Compared with NF hearts, DHD hearts exhibit marked uncoupling of beta 1- and beta 2-adrenergic receptors from adenylyl cyclase and contractile response stimulation as well as decreased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in beta-adrenergic signal transduction as well as changes in the contractile apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.

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The muscarinic acetylcholine receptor from porcine atria has been purified 100,000-fold to homogeneity by solubilization in digitonin/cholate and sequential chromatography on wheat germ agglutinin-agarose, diethylaminoethylagarose, hydroxylapatite, and 3-(2'-aminobenzhydryloxy)tropane-agarose. The yield of purified receptor was 4.3% of that found in the membrane fraction, and the purified receptor bound 11.1-12.8 nmol of L-[3H]quinuclidinyl benzilate per mg of protein, corresponding to a binding component Mr of 78,400-90,000. The purified receptor preparation consisted of two polypeptides in approximately equimolar amounts when examined on silver-stained sodium dodecyl sulfate/polyacrylamide gels. The larger polypeptide (Mr 78,000 on 8% polyacrylamide gels) was specifically alkylated with [3H]propylbenzilylcholine mustard, whereas the smaller polypeptide (Mr 14,800) was not labeled. The possibility that the small polypeptide is a contaminant fortuitously appearing in equimolar amounts with the large polypeptide cannot be ruled out at this time. The purified preparation was highly stable, with no measurable change in the number of ligand binding sites or the gel pattern after 1 month's storage on ice. Scatchard analysis showed a single class of binding sites for the antagonist L-[3H]quinuclidinyl benzilate with a dissociation constant of 61 +/- 4 pM. Equilibrium titration experiments demonstrated that the antagonist L-hyoscyamine displaced L-[3H]quinuclidinyl benzilate from a single class of sites (Kd = 475 +/- 30 pM), whereas the agonist carbamoylcholine interacted at two populations of sites (53% +/- 3% high affinity, Kd = 1.1 +/- 0.3 microM; 47% +/- 3% low affinity, Kd = 67 +/- 14 microM). The ligand binding data were very similar to that for the membrane-bound receptor, suggesting that the receptor has not been altered radically during purification.

Digitoxigenin alpha-L-, beta-L-, alpha-D-, and beta-D-glucosides; alpha-L-, beta-L-, alpha-D-, and beta-D-mannosides; and alpha-L- and beta-L-rhamnosides were stereoselectively synthesized from the corresponding sugar tetrabenzyl trichloroacetimidates. The Na+,K+-ATPase receptor inhibitory activities of these glycosides (as a measure of receptor binding) were compared with those of digitoxigenin, digitoxigenin 6'-hydroxy-beta-D-digitoxoside, digitoxigenin beta-D-galactoside, and digitoxigenin beta-D-digitoxoside. The observed activities reveal that a given sugar substituent may have a role in binding of some glycoside stereoisomers, but not others. With alpha-L- and possibly beta-L-rhamnosides, the 5'-CH3 and 4'-OH appear to have a predominant role in binding to the Na+,K+-ATPase receptor. Addition of a 6'-OH to form the corresponding mannosides dramatically disrupts the effect of both the 5'-CH3 and 4'-OH in prompting receptor binding of the alpha-L isomer. However, with the beta-L isomer, some influence of 4'-OH, 3'-OH, and 2'-OH binding remains. With beta-D-glycosides, binding via the "5'-CH3 site" appears to be of little importance and addition of a 6'-OH diminishes activity only slightly. With these beta-D-glycosides, an equatorial 4'-OH, axial 3'-OH, and equatorial 2'-OH groups appear to contribute to binding.

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Experimental hypertension can be induced by t h e administration of pharmacologic doses of adrenal mineralocorticoids (1, 2); there is considerable species variation in response, however, and the animal model studied most extensively is the saline-loaded, uninephrectomized rat given deoxycorticosterone (DOC) acetate. Based on previous observations in sheep by Scoggins et al. (3, 4) that ACTH administration induced hypertension, it was reasoned that chronic administration of ACTH to rats might stimulate endogenous adrenal steroidogenesis and induce hypertension in this species also. In the present study, the effects of continuous ACTH infusion on blood pressure and electrolyte and water metabolism were evaluated in the rat.Methods. All rats (Sprague -Dawley males) were housed individually in stainless s t e e l m e t a b o l i c c a g e s a n d k e p t in temperature-controlled rooms which were maintained on a 12-hr light-dark cycle beginning at 5 AM. Distilled water and powdered Purina rat chow (sodium content: 1.37-1.50 meq/lO g; potassium content: 2.45-2.68 meq/l0 g) were available ad libitum. Daily sodium and potassium balances were estimated from measurements of ingested and excreted (urinary) sodium and potassium. Urine volume and body weight also were measured daily. Systolic blood pressures were measured daily by the tail artery occlusion method; the recorded value was the average of three or four successive determinations.Hypertensive studies. Both a control group ( n = 7) and an experimental group ( n = 7) were studied. Systolic blood pressures were measured for 3 consecutive days in each rat. Immediately after determining blood pressure on the third day, seven of the rats were lightly anesthetized with ether, a small skin incision was made on the dorsal region of the neck, and a minipump (Alza, Model 1701) containing a saline solution of ACTH (Acthar, Armour Pharmaceutical Co.) was inserted subcutaneously. The concentration of ACTH in the infusate was adjusted so that a pharmacologic dose of 1 .O unit per day of ACTH was delivered in a volume of 24 pl (1.0 pl/hr); ACTH was infused subcutaneously for a total of 7 consecutive days. Systolic blood pressures were measured daily in both the control (no drug; n = 7) and the ACTH-treated rats ( n = 7) for the 7 days of ACTH infusion and for an additional 7 days of recovery.Hormonal studies. Both a control group ( n = 8) and an experimental group ( n = 8) of male rats were used in this part of the study also. After 2 days of systolic blood pressure measurements in each rat, eight rats were prepared with minipumps containing ACTH as described above. Blood pressures were followed daily for 5 days of ACTH infusion (1 .O unit per day). The rats were decapitated on the morning of the sixth day (8 AM) after 5 days of ACTH infusion; plasma renin activity (PRA) was determined from blood collected during the first 5 sec after decapitation while plasma concentrations of aldosterone (PAC) and corticosterone (PCC) were determined from a second sample collected during the ...

C24H3404, M r -~-386.5, orthorhombic, P2~2~2~, a = 12.381(2), b = 15.717(1), c =