Disease‐induced Changes in Α‐adrenoceptor‐mediated Cardiac and Vascular Responses in Rats

Abstract

1. The physiological relevance of cardiac and vascular alpha-adrenoceptors may increase in disease states in which beta-adrenoceptors are altered. To test this, positive inotropic and vasoconstrictor responses to phenylephrine were measured in isolated tissues from rats with experimentally-induced hyperthyroidism, hypothyroidism and diabetes as well as in genetically spontaneous hypertensive rats (SHR). 2. In left atria, positive inotropic responses to phenylephrine were increased in hypothyroid and diabetic rats and abolished in hyperthyroid and SHR. 3. In contrast, phenylephrine produced increased positive inotropy in left ventricular papillary muscles from hyperthyroid rats, increased potency in diabetic rats and negative inotropic responses in hypothyroid rats. 4. The potency of phenylephrine as a vasoconstrictor in thoracic aortic rings was increased in hyperthyroid and SHR and decreased in hypothyroid rats. 5. Thus, disease states which alter beta-adrenoceptor responsiveness can independently regulate atrial, ventricular and vascular responses to the alpha 1-adrenoceptor agonist, phenylephrine. Therefore, these disease states may alter the physiological control of the cardiovascular system by noradrenaline and adrenaline as well as the responsiveness in disease states to therapeutic agents acting via alpha-adrenoceptors.

Inhibition of nitric oxide generation unmasks vascular dysfunction in insulin‐resistant, obese JCR:LA‐cp rats

“…This effect is likely to occur at the vascular smooth muscle cells and is consistent with our recent observations that smooth muscle cells from cp / cp rats are hyper‐proliferative and hyperresponsive to cytokines, including insulin‐like growth factor (Absher et al , 1997). These findings are in agreement with other studies that have also shown that in vascular disease states in rats, such as spontaneous hypertension (Brown et al , 1994) and streptozotocin‐induced diabetes mellitus (Chang & Stevens, 1992), the sensitivity of isolated vasculature to contracting agents is increased.…”

Effects of oral propylthiouracil treatment on nitric oxide production in rat aorta

“…These ®ndings were supported by our immunohistochemical data which showed an apparent increase in endothelial cell eNOS antibody labelling intensity following dietary treatment, whereas immunoreactivity for iNOS was unchanged by PTU. These results con®rm previous ®ndings that PTU-induced hypothyroidism causes marked impairment of the contractile responses seen to PE and other a-adrenoceptor agonists (Rahmani et al, 1987;Brown et al, 1994a), and suggest that this may, in part, be due to enhanced production of NO by the endothelium.…”

“…Nonetheless, these ®ndings indicate that the inhibitory eect of PTU on PEinduced contractions could be reversed by thyroxine treatment alone, suggesting that the observed eects were due to PTUinduced hypothyroidism and not to a direct action of the drug or to other unrelated factors. These results support previous studies which have shown the inhibitory eects of hypothyroidism on the cardiovascular system to be reversed by thyroxine replacement therapy (0.1 mg kg 71 day 71 ) over both short (2 days) and longer (8 weeks) time periods (Rahmani et al, 1987;Brown et al, 1994b). In addition, previous published data suggests that the hyperthyroid state does not in¯uence vascular responsiveness to PE in any way (Sabio et al, 1994).…”

“…It has been well established that both cardiac b-adrenoceptor density and responsiveness to agonists which exert their actions via these receptors are decreased in hypothyroidism (Nakashima & Hagino, 1972;Hawthorn et al, 1988), ®ndings which account for the marked bradycardia observed in this condition (Klein & Ojamaa, 1992). In addition, vascular responsiveness to phenylephrine (PE) and other a-adrenoceptor agonists has been found to be decreased in hypothyroidism (Rahmani et al, 1987;Brown et al, 1994a), although the correlation between this disease state and a-adrenoceptor density has not been well established. The inhibitory eects of PTU on PE-induced contractions, which are observed in the resulting hypothyroid state, were found to be restored by thyroxine replacement therapy (Rahmani et al, 1987;Brown et al, 1994b), which suggests that the actions of PTU are dependent on induction of the hypothyroid state and are not due to a direct action of the drug or to other unrelated factors.…”

“…In addition, vascular responsiveness to phenylephrine (PE) and other a-adrenoceptor agonists has been found to be decreased in hypothyroidism (Rahmani et al, 1987;Brown et al, 1994a), although the correlation between this disease state and a-adrenoceptor density has not been well established. The inhibitory eects of PTU on PE-induced contractions, which are observed in the resulting hypothyroid state, were found to be restored by thyroxine replacement therapy (Rahmani et al, 1987;Brown et al, 1994b), which suggests that the actions of PTU are dependent on induction of the hypothyroid state and are not due to a direct action of the drug or to other unrelated factors.…”