Joseph C. Nolan

Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Tracheal Mucous Gel Layer Thickness

The effect of intravenous injections of 5-, 12- and 15-hydroxyeicosatetraenoic acids (HETE), leukotrienes D4 and E4 (LTD4, LTE4) on tracheal mucous gel layer (TMGL) thickness was assessed in rats. When administered in doses ranging from 0.03 pg to 33 ng per rat, the lipoxygenase metabolites produced significant increases in TMGL thickness. The order of potency of the metabolites was 15-HETE greater than 12-HETE greater than or equal to 5-HETE greater than LTD4 greater than or equal to LTE4. Imidazole (31.6 mg/kg), intravenously, significantly decreased this response. These findings suggest that the mono-HETEs, especially 15-HETE, may be important modulators of airway mucus in the rat.

Carbonic anhydrase inhibitors are antiarthritic in the rat

Adjuvant-induced arthritis in rats was attenuated by the therapeutic administration of carbonic anhydrase inhibitors. Female Lewis rats with established disease were treated daily (day 18 through day 50) with various carbonic anhydrase inhibitors; oedema and joint integrity (X-ray) were determined post-treatment. Acetazolamide, ethoxzolamide, methazolamide, and dichlorphenamide reduced paw oedema and attenuated the deterioration of the joints of rats with adjuvant arthritis. However, no carbonic anhydrase inhibitor tested possessed significant, acute, anti-inflammatory activity in the carrageenan-paw oedema test. The activity of carbonic anhydrase inhibitors in the chronic model of inflammation may be due to their reported inhibition of bone resorption.

AHR-16303B, A NOVEL ANTAGONIST OF 5-HT2 RECEPTORS AND VOLTAGE-SENSITIVE CALCIUM CHANNELS

In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic actions at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [3H] ketanserin binding to rat cerebral cortical membranes (Ic50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose. (MED) = 0.32 mg/kg orally. p.o.): (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.). 1.8 mg/kg p.o.), (d) 5HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) [3H] nimodipine binding to voltage-sensitve calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCI-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radiligands to dopamine2 (DA2) α1. α2. H1. 5-HT1a. β2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT, receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR. 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.