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Vascular B-adrenoceptors and pressor response to B-adrenoceptor antagonists

University of British Columbia

ß-adrenoceptors have been classified into two subtypes, a ß₁-subtype found in the heart and a ß₂-subtype found in the vasculature. However, there is evidence that ß₁-adrenoceptors may also be present in the vasculature. We have examined the role of ß-adrenoceptors in the vasculature, first in the resistance blood vessels and second in the venous system. Firstly, we studied the effects of isoprenaline (mixed ß), isoprenaline plus ICI 118,551 (ß₁) isoprenaline plus atenolol (ß₂) and isoprenaline plus both ICI 118,551 and atenolol on haemodynamics in pentobarbital-anaesthetized rats using the radioactive microsphere technique. This study showed that ß₂- but not ß₁-adrenoceptor stimulation reduced total peripheral resistance (TPR) and mean arterial pressure (MAP). Both ß₁- and ß₂-adrenoceptor stimulation increased coronary and skeletal muscle vascular conductances. Secondly, we examined the effect of isoprenaline on MAP, heart rate (HR) and mean circulatory filling pressure (MCFP) in conscious rats. Isoprenaline was infused into intact, hexamethonium-pretreated or nor-adrenaline-pretreated rats. Our results show that under normal conditions, isoprenaline decreased MAP and increased HR and MCFP. Hexamethonium pretreatment did not affect the tachycardic and hypotensive effects of isoprenaline but it abolished the increase in MCFP indicating that this increase was due to reflex venoconstriction. Under conditions of high venous tone, isoprenaline decreased MAP and MCFP and increased HR. Therefore, our results show that ß-adrenoceptor stimulation mediates direct venodilatation in the presence of a high venous tone and reflex-mediated venocon-striction under normal conditions. Paradoxical pressor responses to ß-adrenoceptor antagonists have been reported in some clinical and experimental conditions. The mechanisms underlying this phenomenon are not known. We examined the conditions under which ß-adrenoceptor antagonists produced a pressor response. Firstly, we examined the haemodynamic changes which occur during α-adrenoceptor blockade by phentolamine, and after the development of the pressor response to ß-adrenoceptor antagonists in urethane-anaesthetized rats and in conscious rats. In urethane-anaesthetized rats, propranolol reversed the increase in conductance induced by phentolamine in skeletal muscle and skin and it also decreased renal vascular conductance. In conscious rats, propranolol or atenolol reversed the increase in conductance induced by phentolamine in skeletal muscle and in addition, it decreased conductance in the intestinal, renal and cutaneous vasculature. The inhibition of angiotensin converting enzyme by captopril attenuated the ß-adrenoceptor antagonist-induced pressor response demonstrating the importance of the renin-angiotensin system in the production of this response. Secondly, experiments were done to investigate the effects of anaesthetic agents on pressor response to ß-adrenoceptor antagonists. Our results show that anaesthetic agents have variable effects on ß-adrenoceptor antagonist-induced pressor responses. Urethane did not alter the pressor response to ß-adrenoceptor antagonists. Halothane and ketamine, on the other hand, attenuated the pressor response while ß-adrenoceptor antagonists did not produce a pressor response with pentobarbital, amobarbital or chloralose. It was further shown in pentobarbital-anaesthetized rats that phentolamine increased arteriovenous conductance and reduced MAP with no effects on other vascular beds and propranolol then did not have any effects on vascular conductance, TPR or MAP. An infusion of adrenaline partially restored the pressor response to both propranolol and atenolol showing the importance of adrenaline in the production of a pressor response. Thirdly. dose-response curves for propranolol, atenolol or ICI 118,551 in the presence of both noradrenaline and phentolamine were constructed in the isolated rat pulmonary artery. All three ß-adrenoceptor antagonists completely restored the phentolamine-induced relaxation response. Therefore, our in vitro and in vivo results are in accordance with a possible interaction of α-and ß-adrenoceptor antagonists which leads to subsequent stimulation of the α-adrenoceptors in the presence of adrenaline. The mechanism of this interaction is not clear. The results of in vivo studies show that additional factors such as the renin-angiotensin system may also be involved in this pressor response.

Text

2011-01-24

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http://hdl.handle.net/2429/30792

Pharmacology

University of British Columbia

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