Acute and chronic cold exposure differentially affect cardiac control, but not cardiorespiratory function, in resting Atlantic salmon (Salmo salar).

No studies have examined the effects of cold temperatures (∼0-1 °C) on in vivo cardiac function and control, and metabolism, in salmonids. Thus, we examined: 1) how acclimation to 8 °C vs. acclimation (>3 weeks) or acute exposure (8-1 °C at 1 °C h-1) to 1 °C influenced cardiorespiratory parameters in resting Atlantic salmon; and 2) if/how the control of cardiac function was affected. Oxygen consumption ( M ˙ O 2 ) and cardiac function [i.e., heart rate (f H) and cardiac output ( Q ˙ ) ] were 50% lower in the acutely cooled and 1oC-acclimated salmon as compared to 8 °C fish, whereas stroke volume (VS) was unchanged. Intrinsic f H was not affected by whether the fish were acutely exposed or acclimated to 1 °C (values ∼51, 24 and 21 beats min-1 in 8 and 1 °C-acclimated fish, and 8-1 °C fish, respectively), and in all groups f H was primarily under adrenergic control/tone (cholinergic tone 13-18%; adrenergic tone 37-70%). However, ß-adrenergic blockade resulted in a 50% increase in VS in the 1oC-acclimated group, and this was surprising as circulating catecholamine levels were ∼1-3 nM in all groups. Overall, the data suggest that this species has a limited capacity to acclimate to temperatures approaching 0 °C. However, we cannot exclude the possibility that cardiac and metabolic responses are evoked when salmon are cooled to ∼ 0-1 °C, and that this prevented further declines in these parameters (i.e., they 'reset' quickly). Our data also provide further evidence that VS is temperature insensitive, and strongly suggest that changes in adrenoreceptor mediated control of venous pressure/capacitance occur when salmon are acclimated to 1 °C.

Does nitric oxide contribute to the basal vasodilation of pregnancy in conscious rabbits?

Pregnancy produces marked systemic vasodilation, but the mechanism is unknown. Experiments were performed in conscious rabbits to test the hypotheses that increased nitric oxide (NO) production contributes to the increased vascular conductance, but that the contribution varies among vascular beds. Rabbits were instrumented with aortic and vena caval catheters and ultrasonic flow probes implanted around the ascending aorta, superior mesenteric artery, terminal aorta, and/or a femoral artery. Hemodynamic responses to intravenous injection of N(omega)-nitro-L-arginine (L-NA; 20 mg/kg or increasing doses of 2, 5, 10, 15, and 20 mg/kg) were determined in rabbits first before pregnancy (NP) and then at the end of gestation (P). L-NA produced similar increases in arterial pressure between groups, but the following responses were larger (P < 0.05) when the rabbits were pregnant: 1) decreases in total peripheral conductance [-3.7 +/- 0.3 (NP), -5.0 +/- 0.5 (P) ml x min(-1) x mmHg(-1)], 2) decreases in mesenteric conductance [-0.47 +/- 0.05 (NP), -0.63 +/- 0.07 (P) ml x min(-1) x mmHg(-1)], 3) decreases in terminal aortic conductance [-0.43 +/- 0.05 (NP), -0.95 +/- 0.19 ml x min(-1) x mmHg(-1) (P)], and 4) decreases in heart rate [-41 +/- 4 (NP), -62 +/- 5 beats/min (P)]. Nevertheless, total peripheral and terminal aortic conductances remained elevated in the pregnant rabbits (P < 0.05) after L-NA. Furthermore, decreases in cardiac output and femoral conductance were not different between the reproductive states. We conclude that the contribution of NO to vascular tone increases during pregnancy, but only in some vascular beds. Moreover, the data support a role for NO in the pregnancy-induced increase in basal heart rate. Finally, unknown factors in addition to NO must also underlie the basal vasodilation observed during pregnancy.

Multilayers of cells growing on a permeable support. An in vitro tumour model.

A system for growing three-dimensional cell culture has been developed which exhibits many features of solid tumours. This system comprises cells growing as a thick mat on a semipermeable membrane suspended in stirred media. SiHa cells grown as these multilayered cell cultures (MCCs) have produced cultures up to ca. 20 cell diameters in thickness. The MCCs, like solid tumours growing in vivo. develop diffusion-dependent necrosis and hypoxia and the cell packing acts as a barrier to the diffusion of drugs. These cultures can, therefore, be used to study aspects of cancer biology and drug transport that are difficult to study using other techniques.

The effect of thalidomide on experimental tumors and metastases.

Thalidomide has recently been shown to antagonize basic fibroblast growth factor-induced angiogenesis in the rat corneal micropocket assay. We have investigated the effect of thalidomide on growth, radiosensitivity and metastasis in murine SCCVII and Lewis Lung tumors. We found that daily thalidomide administration (0.77 mmol/kg/day, i.p.) does not alter primary tumor growth of SCCVII or Lewis Lung tumors. However, thalidomide administration does reduce radiosensitivity of the Lewis Lung tumor, and increases its sensitivity to combined treatment with radiation and the bioreductive cytotoxin tirapazamine. These findings suggest that thalidomide is elevating tumor hypoxia in the Lewis Lung tumor, presumably via an anti-angiogenic mechanism. We also found that thalidomide administration reduces the incidence of lung metastases from primary Lewis Lung tumors. Thalidomide may therefore have utility in the management of solid tumors, especially when combined with drugs that are selectively toxic to cells at reduced oxygen tension (e.g. bioreductive cytotoxins).