure of three peptides possessing high intrinsic GH-releasing activity called hpGRF-40, hpGRF-44, and hpGRF-37, in which hp designates human pancreatic (1). Based upon their common NH2 terminal sequence and lower specific activities in vitro, hpGRF-40 and -37 are most probably proteolytic degradation products of hpGRF-44. Most recently the isolation and structural characterization of bovine (2), porcine (3), and murine (4) hypothalamic GRF have been reported. Both bovine and porcine GRF have 44 amino acid residues and share extensive structural homology with the 44-amino-acid form of hpGRF designated hpGRF1-44 NH2-The experiments reported here were conducted with the synthetic replicate of hpGRFl-44-NH2 (henceforth referred to as GRF or somatocrinin). GRF already has been shown to stimulate GH-release in vivo (5) and in vitro (6) without affecting release of other pituitary hormones. We report here that GRF also stimulates GH mRNA sequences in rat pituitary cells. A portion of these findings has been presented in preliminary form (7).