Hypertension is common in chronic renal failure (CRF). It is an important cardiovascular risk factor and therefor it is important to establish factors contributing to the pathophysiology of this hypertension. Apart from volume overload and activation of the renin-angiotensin system numerous (minor) mechanisms have been found to contribute to the pathophysiology. There is now increasing evidence, that sympathetic overactivity may be crucial in the pathogenesis. In the present thesis we studied sympathetic nerve activity and the pharmacological and physiological modulation of this activity in various forms of hypertensive renal disease. Furthermore we analyzed the effects on sympathetic activity of cyclosporine and tacrolimus, to elucidate the role of the sympathetic nervous system (SNS) in transplantation-associated hypertension. In this theses we use muscle sympathetic nerve activity (MSNA) to assess sympathetic activity. MSNA is a reproducible direct online registration of post-synaptic nerve activity to resistance vessels and there is a direct correlation with MSNA and systemic vascular resistance. MSNA is measured in hypertensive renal disease patients. It has been established that plasma renin activity (PRA) is inappropriately increased in relation to the fluid status in these patients. High levels of PRA reflect high angiotensin II (AngII) levels. AngII can increase sympathetic activity. PRA and MSNA are related to the volume status in a large group of patients. We established that as with PRA MSNA is inappropriately increased with respect to volume status in CRF patients. Reducing the effects of AngII through ACE-inhibition could reduce sympathetic hyperactivity. We compared the effects of an ACE-inhibitor with those of a calcium-channel blocker, amlodipine, which is a drug not affecting the renin system. ACE-inhibition reduced while amlodipine increased the already augmented sympathetic activity. Furthermore the blood pressure lowering effect of a central sympatholytic drug, clonidine, was augmented in CRF compared to healthy controls, underscoring the importance of the effects of sympathetic hyperactivity on hypertension in CRF. AngII receptor blockers may provide a more complete blockade of the renin cascade than ACE-inhibition. This may also result in more pronounced inhibition of the sympathetic activity. We addressed this hypothesis by comparing these two types of drugs with respect to their effect on blood pressure and sympathetic activity. We could not find a clinical relevant difference between the effects of these two agents. Could sympathetic nerve activity already be increased when renal function is still normal? Polycystic kidney disease (PKD) patients are often identified as \u93renal patient\u94 when kidney function is still normal. PKD patients with normal renal function and normal renal function are not different from controls whereas PKD patients with normal renal function but with hypertension already show an increased blood pressure. Thus already in an early stage of a renal disease sympathetic nerve activity is increased. The last two studies in this thesis address the cause of cyclosporine-associated hypertension and renal dysfunction. The pathogenesis of this type of hypertension is probably multifactorial. It is likely that increased sympathetic nerve activity is one of these factors. There are however contrasting findings both in animals and in humans, which may be explained by differences in dosage and duration of treatment. Tacrolimus (TAC) is a newer immunosuppressive agent, which is believed to cause less hypertension. We addressed the question whether cyclosporine (CsA) after single and sustained administration has any effect on MSNA and whether TAC acts differently in this respect in healthy humans. Acute administration of CsA resulted in a dose dependent increase in MSNA while sustained administration reduced MSNA. In contrast acute TAC had no effects on MSNA while it had comparable effects during sustained use. Renal vasoconstriction and subsequent salt retention could be a factor contributing to the pathogenesis of cyclosporine-associated hypertension. Some but not all studies have indicated that TAC may cause less renal vasoconstriction. To clarify this matter, we studied in healthy subjects the effects of both agents on renal hemodynamics. We found a difference between CsA and TAC: CsA caused renal vasoconstriction while TAC did not. Maybe these findings could be beneficial during long-term use in transplant patients In conclusion this theses elucidates the role of sympathetic hyperactivity in the pathogenesis of hypertension in CRF and the effects of important antihypertensive agents with respect to this patient category. While it also establishes the crude effects of CsA and TAC on sympathetic activity in healthy controls
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