K. A. Duggan

Sodium depletion decreases hepatic metabolism of vasoactive intestinal peptide in the rabbit.

1. Reports that a greater natriuresis occurs after gastric rather than intravenous sodium loads suggest that a gastric sodium monitor exists which releases a humoral natriuretic factor. As vasoactive intestinal peptide (VIP) is natriuretic, it might act as this mediator. To determine whether it released from the gut in response to sodium we measured VIP levels in portal and systemic plasma of anaesthetized rabbits after a gastric sodium load. Levels of VIP in systemic plasma were also measured in conscious rabbits after gastric and portal sodium loads to determine the contributions of anaesthesia or increased sodium concentration in the portal tract to any observed rise in systemic VIP levels. 2. In the anaesthetized rabbit study portal and systemic VIP levels had both increased significantly from control values by 5 min after the sodium load in the low salt diet group (P less than 0.025, portal: P less than 0.05, systemic). By 10 min the levels in systemic and portal plasma were equal. 3. In the conscious rabbits an increase in systemic VIP levels was observed in the group on a low salt diet after a gastric but not a portal sodium load. 4. We conclude that VIP is released in response to gastric sodium loads in rabbits on low salt diets and that hepatic metabolism of VIP is reduced in this group.

The effects of a high sodium diet on the metabolism and secretion of vasoactive intestinal peptide in the rabbit

1. In view of previous observations that the metabolism of vasoactive intestinal peptide (VIP) is significantly increased in sodium‐depleted rabbits, we wished to determine whether a high sodium intake also leads to alterations in VIP metabolism. We performed metabolic clearance studies in rabbits maintained on a high sodium diet and normal control diets. These studies were performed both before and after the administration of 1.5 mmol kg‐1 of sodium intravenously to observe the effects of an acute increase in body sodium. 2. The rabbits maintained on the high sodium diet had a significantly lower basal plasma VIP level (P less than 0.025), a lower metabolic clearance rate (MCR) of the peptide (P less than 0.025) and a lower secretion rate (P less than 0.005), compared with the normal control animals. These differences were maintained following the intravenous sodium infusion. 3. The administration of the intravenous sodium infusion resulted in a further decrease in MCR in the rabbits on the high sodium diet (P less than 0.05). 4. These results confirm that VIP metabolism is affected by high dietary intake of sodium, as well as a low sodium intake, adding further support to the hypothesis that VIP may be involved in sodium homeostasis.

Modification of renal and tissue cation transport by cholecystokinin octapeptide in the rabbit.

1. Reports that gastric sodium loads cause a greater natriuresis than those administered intravenously, suggest that a gastric or portal sodium monitor exists which releases a humoral natriuretic factor. To determine whether cholecystokinin octapeptide (CCK‐8) had direct renal natriuretic effects (and was therefore a candidate for this gut‐derived natriuretic factor) we compared the natriuretic response to CCK‐8 infused intravenously with that infused directly into the renal artery of six conscious male rabbits. 2. CCK‐8 produced a significant log dose‐dependent decrease in the fractional excretions of calcium (P less than 0.05) and magnesium (P less than 0.005) and a log dose‐dependent increase in fractional sodium excretion (P less than 0.025). The significant decreases in the fractional excretions of calcium and magnesium were accompanied by log dose‐dependent falls in their plasma levels (calcium, P less than 0.05, and magnesium, P less than 0.005), indicating movement of calcium and magnesium to extravascular sites. Studies of tissue calcium and magnesium levels in response to CCK‐8 infusion showed that calcium accumulated in kidney and skeletal muscle. 3. We conclude that CCK‐8 has direct renal natriuretic effects at the tubular level and could be the gut‐derived natriuretic factor. In addition to its effects on sodium excretion, CCK‐8 causes renal retention and increased gut absorption of calcium and magnesium with movement of these ions to extravascular sites.

Effect of neutral endopeptidase on plasma and tissue concentrations of vaso-active intestinal peptide

1. This study sought to determine if neutral endopeptidase metabolizes vaso‐active intestinal peptide (VIP) and whether changes in the activity of this enzyme might explain the change in VIP metabolism which follows gastric sodium loading. The study also investigated whether prolonged inhibition of neutral endopeptidase was associated with inhibition of further secretion of VIP.

A study of angiotensin II receptors after chronic inhibition of nitric oxide synthase in the spontaneously hypertensive rat.

1. Nitric oxide (NO) synthase inhibition, induces a sustained increase in blood pressure and amplifies the pressor response to infused angiotensin II (AngII). This study was designed to investigate the contribution of AngII receptors to the elevated blood pressure and enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR) chronically treated with NG‐nitro‐l‐arginine‐methyl ester (l‐NAME).

The platelet angiotensin II receptor in type I diabetes: studies in patients with and without nephropathy

Abstract. Experimental studies demonstrate impaired regulation of the mesangial angiotensin II (AII) receptor in diabetes. This could contribute to the disturbance of glomerular blood flow and the development of diabetic nephropathy. The aim of this study was to determine whether a similar receptor abnormality occurs in patients with type I insulin‐dependent diabetes mellitus (IDDM) and if so whether this is more prevalent in patients with micro‐ or macro‐albumi‐nuria. The platelet AII receptor was chosen because of its availability from the circulation and its comparable regulatory properties to tissue‐based receptors. The interaction between plasma All and its platelet receptor was examined in 45 patients with TDDM and 36 age‐ and sex‐matched control subjects. Seven patients had clinical nephropathy and two had persistent micro‐albuminuria. The duration of diabetes varied from 1 month to 42 years.

Early Myocardial Fibrosis is Associated with Depletion of Vasoactive Intestinal Peptide in Rat Heart

In this study we sought to determine whether early myocardial fibrosis is associated with depletion of vasoactive intestinal peptide (VIP) in the heart, thereby suggesting a possible pathogenetic role for depletion of myocardial VIP levels in the development of fibrosis in the heart. Spontaneously hypertensive rats (SHRs) and normotensive control Wistar‐Kyoto rats (WKYs) were assigned randomly to low, intermediate or high sodium diets and their blood pressure was recorded twice weekly for 4 weeks. At the end of this period the rats were anaesthetised, blood was sampled for plasma VIP concentration and the hearts were harvested for histology and determination of the concentration of VIP in the heart. The degree of myocardial fibrosis increased with increasing dietary sodium intake in both the WKYs (P < 0.001) and the SHRs (P < 0.01). Myocardial VIP concentration decreased with increasing dietary sodium intake in the WKYs (P < 0.01) and in the SHRs (P < 0.01). There was a negative correlation between myocardial VIP concentration and the degree of myocardial fibrosis in both the WKYs (P < 0.0005) and the SHRs (P < 0.005). Dietary sodium intake induces myocardial fibrosis in a dose‐dependent manner. Further, in early myocardial fibrosis resulting from increasing dietary sodium intake in both normotensive and hypertensive rats the concentration of VIP in the heart was negatively correlated with the degree of fibrosis. This suggests a possible role for depletion of VIP in the myocardium in the pathogenesis of myocardial fibrosis.

Differential regulation of uterine and glomerular angiotensin II receptors in normal and hypertensive pregnancy in the rat

1. In the non‐pregnant state uterine and glomerular angiotensin II (AII) receptors have been shown to regulate in a similar fashion. This study sought to determine whether such parallel regulation occurred during pregnancy. We also investigated the role of plasma AII in these changes.

Abnormality of the glomerular angiotensin II receptor in experimental diabetic nephropathy

1. The combined effect of diabetes and hypertension on the plasma angiotensin II (AII)/glomerular AII receptor (AII‐R) relationship in streptozotocin‐induced diabetes was investigated as well as the effect of glycaemic control on this relationship.

Changes in angiotensin II metabolism contribute to the increased pressor response to angiotensin after chronic treatment with L-NAME in the spontaneously hypertensive rat.

1. Administration of nitric oxide (NO) synthase inhibitors, such as l‐NAME, is associated with an increase in blood pressure and an increase in pressor responsiveness to infused angiotensin II (AngII). The present study was designed to investigate the contribution of changes in the metabolism of AngII to the enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR; 14 weeks old) chronically treated with l‐NAME.