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Title: Functional and structural abnormalities of the dermal microcirculation in hypertension and hypercholesterolaemia
Author: Noon, Joseph P.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1996
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Essential hypertension and hyperlipidaemia co-segregate in the population and act synergistically in increasing coronary heart disease. Using invasive procedures such as brachial artery infusion of drugs, functional abnormalities of the vascular endothelium have been observed in forearm resistance vessels in essential hypertension, and in hypercholesterolaemia. This 'endothelial dysfunction' has been attributed, at least in part, to impaired generation of nitric oxide. However, it is unclear whether this dysfunction is confined to nitric oxide in the forearm vascular bed, or whether other mediators and other microvessels are involved. Hypertension is characterised by increased peripheral vascular resistance, which may be due to functional or structural abnormalities in the microcirculation, particularly affecting pre-capillary vessels which make the greatest contribution to vascular resistance. However, from studies in established hypertension it is not possible to ascertain whether microvascular abnormalities are a cause or consequence of the rise in blood pressure (see below). This thesis, therefore, aims (i) to examine the importance of nitric oxide in maintaining basal vascular tone and in the control of blood pressure, and to investigate the physiological role of nitric oxide in the human skin microcirculation; (ii) to establish the non-invasive technique of drug iontophoresis combined with laser Doppler fluximetry for assessing endothelial function in dermal microvessels in health, examining the principle mediators involved; (iii) to recruit patients with endothelial dysfunction, to determine whether microvascular abnormalities are present and measurable in the dermis using iontophoresis; (iv) to examine whether functional and/or structural abnormalities in the microcirculation are a cause or consequence of hypertension. Inhibition of nitric oxide synthase with systemic administration of l-A^-monomethyl-arginine (l-NMMA) increased blood pressure and substantially increased peripheral vascular resistance, emphasising the importance of nitric oxide in the maintenance of basal vascular tone. This led to an investigation of the role of nitric oxide at the microvascular level - the seat of greatest contribution to peripheral resistance. Using local brachial artery infusion of l-NMMA, tissue-specific differences in response suggested a selective role for nitric oxide in microvessels. To investigate further the role of nitric oxide and other mediators involved in microvascular function in vivo, the non-invasive technique of drug iontophoresis was used in combination with brachial artery infusion of l-NMMA and noradrenaline. Despite substantial reductions in forearm blood flow caused by these drugs, no differences were observed in dermal blood flow. However, aspirin, which blocks prostanoid synthesis via the cyclo-oxygenase pathway, inhibited the dermal response to acetylcholine (ACh). Thus, iontophoresis measured prostanoid-mediated cholinergic vasodilatation in human dermal vessels. With the pharmacological mechanisms of iontophoretic drug delivery emerging, the technique was extended to investigate endothelial function in 10 hypercholesterolaemic patients compared with 10 matched controls. In the patients, forearm vasodilatation was impaired with ACh but not with the endotheliumindependent vasodilator, sodium nitroprusside (SNP). In contrast, dermal vasodilatation was impaired with SNP and not with ACh. In the presence of aspirin, in hypercholesterolaemic patients, forearm vasodilatation to ACh was partially restored, but dermal vasodilatation to ACh was impaired. Aspirin did not affect SNP responses. Therefore, impaired stimulated nitric oxide generation was confirmed in forearm resistance vessels in hypercholesterolaemic patients. In dermal microvessels in these patients, reduced smooth muscle sensitivity to nitric oxide was observed, and an enhanced, possibly compensatory, role for prostanoid vasodilators. To identify the likely importance of microvascular abnormalities in determining the familial risk of essential hypertension, subjects were recruited from an epidemiological model which identifies young people with contrasting predisposition to high blood pressure. In this model, subjects widi a predisposition to high blood pressure which was familial were found to have structural rarefaction with a substantial increase in minimum vascular resistance in dermal microvessels. These structural abnormalities suggest that capillary rarefaction is a cause rather than a consequence of essential hypertension. As hypertension and hypercholesterolaemia are cofactors which increase the risk of cardiovascular, cerebrovascular and renal diseases, an investigative method which would recognise individuals at risk would be a useful adjunct to their clinical management. Functional abnormalities are present in established essential hypertension, and in hypercholesterolaemia. The non-invasive technique of drug iontophoresis provides important new information about differences between dermal microvessels and forearm resistance vessels. However, further investigation is required if this technique is to become established in assessing endothelial function in large groups of patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available