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Cardiovascular Research 2000 45(1):79-81; doi:10.1016/S0008-6363(99)00290-4
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Effect of methyldopa, clonidine, and hydralazine on cardiac mass and haemodynamics in Wistar Kyoto and spontaneously hypertensive rats

An historical account and some follow-up

Barbara L Pegram, Shozo Ishize and Edward D Frohlich1,*

Alton Ochsner Medical Foundation, New Orleans, LA 70124, USA

* Corresponding author. Tel. +1-504-842-3700; fax: +1-504-842-3258

KEYWORDS Antihypertensive agents; Heart rate (variability); Hemodynamics; Hypertension; Hypertrophy; Ventricular function

At the time that our report was written [1], a major change in our thinking about left ventricular hypertrophy (LVH) in hypertension was emerging. The concept that LVH is an independent risk factor for premature cardiovascular morbidity and mortality had become established [2,3]. As a result, the clinical hypothesis was beginning to be tested based upon the experiences with other risk factors. Thus, if the risk of increased morbidity and mortality, associated with elevated systolic and diastolic arterial pressure or elevated serum cholesterol concentration, could be reversed by their respective therapeutic reductions, could not pharmacological reduction of increased LV mass reduce the independent risk associated with LVH? Our thinking at that time was that the development of LVH was multifactorial in nature and that its reversal, most likely was similar mechanistically [4,5]. Therefore, to my way of thinking, while that hypothesis was highly attractive clinically, it seemed far too simplistic to be established clinically (or, for that matter, experimentally) without highly sophisticated multicenter studies designed to dissociate reversal of LVH from risk associated with elevated arterial pressure, cardiac dysrhythmias, and other outcomes that could be prevented by other pharmacological action induced by the employed antihypertensive drugs.

At the time that our research study was begun, a number of laboratory studies had already appeared from the group at the Cleveland Clinic [6–10] as well as our laboratory [11–13] demonstrating that antihypertensive therapy could decrease LV mass. However, it was my view that reduction in ventricular mass by a pharmacological agent may not be explained solely on the hemodynamic basis of reducing the left ventricular pressure overload; important non-hemodynamic factors may also be responsible for the increased LV mass [14–18]. Moreover, the factors responsible for the increased risk associated with LVH were still unclear and it would be that much more difficult to demonstrate that reduction of LV risk could be related simply to reduction in LV mass [19,20].

For this reason, it seemed important to develop an experimental model to demonstrate pharmacological reduction in LV mass within a very short time period. That time duration should be short enough so that the immediate hemodynamic factors responsible for the increased left ventricular afterload would not be responsible for the reduced cardiac mass. We thereupon decided that a three week treatment period of spontaneously hypertensive rats (SHR) might be appropriate, and this was demonstrated in our study [1]. All of our subsequent studies concerned with this concept, therefore, involved the three week treatment protocol involving male SHR — later studies demonstrating reversal of renal pathophysiological alterations in SHR [21]. Moreover, we had learned from the study that the three agents deliberately selected (i.e., methyldopa, clonidine, and hydralazine), although equally effective in reducing pressure, had very different effects with respect to their hemodynamic and structural responses. Hydralazine reduced arterial pressure but not LV mass. Methyldopa reduced arterial pressure to the same extent (as the other two agents) and it additionally decreased LV mass not only of the SHR but also of the normotensive WKY rats within that three week treatment period. And, in contrast to methyldopa, clonidine, another adrenergic inhibitor, reduced arterial pressure to the same extent as methyldopa, but it failed to decrease LV mass. However, when we tripled the clonidine dose, the peripheral alpha-adrenergic receptor agonistic response of the drug were manifest, increasing arterial pressure and total peripheral resistance while actually decreasing LV mass. Thus, the two adrenergic inhibiting drugs (methyldopa and clonidine) demonstrated independent hemodynamic effects that were unrelated to their effects on mass. These findings supported our initial hypothesis that non-hemodynamic factors must be extremely important in the development and reversal of LV mass [4,11,15]. Further supporting this concept were our other findings demonstrating that both left and right ventricular masses were reduced by methyldopa in the SHR as well as in the normotensive WKY non-hypertrophied left and right ventricles. Our subsequent studies confirmed this observation [22] and further supported our hypothesis with other agents [23–25]. Thus, we found that: (a) certain agents within the same antihypertensive drug class had disparate effects on LV and right ventricular (RV) as well as aortic mass [23,26]; (b) another class of antihypertensive agents also reduced LV and aortic mass, although right ventricular mass increased [25,27]; eight certain agents reduced LV mass in subhemodynamically effective doses as well as in hypotensive doses [24]; (d) reduction in LV mass was not only the result of reduced myocardial mass but also of reduced collagen content [28,29]; and (e) while LV collagen was diminished by calcium antagonists, RV collagen increased, and this increase could be prevented by an ACE inhibitor even though LV collagen was not reduced further with use of the both agents [28,29].

Sen and Bumpus had demonstrated prior to publication of our initial paper, that methyldopa reduced LV mass as a result of decreased myocardial muscle protein and that the resulting percent of collagen in the ventricle was greater following that antihypertensive therapy [8,9]. These findings led us to suggest that, perhaps, reduction of LV mass might favor development of cardiac failure and, perhaps, may not be a reasonable goal for long-term therapy with every antihypertensive agent [30]. We later suggested that myocardial ischemia and LV fibrosis that occurs in hypertensive heart disease might favor the eventual development of cardiac failure [31]. Moreover, we further suggested that these and other findings from our laboratory might explain the shift in our classical concept of hypertensive cardiac failure that not only can pressure overload result in LV systolic dysfunction, but in diastolic dysfunction. This is because more hypertensive patients with heart disease, having been treated for the elevated arterial pressure ultimately develop LV ischemia and fibrosis later on in the disease which predisposes the less distensible and fibrotic LV to diastolic dysfunction [32,33].

Thus, we believe that the findings reported in our paper under discussion provided, at lease in part, a basis for our questioning the established thinking about the pathogenesis of LVH and about the so-called ‘regression’ or reversal of LV mass. Throughout, we have not referred to pharmacological reduction of LVH mass as LVH ‘regression’ since our studies never demonstrated regression of LVH, per se, pathologically. Thus, when one considers the increased LV mass in hypertensive heart disease, it should not be thought of solely as LVH, but as increased LV mass secondary to increased collagen as well as hypertrophied muscle mass. Clearly, non-hemodynamic factors are now known to participate in the development and reversal of increased muscle mass in hypertension.


   Notes
 
1 Vice President for Academic Affairs, Alton Ochsner Distinguished Scientist. Back


   References
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