Cross-talk Between Cardiacκ-Opioid andβ-Adrenergic Receptors in Developing Hypertensive Rats

Theκ-opioid receptor exerts a negative modulatory action on theβ-adrenoceptor and the action is blunted in adult spontaneously hypertensive rats (SHR). In order to determine whether the blunted negative modulation of theβ-adrenoceptor by theκ-opioid receptor contributes to the development of hypertension, the electrically induced intracellular calcium ([Ca2+]i) transient was measured in single ventricular myocytes of SHR at 4, 6, 8 and 13-week-old and the age-matched Wistar Kyoto (WKY) rats. The electrically induced [Ca2+]itransients were augmented by norepinephrine (NE), aβ-adrenoceptor agonist, over four-fold in WKY rats of all ages studied and in SHR of 4 and 6 weeks of age. The enhancing effect of NE in 8- and 13-week-old SHR was, however, only approximately three-fold, significantly lower than the corresponding values in age-matched WKY rats. Similarly, the electrically induced [Ca2+]itransients were also augmented by forskolin, an activator of adenylate cyclase, by approximately two-fold in WKY rats of all ages and SHR aged 4 and 6 weeks. In SHR aged 8 and 13 weeks, the effect of forskolin was only 1.5-fold, significantly lower than the two-fold increase in the corresponding WKY rats. The enhancing effects of NE and forskolin were attenuated by U50,488H, a selectiveκ-opioid agonist, by approximately 50 and 25%, respectively, in both types of rats of all ages studied, with the exception of 13-week-old rats. In rats of this age group, the attenuations by U50,488H on the enhancing effects of NE and forskolin were 17 and 9% in SHR, respectively, significantly less than the corresponding 54 and 29% in WKY. The fact that attenuation of U50,488H on the enhancing effects of NE and forskolin only occurs in 13-week-old SHR when hypertension has been fully developed indicates that the attenuated inhibitory modulation ofκ-opioid receptor stimulation does not contribute to the initiation of hypertension. Interestingly, the enhancing effects of NE and forskolin on the electrically induced [Ca2+]itransient was attenuated in SHR aged from 8 weeks when the blood pressure was rapidly increasing. The different time courses of altered responses to U50,488H, and NE and forskolin suggest that the attenuated negative modulation ofκ-receptor stimulation on theβ-adrenergic receptor is not due to the signal transduction pathway activated byβ-adrenergic stimulation. In 13-week-old SHR with the arterial blood pressure restored to normal by pharmacological manipulations, the blunted responses to NE, U50,488H and forskolin still occurred, indicating that the altered responses to activation ofβ-adrenergic andκ-opioid receptors and adenylate cyclase are not secondary to hypertension.