Caveolin-1, an integral protein of caveolae, is associated with multiple cardiovascular signalling pathways. Caveolin-1 knockout (KO) mice have a reduced lifespan. As changes in artery structure and function are associated with ageing we have investigated the role of caveolin-1 ablation on age-related changes of small artery contractility and passive mechanical properties. Mesenteric small arteries isolated from 3 and 12-month wild-type (WT) and caveolin-1 KO mice were mounted on a pressure myograph and changes in passive and functional arterial properties were continuously monitored. In WT mice ageing was associated with a reduction in arterial contractility to noradrenaline which was reversed by inhibition of nitric oxide synthase with L-NNA. Similarly, in 3-month-old mice, caveolin-1 KO reduced contractility to noradrenaline by an L-NNA-sensitive mechanism. However, ageing in caveolin-1 KO mice was not associated with any further change in contractility. In WT mice ageing was associated with an increased passive arterial diameter and cross-sectional area (CSA), consistent with outward remodelling of the arterial wall, and a reduced arterial distensibility. Caveolin-1 ablation at 3 months of age resulted in similar changes in passive arterial properties to those observed with ageing in WT animals. However, ageing in caveolin-1 KO mice resulted in a reduced arterial CSA indicating different effects on passive structural characteristics from that observed in WT mice. Thus, caveolin-1 mice show abnormalities of small mesenteric artery function and passive mechanical characteristics indicative of premature vascular ageing. Moreover, caveolin-1 ablation modulates the age-related changes usually observed in mesenteric arteries of WT mice.

Background and purpose: The internal anal sphincter has been shown to contract in response to a 1 -adrenoceptor stimulation and therefore a 1 -adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the a 1 -adrenoceptor subtype responsible for mediating contraction of the internal anal sphincter of the pig. Experimental approach: The potency of agonists and the affinities of several receptor subtype selective antagonists were determined on smooth muscle strips for the pig internal anal sphincter. Cumulative concentration-response curves were performed using phenylephrine and noradrenaline. Key results: The potency of the a 1A -adrenoceptor selective agonist A61603 (pEC 50 ¼ 7.79±0.04) was 158-fold greater than that for noradrenaline (pEC 50 ¼ 5.59 ± 0.02). Phenylephrine (pEC 50 ¼ 5.99 ± 0.05) was 2.5-fold more potent than noradrenaline. The a 1D -adrenoceptor selective antagonist BMY7378 caused rightward shifts of the concentration-response curves to phenylephrine and noradrenaline, yielding low affinity estimates of 6.59 ± 0.15 and 6.33 ± 0.13, respectively. Relatively high affinity estimates were obtained for the a 1A -adrenoceptor selective antagonists, RS100329 (9.01±0.14 and 9.06±0.22 with phenylephrine and noradrenaline, respectively) and 5-methylurapidil (8.51 ± 0.10 and 8.31 ± 0.10, respectively). Prazosin antagonized responses of the sphincter to phenylephrine and noradrenaline, yielding mean affinity estimates of 8.58±0.10 and 8.15 ± 0.08, respectively. The Schild slope for prazosin with phenylephrine was equal to unity (1.01 ± 0.24), however the Schild slope using noradrenaline was significantly less than unity (0.50±0.11, Po0.05). Conclusion and implications:The results suggest that contraction of circular smooth muscle from the pig internal anal sphincter is mediated via a population of adrenoceptors with the pharmacological characteristics of the a 1A/L -adrenoceptor, most probably the a 1L -adrenoceptor form of this receptor.

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