Cardiac alpha- and beta-adrenoceptor sensitivity and binding characteristics after chronic reserpine pretreatment

1. The responses of isolated left atria and papillary muscles to isoprenaline, forskolin and calcium have been examined in 3 week streptozotocin-diabetic rats and the effects of oral ponalrestat administration (25 mg kg-1 daily) on diabetes-induced changes in cardiac responsiveness investigated. 2. Three weeks after animals were made diabetic, cardiac responses to isoprenaline were enhanced and this was accompanied by an increase in the density of ventricular [3H]dihydroalprenolol binding sites. Treatment of animals with ponalrestat prevented the increase in cardiac beta-adrenoceptor responsiveness and receptor number. 3. Diabetes also enhanced the sensitivity of cardiac tissues to forskolin, an effect that was not prevented by the treatment of animals with ponalrestat. 4. Ponalrestat treatment increased the resting and maximum tensions developed by cardiac tissues from diabetic animals and increased the maximum tensions developed by tissues from control animals. Diabetes alone had no effect on resting or maximum developed tensions. 5. Ponalrestat therefore prevents the changes in beta-adrenoceptor density and responsiveness induced by short-term diabetes in the rat and also increases the tension developed by cardiac muscle, an effect observed in diabetic and normal animals.

Section: Discussionmentioning

confidence: 99%

Diabetes‐induced changes in cardiac β‐adrenoceptor responsiveness: effects of aldose reductase inhibition with ponalrestat

Austin

Chess‐Williams

1991

“…However, neither KMD‐3213 (an alpha‐1A AR selective antagonist) (Murata et al ., 1999; Zhu et al ., 2000) nor reserpine (a catecholamine depletor) caused up‐regulation of alpha‐1 ARs in the heart, spleen or other tissues. It has been previously reported that reserpine treatment does not induce up‐regulation of alpha‐1 ARs in the heart (Chess‐Williams et al ., 1987; Latifpour & Macneill, 1984). These previous and the present results thus suggest that something about prazosin rather than the simple blockade of sympathetic influence is important in the observed effects.…”

Section: Discussionmentioning

confidence: 99%

Alpha‐1 adrenoceptor up‐regulation induced by prazosin but not KMD‐3213 or reserpine in rats

Zhang

Taniguchi

Tanaka

et al. 2002

1 We have investigated the e ects of chronic administration of prazosin (a subtype-nonspeci®c alpha-1 AR antagonist), KMD-3213 (an alpha-1A AR subtype-speci®c antagonist) and reserpine (a catecholamine depletor) on the density of alpha-1 AR subtypes in various rat tissues (liver, kidney, submaxillary gland, heart and spleen). H]-KMD-3213 of alpha-1 ARs in ®ve rat tissues tested. However, it caused 52% upregulation of alpha-1B AR in the spleen, and 84% and 107% up-regulation of alpha-1A-and alpha-1B ARs, respectively, in the heart. Although major subtypes of alpha-1 AR are alpha-1A AR in the submaxillary gland, alpha-1B AR in the liver, and alpha-1A and alpha-1B ARs in the kidney, these tissues showed no up-regulation. The mRNA levels of alpha-1 AR subtypes were not a ected by prazosin administration in any tissue tested. 3 Neither administration of KMD-3213 (2 mg kg 71 day 71 , i.p.) nor reserpine (0.5 ± 1 mg kg 71 day 71 , i.p.) for 2 weeks caused any change in either the binding a nity for [ 3 H]-prazosin or [ 3 H]-KMD-3213 or the density of the alpha-1 AR subtypes in the ®ve rat tissues. 4 Neither prazosin nor KMD-3213 treatment reduced the noradrenaline content in the ®ve rat tissues, in contrast to reserpine treatment, which markedly reduced it. 5 The ®ndings of the present study demonstrated that up-regulation of alpha-1 AR is selectively caused by prazosin treatment in some tissues but neither by KMD-3213 treatment nor by chemical denervation with reserpine. These results suggest that up-regulation of alpha-1 ARs is not caused by a simple blockade of sympathetic tone.

“…These findings support the notion that ventricular function is more sensitive to a loss of β‐ARs than left atrium, in accord with previous studies ( Butterfield & Chess‐Williams, 1993 ; Chess‐Williams, 1993 ), and indicates that atrial tissues may have a larger β 1 ‐AR reserve than ventricular tissues. Since the ventricles have a higher density of β 1 ‐AR binding sites than atrium ( Chess‐Williams et al ., 1987 ; Matthews et al ., 1996 ), coupling of β 1 ‐ARs to the cyclic AMP signalling pathway appears to be more efficient in the atrium.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of desensitization of the β‐adrenoceptor signalling pathway in rat cardiac tissues following chronic isoprenaline infusion

McMartin

Summers

1999

1 This study examined b-adrenoceptor signalling in cardiac tissues following infusion of isoprenaline (400 mg kg 71 h 71) or vehicle to rats for 14 days. 2 Isoprenaline infusion caused marked hypertrophy of atria and ventricles and reduced the resting rate of spontaneously beating right atria and the basal force of left atrial contraction. 3 In spontaneously beating right atria, concentration-response curves to isoprenaline and forskolin were shifted 7.9 and 3.2 fold to the right following treatment whereas responses to the cyclic AMP analogue 5,6-dichloro-1-û-D-ribofuranosylbenzimidazole-3', 5'-cyclic monophosphorothioate were unchanged. 4 In electrically driven left atria, concentration-response curves to isoprenaline and forskolin were shifted 4 fold to the right and maximum responses reduced. Responses to dibutyryl cyclic AMP were shifted 3.2 fold to the right but those to Ca 2+ were unchanged. 5 Inotropic responses of left and right ventricular papillary muscles to isoprenaline were abolished and markedly reduced respectively by isoprenaline treatment. Responses to forskolin were shifted 5 fold to the right. Responses to dibutyryl cyclic AMP were shifted to the right 3.2 and 2 fold in left and right ventricular papillary muscles. Responses to isobutyl methyl xanthine were shifted to the right 15.8 and 6.3 fold in left and right papillary muscles whereas those to Ca 2+ were not signi®cantly altered. 6 This study indicates dierences in b-adrenoceptor desensitization in dierent regions of the heart following chronic infusion of isoprenaline. Chronotropic responses showed impaired signalling between the receptor and adenylate cyclase whereas inotropic responses exhibited additional desensitization at the level of cyclic AMP dependent protein kinase.