| A major risk factor for the development of cardiovascular disease is hypertension. Although research evidence indicates that management of hypertension significantly reduces cardiovascular risk, the etiology of the most common form of hypertension, primary hypertension, has yet to be elucidated.; In the most commonly used experimental model of hypertension, the spontaneously hypertensive rat (SHR), angiotensin-converting enzyme (ACE) inhibitors have been shown to induce a lowering of arterial pressure that persists even after treatment is stopped. This response represents a partial cure for the hypertension. Further, based on extensive characterization, the magnitude of the persistent lowering of pressure appears to be a useful indicator of the ability of different drug treatment protocols to impact on underlying hypertensive pathophysiology.; The studies presented in this thesis were carried out using in vivo radio-telemetry, mean arterial pressure (MAP) recordings, in situ renal and hindlimb perfusion preparations and kidney cross transplantation experiments. These studies established the equivalency of ACE inhibitors and AT1 antagonists both on treatment and with respect to the persistent lowering of pressure. In addition, the drug effects on persistent regression of structurally-based renal vascular resistance properties were found to be similar. These data indicate that removal of Ang II, rather than other secondary mechanisms, is responsible for these equivalent effects. Another finding was that prolonged treatment with both agents induced the development of a drug tolerance to the mechanisms related to persistent effects on arterial pressure. An overall integration of the data demonstrated that there was a direct, linear relationship between the depressor response achieved during treatment both with drugs that inhibit the RAS and also with non RAS-inhibiting agents. This characterization revealed that inhibiting the RAS is not obligatory to achieve a persistent lowering of pressure after stopping treatment. Additional experiments have shown that 2 weeks of aggressive ACE inhibitor therapy can induce a persistent lowering of pressure that is nearly the equivalent of that induced by 10 weeks of conventional treatment. Although these results demonstrated that 2 weeks can now be considered as close to the minimum treatment duration required to induce a persistent lowering of pressure, we also found that 2 weeks did not provide sufficient time to allow for the full extent of persistent lowering possible with enhanced depressor responses (i.e. >30% lowering of MAP). Finally, these studies confirmed that mechanisms residing in the kidney, specifically a regression of structurally-based vascular resistance, contribute importantly to the persistent lowering of pressure after both long and short term treatment in adult animals.; Overall, the present studies have greatly enhanced the breadth and depth of knowledge concerning the processes involved in the persistent actions of antihypertensive drugs after cessation of treatment. The application of this knowledge may in turn lead to new therapeutic targets and/or improved treatment strategies to minimize cardiovascular risk in patients with hypertension. |
