Loss of maximum attenuation and receptor reserve for isoprenaline at the beta 2-adrenoceptors of the portal veins of hypertensive rats.

OBJECTIVE: To test the hypothesis that vascular beta 2-adrenoceptor hyporesponsiveness in spontaneously hypertensive rats (SHR) is not induced by increased blood pressure or venous hypertrophy. DESIGN: We compared the attenuating effects or isoprenaline, sodium nitroprusside and verapamilon the portal veins from Wistar-Kyoto (WKY) rats and SHR. studied the effects of slowly reversible beta-adrenoceptor antagonists, bromoacetylalprenololmenthane (BAAM) and ICI 147798, on the isoprenaline responses in order to determine the affinity and fractional beta 2-adrenoceptor occupancy-response relationships for isoprenaline. RESULTS: The SHR portal veins did not develop hypertrophy. There was a small reduction in the sensitivity to isoprenaline and a marked reduction in the maximum attenuation of hypertension caused by isoprenaline. The sensitivity and efficacy of sodium nitroprusside and verapamil were not altered by hypertension. BAAM and ICI 147798 inhibited the isoprenaline responses and reduced the maximum attenuation to isoprenaline. In the WKY rat portal vein the dissociation constant (KA) values for isoprenaline were independent of BAAM concentration, and was 1.78 +/- 0.32 x 10(-7) mol/l. Similar isoprenaline KA values were obtained from the ICI 147798 data and in the SHR portal vein. In the WKY rat portal vein, from the BAAM data, it was calculated that isoprenaline produced 50, 95 and 100% maximum responses by occupying 6 +/- 1, 20 +/- 3 and 43 +/- 5% (n = 21) of the available beta 2-adrenoceptors, respectively. Similar occupancy-response relationships were obtained in the WKY rat portal vein from the ICI 147798 data. At each level of isoprenaline response the receptor reserve was significantly smaller in the SHR than it was in the WKY rat portal vein. Thus, from the BAAM data, isoprenaline produced 50, 95 and 100% maximum responses by occupying 14 +/- 3, 33 +/- 6 and 58 +/- 7% (n = 15) of the available SHR portal vein beta 2-adrenoceptors, respectively. CONCLUSIONS: The SHR portal vein displays a selective beta 2-adrenoceptor hyporesponsiveness in the absence of a raised blood pressure or hypertrophy. This beta 2-adrenoceptor-associated hyporesponsiveness consisted of a marked loss of maximum attenuation in response to isoprenaline and of beta 2-adrenoceptor reserve for isoprenaline responses.

Functional beta-adrenoceptors in the left atrium of normotensive and hypertensive rats.

1. The aim of the study was to characterize the functional beta 1-and beta 2-adrenoceptors of the rat left atrium and to investigate how these functional beta-adrenoceptor responses were altered in hypertension. The contractile responses of the left atrium from Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats to isoprenaline, T-0509 and procaterol were characterized. Subsequently, the effects of selective beta 1-(bisoprolol) and beta 2 (ICI 118,551)-adrenoceptor antagonists were investigated on these responses. 2. The maximal combined contractile responses of the rat left atrium to cardiac stimulation and CaCl2, isoprenaline, T-0509 or procaterol were not altered by hypertension. 3. The sensitivities to CaCl2 (pD2 on WKY left atrium = 2.99), isoprenaline (8.82) and T-0509 (8.84) were not altered by hypertension. There was an increase in sensitivity to procaterol from a pD2 value of 7.21 to 7.61 in the left atrium of the SH rat. 4. The basal tension induced by cardiac stimulation alone was inhibited by bisoprolol at > or = 10(-8) M and by ICI 118,551 at > or = 10(-7) M and this inhibitory effect is probably due to membrane stabilizing activity. 5. The pKB values for bisoprolol against isoprenaline, T-0509 and procaterol on the WKY were 8.43, 8.68 and 8.18, respectively, and were not different from SH rat left atrium. 6. The pKB value for ICI 118,551 against isoprenaline was increased from 7.06 on the WKY to 7.44 on the SH rat left atrium. The pKB values for ICI 118,551 against T-0509 and procaterol on the WKY were 7.18 and 8.14, respectively and were not significantly different from the SH rat left atrium values. 7. These results suggest that: (a) procaterol stimulates the beta 1-, in addition to, the beta 2-adrenoceptors of the rat left atrium; (b) functional beta 1-adrenoceptors are not altered in hypertension, and (c) there is probably an increase in the affinity of procaterol and isoprenaline for the beta 2-adrenoceptors which underlies the small increase in the functional beta 2-adrenoceptor response in hypertension.

Alprenolol and bromoacetylalprenololmenthane are competitive slowly reversible antagonists at the beta 1-adrenoceptors of rat left atria.

We studied the effects of alprenolol and bromoacetylalprenololmenthane (BAAM) on rat left atria. Alprenolol and BAAM at 10(-7), 3 x 10(-7), and 10(-6) M inhibited the cardiac stimulation response slightly, which is indicative of membrane-stabilizing activity independent of beta-adrenoceptor blockade. This membrane-stabilizing activity was readily reversible. Alprenolol and BAAM also caused surmountable antagonism of isoprenaline responses, and this beta 1-adrenoceptor antagonism was slowly reversible. Inhibition of the isoprenaline responses with alprenolol and BAAM at 10(-6) M was at equilibrium after 60 min, which is indicative of reversible antagonism. We conclude that alprenolol and BAAM are competitive slowly reversible beta 1-adrenoceptor antagonists on rat left atria.

Characterization of the antagonism with metoprolol, ICI 147,798, pindolol, mepindolol and bopindolol on the responses of the rat left atria to isoprenaline.

The aim of the study was to determine whether the antagonism with pindolol, mepindolol and bopindolol at the beta 1-adrenoceptor of the rat left atria, a tissue with plenty of spare beta 1-adrenoceptors for isoprenaline maximum responses, was readily reversible or not. The effects of these drugs were compared to those of metoprolol, a readily reversible, and of ICI 147,798, an irreversible beta-adrenoceptor antagonist. Metoprolol at 10(-7) and 10(-6) M, ICI 147,798, pindolol, bopindolol (all at 10(-8) and 10(-7) M) and mepindolol at 10(-9) and 10(-8) M inhibited the cardiac stimulation responses to a small extent, which is indicative of membrane stabilizing activity, and also caused surmountable antagonism of isoprenaline responses. The inhibitory effects on the isoprenaline responses of metoprolol and pindolol were readily reversible, that of mepindolol was slowly reversible and those of ICI 147,798 and bopindolol were not reversed in 3 h. The inhibitory effects on isoprenaline responses of metoprolol at 10(-6) M, pindolol and bopindolol at 10(-7) M and mepindolol at 10(-8) M were at equilibrium, which is indicative of reversible, whereas the inhibitory effects of ICI 147,798 were increased, which is indicative of irreversible antagonism, when the beta-blocker treatment time was increased from 1 to 2 h. We conclude that the antagonism with pindolol at the beta 1-adrenoceptors of the rat left atria is readily reversible, that of mepindolol is slowly reversible and that of bopindolol is very slowly reversible.