Janette J. Tresham

HAEMODYNAMIC AND HORMONAL EFFECTS OF N-NITRO-l-ARGININE, AN INHIBITOR OF NITRIC OXIDE BIOSYNTHESIS, IN SHEEP

1. The haemodynamic and hormonal responses to N‐nitro‐l‐arginine (NOLA), a potent inhibitor of nitric oxide biosynthesis in endothelial cells, were investigated in conscious sheep.

Effects of prednisolone and deflazacort on osteocalcin metabolism in sheep

SummaryGlucocorticoids adversely affect bone and mineral metabolism through a number of mechanisms, including inhibition of bone formation. Deflazacort is a glucocorticoid which has been reported to be relatively “bone-sparing.” We compared the effects in oophorectomized sheep of deflazacort and prednisolone on the metabolism of osteocalcin (OC), a marker of osteoblast function. An [125I]OC infusion method was used to measure the OC plasma clearance rate (PCR) and OC plasma production rate (PPR).Six-day intravenous infusion of deflazacort and prednisolone (in the dose range 0.007–1.00 mg/hour) induced dose-dependent decreases in OC PPR which were of a similar pattern but significantly different magnitude (P < 0.02); deflazacort demonstrated a potency about 150% that of prednisolone. Both steroids decreased plasma OC levels on a dose-related basis but at the lower doses 0.05 mg/hour (P < 0.05) and 0.013 mg/hour (P < 0.0005), deflazacort caused greater decrements. OC PCR was significantly increased only by higher doses of deflazacort (1.00 mg/hour, 0.25 mg/hour;P < 0.05). Deflazacort and prednisolone increased both postabsorptive plasma glucose and plasma calcium levels, but there were no significant differences between their effects.We conclude that plasma OC levels and OC PPR in sheep were more sensitive to the effects of deflazacort than to prednisolone. At high doses, the depressive effect of deflazacort on plasma OC levels may have been due in part to an increased OC PCR which was not evident with prednisolone treatment. However, the agents appeared to have a similar dose-dependent hyperglycemic effect, and both caused a small dose-dependent increase in plasma calcium. These findings indicate that prednisolone had similarly potent effects on both bone and glucose metabolism while deflazacort exhibited differential potency on the two systems. The greater potency of deflazacort on bone in sheep may be due to species differences in steroid metabolism or steroid-receptor interaction.

Stress, ACTH, salt intake and high blood pressure.

Epidemiological evidence supports the thesis that high salt intake is involved in the aetiology of hypertension. If sodium intake is not causal, it appears other factors do not cause high blood pressure in unacculturated societies with low sodium intake. In this context, it is potentially important that stress causing ACTH release, as well as other neurohumoral effects, causes increased salt appetite and can impair renal sodium excretion.

INTRACEREBROVENTRICULAR INFUSIONS OF CORTICOTROPHIN RELEASING FACTOR (CRF) AND ACTH RAISE BLOOD PRESSURE IN SHEEP

1. Infusion of synthetic ovine CRF (10 or 100 μg/h) into the lateral cerebral ventricle for 24 h increased mean arterial blood pressure of conscious sheep.

Onset and dose relationships of ACTH effects on blood pressure in sheep.

The threshold and dose-response relationships for the blood pressure and metabolic effects of adrenocorticotropic hormone (corticotropin, ACTH) were examined in conscious sheep. Corticotropin was infused at five rates (0.5 micrograms/kg/day, n = 4; 1 micrograms/kg/day, n = 4;2 micrograms/kg/day, n = 6; 5 micrograms/kg/day, n = 5; and 10 micrograms/kg/day, n = 5) for 3 days, and the time of onset of the rise in blood pressure was assessed with a computer-based system. The effects of equimolar infusion of beta-endorphin and ACTH at 5 micrograms/kg/hour also were examined. Corticotropin infusion at 0.5 microgram/kg/day had no effect on mean arterial pressure. An ACTH infusion of 1.0 microgram/kg/day significantly increased mean arterial pressure (p less than 0.001), but the rise was less than that at the three higher doses, all of which produced similar effects. Changes in heart rate were significant at the 10 micrograms/kg/day level only (p less than 0.01). Initial urinary sodium retention was present at the three higher but not the two lower rates of infusion. Corticotropin infusion had no effect on urinary potassium excretion at any rate but produced hypokalemia at rates of 1.0 microgram/kg/day and above, which appeared to be dose related. Plasma sodium concentration was increased significantly only at the three higher rates (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

THE HAEMODYNAMIC EFFECTS OF CYCLOSPORIN A IN SHEEP

SUMMARY

Prolonged regional vasoconstriction produced by NG-nitro-L-arginine in conscious sheep.

Nitric oxide (NO) is a potent endothelium-derived vasodilator whose synthesis can be blocked both in vitro and in vivo by structural analogues of its precursor, L-arginine (L-ARG). We examined the dose-response profile of one such analogue, NG-nitro-L-arginine (NOLA) in conscious sheep (n = 4) and used continuous monitoring techniques to study long-term changes in mean arterial pressure (MAP), heart rate (HR), and cardiac output (CO) and the relative responsiveness of the coronary, mesenteric, renal, and hindlimb vascular beds to NOLA [10 mg/kg, intravenous (i.v.) bolus] in 5 sheep. NOLA (3 and 10 mg/kg) increased MAP at 1 h from 73 +/- 4 to 86 +/- 3 mm Hg (p < 0.05) and 73 +/- 1 to 106 +/- 8 mm Hg (p < 0.05), respectively. CO and HR decreased significantly after 10 mg/kg NOLA. Plasma endothelin (ET) level was unchanged after all doses of NOLA. Continuous monitoring of MAP, CO, and blood flow for 24 h before and after NOLA injection showed that MAP increased rapidly owing to a decrease in total peripheral conductance (TPC), with short-term reflex decreases in HR and prolonged decreases in CO and stroke volume (SV). Coronary and iliac conductances changed comparatively little. Renal conductance decreased by 43% at 80 min, but was not different from control after 6 h. The greatest and most sustained decrease in conductance, by a maximum of 55% of control levels at 110 min, occurred in the mesenteric bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Somatostatin centrally inhibits vasopressin secretion during haemorrhage

Somatostatin is a hypothalamic inhibiting factor which has been reported to be involved in the regulation of the secretion of several anterior pituitary hormones. To determine if somatostatin plays a role in the control of vasopressin secretion from the posterior pituitary, we examined the effects of intracerebroventricular infusion of somatostatin-14 and a super-active analogue, cyclo-(N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), on the concentration of plasma vasopressin in response to haemorrhage in conscious sheep. Haemorrhage (15 ml/kg over 15 min) elevated plasma vasopressin. Treatment with either somatostatin-14 or the analogue inhibited the elevation of plasma vasopressin induced by haemorrhage. The inhibition may result from an effect of somatostatin on neurotransmitter afferent inputs to the hypothalamus which trigger vasopressin release during haemorrhage. Our study demonstrates for the first time that somatostatin administered centrally inhibits vasopressin secretion during haemorrhage in the conscious animal.

Cyclosporine-induced hypertension in sheep. The role of thromboxanes.

Thromboxanes have been implicated in the CsA-induced hemodynamic changes and impairment in renal function in humans and in rats. We have previously shown that administration of intravenous CsA to sheep for 5 days at 12 mg/kg/day produces a hypertension that is resistance mediated and independent of nephrotoxicity. In this study we used a thromboxane synthetase inhibitor, U63,557A, to examine the role of thromboxanes in the CsA-induced hypertension in the sheep. The thromboxane synthetase inhibitor had no effect on blood pressure in normotensive sheep. Serum thromboxane levels were not elevated with CsA, and the inhibitor had a minimal effect on blood pressure during CsA treatment, suggesting that thromboxanes are not a major contributor to the rise in blood pressure seen in the sheep. A study of the dose-response relationship for CsA at 3, 6, and 24 mg/kg/day for 5 days indicated that maximal blood pressure responses were attained with 6 mg/kg/day.

The cardiovascular effects of human calcitonin gene-related peptide in conscious sheep

Calcitonin gene-related peptide (CGRP) is localized in nerve fibres in close association with the vasculature. The in vivo effect of human CGRP upon the cardiovascular system was investigated by intravenous infusion of CGRP into seven conscious sheep at doses of 1.5 and 10-pmol/kg per min for 75 min. CGRP at the 5- and 10-pmol/kg per min infusions decreased mean arterial pressure (maximal decrease of 10 mmHg) and stroke volume (maximal decrease of 42 ml/min), and increased heart rate by 60 beats/min. No changes in cardiac output were observed and total peripheral resistance only fell with the 5-pmol/kg per min infusion. Increases in both plasma arginine vasopressin and plasma renin concentration and a decrease in total and ionized plasma calcium were also observed. CGRP appears to be a potent vasodilator acting upon both arterioles and capacitance vessels in vivo.