Effects Of Alpha 1-adrenoceptor Blockade Research Articles

The effects of alpha 1-adrenoceptor blockade and angiotensin converting enzyme inhibition on central and brachial blood pressure and vascular reactivity: the doxazosin\u2013ramipril study

We aimed to study whether inhibition of the renin–angiotensin–aldosterone system has effects on vascular structure and function beyond the effects on blood pressure reduction alone. Patients with mild-to-moderate hypertension (n = 61, age 54 ± 12 years, 34% women) received the angiotensin converting enzyme inhibitor ramipril 10 mg or the alpha 1-adrenoceptor blocker doxazosin 8 mg double-blind for 12 weeks. Aortic blood pressure, pulse wave velocity, and augmentation index were assessed by applanation tonometry. Endothelial function was studied by forearm post-ischemic flow mediated vasodilatation and by pulse wave analysis with beta 2-adrenoceptor agonist stimulation. Skin microvascular reactivity was assessed by laser Doppler fluxmetry and iontophoresis. Treatment with doxazosin or ramipril reduced aortic and brachial blood pressures (all P < 0.001), with greater reductions in aortic than brachial systolic blood pressures (P = 0.021) and aortic/brachial pulse pressure ratio (P = 0.005). Compared to doxazosin, ramipril reduced carotid-femoral and carotid-radial pulse wave velocity (both P < 0.05). Forearm endothelial dependent and independent vasodilatation, assessed by post-ischemic flow mediated vasodilatation and glyceryl trinitrate, and by pulse wave analysis remained unchanged by both doxazosin and ramipril. In addition, skin microvascular endothelial dependent (acetylcholine) and independent vasodilatation (sodium nitroprusside) remained unchanged. In conclusion, ramipril reduced indices of aortic stiffness, suggesting that angiotensin converting enzyme inhibitor therapy may have effects beyond blood pressure reduction. However, treatment did not appear to influence endothelial function. Evidence of endothelial dysfunction and its possible improvement by antihypertensive treatment might require more advanced hypertension.This study is registered at ClinicalTrials.gov (NCT02901977) and at EudraCT (# 2007-000631-25).

Alpha-1 adrenoceptor blockade: potential new treatment for anal fissures.

Patients with chronic anal fissures are known to have high resting anal pressures that return to normal after successful surgical treatment. Internal anal sphincter activity is increased by sympathetic excitatory innervation via alpha adrenoceptors. The objective of this study was to determine the effect of alpha-1 adrenoceptor blockade on anal sphincter pressure in patients with and without chronic anal fissures. The effect on the anal canal pressure profile of a single oral 20 mg dose of indoramin, an alpha-1 adrenoceptor antagonist, on seven patients with chronic anal fissure and six healthy patients without a fissure was investigated. Indoramin reduced anal resting pressures in those with anal fissure by a mean of 35.8 percent, from 106.9 +/- 22.15 cm H2O to 68.6 +/- 20.35 cm H2O, and in those without anal fissure by a mean of 39.9 percent, from 84.17 +/- 27.46 cm H2O to 52.17 +/- 24.78 cm H2O, after one hour. This pressure reduction persisted at three hours, and its magnitude is comparable to that obtained after internal sphincterotomy. The pressure reduction occurred over the whole length of the anal canal. It is proposed that alpha-1 adrenoceptor antagonists could be a suitable treatment for chronic anal fissure and other painful conditions where reduction in anal pressure is warranted.

Correction of neurovascular deficits in diabetic rats by beta2-adrenoceptor agonist and alpha1-adrenoceptor antagonist treatment: interactions with the nitric oxide system.

The aims were to test whether 2 weeks treatment with the beta2-adrenoceptor agonist, salbutamol, or the alpha1-adrenoceptor antagonist, doxazosin, could correct nerve blood flow and conduction velocity deficits in 8 week streptozotocin-diabetic rats and to examine neurovascular mechanisms using co-treatment with the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Sciatic motor conduction velocity, 20.3% reduced by diabetes, was corrected by 88.2 and 88.5% for salbutamol and doxazosin, respectively. A 47.6% diabetic deficit in sciatic nutritive endoneurial blood, was substantially reversed by salbutamol (117.0%) and doxazosin (61.0%) treatment. The effects of alpha1-adrenoceptor blockade and beta2-adrenoceptor stimulation on nerve blood flow and conduction velocity were almost completely (76.7-91.7%) attenuated by NG-nitro-L-arginine co-treatment. Thus, the data stress the importance of vasa nervorum alpha1 and beta2 adrenoceptors and the permissive role of nitric oxide in nerve blood flow control mechanisms. They also indicate that beta2-adrenoceptor agonists may be suitable for clinical trials of diabetic neuropathy.

Effect of alpha 1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans.

In the present study we aimed to assess the effect of alpha 1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans. Myocardial blood flow, at baseline and after dipyridamole, was measured with positron emission tomography and 15O-labeled water in 11 normal volunteers at control and during alpha 1-blockade with doxazosin. Baseline myocardial blood flow during alpha 1-blockade was not different from control, whereas coronary resistance was significantly lower (73.48 +/- 18.31 vs. 89.84 +/- 27.96 mmHg.min.ml-1.g-1; P < 0.05). After dipyridamole, myocardial blood flow during alpha 1-blockade was significantly higher (3.50 +/- 0.75 vs. 2.58 +/- 0.54 ml.min-1.g-1; P < 0.01) and coronary resistance lower (25.30 +/- 7.37 vs. 33.89 +/- 7.04 mmHg.min.ml-1.g-1; P < 0.01) compared with control. In conclusion, in normal humans, dipyridamole-induced increase in myocardial blood flow is limited by alpha 1-mediated coronary vasoconstriction.

Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog.

Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007). High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.

Effect of a1-Adrenoceptor Blockade on Maximal V02 and Endurance Capacity in Well- rained Athletic Hypertensive Men

The effect of alpha 1-adrenoceptor blockade (doxazosin, 4 mg daily) on maximal VO2 and physical endurance capacity in 16 mildly hypertensive, athletic men was investigated in a randomized, placebo-controlled, double-blind, two-period of 4 weeks, cross-over study. The maximal workload obtained during graded bicycle ergometer exercise and the corresponding maximal VO2 were reduced by 16 +/- 3 W (mean +/- SE), (P = .00003) and 3 +/- 1 mL/(kg.min) (P = .0004), respectively, on doxazosin compared with placebo. The running time on a 5000 m track increased by 43 +/- 12 sec on doxazosin (P = .04). Heart rate was unchanged during the running session. Systolic blood pressure was reduced by 9 +/- 4.1 mm Hg (P = .04) immediately after finishing 5000 m. Six subjects reported side effects from doxazosin (headache, fatigue, and leg pain). Thus, antihypertensive treatment with alpha 1-selective adrenoceptor blockade moderately, but significantly, reduces maximal O2 consumption and high intensity physical endurance capacity in mildly hypertensive athletic men. Significantly reduced systolic blood pressure and unchanged heart rate immediately after running, combined with unchanged heart rate during the race may, however, suggest a safer exercise performance.

Influence of alpha 1-adrenoceptor blockade and/or 5-HT1A agonism on blood pressure and heart rate at rest and during exercise in hypertensive dogs.

1. Antihypertensive effects resulting from alpha 1-adrenoceptor blockade and stimulation of central nervous 5-HT1A receptors were compared with the effects arising from stimulation of 5-HT1A receptors alone during arterial hypertension. 2. Urapidil and 5-methyl-urapidil were less effective in decreasing arterial blood pressure than the lowest dose of the selective 5-HT1A receptor agonist, flesinoxan. After the higher dose of urapidil, a certain dampening of barareceptor reflex was found which was also seen with flesinoxan. 3. Flesinoxan was the only drug which did not reduce the exercise-induced increase in systolic arterial blood pressure. 4. Stimulation of 5-HT1A receptors alone, which is assumed to occur with flesinoxan, exerted antihypertensive activity only at low doses, without inducing reflex tachycardia at rest. 5. Only the combined effects of alpha 1-adrenoceptor blockade and 5-HT1A receptor stimulation, as assumed to occur with urapidil and 5-methyl-urapidil, lead to both a decrease in arterial blood pressure at rest and during exercise.

α1‐adrenoceptor blockade and/or 5‐HT1A agonism during treadmill exercise in dogs

1. The hypotensive effects of alpha 1-adrenergic blockade and/or stimulation of central nervous 5-HT1A receptors were studied using drugs with different affinity for central nervous 5-HT1A and peripheral alpha 1-adrenoceptors. Urapidil, 5-methylurapidil, flesinoxan and 8-OH-DPAT were compared under states of different activation of the autonomic nervous system, i.e. at rest and during graded treadmill exercise. 2. The rank order of hypotensive potency as derived from the most extensive decrease in resting diastolic arterial blood pressure was urapidil greater than 5-methylurapidil greater than flesinoxan much greater than 8-OH-DPAT. 3. The reflex increase in heart rate due to the decrease in arterial blood pressure at rest was suppressed after 0.1 mumol kg-1 flesinoxan. 4. The reflex increase in heart rate due to the decrease in arterial blood pressure at rest was less accentuated after high doses of urapidil and 5-methylurapidil. 5. During exercise both 5HT1A receptor agonists, flesinoxan and 8-OH-DPAT, decreased sympathetic tone. 6. The combined effects of alpha 1-adrenoceptor blockade and 5-HT1A receptor stimulation (urapidil and 5-methylurapidil) result in distinct decreases in blood pressure and slight suppression of reflex tachycardia at rest after high doses. Stimulation of 5-HT1A receptors alone (flesinoxan) suppresses reflex tachycardia by modulation of baroreceptor reflex and at high dose also diminishes exercise-induced increase in sympathetic tone.

Renal and hormonal effects of alpha1-adrenoceptor blockade by bunazosin in essential hypertension

The renal and hormonal effects of the alpha 1-adrenoceptor blocker bunazosin were examined in 6 patients with essential hypertension. Oral bunazosin for 4 to 12 weeks significantly decreased mean blood pressure by 10%, increased effective renal blood flow and creatinine clearance by 34% and 37%, respectively, the plasma norepinephrine concentration was elevated by 60%, and the plasma atrial natriuretic peptide level was lowered by 22%. The plasma renin activity and aldosterone concentration were unchanged. Thus, a moderate reduction in blood pressure was produced by bunazosin treatment while maintaining renal perfusion.

Effect of alpha-1 adrenoceptor blockade on plasma levels of atrial natriuretic peptide during dynamic exercise in normal man.

Effect of alpha-1 adrenoceptor blockade on plasma levels of atrial natriuretic peptide during dynamic exercise in normal man.

Antianginal and Haemodynamic Effects of α1-Adrenoceptor Blockade

We studied the effects of alpha 1-adrenoceptor blockade with indoramin on exercise tolerance in 15 patients with chronic stable angina using a double-blind crossover protocol. Thirteen patients had been receiving beta-adrenoceptor blocking drugs and nitrates. The therapy of these patients was continued unchanged throughout the study. Indoramin, in a dose of 25 mg three times daily, prolonged exercise duration by 17% (p less than 0.01) and increased oxygen consumption during exercise by 21% (p less than 0.01), while the maximal double product was unchanged. This increase in exercise capacity was associated with significant attenuation in ST segment depression during exercise. To investigate the mechanism of this antianginal effect, we studied the effects of indoramin (0.2 mg/kg i.v.) on coronary and systemic haemodynamics in a further 11 male patients with chronic stable angina who were receiving beta-adrenoceptor blocking drugs. Measurements were obtained during sinus rhythm and during atrial pacing from 100 beats/min, incremented by 20 beats/min at intervals of 3 min until the onset of angina. Indoramin had no effect on resting heart rate (64 +/- 2 vs. 67 +/- 2 beats/min), but did prolong pacing time to angina (7.4 +/- 0.7 vs. 5.4 +/- 0.5 min; p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Cardioprotective and Antidysrhythmic Effects of α1-Adrenoceptor Blockade During Myocardial Ischaemia and Reperfusion in the Dog

Recent research in cats suggests that cardiac alpha 1-adrenoceptors are involved in the genesis of early life threatening ventricular dysrhythmias following myocardial infarction. Evidence for the existence of cardiac alpha 1-adrenoceptors has been obtained in all the mammalian species investigated to date and includes guinea pig, rabbit, cat, dog, rat and humans. The present series of experiments was conducted in dogs, a species in which reperfusion is associated with higher mortality than the cat. It was found that alpha-adrenoceptor block with prazosin significantly reduced ventricular ectopic activity during coronary artery occlusion and reperfusion and reduced mortality associated with reperfusion. To ascertain the site of action of prazosin and other alpha 1-adrenoceptor antagonists in this context it is necessary to consider their effects on haemodynamics, the coronary vasculature and the myocardium. Prazosin and related alpha 1-adrenoceptor antagonists have been shown to be extremely effective in abrogating catecholamine induced ventricular arrhythmias in the dog and are additive with beta-adrenoceptor antagonists in this respect. However, in the present experiments prazosin caused a significant attenuation of the repayment of coronary flow debt on reperfusion, reduced the ischaemia induced rise in filling pressure and increased coronary blood flow during coronary artery occlusion. Thus, whether the beneficial effects of alpha 1-adrenoceptor blockade are solely the result of blockade of myocardial alpha 1-adrenoceptors and not, at least in part, improved coronary blood flow within the ischaemic bed requires further study.