Long-term hemodynamic effects at rest and during exercise of newer antihypertensive agents and salt restriction in essential hypertension: review of epanolol, doxazosin, amlodipine, felodipine, diltiazem, lisinopril, dilevalol, carvedilol, and ketanserin.
ABSTRACT Hypertension is due to disturbance of the complex interplay between numerous known and unknown mechanisms that normally control blood pressure. Antihypertensive agents may, therefore, reduce blood pressure through widely different actions and, at the same time, elicit counterregulatory responses. This is a review of the long-term hemodynamic effects at rest as well as during exercise of nine relatively new antihypertensive compounds: a beta-blocker (epanolol), an alpha-receptor blocker (doxazosin), two double-acting compounds (dilevalol and carvedilol), three calcium antagonists (amlodipine, felodipine, and diltiazem), an angiotensin-converting enzyme inhibitor (lisinopril), a serotonin antagonist (ketanserin), and low-salt diet as a nonpharmacological treatment in 171 patients with mild to moderate essential hypertension. The results in the treatment groups are compared to the hemodynamic changes seen in 28 hypertensive patients left untreated for 10 years. The patient populations of the different groups were comparable. The invasive hemodynamic technique, including intraarterial blood pressure recording and measurements of cardiac output by Cardigreen, was the same in all studies. While blood pressure remained nearly unchanged in the untreated group, all antihypertensive compounds induced significant and sustained blood pressure reduction both at rest and during exercise. The modest reduction (3-5%) in blood pressure during a low-salt diet was also statistically significant. This review shows the multiplicity of the long-term hemodynamic changes, ranging from a reduction in cardiac output to peripheral vasodilatation, during chronic antihypertensive therapy. In untreated hypertensives, the cardiac output is reduced by 1-2% per year and total peripheral resistance is increased by 2-3% per year. The review also focuses on counterregulatory responses and modify the initial reduction in blood pressure after drug treatment for hypertension. It is concluded that proper understanding of the hemodynamic effects of antihypertensive agents is useful in the selection of the right treatment for specific groups of hypertensive patients.
SourceAvailable from: Kurt Stenmark[Show abstract] [Hide abstract]
ABSTRACT: Recent studies have indicated that systemic arterial stiffening is a precursor to hypertension and that hypertension, in turn, can perpetuate arterial stiffening. Pulmonary artery (PA) stiffening is also well documented to occur in pulmonary hypertension (PH), and there is evidence that pulmonary vascular stiffness (PVS) may be a better predictor of outcome than pulmonary vascular resistance (PVR). We have hypothesized that the decreased flow-damping function of elastic PAs in PH likely initiates and/or perpetuates dysfunction of pulmonary microvasculature. Recent studies have shown that large-vessel stiffening increases flow pulsatility in the distal pulmonary vasculature, leading to endothelial dysfunction within a proinflammatory, vasoconstricting, and profibrogenic environment. The intricate role of stiffening-stimulated high pulsatile flow in endothelial cell dysfunction includes stepwise molecular events underlying PA hypertrophy, inflammation, endothelial-mesenchymal transition, and fibrosis. In addition to contributing to microenvironmental alterations of the distal vasculature, disordered proximal-distal PA coupling likely also plays a role in increasing ventricular afterload, ultimately causing right ventricle (RV) dysfunction and death. Current therapeutic treatments do not provide a realistic approach to destiffening arteries and, thus, to potentially abrogating the effects of high pulsatile flow on the distal pulmonary vasculature or the increased work imposed by stiffening on the RV. Scrutinizing the effect of PA stiffening on high pulsatile flow-induced cellular and molecular changes, and vice versa, might lead to important new therapeutic options that abrogate PA remodeling and PH development. With a clear understanding that PA stiffening may contribute to the progression of PH to an irreversible state by contributing to chronic microvascular damage in lungs, future studies should be aimed first at defining the underlying mechanisms leading to PA stiffening and then at improved treatment approaches based on these findings.
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ABSTRACT: The effect of the long-acting dihydropyridine calcium channel antagonist, amlodipine, on the exercise performance of hypertensive patients is not known. The aim of this study was to determine the effects of amlodipine on maximal (MAX) and prolonged submaximal (PSX) exercise and on skeletal muscle function (SMF) in patients with mild hypertension. In a double-blind, randomised, crossover trial, 10 physically active hypertensive patients performed: (a) graded exercise to exhaustion for determination of maximal oxygen consumption (VO2max), peak heart rate (HR) and systolic blood pressure (SBP); (b) PSX at 75% VO2max to determine cardiorespiratory responses, cardiac output (Q), blood lactate (La), free fatty acid (FFA), glucose (G) concentrations and ratings of perceived exertion (RPE); and (c) tests of isometric SMF including maximal voluntary contraction (MVC) and time to fatigue during repetitive isometric MVCs. Tests were performed following 2-week ingestion of amlodipine (5mg daily) or placebo separated by a 2-week washout period. Resting SBP was decreased following ingestion of amlodipine [ 142 ± 13 vs 133 ± 12mm Hg, amlodipine vs placebo (mean ± SD); p < 0.05]. However, VO2max (31 ±5 vs 33 ±5ml O2/kg/min, amlodipine vs placebo), peak HR (168 ± 13 vs 165 ± 16 beats/min, amlodipine vs placebo) and peak SBP (181 ± 21 vs 170 ± 16mm Hg, amlodipine vs placebo) were not reduced following ingestion of amlodipine. Submaximal cycling time, VO2, Q, BP, HR, ventilation, RPE, FFA, La and G during PSX were unaltered following ingestion of amlodipine. Similarly, ingestion of amlodipine did not alter tests of isometric SMF. These data suggest that: (a) ingestion of amlodipine lowers resting SBP but does not alter the normal haemodynamic response during exercise; (b) MAX and PSX exercise performance and SMF are unaltered following ingestion of amlodipine in athletic hypertensive patients. These findings suggest that the regulatory mechanisms that maintain haemodynamic homeostasis during maximal and submaximal exercise are not influenced by ingestion of amlodipine in athletic hypertensive patients.Clinical Drug Investigation 01/1996; 28. DOI:10.1097/00005768-199605001-00120 · 1.70 Impact Factor
Article: Choosing the Right β-Blocker[Show abstract] [Hide abstract]
ABSTRACT: β-Blockers have been in clinical use for 30 years, and have an accepted role in (among others) the treatment of high blood pressure, the secondary prevention of myocardial infarction and the treatment of arrhythmias. Their place in the treatment of heart failure is currently under investigation. The drugs available in the 1970s and early 1980s were subjected to intense investigation. A new generation of β-blockers, including some such as carvedilol and bucindolol, with vas-odilating properties, is now appearing. As yet these later agents have not been the subject of large clinical trials. Clinical practice involves the treatment of individual patients with defined dosages of particular drugs. It is, therefore, not acceptable to base practice on theories derived from the clinical pharmacology of a particular drug, on the results of small trials or on a meta-analysis of results from a number of trials that were individually inadequate. Clinical practice must follow the results of large-scale trials in defined populations. The major trials in hypertension, myocardial infarction, arrhythmias and heart failure provide the best evidence for the use of individual β-blockers in each of these clinical situations. In patients with high blood pressure, β-blockers do not seem to have any particular advantage over other hypotensive agents. In myocardial infarction, relatively late use of a β-blocker undoubtedly reduces fatality, though the value of early treatment is less clear. β-Blockers are not powerful antiarrhythmics, but they do appear to prevent sudden death. Their possible role in heart failure is perhaps the most interesting current field of β-blocker research. There are very few comparative studies of β-blockers, and it is difficult to make precise recommendations. None of the new generation of β-blockers has yet been used in a trial that is large enough trial for any of them to be accepted for routine use in preference to older drugs. The use of individual β-blockers, as with any drug, should follow the results of clinical trials. Propranolol and atenolol have been studied most intensely in hypertension. For secondary prevention of myocardial infarction, the evidence is best for timolol. Sotalol is probably the best antiarrhythmic among the β-blockers. Whether any individual β-blocker is best for heart failure remains to be seen.Drugs 10/1994; 48(4). DOI:10.2165/00003495-199448040-00005 · 4.13 Impact Factor