Lars-Owe D. Koskinen

Effect of low intravenous doses of TRH, acid-TRH and cyclo(His-Pro) on cerebral and peripheral blood flows.

1 Local cerebral and peripheral blood flow in conscious and anaesthetized rabbits were investigated with the microsphere method, before and after the i.v. administration of 25 or 50 μg kg−1 thyrotropin‐releasing hormone (TRH). Before the experiment, the cervical sympathetic chain was sectioned on one side in order to evaluate the possible effect of the sympathetic nerves on cranial and extracranial blood flows. 2 Blood flow was also determined in anaesthetized rabbits before and after the administration of the TRH metabolites cyclo(His‐Pro) and acid‐TRH and after subsequent administration of 50 μg kg−1 TRH. 3 TRH caused an increase in mean arterial blood pressure (MAP) of about 1 to 2 kPa whereas cyclo(His‐Pro) and acid‐TRH had no effect on MAP. 4 In the anaesthetized animal an increase in total cerebral blood flow (CBFtot), from 71 ± 7 to 107 ± 12 g min−1 100g−1 (P < 0.05) was observed on the sympathetic intact side after 25 μg kg−1 TRH and a further increase to 130 ± 9 g min−1 100g−1 (P < 0.01) after 50 μg kg−1 TRH. A similar effect was observed on the sympathotomized side. 5 An effect on CBF in the conscious animal was not detected. The control CBFtot (104 ± 8 g min−1 100g−1) was higher in these animals than in the anaesthetized animals (P < 0.02). 6 Neither cyclo(His‐Pro) nor acid‐TRH mimicked the effect of TRH on CBF. 7 In several peripheral tissues, e.g. skin, pancreas and gastric mucosa, a reduction in blood flow was noted after the administration of TRH in both anaesthetized and conscious rabbits. 8 It was concluded that TRH can induce cerebral vasodilatation in animals with a depressed CBF, whereas the vasoconstrictor effect of TRH in peripheral organs is not markedly affected by the state of consciousness. I wish to thank Professor Anders Bill for advice, Ms Ann‐Sofi Hoist for technical assistance, Ms Lena Henriksson for secretarial work and Ms Monica Thorén for drawing the figures. This study was supported by grant No. B84‐14X‐00147 from the Swedish Medical Research Council and grant No. 5 ROI Ey 00475 from the National Eye Institute, U.S. Public Health Service.

Cerebral and peripheral blood flow effects of TRH in the rat—A role of vagal nerves

The cardiovascular effects of the IV infusion of TRH were studied in the rat. TRH tended to increase the MAP and markedly increased the CBF(tot) in the control group, in vagotomized animals and in methylatropine-pretreated rats. A marked vasodilation was noted in the pancreas, gastric mucosa, duodenum and cardiac muscle. This effect was turned to vasoconstriction, the heart excluded, in vagotomized animals. Muscarinic blockade attenuated the vasodilating effect of TRH in the duodenum and gastric mucosa. The results indicate that TRH elicits cerebral vasodilation and a partly nonmuscarinic parasympathetically mediated vasodilation in several gastrointestinal organs in parallel with a vasoconstriction which is unmasked by vagotomy.

Effects of raised intracranial pressure on regional cerebral blood flow: a comparison of effects of naloxone and TRH on the microcirculation in partial cerebral ischaemia.

1 The effects on regional cerebral blood flow (rCBF) of raised intracranial pressure (ICP) and of naloxone and thryrotropin releasing hormome (TRH) during this condition were studied in anaesthetized rabbits. 2 The ICP was elevated until a central ischaemic response was observed. The regional blood flow was determined with the microsphere technique before and during elevation of the ICP (ICPc) and after drug treatment. 3 Total CBF was reduced by about 70% during ICPc while the uveal blood flow increased slightly and some other peripheral tissue blood flows remained unaffected. 4 The administration of TRH caused an increase in mean arterial blood pressure (MAP) from 11.9 ± 0.6 to 14.6 ± 0.7 kPa and a normalization of the rCBF. In some peripheral tissues, e.g. gastric mucosa and spleen, TRH reduced the blood flow by 53% and 76%, respectively. In blood pressure stabilized animals no effect on rCBF was seen after TRH. 5 Naloxone had no consistent effect on MAP or local blood flow. 6 It was concluded that in the range of cerebral perfusion pressure studied there was a passive relationship between cerebral blood flow and perfusion pressure. The lack of effect of naloxone and the marked effect of TRH during cerebral ischaemia are consistent with a mechanism of action of TRH not related to a ‘physiological’ antagonism of opioids.

Naloxone and TRH affect regional blood flows in the anesthetized rabbit

The cardiovascular effects of IV naloxone and a subsequent administration of TRH IV were studied in the rabbit. Naloxone caused a vasodilation in the myocardium and adrenal glands. Naloxone elicited an increment in cerebral blood flow in several regions which attenuated the cerebrovasodilating effect of TRH in a few regions. The blockade of endogenous opioids with naloxone did not modify the peripheral vasoconstricting effect of TRH or affect the vascular effects of TRH mediated by the peripheral sympathetic nerves. The results indicate that naloxone has a vasodilating effect in the myocardium and CNS in anesthetized rabbits. The major part of the cardiovascular effect of TRH is not dependent on mechanisms sensitive to naloxone.

TRH-induced blood flow and mean arterial pressure changes in the rabbit are not dependent on the anaesthetic used.

1 The effects of thyrotropin releasing hormone (TRH) on regional cerebral blood flow were studied in rabbits anaesthetized with pentobarbitone or ketamine. The blood flow was determined with the labelled microsphere method before and after the i.v. administration of either 50 μg kg−1 or 2 mg kg−1 TRH. 2 In order to measure the cerebral O2 consumption the arteriovenous difference in oxygen saturation in the brain (CAVOD) was measured before and after the administration of 2 mg kg−1 TRH. 3 In animals under pentobarbitone anaesthesia 50 μg kg−1 TRH elicited an increase in mean arterial blood pressure (MAP) of about 1 kPa and 2 mg kg−1 TRH elevated the MAP by about 2 kPa. With ketamine as the anaesthetic the corresponding values were 0.5 kPa and 7 kPa, respectively. TRH induced significant vasoconstriction in several peripheral tissues. 4 The total cerebral blood flow (CBFtot) increased from 54 ± 4 to 78 ± 5 g min−1 100 g−1 after the administration of 50 μg kg−1 TRH in pentobarbitone‐anaesthetized animals. An even greater effect was elicited by 2 mg kg−1 TRH, from 48 ± 6 to 113 ± 19 g min−1 100 g−1. In ketamine‐anaesthetized rabbits, 50 μg kg−1 TRH tended to enhance the CBFtot and 2 mg kg−1 increased it from 71 ± 6 to 141 ± 19 g min−1 100g−1. 5 In animals anaesthetized with pentobarbitone, the CAVOD decreased from 47.3 ± 1.7% to 35.1 ± 2.2% at 3 min after TRH delivery, and then gradually increased to the control level. In animals under ketamine anaesthesia the CAVOD decreased from 63.3 ± 2.0% to 45.2 ± 7.4% after the administration of 2 mg kg−1 TRH. 6 It is concluded that TRH elicits cerebral vasodilatation in excess of that required by the change in cerebral metabolism which may have taken place. The pattern of responses was similar to that produced in rabbits under urethane anaesthesia.

Thermic and tremorogenic effects of thyroliberin (TRH) in reserpine-treated mice—the non-involvement of GABA-ergic mechanisms

Administration of thyroliberin (TRH) to reserpinized mice causes tremor and counteracts the hypothermia in a dose‐dependent fashion. The thyroliberin response is inhibited by γ‐hydroxybutyric acid (GHB) and baclofen, but not by other, more specific GABA‐ergic agents, such as THIP, γ‐acetylenic GABA, and sodium valproate. Picrotoxin neither potentiates nor inhibits the thyroliberin actions. Nor are the thyroliberin effects dependent on cholinergic, monoaminergic or histaminergic mechanisms. The results repudiate a current hypothesis, that the peptide actions may be mediated by GABA‐ergic pathways in the brain.

TRH‐induced Effects on Blood Flow in Pentobarbital and Ketamine‐anesthetized Rabbits

TRH is known to give rise to a number of physiological These include a sympathetic activation resulting in vasoconstriction in some peripheral tissues and cerebral vasodilatation in rabbits under urethane ane~thesia.~ The present study was carried out in order to evaluate whether the anesthetic used is critical for the effects of TRH on regional blood flows. New Zealand albino rabbits anesthetized with pentobarbital sodium (Membumala) or ketarnine chloride (Ketalara) were used. Each animal was tracheotomized and artifically ventilated. Unilateral cervical sympathotomy was performed in order to elucidate possible effects of the sympathetic nerves on the cerebral and extracranial blood flows. The regional blood flow was determined with the labeled microsphere technique before and after the i.v. administration of either 50 pg kg-I or 2 mg kg-l TRH. The cerebral oxygen extraction was measured in separate experiments by determination of the arteriovenous difference in oxygen saturation. Blood was collected from the superior sagittal sinus and the femoral artery and examined for oxygen saturation, pH, PC02, and P02. Statistical evaluations were made with the Students t test for paired observations or using the Wilcoxon signed rank test. The results are expressed as means +SEM. Arterial blood gases were stable during the experiments.