Angiotensin II-mediated vasodilation is reduced in adult spontaneously hypertensive rats despite enhanced expression of AT2 receptors

1. The vasodilator action of angiotensin (Ang) II has not yet been demonstrated in spontaneously hypertensive rats (SHR), nor have any possible changes in this response during the development of hypertension. 2. In the present study, the vasodilator effect of AngII was evaluated in the rat isolated, preconstricted mesenteric arterial bed (MAB) from 6- (young) and 24-week-old (adult) SHR and compared with effects on MAB from age-matched normotensive rats (control). 3. Angiotensin II (10-300 nmol) induced vasodilation in noradrenaline (NA)-preconstricted MAB that was greater in vessels from young compared with adult rats in both the control and SHR groups. Angiotensin II-induced vasodilation was reduced by the angiotensin AT(2) receptor antagonist PD 123319 (10 micromol/L), the angiotensin-(1-7) receptor antagonist A779 (1 micromol/L) and the bradykinin B(2) receptor antagonist HOE-140 (0.01 micromol/L), but not by the AT(1) receptor antagonist losartan (30 micromol/L). Expression of AT(2) receptors was weak in vessels from adult control rats compared with that in young control rats, whereas in young SHR AT(2) receptor expression was increased compared with that in young control rats. This increased expression of AT(2) receptors was maintained in adult SHR and there was no significant difference in AT(2) receptor expression between young and old SHR. 4. The findings of the present suggest that AngII induces an AT(2) receptor-mediated vasodilator effect in the MAB via activation of angiotensin-(1-7) and bradykinin receptors, an action that is reduced in adult control rats and adult SHR. In adult control rats, the attenuated response of AngII is probably due to endothelial dysfunction and reduced expression of AT(2) receptors, whereas in adult SHR it is associated with endothelial dysfunction alone. Increased expression of AT(2) receptors in SHR may represent a counteracting response for modulating blood pressure.     

Effects of cytokines on contractile and dilator responses of airway smooth muscle

1. Increased bronchoconstrictor responses to contractile agonists and decreased dilator responses to beta-adrenoceptor agonists are characteristics of human asthma. One explanation for these features of asthma is that cytokines released in the asthmatic airway have direct effects on airway smooth muscle cells that alter their phenotype. 2. The present review summarizes data indicating that inflammatory cytokines, such as interleukin (IL)-1 beta and tumour necrosis factor-alpha, T helper (h) 1 cytokines, such as interferon-gamma, and Th2 cytokines, such as IL-13 and IL-5, have the capacity to enhance contractile responses and/or decrease relaxant responses of airway smooth muscle. These effects are observed in smooth muscle from human airways and airway smooth muscle of other species. 3. Understanding the mechanistic basis for the effects of these cytokines may prove to be an important step in improving the efficacy of beta-adrenoceptor agonists for the treatment of asthma.     

A prospective study of the effects of prolonged timolol therapy on α- and β-adrenoceptor and angiotensin II receptor mediated responses in normal subjects

Aims Long-term treatment with β₁-selective adrenergic antagonists gives rise to cross-sensitisation of cardiac β₂-adrenoceptor responses, with no corresponding alteration in β₁-adrenoceptor responses. We performed a prospective randomised double-blind placebo-controlled cross-over study of the effects of nonselective β-blockade with timolol on α-adrenergic and angiotensin II receptor mediated responses in normal subjects. We also wished to study the time course of β₁- and β₂-adrenergic responses after withdrawal of timolol. Methods Six healthy males received timolol 10 mg twice daily or placebo for 14 days. On day 11 of treatment, vascular α₁-, α₂- and angiotensin II receptor responses were assessed by measuring the blood pressure increases in response to intravenous phenylephrine, α-methylnoradrenaline and angiotensin amide respectively, following one dose of timolol 10 mg (to block the β-adrenergic effects of phenylephrine and α-methylnoradrenaline). Both systolic and diastolic blood pressure increased in response to each of these drugs, but these increases were not different on timolol treatment or placebo. Following cessation of treatment with timolol or placebo, β₁- and β₂-adrenoceptor mediated responses were assessed by measuring the heart rate responses to treadmill exercise and intravenous salbutamol infusion respectively. Half each of the subjects underwent this 2 days and 3 days respectively, after the end of treatment. Results Both exercise-induced and salbutamol-induced tachycardia were not different following placebo or 3 days following the end of timolol treatment. However, 2 days following timolol treatment, both were attenuated; the reduction in salbutamol-induced tachycardia was significant, whilst the reduction in exercise tachycardia did not reach statistical significance. We also measured metabolic responses to exercise and to salbutamol infusion. Exercise induced a rise in plasma potassium and noradrenaline. Salbutamol produced a fall in plasma potassium, a rise in plasma glucose and insulin and also a rise in plasma noradrenaline. All of these changes were not different following placebo or 3 days after the end of timolol treatment; by contrast, 2 days following timolol treatment, all were significantly attenuated, with the exception of the rise in plasma glucose. In addition, the rise in both plasma glucose and insulin in response to an oral load of 75 g glucose were not different post-placebo, 2 or 3 days post-timolol. Conclusions These results show that, following 14 days of nonselective β-adrenoceptor blockade with timolol, there is evidence of residual β-adrenoceptor blockade 2 days after drug withdrawal; this finding is in contrast with the known plasma profile of timolol (half-life 3–6 hours), but is consistent with our previous observations of the slow speeds of association and dissociation of timolol with β-adrenoceptors in vitro. There is no evidence, in this study, of β-adrenergic sensitisation following timolol withdrawal, nor of cross-regulation of vascular α₁-, α₂- or angiotensin II receptors in response to nonselective β-adrenoceptor blockade.     

Cytokine regulation of Group II phospholipase A2 expression in glomerular mesangial cells

Phospholipase A₂ (PLA₂) is believed to play an essential role in inflammatory processes by releasing arachidonic acid from membrane phospholipids for synthesis of important lipid mediators, such as prostaglandins, leukotrienes and platelet activating factor.We have used glomerular mesangial cells as a model system to study the regulation of PLA₂ under inflammatory conditions. Potent pro-inflammatory cytokines, such as interleukin 1 (IL-1) and tumour necrosis factor (TNF), as well as agents that increase cellular cAMP levels have been found to increase Group II PLA₂ gene expression in a time- and dose-dependent manner.