Agonist-specific alterations in receptor-phospholipase coupling following inactivation of Gi2alpha gene.

Different forms of phospholipase A2, together with pertussis toxin-sensitive G-proteins, [Ca2+]i (intracellular Ca2+ concentration), protein kinase C, calmodulin, protein tyrosine kinases, mitogen-activated protein kinases and Ca2+/calmodulin-dependent protein kinase appear to play a role in agonist-mediated release of arachidonic acid. Here we report that fibroblasts from 14-day-old mouse embryos with inactivated Gi2alpha (alpha-subunit of the heterotrimeric G-protein Gi2) gene display a marked decrease in the ability of lysophosphatidic acid, thrombin and Ca2+ ionophores to release arachidonic acid compared with their normal counterparts. The requirement for Gi2alpha in the release of arachidonic acid following increased [Ca2+]i may be explained by the incomplete translocation of cytosolic phospholipase A2 observed in Gi2alpha-deficient cells. Paradoxically, inactivation of the Gi2alpha gene resulted in up-regulation of bradykinin receptors and their coupling to increased arachidonic acid release, phospholipase C activity and [Ca2+]i. A concomitant increase in basal phospholipase C activity was also observed in the Gi2alpha-deficient cells. These observations establish a pleiotropic and essential role for Gi2alpha in receptor-phospholipase coupling that contrasts with its less obligatory participation in agonist-mediated inhibition of adenylate cyclase.

Closed head injuries in children: is hospital admission always necessary?

The objective of this study was to identify a group of patients with mild closed head injury, lack of other significant trauma, and normal head computerized tomograph (CT), who could be safely observed at home by a reliable caretaker. Data were from a retrospective chart review of pediatric emergency department (PED) and hospital course of an urban university children's hospital. The pediatric trauma registry was used to identify patients one to 17 years old seen in the PED with closed-head injury and normal head CT between June 1991 and August 1992. A total of 746 patients with heads injury were seen in the PED, and 161 patients with closed-head injury were admitted during the study period. Sixty-two patients (mean age = 8.5 +/- 5 years) met inclusion criteria with hospital admission, mild head injury, Glasgow Coma Scale > or = 13, and normal head CT. Of the patients 63% (34) were male and 37% (23) were female, with 74% (46) African-American and 26% (16) Caucasian. The most frequent mechanisms of injury were 27% (17) fall from height (mean height = 6.7 +/- 4.6 feet) and 18% (11) passenger in a motor vehicle accident. Patients had a median Glasgow Coma Scale of 15 (mean 14.8) and median abbreviated injury score of 2 (mean = 1.8). Thirty-seven percent of patients (23) had a history of loss of consciousness (range one to five minutes) and 6% (4) had generalized tonic-clonic seizure after the injury.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel mechanism of action for hypertension control: moxonidine as a selective I1-imidazoline agonist.

Sympathoadrenal inhibition by a direct action within the central nervous system is an advantageous route to blood pressure control. Stimulation of brain alpha 2-adrenergic receptors is one mechanism for sympathoadrenal suppression, but comes at the cost of nonspecific depression of CNS function, including sedation and decreased salivary flow. Evidence is accumulating for a second pathway for pharmacological control of sympathoadrenal outflow, mediated by a novel receptor specific for imidazolines. First-generation central antihypertensive agents, which are imidazolines such as clonidine, act primarily to stimulate these I1-imidazoline receptors in the rostral ventrolateral medulla oblongata (RVLM) to lower blood pressure, but have sufficient agonism at alpha 2-adrenergic receptors to produce side effects. Second-generation centrally acting antihypertensive agents, such as moxonidine and rilmenidine, are selective for I1 relative to alpha 2 receptors. The reduced alpha 2 potency of these agents correlates with reduced severity of side effects. In this study we further established the selectivity of moxonidine for I1-imidazoline sites by characterizing the direct interaction of [3H]moxonidine with these receptors in the RVLM and in adrenomedullary chromaffin cells. [3H]Moxonidine preferentially labeled I1-imidazoline sites relative to alpha 2-adrenergic sites, only a small portion of which were labeled in the RVLM. [3H]Moxonidine binding to I1-imidazoline sites was modulated by guanine nucleotides, implying that I1-imidazoline sites may be membrane receptors coupled to guanine nucleotide binding regulatory proteins (G proteins). Receptor autoradiography with [125I]p-iodoclonidine confirmed the presence of I1-imidazoline sites in the RVLM and other areas of the brainstem reticular formation. In contrast, alpha 2-adrenergic sites were mainly localized to the nucleus of the solitary tract. Moxonidine selectively displaced [125I]p-iodoclonidine binding from reticular areas, including the RVLM. In vivo studies in SHR rats confirmed the ability of moxonidine to normalize hypertension by an action within the RVLM and confirmed the correspondence of I1 binding affinity and antihypertensive efficacy. We also discuss prior literature on the cardiovascular pharmacology of imidazolines, reinterpreting previous studies that only considered alpha-adrenergic mechanisms.