Williams, David John; (2003) The control of vascular tone in pregnancy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis examines the regulation of peripheral and renal blood flow during human and rat pregnancy. In healthy pregnancy, hand blood flow increases in order to release heat generated by metabolic activity. Using venous occlusion plethysmography, inhibition of nitric oxide (NO) synthase with intra-arterial NG-monomethyl-L-arginine (L-NMMA) caused a greater reduction of hand blood flow in pregnant compared with non-pregnant subjects. This suggests that increased NO synthase contributes to the gestational increase in peripheral blood flow. A rise in local temperature also causes an increase in hand blood flow, which was attenuated by inhibition of NO synthase with intra arterial L-NMMA. Furthermore, the sensitivity of hand vasculature to noradrenaline and L-NMMA was temperature-dependent. Noradrenaline was more potent at low compared with high local temperatures and L-NMMA was more potent than noradrenaline at high temperatures. Pre-eclampsia is a vasoconstricted state, unique to human pregnancy. Using high performance liquid chromotography (HPLC), plasma levels of the endogenous inhibitor of NO synthase, asymmetric dimethyl-L-arginine (ADMA), were higher in pre-eclamptic compared with normotensive pregnant women. ADMA excreted by fetal kidney contributed to rising ADMA levels in amniotic fluid as pregnancy progressed. The isolated-perfused rat kidney (IPRK) was used to investigate the role of perivascular nerves in the gestational increase in renal blood flow. The vasoconstrictor response to electrical field stimulation (EFS) of perivascular nerves was attenuated in IPRK of late pregnant compared with virgin rats and was associated with a large fall in renal cortical neuropeptide Y levels. EFS of sensory-motor nerves and capsaicin caused renal vasodilatation, but desensitization of the responses to sensory-motor nerve stimulation did not augment the vasoconstrictor response to EFS. The vasodilator response to exogenous calcitonin gene related peptide (CGRP) was greater in kidneys from late pregnant compared with virgin rats. CGRP was identified by immuno-histochemistry in nerve fibres supplying arterioles in both pregnant and virgin rat kidneys. Increased NOS-III was noted in the coronary arteries of pregnant compared with non-pregnant rats. Increased NOS-I was identified in the macula densa of the kidney and may play a role in altered auto-regulation of renal blood flow during pregnancy. In conclusion, this thesis provides evidence that diverse vasoactive pathways in the peripheral and renal vasculature adapt to pregnancy and changes in temperature.

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