Loss of maximum attenuation and receptor reserve for isoprenaline at the beta2-adrenoceptors of the portal veins of hypertensive rats

Journal of Pharmacy and Pharmacology

2002

The objective of this study was to determine the responsiveness, affinity constants and beta-adrenoceptor reserves for isoprenaline on the isolated aorta in the maturation of normotensive and hypertensive rats. The effects of a very slowly reversible antagonist, bromoacetylal-prenololmenthane (BAAM), on the relaxant responses of the aortae of 5- and 14-week-old Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) to isoprenaline were determined. Five-week-old SHRs are pre-hypertensive and the aortic rings are less responsive to isoprenalinethan age-matched WKY (pD2 values: WKY, 8.40; SHRs, 8.03). Similar relaxant responses to forskol in were obtained on the aortae of 5- and 14-week-old WKY and SHRs. The K(A) value for isoprenaline at the aortic beta2-adrenoceptors of the 5-week-old WKY was 2.1 x 10(-7) M, and similar values were obtained on the aortae of 5-week-old SHR and 14-week-old WKY and SHRs. In the maturation of the WKY aortae from 5 to 14 weeks, there was a reduction in the maximum response, a major loss of sensitivity and a loss of beta2-adrenoceptor reserve for isoprenaline. On 5-week-old SHR aorta, the sensitivity to isoprenaline was 2.5-fold lower, and the beta2-adrenoceptor reserve was less than on age-matched WKY. In the development of hypertension on the SHR aorta from 5 to 14 weeks, there was a reduction in the maximum response to isoprenaline. At 14 weeks, the sensitivity and the beta-adrenoceptor reserve to isoprenaline were similar, but the maximum responses were lower on the SHR than WKY. As there are differences in pre-hypertensive SHR and age-matched WKY aortic responses to isoprenaline, it is no longer valid to consider that the loss of responsiveness to isoprenaline in hypertension is solely owing to the hypertension. There are no changes in affinity, but major changes in the sensitivity, maximum responses and aortic beta2-adrenoceptor reserves to isoprenaline in the maturation of normotensive and pre-hypertensive aortae.

Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Responsiveness, affinity constants and β-adrenoceptor reserves for isoprenaline on aortae from normo-, pre-and hypertensive rats

Chen

Journal of Pharmacy and Pharmacology

2002

“…There have been few attempts to determine the KA values of isoprenaline at PIor P2-adrenoceptors using contractility studies with irreversible b-adrenoceptor antagonists, probably because many of the previous antagonists tested have had other actions. We have previously used irreversible antagonists to determine isoprenaline KA values of approximately lop6 M for isoprenaline at PIand P2-adrenoceptors on cardiovascular tissues, including the left atrium from Wistar rats bred in Auckland (Wistar Auckland rats) (Doggrell 1990;Doggrell & Surman 1995;Doggrell et a1 1997). Consistent with these previous findings, we now report KA values of approximately 10p6M for the action of isoprenaline on the left papillary muscles from WKY and SHR.…”

Section: Discussionmentioning

confidence: 99%

“…The second part of the study was to determine the KA values and receptor occupancy-response relationships for isoprenaline on cardiac tissue when the SHR were in the early stages of established hypertension-induced hypertrophy by studying the effects of two very slowly reversible P-adrenoceptor antagonists, bromoacetylalprenololmenthane (BAAM) and ([3,5-diamino-6-chloro-N-( 1 [N-P-(2hydroxyl-3 -a-naphthoxypropy 1amino)ethylcarbamoyll-1 -methylethyl)pyrazine-2-carboxamide {ICI 147 798), on the isoprenaline responses of the left ventricular papillary muscles and atria of 6-monthold WKY and SHR. We have previously used BAAM and ICI 147 798 to determine isoprenaline KA values (Doggrell & Surman 1995). A preliminary account of the current data has been published elsewhere (Doggrell et a1 1995).…”

mentioning

confidence: 99%

Affinity Constants and β-Adrenoceptor Reserves for Isoprenaline on Cardiac Tissue from Normotensive and Hypzrtensive Rats

Journal of Pharmacy and Pharmacology

Petcu

Barnett

1998

To determine whether there are differences in cardiac beta-adrenoceptor responsiveness, isoprenaline affinity constants and fractional beta-adrenoceptor occupancy-response relationships for isoprenaline in the early stages of established hypertension, we studied the effects of bromoacetylalprenololmenthane (BAAM) and ([3,5-diamino-6-chloro-N-(1[N-beta-(2-hydroxyl-3-alpha-naphthoxypropy lamino)ethylcarbamoyl]-1-methylethyl)-pyrazine-2-carboxamide (ICI 147 798), slowly reversible beta-adrenoceptor antagonists, on the isoprenaline responses of the left ventricular papillary muscle and the left and right atria of 6-month-old Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The papillary muscles, but not the right and left atria, of the SHR were less responsive to isoprenaline than those of the WKY. The isoprenaline pD2 values (the negative logarithms of the molar concentrations of agonist producing 50% of the maximum response) were 7.72 and 8.00 on the SHR and WKY papillary muscles, respectively. On the WKY papillary muscle the isoprenaline KA values were 2-3 x 10(-6) M, which is as expected for isoprenaline at beta1 or beta2-adrenoceptors. Isoprenaline had 100-fold greater affinity on the WKY and SHR left atria than on the papillary muscles; the isoprenaline KA values were 2-4 x 10(-8) M. On the WKY papillary muscle and left atrium, isoprenaline had to occupy 3-4% of the beta-adrenoceptors to produce a 50% maximum response; on the WKY papillary muscle and left atrium isoprenaline had to occupy 25-35% and 55%, respectively, of the beta-adrenoceptors to produce a 90% maximum response. The SHR papillary muscles and left atrium had smaller beta-adrenoceptor reserves for isoprenaline than did the WKY tissues. We were unable to obtain isoprenaline KA values on the WKY right atrium. The isoprenaline KA value on the SHR right atrium was 1-4 x 10(-8) M. Because the isoprenaline KA values for the left and right atria are markedly different from those previously reported for isoprenaline at beta1 or beta2-adrenoceptors, we suggest that atypical beta-adrenoceptors might be present on the atria of WKY and SHR. We have also demonstrated a lower beta-adrenoceptor reserve on SHR papillary muscle and atria in the early stages of established hypertension.

“…We investigated the effects of bromoacetylalprenololmenthane (BAAM), an irreversible β ‐adrenoceptor blocker, on the isoprenaline responses of portal veins of 5‐ and 14‐week‐old WKY and SHRs. We have previously used BAAM successfully to generate reproducible K A values and the fractional β 2 ‐adrenoceptor occupancy–response relationships on the portal veins of older WKY and SHRs (Doggrell & Surman, 1995). We demonstrate that there are ongoing changes in β 2 ‐adrenoceptor structure and reserve in maturation on the portal vein that are irrespective of the development of hypertension.…”

Section: Introductionmentioning

confidence: 99%

Responsiveness, affinity constants and ₂‐adrenoceptor reserves for isoprenaline on portal veins from normo‐ and pre‐ and hypertensive rats

Chen

Auton Autocoid Pharmacol

2003

1. This study used contractility methods with the portal veins of 5- and 14-week-old Wistar-Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs). The SHRs are prehypertensive at 5 weeks. 2. The first part of our study was to determine whether the responsiveness to isoprenaline and forskolin was altered in the maturation of portal veins from normo- and prehypertensive rats. The responses to forskolin were similar on the portal veins of 5- and 14-week-old WKY and SHRs. 3. The sensitivity and maximum responses to isoprenaline were similar on portal veins of 5- and 14-week-old WKY. The sensitivity and maximum responses to isoprenaline were lower on the portal veins of 5-week-old SHRs (pD2 = 8.25, maximum = 85%) than age-matched WKY (pD2 = 8.79, maximum = 96%); these differences are not caused by hypertension. At 14 weeks, the sensitivity was similar (WKY pD2 = 8.74, SHR pD2 = 8.65) but the maximum responses to isoprenaline were lower on the portal veins SHRs (77%) than WKY (97%). Thus, the sensitivity to isoprenaline increases with the development of hypertension in the SHR portal vein. 4. The second part of the study was to determine whether the affinity for isoprenaline at beta2-adrenoceptors and the fractional beta2-adrenoceptor occupancy-response relationships on the portal vein were altered in maturation from normo- and pre-hypertensive rats. The effects of bromoacetylalprenololmenthane (BAAM), an irreversible beta-adrenoceptor blocker, on the isoprenaline responses of 5- and 14-week-old WKY and SHRs were studied. Maturation of the WKY portal vein between 5 and 14 weeks was associated with a loss of affinity for isoprenaline (from pKA of 7.13 to 7.87), and increase in beta2-adrenoceptor reserve (from 72 to 92% at the 95% response). There were similar affinity and reserve findings in the maturation of the SHR portal vein. Thus, there are major changes in beta2-adrenoceptor structure and reserve in maturation on the portal vein that are irrespective of the development of hypertension.