The intravenous administration of heparin to patients before open heart surgery reduced ristocetin cofactor activity by 58% (P < 0.01, t test), and this impairment of von Willebrand factordependent platelet function was closely related to plasma heparin levels (r2 = 0.9), but not to plasma von

Pertussis toxin treatment of rabbit peritoneal neutrophils causes a concentration-dependent inhibition of granule enzyme secretion induced by formylmethionyl-leucyl-phenylalanine, C5a, and leukotriene B4. It also inhibits chemotaxis induced by formylmethionyl-leucyl-phenylalanine. The same toxin treatment, however, has no effect on granule enzyme secretion induced by the calcium ionophore A23187 or phorbol 12-myristate 13-acetate. Moreover, pertussis toxin treatment does not affect either the number or affinity of the formylpeptide receptors on the neutrophil nor does it have any effect on the unstimulated levels of cyclic AMP (cAMP) or the transient rise in cAMP induced by chemotactic factor stimulation in these cells. We hypothesize that pertussis toxin, as in other cells, interacts with a GTP binding regulatory protein identical with or analogous to either Ni or transducin which mediates the receptor-induced inhibition or activation of a target protein or proteins required in neutrophil activation. The nature of the target protein is unknown, but it is not the catalytic unit of adenylate cyclase. The target protein acts after binding of chemotactic factor to its receptor in the sequence that leads to the receptor-induced rise in intracellular Ca2+. It does not affect the responses elicited by the direct introduction of calcium into the cells or the activity of protein kinase C.

1. Serum levels of TSH, thyroxine (T4) and triiodothyronine (T3) have been measured during treatment and follow-up of patients with thyroid carcinoma. 2. Serum TSH and thyroid hormone levels were initially normal. Three weeks after total thyroidectomy, TSH was elevated in about 50% of patients and after a subsequent therapy dose of 131I it exceeded 30 mU/l in 90% of patients. Occasionally, TSH did not rise until after the second dose of 131I. Low serum T4 and T3 concentrations were associated with the increase of TSH. 3. Withdrawal of l-thyroxine replacement treatment in athyreotic patients for four weeks before test doses of 131I, led to falls of serum T4 and T3 concentration and a progressive rise of serum TSH after the first weeks but there was considerable variation in the final level reached. In the majority, values greater than 30 mU/l were attained despite some patients having received l-thyroxine for many years. A few patients on prolonged thyroxine maintenance had little or no increase in TSH despite considerable reduction in serum T4 and T3 concentrations. 4. The 131I concentration (muCi/g) developed in tumour tissue was also examined in relation to the serum TSH level. In general a tumour should not be considered as incapable of concentrating 131I adequately until serum TSH levels have exceeded 30 mU/l.

Most drugs target a receptor for a hormone or neurotransmitter. A newer strategy for drug development is to target a downstream signaling element, such as the G protein associated with a receptor. Suramin is considered a lead compound targeting this moiety. It inhibits binding of guanosine 5Ј-O-(3-thiotriphosphate) (GTP␥S) to G proteins and reduces agonist binding to G protein-coupled receptors. Suramin is thought to uncouple the G protein from its associated receptor, although there is no direct evidence for this mechanism. We have now examined the effect of suramin on G protein signaling for the vasoactive intestinal peptide (VIP) receptor in lung. The primary experimental strategy was a two-step cross-linking reaction that covalently captures the VIP-receptor-G protein ternary complex. Such cross-linking provided the first direct evidence that suramin physically disrupts receptor-G protein coupling. We investigated how this uncoupling relates to the inhibition of GTP␥S binding. Suramin indiscriminately hindered the dissociation of various guanine nucleotides from the G protein, implying that its action is not allosteric. Further cross-linking studies suggested that suramin does not obstruct the receptor docking site directly but appears to block the interface between G protein ␣ and ␤␥ subunits. Observations with a purified system of recombinant G protein subunits without a receptor yielded direct evidence that suramin suppresses the association between these subunits. This action can explain how it both disrupts receptor-G protein coupling and inhibits guanine nucleotide release. The improved understanding of suramin's action advances the development of selective inhibitors of G protein signaling.

No abstract