Search

1 A survey has been made of the literature on acute and long-term haemodynamic effects of ten different β-adrenoceptor antagonists. The β-adrenoceptor blockers are: pindolol, practolol, alprenolol, oxprenolol, acebutolol, penbutolol, metoprolol, atenolol, propranolol and timolol. The total numbers of patients included in this review are 396 patients in 41 acute studies and 410 patients in 36 long-term studies. 2 The effects of β-adrenoceptor blockers on the concentrations of plasma noradrenaline have also been reviewed. Ten studies including 110 patients on non-ISA-β-adrenoceptor blockers and eight studies including 116 patients on pindolol are presented. 3 In the acute studies (i.e. 15-90 min) arterial pressure was lowered by 1-7% and in the long-term studies (i.e. 3 days-5 years) by 6-17%. 4 The degree of cardio-depression induced by the various β-adrenoceptor blockers was inversely correlated with their pharmacologically defined quantity of intrinsic sympathomimetic activity (ISA) both in acute and in long-term studies. 5 In the acute studies the increments in peripheral vascular resistance were directly correlated with the degree of cardio-depression. This suggests that a fall in arterial pressure immediately after administration of a β-adrenoceptor blocker is prevented by increased vasoconstrictor nerve activity mediated through the arterial baroreflex. 6 The compensatory response of vascular resistance to cardio-depression was similar for β1-selective and non-selective blockers, thereby indicating that extra-junctional vascular β-receptors are relatively unimportant for maintaining basal vascular tone. 7 In the long-term studies the correlation between changes in cardiac output and changes in vascular resistance was shifted to a lower level of vascular resistance. This means that the onset of blood pressure reduction during β-adrenoceptor blockade was associated with a fall in vascular resistance at any level of cardiac output. Thus vascular resistance was higher during treatment with a non-ISA-β-adrenoceptor blocker than during treatment with an ISA-β-adrenoceptor blocker. 8 The level of vascular resistance ultimately attained during treatment with the various β-adrenoceptor blockers appears to be inversely related to their effects on plasma renin activity. 9 The concentration of noradrenaline in plasma rose by approximately 30% during treatment with non-ISA-β-adrenoceptor blockers and fell by more than 30% after pindolol. 10 There is evidence that under propranolol, which reduces cardiac output and hepatic blood flow, the plasma noradrenaline clearance is diminished. Since noradrenaline is mainly cleared from the circulation by the lungs and by the liver, and since pindolol has no effect on cardiac output and hepatic blood flow, one may expect the plasma noradrenaline clearance not to be diminished by pindolol. 11 The reported effects of β-adrenoceptor blockers on plasma noradrenaline may indicate that the release of neurotransmitter is diminished, but in the case of non-ISA-β-adrenoceptor blockers this effect is not reflected by a decreased concentration of noradrenaline in plasma, because its clearance is also reduced. 12 The hypotensive effect of β-adrenoceptor blockers appears to be independent of blockade of postjunctional cardiac-β-receptors, juxtaglomerular-β-receptors and extrajunctional vascular β-receptors. This indicates that blockade of β-receptors at other sites (i.e. centrally and/or prejunctionally) is more important.

1 Seven patients with severe orthostatic hypotension due to peripheral autonomic neuropathy were studied. 2 In four patients, heart rate did not change after the β-adrenoceptor antagonists propranolol or metoprolol. After the partial β-adrenoceptor agonist pindolol heart rate rose in a dose-dependent manner. After α-adrenoceptor antagonists phentolamine and yohimbine heart rate and blood pressure did not change, which confirmed that these patients were indeed sympathetically denervated. 3 The non-selective β-adrenoceptor agonist isoprenaline and the β2-selective β-adrenoceptor agonist salbutamol increased heart rate and lowered arterial pressure, whereas the β1-adrenoceptor agonist prenalterol increased both heart rate and arterial pressure. After treatment with pindolol, the patient was desensitized for the chronotropic effects of the β-adrenoceptor agonists in the order: salbutamol > isoprenaline > prenalterol. The desensitization of the depressor effects of the β-adrenoceptor agonists was in the order isoprenaline > salbutamol. These data suggest preferential cardiovascular β2-adrenoceptor sensitization in patients with chronic autonomic failure, which can be reversed by treatment with pindolol. They also provide in vivo evidence for the existence of cardiac chronotropic β2-adrenoceptors in man. 4 The α-adrenoceptor agonists methoxamine, phenylephrine, noradrenaline, clonidine and guanfacine increased arterial pressure. The vascular reactivity for the different α-adrenoceptor agonists differed markedly, as was shown by the declining steepness of the dose-response curves in the order methoxamine and phenylephrine > noradrenaline > clonidine > guanfacine. The pressor profiles of these agonists were also different. These data suggest, that different α-adrenoceptor populations are involved in the contractile responses to these α-agonists, being methoxamine and phenylephrine α1, noradrenaline α1 > α2 and clonidine and guanfacine α2 > α1. 5 Two patients were treated with clonidine, slow release, 250 μg daily, which increased supine and standing arterial pressure and relieved orthostatic symptoms. In one patient the pressor-depressor response to adrenaline was converted to a pure pressor response after clonidine, which contrasted with a pure pressor response to adrenaline after treatment with pindolol. Treatment with clonidine shifted the dose-response curves of the α-adrenoceptor agonists in the order clonidine > noradrenaline > phenylephrine, suggesting preferential α2-adrenoceptor desensitization by clonidine in this patient. 6 These data provide further evidence for the view that α1-β1- and α2-β2-adrenoceptor sensitivity and/or responsiveness are independently regulated and lend support to the hypothesis that peripheral α2-β2-adrenoceptors are not innervated.

1. We attempted to collect information on the metabolism and production of angiotensins (ANG) in different vascular beds in humans by constant i.v. infusion of mono-iodinated [125I]-ANG I into subjects with essential hypertension, at the time of renal vein catheterization as part of the diagnostic work-up for renovascular hypertension. 2. Blood samples were taken from the aorta and the renal, antecubital, femoral and hepatic veins. ANG I, ANG II, [125I]-ANG I and [125I]-ANG II were extracted from plasma, separated by h.p.l.c. and quantitated by radio-immunoassay or gamma counting. 3. Our studies so far are restricted to subjects on captopril 50 mg twice daily. Under ACE inhibition (4-6 h after dosing of captopril) no differences in elimination half-life and regional extraction were found between infused [125I]-ANG and unlabelled ANG I. Extraction of arterially delivered [125I]-ANG I was 80% in the kidney, 45% in the forearm, 58% in the leg and 95% in the hepato-mesenteric vascular bed. 4. Measurements of arterial and venous [125I]-ANG II levels indicated that [125I]-ANG I-II conversion had occurred in the cardio-pulmonary vascular bed. 5. ANG I production in the hepato-mesenteric region could be largely accounted for by the renin activity of circulating plasma, but in kidney and limbs only 20-30% of regionally produced ANG I could be accounted for by plasma renin activity. 6. Thus, a major fraction of regionally produced ANG I appears to be formed locally, i.e. not in circulating plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

1 Dose-dependent increments of plasma noradrenaline were observed during graded infusions of (±)isoprenaline (3.5-35 ng kg-1 min-1 i.v.) in seven normal subjects and in ten subjects with borderline hypertension. At the highest dose of isoprenaline, noradrenaline rose by 166 ± 16 pg/ml in normals and by 169 ± 34 pg/ml in hypertensives (mean ± s.e. mean). 2 In the subjects with borderline hypertension isoprenaline infusions were repeated after 7 days of treatment with (±)propranolol (320 mg/day, divided into 4 doses) and subsequently after 7 days of treatment with (±)atenolol (100 mg/day) 2-3 h after the morning dose of β-adrenoceptor blocker. The dose-response curve for plasma noradrenaline was shifted to higher doses of isoprenaline by a factor of 4 by atenolol and the heart rate response was similarly shifted. The heart rate response was shifted by a factor of 16 by propranolol, but plasma noradrenaline did not change after isoprenaline under propranolol treatment, even when isoprenaline was given at doses high enough to induce increments of heart rate similar to those without β-adrenoceptor blocker treatment. 3 In the subjects with borderline hypertension mean and diastolic intra-arterial pressures fell at the highest dose of isoprenaline by 9 ± 2 and 13 ± 2 mm Hg respectively. These effects were antagonized by propranolol and not by atenolol. 4 The observed rise in plasma noradrenaline after isoprenaline might have been caused by baro-reflex-stimulation of central sympathetic outflow. The isoprenaline-induced decrease in mean arterial pressure, however, was small. Moreover pulse pressure rose and this tends to suppress rather than stimulate baroreflex-mediated sympathetic activity. Activation of presynaptic β-adrenoceptors, allegedly of the β2-subtype, is known to facilitate noradrenaline release upon nerve stimulation of isolated tissues. Our results lend support to the hypothesis that such a facilitatory mechanism is also operative in intact man.