Gene therapy for hypertension and restenosis

JRAAS 2000;1:211-6 Introduction Hypertension is a complex pathophysiological state that is characterised by high blood pressure. The progression of untreated hypertension is highly variable and can result in damage to vital organs such as the heart, brain, kidneys, adrenal glands, and vasculature, qualifying hypertension as a major risk factor for renal failure,coronary artery disease, cardiac failure and stroke. Since the cause for essential hypertension is unknown, antihypertensive therapy must be directed at normal physiological mechanisms that regulate blood pressure. The involvement of the RAAS in the development and progression of hypertension is well established. Accordingly, the RAAS has been a popular and effective target for therapeutic intervention. Two different systems, the endocrine RAAS and the paracrine/autocrine RAAS, contribute to the shortand long-term regulation of blood pressure. The endocrine RAAS generates circulating angiotensin II (Ang II) by the co-ordinated activities of the kidneys, liver, and lungs, which produce renin, angiotensinogen, and angiotensin-I converting enzyme (ACE) respectively. Circulating Ang II is responsible for the short-term effects of Ang II such as blood pressure regulation, arteriolar vasoconstriction, sodium and water reabsorption, renal haemodynamics, cardiac inotropic effects, control of ischaemia, aldosterone secretion by the adrenal glands, water consumption, vasopressin secretion, regulation of the baroreflex, and regulation of sympathetic activity by the central nervous system. In contrast, Ang II produced by the tissue-specific paracrine/autocrine RAAS seems to have long-term effects such as regulation of cardiac hypertrophy and vascular remodelling. Both systems are important in the normal regulation of blood pressure and have been implicated in the development and maintenance of hypertension. Evidence that the RAAS is critically involved with hypertension is provided by two key indications. First, interruption of the RAAS lowers high blood pressure and attenuates some pathophysiological changes associated with hypertension. Second,several gene loci that include components of the RAAS may be involved in essential hypertension. 13-22 For example, an Ang II type 1 receptor (AT1-receptor) variant was found more frequently in hypertensive patients, suggesting that a variant of the AT1-receptor may contribute to elevated blood pressure. Further, increased frequency of an allele of the AT1-receptor was seen when hypertensive twins were examined. The angiotensinogen gene is also strongly linked to hypertension. In one study, an excess of angiotensinogen allele sharing was found in hypertensive sibling pairs, and, more recently, transfer of a segment of chromosome 19 near the angiotensinogen gene from normotensive Brown Norway rats to spontaneously hypertensive rats (SHR) induced a decrease in blood pressure, although plasma angiotensinogen levels and renin activity were unchanged. In human patients, the strategy for hypertension symptom management is highly individualised.Often deciding which drugs are used (alone or in combination) is based on the presence of other diseases or drug tolerance. Diuretics, calcium channel antagonists, and beta-blockers are all examples of effective traditional antihypertensive agents. While these can effectively lower blood pressure, they may not counter the morphological changes associated with hypertension. Pharmacological agents which target the RAAS, either by inhibiting the formation of Ang II (ACE and renin inhibitors) or blocking Ang II at the receptor level (AT1-receptor antagonists) have more recently been developed.ACE inhibitors are well tolerated and frequently prescribed, not only because they attenuate vasoconstriction, but also because they have vasoprotective effects such as improvement of arterial compliance, restoration or improvement of endothelial function, antiplatelet effects, antiatherogenic effects, and enhancement of fibrinolysis. These agents are reliable and affordable, and their short duration of action makes them an ideal choice for reversible, short-term drugs.At the same time, their short-lived effect means that they must be administered on a regular basis. Additionally, some of these drugs can lead to undesirable side-effects.These deficiencies can lead to problems with patient compliance. Finally, if the principal goal in treating hypertension is to prevent end organ damage, reduce the risk of other diseases as a result of hypertension, or provide a cure, then antihypertensive agents, which decrease high blood pressure, are completing only part of the task.