Elsevier

Life Sciences

Volume 78, Issue 6, 2 January 2006, Pages 592-597
Life Sciences

Effect of chronic exposure to cold on isoprenaline-induced cAMP accumulation and relaxation in the rat aorta

https://doi.org/10.1016/j.lfs.2005.05.092Get rights and content

Abstract

Rats chronically exposed to cold (5 °C for 5 weeks) develop hypertension. Isoprenaline-induced vascular smooth muscle relaxation is increased in these animals. Our main objective was to compare isoprenaline-induced relaxation of aortae isolated from control and cold-acclimated rats and attempt to relate the differences to changes in receptor parameters (affinity and reserve) and signaling mechanisms. Isoprenaline (10 9–10 5 M)-induced relaxation was enhanced significantly (p < 0.05) in aorta segments from cold-acclimated rats. There was a significant (p < 0.05) increase in the potency of isoprenaline but with no change in affinity. Isoprenaline produced 50% of the maximum response while occupying about 50% and about 15% of the receptors in isolated rat aorta segments from control and cold-treated rats, respectively. Forskolin and db-cAMP also concentration-dependently relaxed aorta segments from control and cold-acclimated rats. There was no difference in potency or maximum response to forskolin (which directly activates adenylyl cyclase) and db-cAMP. cAMP concentrations in the presence of isoprenaline were significantly (p < 0.05) higher in aorta segments from rats chronically exposed to cold when compared with aorta segments from control rats. These findings suggested that altered mechanisms upstream of activation of adenylyl cyclase are involved in the increased β-adrenoceptor-induced relaxation.

Introduction

Rats chronically exposed to cold temperature develop hypertension, tachycardia and cardiac hypertrophy (Fregly et al., 1989, Papanek et al., 1991). These rats showed greater metabolic, cardiac and vascular responsiveness to noradrenaline and β-adrenergic agonists. For example, Wickler et al. (1984) have shown that isoprenaline, a β-adrenergic agonist, greatly increased blood flow to brown fat, cardiac and skeletal muscles in cold-adapted rats. Fregly et al. (1977) reported that isoprenaline-induced increase in tail skin and colonic temperature was greater in cold-adapted rats compared with rats maintained at room temperature. Similar observations have been made by other workers (Evonuk and Hannon, 1963, Depocas, 1960, Himms-Hagen, 1969, Jansky et al., 1967). Increased responsiveness to β-adrenergic agonists has also been observed in other systems. Isoprenaline-induced increase in heart rate is significantly greater in cold-acclimated rats (Barney et al., 1980, Fregly et al., 1977, Miller et al., 1979). In the vasculature, isoprenaline induced greater relaxation in arterial smooth muscles from cold-adapted rats (Bryar et al., 1983) compared with control rats maintained at room temperature. The fact that β-adrenoceptor blockade with propranolol enhanced the maximal contactile response to noradrenaline more in cold-acclimated rats (Bryar et al., 1983) would confirm greater β-adrenoceptor-mediated vascular smooth muscle relaxation in rats chronically exposed to cold temperature.

However, the mechanism responsible for the increased responsiveness to β-adrenoceptor activation was not addressed in any of the studies cited above (Fregly et al., 1977, Fregly et al., 1989, Wickler et al., 1984, Papanek et al., 1991, Evonuk and Hannon, 1963, Depocas, 1960, Himms-Hagen, 1969, Jansky et al., 1967, Bryar et al., 1983). Even though Bryar et al. (1983) suggested that cold acclimation could alter the biochemical events coupling receptor activation to response, no experimental data were provided to support this hypothesis. Stimulation of β-adrenoceptors on vascular smooth muscle results in relaxation, through activation of membrane-bound adenylyl cyclase. This results in an increase in cAMP with subsequent increase in activation of cAMP-dependent protein kinases (Anderson and Wilsson, 1977, Hardman, 1981, Krall et al., 1983). Increase in β-adrenoceptor activity could occur as a result of changes in pre-receptor (affinity and/or density) or post-receptor signaling mechanisms. Our main objective in this study was to compare isoprenaline-induced relaxation of isolated rat aorta from control and cold-acclimated rats and attempt to relate the differences to changes in receptor parameters (affinity and reserve) and signaling mechanisms.

Section snippets

Methods

Male Sprague–Dawley rats approximately 100 g were kept (1 rat per cage) in the cold room (5 °C) for a period of 5 weeks while age-matched littermates kept at room temperature (25 °C) served as controls. Rats in both groups were fed ad libitum and had access to water throughout the duration of the study. The study was approved by the Institutional research committee.

At the end of 5 weeks, each rat was anaesthetized with pentobarbital (sagatal, 50 mg/kg). Thereafter, one carotid artery was

Effect of cold exposure on arterial blood pressure

Chronically exposed rats to cold temperature (5 °C) for weeks developed hypertension. Arterial blood pressure was 119.4 ± 6.3 (n = 9) and 145.8 ± 11.5 (n = 6) in control and cold-treated rats, respectively. These values were significantly (p < 0.05) different from each other.

Effect of cold exposure on agonist-induced relaxations

Isoprenaline (10 9–10 5 M) produced reproducible concentration-dependent relaxation of the isolated rat aorta from control rats as well as rats chronically exposed to cold (Fig. 1). Tachyphylaxis was not observed in any of the

Discussion

Impaired β-adrenoceptor-mediated vascular smooth muscle relaxation is an established feature of hypertension. This has been demonstrated in humans (Brodde et al., 1987, Feldman, 1987, Michel et al., 1990) and various animal models (Feldman, 1987, Michel et al., 1990, Brodde and Michel, 1992) of hypertension. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats and SHR, it has been shown that the facilitatory action of presynaptic β2-adrenoceptors was enhanced, while the number and

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