Abstract
Introduction & objectives
The RhoA/Rho-kinase pathway is important in the normal physiology and pathophysiology of the cardiovascular system, and has become a potential therapeutic target for cardiovascular disorders. In particular, Rho-kinase inhibitors are under investigation as an approach to target vascular smooth muscle tone in the treatment of hypertension, a disorder more common with ageing. The aim of the present study was to investigate whether the role of the Rho-kinase pathway in arterial smooth muscle contractility varies across vascular beds and with ageing.
Methods
Isolated rings of vesical, mesenteric, renal and pulmonary artery from young (6 month) and older (3 years) pigs were mounted in gassed Krebs-bicarbonate solution at 37°C. Arterial rings were contracted with cumulative concentrations of the alpha1-adrenoceptor agonist phenylephrine and the inhibitory effects of the Rho-kinase inhibitor Y-27632 (10μM) were compared.
Results
Maximal contractile responses of vesical arteries from older pigs to phenylephrine were significantly reduced compared to those from young pigs (270.3±81 vs 466.8±8 g/g tissue, p<0.05). Potency of phenylephrine was also reduced (pEC50: 4.9±0.2 vs 5.8±0.1, p<0.05). Age did not affect maximal responses to phenylephrine in mesenteric, renal or pulmonary arteries, although potency of phenylephrine was increased in mesenteric arteries from old pigs vs young (pEC50 5.4±0.1 vs 4.8±0.1, p<0.001) and decreased in renal arteries from old pigs (pEC50 5.7±0.1 vs 6.6±0.1, p<0.001). Y-27632 inhibited maximal phenylephrine contractions in all artery types. Whilst age did not alter the inhibitory effects of Y-27632 on contractions of renal (81.9±3.7% vs 76.9±3.6% inhibition, old vs young) and pulmonary arteries (96.3±3.7% vs 91.5±4.5%), Y-27632 produced significantly less inhibition of contraction in mesenteric arteries from older pigs vs young (68.1±9.9% vs 97.4±1.4%). In contras, in vesical arteries less inhibition was observed in arteries from young pigs vs old (53.3±6.2% vs 83.1±3.1%).
Conclusion
These results show that ageing has differential effects on alpha1-adrenoceptor mediated vasoconstriction of arteries in different porcine vascular beds and on the contribution of the rho-kinase pathway to calcium sensitisation and smooth muscle tone. These age-related changes should be a consideration when investigating the potential use of rho-kinase inhibitors for the treatment of vascular disorders such as hypertension.
