A temporally intermediate mode of gonadotropin releasing hormone-induced desensitization of luteinizing hormone secretion.

The classical mode of luteinizing hormone (LH) secretory desensitization in the rat appears after 3-6 h of continuous in vitro administration of gonadotropin (GnRH). A second mode has been reported to occur very rapidly (< 2 min) after the onset of GnRH administration, and to reverse within 3 min after its withdrawal. Here, the existence of a third mode of desensitization is reported. occurring at 40-50 min after initiation of continuous GnRH administration. Rat pituitary cells were perifused with 10(-8) M GnRH for 6 h: 10 min samples were collected for LH measurements by radioimmunoassay. As expected, the pattern of LH release was biphasic: LH levels peaked in the first phase at 30 min, decreased at 40-50 min, increased in the second phase to maximal levels at 90-110 min, and then decreased in the classical desensitization mode to near-baseline values by 300-360 min. Static incubations of pituitary cells in Petri dishes in the presence of high (10(-8) M) or submaximal (10(-9) M) GnRH concentrations confirmed the decrease in LH secretion at 40-50 min. Measurement of LH by reverse hemolytic plaque assay (RHPA) confirmed the existence of this new mode of desensitization; since 93% of all gonadotropes had become secretory at 40-50 min, the possibility of two subpopulations of gonadotropes accounting for the two phases of LH secretion appears to be ruled-out. GnRH receptor binding studies demonstrated a approximately 50% decrease in cell-surface binding in association with the desensitization at 40-50 min. These studies suggest the existence of a third mode of GnRH-induced LH secretory desensitization that is not due to gonadotrope subpopulations but may be causally associated with decreased GnRH receptor binding.

Effects of cholinergic blockade on hemodynamic disturbances and intestinal lesions in endotoxic shock in newborn piglets.

The parasympathetic nervous system actively participates in the regulation of pathophysiologic responses in circulatory shock. To determine the effects of cholinergic blockade in endotoxic shock in newborn piglets, 16 chronically instrumented newborn piglets were infused with 10 mg/kg of endotoxin over 10 min. Eight animals were injected intravenously with 10 mg/kg of anisodamine, an anticholinergic drug, 10 min before endotoxin and then with escalating doses of 2, 5, 10, and 20 mg/kg every 10 min, beginning 60 min after endotoxin. The other eight animals were given saline as a control. Endotoxin infusion caused elevations in mean pulmonary artery pressure and vascular resistance index and an initial increase in systemic artery pressure followed by hypotension. Heart rate was stable for 45 min and then increased. Cardiac index fell from a baseline of 173 +/- 20 (mean +/- S.E.) to 136 +/- 23 mL.min-1.kg-1 60 min after endotoxin. Pretreatment with anisodamine increased heart rate from 163 +/- 15 to 289 +/- 10 beats.min-1 and cardiac index from 195 +/- 15 to 238 +/- 14 mL.min-1.kg-1 before endotoxin infusion. These variables remained at higher levels than in the control group until 60 min after endotoxin infusion; thereafter, the two groups were similar. The changes in pulmonary and systemic artery pressures were not significantly altered by anisodamine. After 60 min, additional doses of anisodamine caused no significant hemodynamic responses, and the differences between the two groups were not significant. Arterial plasma thromboxane B2 levels rose immediately and tumor necrosis factor-alpha levels increased 60 min after endotoxin infusion; no significant differences were noted between groups at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-related differences in responses to endotoxin infusion in unanesthetized piglets.

Newborn endotoxic shock syndrome is associated with high morbidity and mortality, yet presents with different clinical manifestations than in older patients. To determine the influence of age on hemodynamic and metabolic responses to endotoxin, we developed a chronically instrumented endotoxic shock model using eight 1-3-day-old and seven 2-3-week-old piglets. Three days after surgery, 10 mg/kg of endotoxin was infused intravenously over 10 min in the younger group, and 5-10 mg/kg was given to the older animals. Two older piglets died immediately after infusion of 5 mg/kg of endotoxin, and five of the seven died within 4 hr, while all eight younger animals lived longer than 4 hr. Pulmonary artery pressure increased significantly after endotoxin in both groups, and there were no differences between groups. Systemic artery pressure and cardiac index fell by 44 +/- 10% and 70 +/- 15%, respectively, 5 min after endotoxin infusion in the older group, while these values did not change significantly in the younger group. Endotoxin infusion also caused greater elevation in pulmonary vascular resistance index in the older animals. In the later phase, which began 30 min after endotoxin, both groups displayed systemic hypotension and pulmonary hypertension, and the groups did not differ from one another in this regard. With progression of endotoxic shock, more severe metabolic acidosis developed in the older animals than in the younger animals. Plasma thromboxane B2 levels in the older group were about double those in younger piglets. Plasma 6-keto-PGF1 alpha and TNF alpha levels in both groups were similar and were significantly increased in the later phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Capsular type-specific polysaccharide partially inhibits group B Streptococcus-induced pulmonary hypertension.

Capsular type-specific polysaccharide is thought to be an important pathogenetic factor in Group B streptococcus (GBS) sepsis. To determine the effects of capsular type-specific polysaccharide on GBS-induced hemodynamic responses, anesthetized infant piglets were infused for 3 h with three related GBS Type lb strains that express different amounts of capsular type-specific polysaccharide. A larger capsule strain and a smaller capsule strain were isolated from an infected infant and its mother, respectively. A capsule-deficient mutant was then made from the larger capsule strain by transposon insertion mutagenesis. The smaller capsule strain and capsule-deficient mutant caused similar elevations in mean pulmonary artery pressure and pulmonary vascular resistance index and reductions in cardiac index. The larger capsule strain caused moderate pulmonary hypertension, but this response was smaller than for the other two GBS strains. Further comparisons in responses between the large capsule strain and its capsule-deficient mutant were then performed using unanesthetized piglets. The mutant caused significantly greater pulmonary hypertension and arterial plasma thromboxane B2 levels than the large capsule strain. The pulmonary hypertension induced by both strains was reversed by dazmegrel, a thromboxane A2 synthase inhibitor. These results suggest that (1) capsular type-specific polysaccharide is not an essential component in the generation of acute hemodynamic responses; (2) expression of large amounts of capsular type-specific polysaccharide on the organism surface partially inhibits GBS-induced pulmonary hypertension; and (3) the inhibition of the pulmonary responses is due to reduced thromboxane A2 release.(ABSTRACT TRUNCATED AT 250 WORDS)