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Evidence for an age-dependent functional expression of α1D-adrenoceptors in the rat vasculature

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Abstract

The role of the α1-adrenoceptor subtypes, and their possible change with maturation, in α1-adrenoceptor-induced pressor responses in the rat has not been established. Thus, the effects of the α1D-, α1A/1D- and α1B/1D-adrenoceptor antagonists, BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl) 8-azaspiro (4.5) decane-7,9-dione 2HCl), 5-methyl-urapidil and chloroethylclonidine, respectively, on the pressor responses induced by phenylephrine in 1- and 5-month-old pithed rats were investigated. The pressor responses induced by phenylephrine were competitively antagonized by both BMY 7378 and chloroethylclonidine in 5-month-old, but not in young immature animals; in marked contrast, 5-methylurapidil antagonized with similar potency the phenylephrine-induced pressor responses in animals of both ages. The present pharmacological data suggest that functional expression of α1D-adrenoceptors in the rat resistance vessels increases with age; α1A-, but not α1B- or α1D-adrenoceptors, seem to predominate in immature animals. These findings represent the first evidence that age-related changes in functional α1-adrenoceptor subtypes occur in the systemic vasculature in vivo. © 1997 Elsevier Science B.V.

Introduction

It is well documented that the responsiveness of vascular smooth muscle to α1-adrenoceptor stimulation changes with age though the precise mechanisms have not been elucidated (Docherty, 1990). In this regard, it has been recently suggested that the age-related alterations in α1-adrenoceptor-mediated vasoconstrictor responses in isolated blood vessels may result from changes in the expression of the α1-adrenoceptor subtypes; thus, functional, radioligand binding and molecular biology studies using rat aortic tissue have demonstrated that with age the expression of the α1A subtype is increased whereas that of the α1B subtype is decreased; the expression of the α1D subtype, however, does not change (Gurdal et al., 1995a, Gurdal et al., 1995b). Though interesting, these results in isolated conduit blood vessels are far from being conclusive as to the role of the α1-adrenoceptor subtypes, and their possible change with maturation, in the responsiveness of the cardiovascular system to α1-adrenoceptor stimulation. On these bases, we investigated the relative contribution of the different α1-adrenoceptor subtypes in the pressor responses induced by phenylephrine in pithed rats, and the role of each subtype with maturation. The results suggest that the functional expression of α1D-adrenoceptors in the resistance vessels of the rat increases with age whilst that of the α1A-adrenoceptor subtype predominates in young immature animals.

Section snippets

Materials and methods

Male Wistar rats of 1 and 5 months of age (n=14 each) were used. After anaesthesia with ether and cannulation of the trachea, the rats were pithed, artificially respired using an Ideal Palmer pump (56 cycles/min; volume: 20 ml/kg), and bilaterally vagotomized. Catheters were placed in the right femoral vein and the left carotid artery for drug administration and recording of diastolic blood pressure and heart rate, respectively; the carotid cannula was connected to a TXD-300 pressure transducer

Results

Baseline values of diastolic blood pressure and heart rate in 1- and 5-month-old pithed animals (n=14 each) were 33±2 mm Hg and 245±7 beats/min and 36±1 mm Hg and 292±4 beats/min, respectively. Although these values remained unmodified 15 min after administration of either saline, BMY 7378 or 5-methylurapidil, and 60 min after chloroethylclonidine, all the antagonists produced immediate pressor responses. In the case of chloroethylclonidine, this response was particularly prominent and

Discussion

The present results demonstrate, for the first time, that the age-dependent changes in vascular smooth muscle responsiveness to α1-adrenoceptor stimulation do occur in the systemic vasculature in vivo. Consistent with previous investigations in both conscious (Piascik et al., 1990) and pithed (Schwietert et al., 1992) rats, the relatively selective α1A-adrenoceptor antagonist, 5-methylurapidil (Hieble et al., 1995), which also shows relatively high affinity for the α1D-adrenoceptor subtype (

Acknowledgements

Supported in part by grant 5110-M9406 from CONACYT.

References (15)

  • Buckner, S.A., Oheim, K.W., Morse, P.A., Knepper, S.M., Hancock, A.A., 1996. α1-Adrenoceptor-induced contractility in...
  • Docherty, J.R., 1990. Cardiovascular responses in ageing: a review. Pharmacol. Rev. 42,...
  • Forray, C., Bard, J.A., Wetzel, J.M., Chiu, G., Shapiro, E., Tang, R., Lepor, H., Hartig, P.R., Weinshank, R.L.,...
  • Goetz, A.S., King, H.K., Ward, S.D.C., True, T.A., Rimele, T.J., Saussy Jr., D.L., 1995. BMY 7378 is a selective...
  • Gurdal, H., Cai, G., Johnson, M.D., 1995a. α1-Adrenoceptor responsiveness in the aging aorta. Eur. J. Pharmacol. 274,...
  • Gurdal, H., Tilakaratne, N., Brown, R.D., Fonseca, M., Friedman E., Johnson, M.D., 1995b. The expression of...
  • Hieble, J.P., Bylund, D.B., Clark, D.E., Eikenburg, D.C., Langer, S.Z., Lefkowitz, R.J., Minneman, K.P., Ruffolo Jr.,...
There are more references available in the full text version of this article.

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