Persistent lowering of arterial pressure after continuous and intermittent therapy

Abstract

This study provides new evidence that combination therapy, not directly targeting the RAS, can be efficacious in persistently reducing MAP off-treatment. Furthermore, we demonstrated that the 6-week treatment with RAS inhibitors induced equivalent persistent changes as a 10-week treatment. That is, the additional 4 weeks of continuous therapy was ineffective in further altering the off-treatment MAP. In contrast, with the intermittent treatment protocol (the 14-week 'drug holiday') a further effect on persistent lowering of MAP was regained. These findings suggest continuous long-term treatment with antihypertensive drugs may not be the most effective means of reversing underlying circulatory abnormalities and that the introduction of a drug holiday may be beneficial.

Time Course of Vascular Structural Changes During and After Short-Term Antihypertensive Treatment

“…Based on these results, investigations into the mechanisms of antihypertensive drug-induced vascular remodeling in SHR can focus on a time frame spanning days to weeks and not months as has been done previously. In addition, particularly when combined with those of Woolard et al, 9 the results emphasize that treatments that effectively reduce blood pres- …”

“…[1][2][3][4] These effects have been shown in several models of experimental hypertension, including the Prague hypertensive rat 5 and the genetically hypertensive rat, 6,7 although this is best documented in the spontaneously hypertensive rat (SHR). [1][2][3]8,9 The concept that the persistent reduction in MAP and the regression of vascular structure are linked mechanistically has also been widely discussed, although without resolution. 1-4,10 -14 Further, the vascular structural changes that persist off-treatment have been proposed to result from extended inhibition of the trophic actions of angiotensin II, 8,15,16 prolonged reduction in arterial pressure, 16 -18 or from the combined effects.…”

“…In contrast, we recently demonstrated in adult SHR that a 6-week antihypertensive treatment using a combination of agents (diuretic, calcium channel blocker, and vasodilator) was able to induce a persistent reduction in MAP. 9 In analyzing data from publications before 1997, Lundie et al 2 found that the longer the treatment, the greater the effect on MAP and vascular structure, and suggested that a minimum of 4 weeks was required to induce persistent changes in the circulation. More recently, however, experimental evidence has revealed that only 2 weeks of treatment using an angiotensin converting enzyme (ACE) inhibitor was required to induce regression of both hindlimb and penile structurally based vascular resistance 3,24 and persistent reduction in MAP.…”

Treatment of Spontaneously Hypertensive Rats With Rosiglitazone and/or Enalapril Restores Balance Between Vasodilator and Vasoconstrictor Actions of Insulin With Simultaneous Improvement in Hypertension and Insulin Resistance

“…To gain insight into mechanisms by which enalapril and/or rosiglitazone therapy may simultaneously improve the metabolic and hemodynamic phenotype of SHRs, we evaluated endothelial function in MVBs isolated from SHRs after 3-week therapy with drugs or vehicle. Although the doses of rosiglitazone and enalapril that we used in our study are higher than those usually used in humans, the doses that we used are typical for rodent studies (62)(63)(64). Given the large surface area and synthetic capacity of microvascular endothelium, small resistance vessels in the MVBs represent important determinants of plasma levels of endothelium-derived mediators and total peripheral vascular resistance.…”

Neonatal sympathectomy reduces NADPH oxidase activity and vascular resistance in spontaneously hypertensive rat kidneys

“…This finding indicates that, in SHR, hydralazine given early after birth has a prolonged antihypertensive action similar to that of sympatholytic drugs (14,19) or angiotensin-converting enzyme inhibitor treatment (34). Consistent with this observation, radio-telemetric studies have shown that hydralazine with a diuretic and a Ca 2ϩ antagonist lowers arterial pressure for several weeks beyond cessation of drug administration in adult SHR (40). The different potency of these treatments to induce chronic changes in renal function that contribute to the maintenance of the arterial pressure reduction becomes apparent in transplantation experiments (14,34).…”