The aim of this study was to study the changes in the structure and function of the SAN during ageing. Right atrial preparations from male Wistar-Hanover rats aged 3 and 24?months (equivalent to young adult and ??69-year-old humans, respectively ) were used. SAN function was studied using extracellular potential and intracellular action potential recording. Protein and mRNA expression was studied using immunohistochemistry and quantitative PCR (qPCR), respectively. Collagen protein was studied using Picro Sirius red staining. The methods are described Transducin
in full in the Data Supplement. Old animals were heavier than young animals and their hearts were also heavier (Data Supplement, Fig. S1). However, there was a significant decrease in the heart-to-body weight ratio (Data Supplement, Fig. S1). In the anaesthetised rat, the normal heart rate is not significantly different between young and old animals (aged 3 and 25?months) . The normal heart rate is set by the autonomic nervous system, and therefore, it is important to measure the intrinsic heart rate. This was measured in isolated right atrial preparations (using extracellular potential recording from dorsal epicardial surface). The intrinsic heart rate in old animals was slower (i.e. spontaneous cycle length was longer) than in young animals (Data Supplement, Fig. S1). The spontaneous cycle length was 297?��?9?ms (n?=?7) in young animals and 351?��?13?ms (n?=?6) in old animals (t test; P?<?0.05). The age-dependent decline in SAN function has been suggested to be the result of a decline in INa (see Introduction). This is a possibility, because <a href="http://www.selleckchem.com/products/gsk126.html
">www.selleckchem.com blockade of INa can slow pacemaking and familial sick sinus syndrome has been linked to mutations in Nav1.5 (main ion channel responsible for INa), although paradoxically there is little or no INa and Nav1.5 in the centre of the SAN . Another possibility see more
is that it is the result of a decline in the funny current, If, because blockade of If slows pacemaking and familial sick sinus syndrome has also been linked to mutations in HCN4 (main ion channel responsible for If) ; If and HCN4 are present in the SAN . To test these possibilities, the effect of blockade of Nav1.5 and HCN4 on the spontaneous activity of right atrial preparations was investigated��if the age-dependent decrease in the intrinsic heart rate is the result of a decline in either INa or If, blockade of the corresponding ion channel should have a smaller effect on the heart rate in the older animal. TTX was used to block Nav1.5. ��Neuronal Na+ channels��, such as Nav1.1, which have a high sensitivity to TTX, as well as the cardiac Na+ channel, Nav1.5, which has a low sensitivity to TTX, are responsible for INa . Blockade of neuronal Na+ channels by 100?nM TTX caused small changes in cycle length (significantly different in young and old preparations; Fig. 1).