The characterization of cerebrovascular dysfunction associated with hypertensive encephalopathy in Dahl salt-sensitive rats

Payne, Geoffrey W. (2003) The characterization of cerebrovascular dysfunction associated with hypertensive encephalopathy in Dahl salt-sensitive rats. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

We initially assessed the characteristics of stroke development in Dahl salt-sensitive rats (Dahl-SS). Dahl-SS developed high blood pressure (BP) when fed a high salt diet (8.7% NaCl) from weaning and a 50% mortality after being fed the diet for 4 to 5 weeks. Prior to death, Dahl-SS exhibited behavioural symptoms (convulsions, seizures, paralysis and stupor) consistent with the possible development of stroke. However, unlike true stroke, the behavioural dysfunctions observed were not associated with cerebral ischemia and occurred in the virtual absence of cerebral hemorrhage. An investigation of the cerebrovascular pathology indicated a breakdown in the integrity of the blood brain barrier and fluid movement into the extravascular space (edema). It was concluded that Dahl-SS best represents a model of hypertensive encephalopathy (HE). In humans HE is produced by brain edema as a result of hypertension in the absence of cerebral ischemia or hemorrhage. It produces convulsions, confusion, and stupor and can result in death. The latter symptoms are consistent with those observed in Dahl-SS fed high salt. Antihypertensive intervention (captopril) was ineffective in lowering blood pressure or reducing the incidence of mortality. Non-cerebral organ failure was also evident prior to death as demonstrated by kidney dysfunction associated with increased plasma creatinine, urea, urinary protein excretion and decreased plasma albumin levels. In subsequent experiments we tested the hypothesis that a breakdown in the ability to autoregulate cerebral blood flow (CBF) may contribute to the development of HE in Dahl-SS fed high salt. Such a defect could promote cerebrovascular overperfusion and elevate microvascular blood pressure, alterations that would facilitate blood brain barrier disruption and HE development. Laser Doppler techniques were used to assess the changes in relative CBF with varying BP in the perfusion domain of the middle cerebral arteries (MCA's). Dahl-SS fed 8.7% NaCl for 1 week exhibited an ability to autoregulate near constant CBF up to an upper mean BP of 168 mmHg. Two thirds of the rats lost the ability to autoregulate CBF after they were fed a high salt diet: for 3 weeks at a time prior to the development of HE. These rats exhibited a linear increase in CBF with elevations in arterial pressure. The characteristics of the CBF autoregulatory curves suggested that CBF autoregulation was lost under conditions of cerebrovascular constriction. In other experiments we assessed the hypothesis that the loss of CBF autoregulation in the MCA perfusion domain of Dahl-SS was associated with an inability of the MCA's to elicit pressure dependent constriction (PDC). PDC is an important mechanism involved in promoting CBF autoregulation. Elevations in BP promote cerebrovascular constriction, which raises vascular resistance to blood flow. This counteracts the potential elevation in CBF enabling CBF to remain constant under conditions of elevated BP. Isolated MCA's from asymptomatic Dahl-SS exhibited constriction in response to elevated pressure and protein kinase (PKC) activation (a signaling intermediate for PDC in MCA's). In addition the MCA's vasodilated in an endothelium dependent manner in response to bradykinin. These functions were lost in the MCA's of Dahl-SS with HE. MCA's from post-HE Dahl-SS that were unable to constrict to pressure lacked the ability to constrict in response to PKC activation via phorbol esters. They exhibited high levels of basal tone and no response to the endothelial specific vasodilator, bradykinin. The loss of PDC in MCA's of Dahl-SS preceded the development of HE and occurred in asymptomatic rats fed high salt for 3 weeks at a time when CBF autoregulation was lost. It was concluded that defects in the ability of the cerebrovasculature to autoregulate CBF in conjunction with the development of renal dysfunction could contribute to the development of HE in Dahl-SS fed high salt. Cerebrovascular PDC is thought to play an important role in facilitating CBF autoregulation. The loss of this function could contribute to a loss of CBF autoregulation under hypertensive conditions. This could increase cerebrovascular pressures and promote overperfusion in the brain, leading to the development of cerebral edema and HE. The development of HE could be further augmented by a decrease in plasma oncotic pressure promoted by the loss of plasma proteins due to the occurrence of proteinuria. The presence of a dysfunctional PKC system in the vascular smooth muscle of MCA's sampled from Dahl-SS with HE could contribute to the loss of PDC in the arteries.

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