Shock and lethality with anthrax edema toxin in rats are associated with reduced arterial responsiveness to phenylephrine and are reversed with adefovir

Although edema toxin (ETx) and lethal toxin (LTx) contribute to Bacillus anthracis shock and lethality, the mechanisms underlying their cardiovascular effects are unclear. We have previously shown that ETx but not LTx inhibited phenylephrine-stimulated contraction of aortic rings prepared from healthy rats and that adefovir, a selective inhibitor of ETx cAMP production, blocked this effect. Here, we examined arterial function in rats that received 24-h ETx or LTx infusions. Compared with control rats, ETx reduced mean arterial pressure (MAP) and survival over 48 h ( P ≤ 0.0003) and increased plasma cAMP at 4, 24, and 48 h ( P < 0.0001) and nitric oxide (NO) at 24 and 48 h ( P ≤ 0.01). Compared with control animals, at 24- and 48-h phenylephrine stimulation of aortic rings from ETx animals produced decreased maximal contractile force (MCF; P = 0.05 and 0.006) and in vivo phenylephrine infusion in ETx animals produced decreased proportional increases in MAP ( P < 0.0001 and P = 0.05). In ETx-treated animals, compared with placebo-treated animals, adefovir treatment prevented all lethality ( P = 0.01), increased MAP ( P ≤ 0.0001), decreased plasma and aortic tissue cAMP at 24 and 48 h, respectively ( P ≤ 0.03), and plasma NO at both times ( P ≤ 0.004), and increased phenylephrine-stimulated increases in MCF in aortic rings and MAP in vivo at 48 h ( P = 0.02). LTx decreased MAP and survival also, but it did not alter the response to phenylephrine of MCF in aortic rings prepared from LTx animals or of MAP in vivo. In conclusion, in rats, hypotension and lethality are associated with reduced arterial contractile function with ETx but not LTx and adefovir improves ETx-induced hypotension and lethality. NEW & NOTEWORTHY The most important aspects of the present study are the findings that 1) in vivo challenge with anthrax edema but not lethal toxin depresses arterial contractile function measured both ex vivo and in vivo and 2) adefovir inhibits the effects of edema toxin on arterial hypotension and improves survival with lethal dose of edema toxin challenge.

Identification and biological activity of ovine and caprine calcitonin receptor-stimulating peptides 1 and 2

We have recently reported the isolation of three new members of the calcitonin (CT) gene-related peptide family of peptides, the CT receptor (CT-R)-stimulating peptides (CRSPs). We now report the sequencing and characterization of ovine/caprine CRSP-1 and caprine CRSP-2. Mature ovine and caprine CRSP-1 are identical and have strong structural homology to CRSP-1s identified to date from other species. As with other CRSP-1s, ovine/caprine CRSP-1 binds to and activates the CT-R but not the CT-like receptor (CL-R) in combination with the receptor activity-modifying proteins (RAMPs). By contrast, caprine CRSP-2 does not activate any of these receptor-RAMP complexes. Intravenous infusions of ovine CRSP-1 to normal conscious sheep induced dose-dependent reduction in plasma total Ca levels (P=0.02) and corrected Ca levels (P=0.017) associated with increases in plasma cAMP (P=0.002). CRSP-1 reduced both plasma amino-terminal pro-C-type natriuretic peptide levels (P=0.006) and plasma renin activity (P=0.028). There were no significant effects observed on hemodynamic or renal indices measured. In conclusion, we have sequenced ovine/caprine CRSP-1 and caprine CRSP-2 precursors. This newly identified CRSP-1 has been shown to share the structural and biological features of CRSP-1s known to date. In vivo studies confirm that ovine CRSP-1 reduces plasma Ca levels in sheep, presumably via a cAMP-mediated mechanism. By contrast, caprine CRSP-2 did not stimulate any combination of CT-R, CL-R, and RAMPs. Accession numbers of cDNA determined in this study are caprine CRSP-1, AB364646; caprine CRSP-2, AB364647; and ovine CRSP-1, AB364648.

Effects of bright light on circadian patterns of cyclic adenosine monophosphate, melatonin and cortisol in healthy subjects

Lemmer B, Brühl T, Witte K, Pflug B, Köhler W, Touitou Y. Effects of bright light on circadian patterns of cyclic adenosine monophosphate, melatonin and cortisol in healthy subjects. Eur J Endocrinol 1994; 130:472–7. ISSN 0804–4643 Bright light is known as a strong zeitgeber on human circadian rhythms and influences several endocrine and neuroendocrine functions. In the present study we examined the influence of a 3-h bright light stimulus, given at different times during the day (morning or evening), on circadian patterns of cyclic adenosine monophosphate (cAMP), melatonin and cortisol. Two groups of synchronized healthy volunteers (lights on: 05.00–23.00 h) were exposed to bright light (2500 lux) for 3 h over 6 days either in the morning (05.00–08.00 h) or in the evening (18.00–21.00 h). The results showed a significant phase advance in the circadian rhythms of melatonin and cortisol when bright light was given in the morning but not when given in the evening. Rhythm in plasma cAMP basically was not affected by either light treatment. Björn Lemmer, Zentrum der Pharmakologie, JW Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt/M, Germany

cAMP and extrarenal vasopressin V2 receptors in dogs

The effect of vasopressin analogues on plasma adenosine 3',5'-cyclic monophosphate (cAMP) concentration was examined in a group of five conscious dogs instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter). These dogs were infused for 20 min with a selective antidiuretic (V2) agonist, desamino-8-D-arginine vasopressin (DDAVP, 10 ng.kg-1 x min-1). This infusion was repeated on another day in the presence of the combined V1-V2 antagonist d(CH2)5-D-Tyr(Et)-4-valine,8-arginine vasopressin. The dogs also received an infusion of the selective V1 agonist 2-phenylalanine,8-ornithine oxytocin (Phe-OrnOT) at a rate of 10 ng.kg-1 x min-1. The effect of these infusions was compared with those of an isotonic saline infusion. Plasma cAMP measured in the aorta remained unchanged during all infusions but that of the selective V2 agonist DDAVP alone, during which it increased significantly from 22.4 +/- 0.8 to 32.6 +/- 4.6 and 37.0 +/- 4.1 pmol/ml after 10 and 20 min, respectively. In the plasma sampled from the inferior vena cava caudal to the renal veins, cAMP increased during DDAVP infusion from 22.2 +/- 2.5 to 39.2 +/- 3.8 and 36.0 +/- 4.0 pmol/ml after 10 and 20 min, respectively. The infusion of DDAVP was later given to the same dogs under anesthesia after bilateral nephrectomy, which did not modify the effect of DDAVP on arterial plasma cAMP. In another group of four conscious dogs, infusion of DDAVP at the same rate did not induce significant changes in plasma catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Endocrine, metabolic and cardiovascular responses to adrenaline after abdominal surgery

Adrenaline-induced changes in heart rate, blood pressure, plasma adrenaline and noradrenaline, cortisol, glucagon, insulin, cAMP, glucose, lactate, glycerol and β-hydroxybutyrate were studied preoperatively and 4 and 24 h after skin incision in 8 patients undergoing elective cholecystectomy. Late postoperative responses of blood glucose, plasma cAMP, lactate and glycerol to adrenaline infusion were reduced, whereas other responses were unaffected. Blood glucose appearance and disappearance rate as assessed by [3H]3-glucose infusion was unchanged pre- and postoperatively. The increase in glucose appearance rate following adrenaline was similar pre- and postoperatively. These findings suggest that several β-receptor-mediated responses to adrenaline are reduced after abdominal surgery.