Elements of cerebral microvascular ischaemia.

Although neuronal cells have long been thought to be the prime target of ischaemic insults, events which occur at the blood-vascular-parenchymal interface are necessary for the initiation of ischaemic tissue injury. This cascade of microvascular events includes fibrin accumulation, endothelium expression of leukocyte adhesion receptors, breakdown of the basal laminae with loss of astrocyte and endothelial cell contacts leading to blood-brain barrier disruption and consequently oedema formation and haemorrhagic transformation. Potential stroke treatments have been studied in the clinic and many have not been particularly successful, probably due to the delicate balance between improved outcome and adverse reactions as well as the window of opportunity for drug treatment after symptom onset. The only acute intervention trial demonstrating any benefit in patients was that of intravenous tissue plasminogen activator (tPA), administered within 3 h of the onset of symptoms of ischaemic stroke. Such treatment improved clinical outcome at 3 months, although there was an increased incidence of symptomatic haemorrhage [New Engl. J. Med. 333 (1995) 1581]. The recent progress made in defining the mechanisms involved in the initiation of ischaemic events, as described in this review, may lead to the identification of new strategies for intervention in the ischaemic cascade.

White matter ischaemia.

Brain and spinal cord white matter are vulnerable to the effects of ischaemia. Reduction of the energy supply leads to a cascade of events including depolarization, influx of Na(+) and the subsequent reverse operation of the membrane protein the Na(+)/Ca(2+) exchanger which ultimately terminates in intracellular Ca(2+) overload and irreversible axonal injury. Various points along the white matter damage cascade could be specifically targeted as a potential means of inhibiting the development of axonal irreversible injury.

A method using a liquid chromatographic-electrospray-mass spectrometric assay for the determination of antimigraine compounds: preliminary pharmacokinetics of MDL 74,721, sumatriptan and naratriptan, in rabbit.

MDL 74,721 (I), sumatriptan(II) and naratriptan(III) are new 5-HT1-like agonists that have potential as a novel treatment for migraine. Liquid chromatographic-electrospray-mass spectrometric (LC-ESI-MS) assay have been developed to compare the pharmacokinetics of these three antimigraine compounds. The concentration of each parent drug was determined using a solid-phase extraction method and LC-ESI-MS analysis demonstrating the high sensitivity and specificity of the methods down to subnanogram levels in rabbit plasma samples. Pharmacokinetic parameters evaluated after administration of single intravenous and oral doses were very similar and the ANOVA analysis did not show any statistically significant differences for t1/2, Cmax, V or AUC (normalised). The pharmacokinetic parameters showed short t1/2 (range 1.14-1.9 h) either after intravenous (i.v.) or oral (p.o.) administration and high total body clearance (CL) after the p.o. dose both probably due to extensive and rapid metabolism of the parent drugs as suggested by the low values for bioavailability (range 13.4-22.8%).

Preclinical characterization of MDL 27,192 as a potential broad spectrum anticonvulsant agent with neuroprotective properties.

The compound 5-(4-chlorophenyl)-2,4-dihydro-4-ethyl-3H-1,2,4-triazol-3-one (MDL 27,192) was evaluated in a variety of rodent models to assess its anticonvulsant profile and its potential neuroprotective activity. MDL 27,192 demonstrated anticonvulsant activity in a wide range of epilepsy models that are genetically-based (audiogenic seizures in the seizure susceptible DBA/2J or Frings mouse; spike wave seizures in genetic absence epilepsy rats of Strasbourg (GAERS), electrically-based (MES seizures in mice and rats, corneally-kindled seizures in rats) and chemically-based (bicuculline, PTZ, picrotoxin, 3-mercaptopropionic acid, quinolinic acid and strychnine). When compared to valproate, orally administered MDL 27,192 was 17-48-fold more potent as an anticonvulsant and showed a safety index one to three-fold greater. Following a timed intravenous administration of PTZ to mice, MDL 27,192, but not phenytoin or carbamazepine, consistently increased the latencies to first twitch and clonus. MDL 27,192 was active in a genetic model of absence epilepsy, the GAERS rat model. These data indicate that MDL 27,192 likely exerts its anticonvulsant action by affecting seizure spread and by raising seizure threshold. MDL 27,192 did not display any signs of tolerance following subchronic (15 day) administration. In tests of neuroprotective potential, MDL 27,192 reduced infarct volume in a permanent middle cerebral artery occlusion model of focal cerebral ischemia in rats and reduced the loss of hippocampal dentate hilar neurons in an animal model of unilateral head injury. In summary, MDL 27,192 possesses a broad-spectrum anticonvulsant profile. The potential for reduced tolerance and neuroprotective activity are additional positive features of MDL 27,192's preclinical profile.

The selectivity of MDL 74,721 in models of neurogenic versus vascular components of migraine.

MDL 74,721 (R)-2-(N1,N1-dipropylamino)-8-methylaminosulfonylmethyl-1,2,3,4-te trahydronaphthalene, a sulfonamidotetralin, has been found to exhibit a 10,000-fold greater potency in neurogenic versus vascular models of migraine. Sumatriptan, a relatively pure 5-HT1D/5-HT1B receptor agonist, also showed higher potency versus neurogenic inflammation. However, for sumatriptan the potency difference (100-fold) in the two pathophysiological models was less pronounced than seen for MDL 74,721. The affinity profile of MDL 74,721 at 5-HT1 receptor subtypes may in part explain its ability to differentiate these two physiological responses. MDL 74,721 demonstrated nanomolar affinity for 5-HT1A (12.7 +/- 0.3 nM) and 5-HT1D (41.3 +/- 10.9 nM) but considerably lower affinity for 5-HT1B receptors (> 1000 nM). Serotonin-like activity was seen in in vitro functional assays including inhibition of forskolin-stimulated cAMP accumulation in human 5-HT1D receptor-transfected fibroblasts or eliciting vasoconstriction in isolated human pial arteries. The intrinsic activity (relative to 5 - HT[E(Amax)]) and affinity (pD2) for the human cerebrovascular 5-HT receptors were: 5-HT (100%, 7.51 +/- 0.09), sumatriptan (94%, 6.85 +/- 0.1) and MDL 74,721 (66%, 5.70 +/- 0.23). In anaesthetised cats, treatment with MDL 74,721 resulted in a dose-related reduction in the percentage of carotid flow going through the arteriovenous anastomoses to the lungs, with an ED50 of 0.3 mg/kg i.v., the same as sumatriptan. However, in the guinea-pig neurogenic model, MDL 74,721 inhibited plasma protein extravasation with an ED50 of 0.023 microg/kg compared to 2.5 microg/kg for sumatriptan. MDL 74,721 was also effective in this model (in rats) after oral administration. In conclusion, MDL 74,721 demonstrates a preclinical profile consistent with anti-migraine efficacy. Its marked preference for inhibiting neurogenic inflammation makes this compound a useful tool for assessing the relative contribution of this pathophysiological mechanism to the human disease state.

Reduction of traumatic brain injury-induced cerebral oedema by a free radical scavenger.

Oxygen derived free radicals have been proposed to be in part responsible for the cerebral oedema resulting from head injury. In the present study the effects of free radical suppression with MDL 74,180 (2,3-dihydro-2,2,4,6,7-pentamethyl-3-(4-methylpiperazino)-methyl-1 - benzofuran-5-ol dihydrochloride), an alpha-tocopherol analogue free radical scavenger, on the development of cerebral oedema resulting from head injury has been assessed. Fluid percussion head injury in rats caused a regional oedema 48 h after injury. Infusion of MDL 74,180 for 2 h after the injury significantly attenuated oedema development in a dose-related manner. Using magnetic resonance imaging, cerebral oedema development was monitored in head injured mice. Oedema was apparent 4 h after head injury and was greatest in the vicinity of the olfactory bulb and surrounding the ventricles. Treatment with MDL 74,180 (1-10 micrograms/kg intravenously, administered 3-5 min after the injury) significantly reduced the oedema development. MDL 74,180 is a potential treatment for the oedema caused as a result of head injury.

MDL 74,180 reduces cerebral infarction and free radical concentrations in rats subjected to ischaemia and reperfusion.

The protective effect of MDL 74,180 (2,3-dihydro-2,2,4,6, 7-pentamethyl-3-(4-methylpiperazino)-methyl-1-benzofuran-5-ol dihydrochloride) and alpha-tocopherol analogue free radical scavenger, against cerebral ischaemia and reperfusion in conscious rats has been demonstrated. Tissue damage following middle cerebral artery occlusion (2 h) and reperfusion (8 days) was decreased by MDL 74,180 (0.1 and 1.0 mg/kg per h) infusion beginning 15 min before the onset of reperfusion and continuing for 2 h into the reperfusion period, in a dose-related manner. Nitroxide radical adducts, characterized and quantified by electron spin resonance spectroscopy, were formed on the addition of spin traps to homogenized rat brain tissue previously subjected to global ischaemia and reperfusion. The primary oxidative chain free radicals form diamagnetic intermediates whose slow homolytic decomposition subsequently yields the observed stable spin adducts. Infusion of MDL 74,180 (1-10 mg/kg per h) beginning 15 min before the induction of global cerebral ischaemia (20 min) until the end of reperfusion (5 min), led to a dose-dependent reduction in the final concentration of spin adducts.

2,3-Dihydro-1-benzofuran-5-ols as analogues of alpha-tocopherol that inhibit in vitro and ex vivo lipid autoxidation and protect mice against central nervous system trauma.

A series of alpha-tocopherol analogues was synthesized with potential therapeutic value for such pathological conditions as stroke and trauma. A set of criteria such as the inhibition of in vitro lipid peroxidation, superoxyl radical scavenging, and brain penetration, as measured by ex vivo inhibition of lipid peroxidation, was applied to select the most effective compound. 2,3-Dihydro-2,2,4,6,7-pentamethyl-3-[(4-methylpiperazino)methyl]-1 - benzofuran-5-ol dihydrochloride (22) was selected because of its superior antioxidant properties and better brain penetration. This compound also protected mice against the effects of head injury. The criteria thus turned out to be useful for the characterization of a neuroprotective analogue of alpha-tocopherol.

Receptor density in the rat heart following ischaemia and prolonged reperfusion.

1. The free radical scavenger MDL 73,404 decreases infarct size and improves heart performance after myocardial ischaemia and prolonged reperfusion. In the present study the possibility that changes in receptor density might contribute to the MDL 73,404-induced increase in contractility has been investigated in rats subjected to myocardial ischaemia and 8 days of reperfusion. 2. Both in saline- and MDL 73,404-treated rats a significant decrease in beta1- and increase in beta2-adrenoceptor densities was apparent in the infarcted tissue. 3. In non-infarcted septum and right ventricle tissue ischaemia followed by reperfusion tended to increase the density of beta2-adrenoceptors which was significantly increased after MDL 73,404 treatment. 4. The increased density of beta2-receptors in the non-infarcted tissue may contribute to the MDL 73,404 induced improvement of cardiac performance.

Myocardial protection by a cardioselective free radical scavenger.

Oxygen-derived free radicals are involved in myocardial reperfusion injury. In the present study MDL 74,405 (S-(-)-3,4-dihydro-6-hydroxy-N,N,N-2,5,7,8-heptamethyl-2H-1-benzo pyran-2-ethanaminium 4-methylbenzenesulfonate), a hydrophilic derivative of alpha-tocopherol, has been shown to inhibit lipid peroxidation in rat brain homogenate, ex vivo lipid peroxidation in mouse heart and to accumulate in myocardial tissue. Infused i.v. MDL 74,405 induced a dose-related reduction of myocardial infarct size in pentobarbitone-anaesthetised rats subjected to 60 min coronary artery ligation followed by 30 min reperfusion. Similarly i.v. infusion of MDL 74,405 beginning 10 min before coronary artery occlusion (60 min) until 30 min after the onset of reperfusion (8 days) caused a decrease of infarct size associated with an increase in aortic flow. Plasma levels of creatine phosphokinase were significantly reduced. In isolated infarcted hearts, obtained from MDL 74,405-treated rats after 8 days of reperfusion and perfused according to the Langendorff technique, an increase in the contractility index (+) and (-) dP/dtmax was apparent. In isolated non-infarcted rat hearts subjected to 30 min no-flow global ischaemia, perfusion with MDL 74,405 resulted in an increase in heart rate and the contractility indices (+) dP/dtmax, and left ventricular systolic pressure during reperfusion. In conclusion MDL 74,405, is a cardioselective free radical scavenger, that reduces myocardial infarct size and attenuates post-ischaemic dysfunction.

Protection of infarcted, chronically reperfused hearts by an alpha-tocopherol analogue.

Free radicals may cause part of the irreversible injury which occurs during myocardial infarction and reperfusion. In the present study MDL 73404, a hydrophilic, cardioselective, free radical scavenger analogue of alpha-tocopherol, was evaluated for its effects on infarct size as well as on indicators of reperfusion injury. A pentobarbitone-anaesthetised rat model of coronary artery ligation (60 min; followed by 8 days of reperfusion) was used. Intravenous infusion of MDL 73404 (3 mg/kg per h) began 10 min before occlusion until 30 min after the onset of reperfusion. MDL 73404 reduced (P < 0.02) the elevated serum levels of thiobarbituric acid reactive substances and plasma levels of creatine phosphokinase (P < 0.01). An increase in cardiac output and heart rate together with a decrease (P < 0.01) in infarct size was evident in rats that had received MDL 73404, 8 days previously. Isolated infarcted hearts obtained from rats after 8 days of reperfusion had greater (P < 0.01) + dP/dt max, -dP/dt max, left ventricular systolic pressure and coronary flow after MDL 73404 compared to saline-treated controls. Infusion of [14C]MDL 73404, during the time of occlusion resulted in a concentration of 14.5 +/- 2.2 mg eq/g in the non-ischaemic ventricular tissue and a concentration of 3.0 +/- 0.4 mg eq/g in the area at risk. After infusion for the 30 min of reperfusion, 6.4 +/- 0.2 mg eq/g was detected in the non-ischaemic ventricular tissue but only 3.1 +/- 0.5 mg eq/g in the area at risk.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effects of an alpha-tocopherol analogue against myocardial reperfusion injury in rats.

Free radicals may cause part of the irreversible injury which occurs during myocardial infarction and reperfusion. In the present study MDL 73404, an alpha-tocopherol analogue which is a free radical scavenger has been evaluated for its effects on infarct size in an anaesthetised rat model of coronary artery ligation (60 min) and reperfusion (30 min). Intravenous infusion of the compound began 10 min before occlusion until the end of reperfusion. MDL 73404 (0.3-3 mg/kg per h) reduced infarct size, although not in a dose-related manner. Infusion of MDL 73404 (3 mg/kg per h) commencing 30 min before reperfusion until the end of reperfusion also induced a significant reduction in infarct size. In the isolated rat heart (Langendorff technique) subjected to 30 min no-flow global ischaemia, pretreatment with MDL 73404 (0.03 and 0.1 mM) in the perfusion buffer and during 30 min of reperfusion resulted in a significant increase in the maximal pressure development (+dP/dt max) and relaxation (-dP/dt max), left ventricular systolic pressure and heart rate during reperfusion, whereas left ventricular diastolic pressure was significantly reduced. In contrast, only one control heart out of five exhibited signs of recovery. Replacement, for 2 min, with a cardioplegic solution before the 30 min period of ischemia resulted in an increased heart rate and contractility during reperfusion compared to hearts that did not receive the cardioplegic solution. The presence of MDL 73404 (0.03 and 0.1 mM) in the perfusion fluid induced an additional increase in left ventricular systolic pressure to the pre-ischaemic levels. MDL 73404 may have potential for cardioprotective use in acute reperfusion of the myocardium following ischaemia.

Cardioselectivity of alpha-tocopherol analogues, with free radical scavenger activity, in the rat.

MDL74270 (6-acetyloxy-3,4-dihydro-N,N,N,2,5,7, 8-heptamethyl-2H-1-benzopyran-2-ethanaminium, 4-methylbenzenesulfonate) is a quaternary amine analogue of alpha-tocopherol with free radical scavenger properties. Rats were injected iv with [14C]MDL74270 (0.91 mg/kg), and whole blood and heart tissue were sampled. Five min after drug, the heart tissue/blood ratio (T/B) of radioactivity was 3.5, whereas at 1 hr it was 20.1 and remained at this value up to at least 6 hr. After iv administration the t 1/2 of radioactivity in blood was 6.3 hr, but po blood levels could not be quantified. The 0- to 96-hr urinary elimination of radioactivity was 39.9 +/- 5.7% of the dose after iv and only 1.2 +/- 0.4% after po administration, conversely, 44.7 +/- 5.2% was excreted in feces after iv and 79.1 +/- 17.4% after po administration. These results confirmed poor oral absorption of the compound. Tissue distribution of [14C]MDL74270 was compared with that of its tertiary amine analogue [14C]MDL74366 in rat heart, skeletal muscle, brain, and whole blood, after iv administration (1 mg/kg). The heart T/B was above 20, 1-6 hr after [14C]MDL74270, whereas it was less than 2 after [14C]MDL74366. Over the 1- to 6-hr time interval, skeletal muscle T/B varied from 1.8 to 5 compared with 1.5 to 0.6 for [14C] MDL74366. Brain T/B was higher after the tertiary amine compound. Results showed marked cardioselectivity of radioactivity after [14C] MDL74270. Differential centrifugation of heart homogenates showed that radioactivity was equally distributed between the major subcellular fractions studied.(ABSTRACT TRUNCATED AT 250 WORDS)

A cardioselective, hydrophilic N,N,N-trimethylethanaminium alpha-tocopherol analogue that reduces myocardial infarct size.

The alpha-tocopherol analogue 3,4-dihydro-6-hydroxy-N,N,N,2,5,7,8- heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate (1a, MDL 73404) and its O-acetate 1b (MDL 74270) were synthesized. Compound 1a was found to be hydrophilic (log P = -0.60) and to prevent lipid autoxidation in rat brain homogenate with an IC50 of 1.7 +/- 0.9 microM. Tissue distribution studies with [14C]-1b in rats (1 mg/kg iv) showed that radioactivity accumulates in the heart (ratio 20:1 vs blood after 1 h). Infusion of 1 mg/kg per h of 1b bromide reduced infarct size by 54% in rats subjected to coronary artery occlusion for 60 min followed by reperfusion for 30 min, compared to saline-infused controls. By comparison, the tertiary amine analogue 5 was found not to accumulate in heart tissue, to be an equally effective free-radical scavenger in vitro, but to require a higher dose to reduce infarct size in rats. This shows that the cardioselectivity of compound 1 contributes to its potency in salvaging myocardial tissue in rats after ischemia and reperfusion.

Effect of a cardioselective alpha-tocopherol analogue on reperfusion injury in rats induced by myocardial ischaemia.

Free radicals may cause some of the irreversible injury which occurs during myocardial ischaemia and reperfusion. In the present study the effects of a cardioselective, free radical scavenger, MDL 74270, which is an analogue of alpha-tocopherol, on myocardial infarct size in an anaesthetised rat model of coronary artery ligation (60 min) and reperfusion (30 min) has been evaluated. Infusion of MDL 74270 (0.3-3.0 mg/kg per h) commencing 10 min before occlusion until the end of reperfusion significantly reduced infarct size. The highest dose also caused a significant reduction in serum creatine phosphokinase levels. Similar findings have been obtained with the bromide salt of MDL 74270. Tissue distribution studies with 14C-labelled MDL 74270 and its tertiary amine analogue (MDL 74366) showed heart/blood ratios of total radioactivity, 1-6 h after i.v. administration, greater than 20 after MDL 74270 and around 1 after MDL 74366. The importance of accumulation of total radioactivity in the heart after MDL 74270 is supported by the fact that MDL 74366 was 30 times less potent as a myocardial protector in the ligation/reperfusion studies. It is concluded that MDL 74270 has potential for cardioprotective use in conditions of acute reperfusion.

The effects of taurine on atherosclerosis development in cholesterol-fed rabbits.

The effect of taurine on the development of atherosclerotic lesions in rabbits maintained on a 2% cholesterol diet for a 14 week period has been examined. Taurine (0.2 and 0.5%) administered in the drinking water reduced thoracic aorta involvement. The area covered by atherosclerotic lesions was 58 +/- 15 and 52.5 +/- 12% (P less than 0.05) respectively, compared to 72.4 +/- 19% in the control group. Taurine had no significant effect on serum or tissue cholesterol, calcium, triglyceride or phospholipid concentrations. Nevertheless 0.2% taurine caused an increase in dP/dtmax (measured from the systemic blood pressure) and 0.5% lowered systemic blood pressure. The anti-atherosclerotic effects of taurine appear to be unrelated to a fall in blood pressure. The possibility that taurine is reducing the development of atherosclerotic lesions through a mechanism involving its antioxidant activity is discussed.

The cardiovascular effects of centrally administered taurine in anaesthetised and conscious rats.

The effects of pentobarbitone anaesthesia on the cardiovascular changes induced by centrally administered taurine have been investigated in spontaneously hypertensive (SHR) and normotensive rats. Administration of taurine (100-400 micrograms) into the lateral cerebral ventricle (i.c.v.) of anaesthetised SHR and normotensive rats induced a dose-related fall in systemic blood pressure and heart rate, which tended to be of a greater magnitude in the SHR. In anaesthetised rats attached to a ventilator, taurine was not as potent at inducing a fall in systemic blood pressure, approximately double the dose being required to produce the same cardiovascular changes as that which occurred in anaesthetised rats without a ventilator. In conscious normotensive rats taurine had no effect on blood pressure until a dose of 800 micrograms was administered i.c.v., whereas in conscious SHR, a small, but significant depressor response was evident with 400 micrograms. These findings demonstrate that pentobarbitone anaesthesia sensitises the rats to the cardiovascular effects of taurine, partially through a mechanism which involves respiratory depression. Conversely in conscious rats a much higher dose of taurine is required to induce a fall in arterial pressure and heart rate per se.

Comparison between the cardiovascular effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and clonidine in the conscious sino-aortic denervated rat.

1. The purpose of this study was to investigate the role of an intact baroreceptor reflex mechanism in the expression of the cardiovascular response to 8-OH-DPAT and to determine whether there are any differences between the activation of central alpha 2-adrenoreceptors and 5-HT1A receptors in this respect. To this end, the effects of 8-OH-DPAT and clonidine have been assessed on blood pressure, heart rate, ECG and cardiac contractility indices in conscious sino-aortic baroreceptor denervated (SAD) rats and their sham-operated controls. 2. In both sham-operated and SAD rats, intravenous (i.v.) administration of 8-OH-DPAT (32 micrograms kg-1) and clonidine (8 micrograms kg-1) produced falls in systemic blood pressure, left ventricular systolic pressure and dP/dtmax. 3. 8-OH-DPAT produced similar bradycardia in each group of rats; in contrast, clonidine had a greater effect in the SAD animals. Increases of the PQ interval mirrored the heart-rate changes with both compounds. 4. No significant changes in end diastolic blood pressure or in the myocardial contractility indices dP/dtmax/P and Vmax were evident. 5. This study provides support for the view that i.v. 8-OH-DPAT lowers blood pressure and heart rate through a central mechanism. The effects occur independently of an intact baroreceptor reflex and are not associated with effects on myocardial contractility. 8-OH-DPAT shows close qualitative similarities to clonidine in this model.

Comparison of the cardiovascular effects of trans-diclofurime with different types of calcium antagonists in conscious spontaneously hypertensive rats.

1. Trans-diclofurime has been shown to be a potent group II calcium antagonist in in vitro and in vivo test systems. In contrast to the dihydropyridines, group II calcium antagonists have a reduced propensity to cause reflex tachycardia due to well-balanced inhibitory effects in smooth muscle and heart. Since effects on autonomic reflexes are more reliably assessed in conscious animals, the cardiovascular effects of trans-diclofurime have been examined and compared to those of nifedipine, verapamil and diltiazem in the conscious spontaneously hypertensive rat (SHR). 2. Each SHR had an indwelling catheter in the femoral artery to record mean arterial pressure (MAP) and heart rate (HR) and a cannula in the femoral vein for drug infusion over 1 min. 3. Nifedipine (0.1-3.0 mumol kg-1 i.v.) caused dose-related falls in MAP accompanied by dose-related increases in HR. Trans-diclofurime and verapamil (0.3-3.0 mumol kg-1 i.v.) also caused dose-related decreases in MAP, but significant tachycardia was only seen at 1.0 and 3.0 mumol kg-1. Trans-diclofurime (0.3 mumol kg-1) induced a significant fall in HR. Diltiazem (1.0-10.0 mumol kg-1 i.v.) induced dose-related falls in MAP, significant bradycardia was evident with 1.0 mumol kg-1 and tachycardia with 10 mumol kg-1. Trans-diclofurime and diltiazem induced less tachycardia than nifedipine and verapamil for equivalent falls in MAP. 4. These results suggest that trans-diclofurime is a potent antihypertensive agent in conscious SHR and, like diltiazem, the hypotensive effects are associated with less tachycardia than is usually apparent with calcium antagonists such as nifedipine or verapamil. S. The cardiovascular effects of trans-diclofurime in conscious SHR are those expected of a class II calcium antagonist and are consistent with its proposed mode of interaction with the diltiazem site in the calcium channel.

Antihypertensive effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in conscious dogs.

Low doses of 8-OH-DPAT (10 and 25 micrograms/kg) administered subcutaneously (s.c.) to renal hypertensive mongrel dogs caused decreases in systolic blood pressure which persisted for 3 h. Mild salivation and hyperventilation were observed with both doses. A short-lasting (less than 60 min) depressor response was seen with 100 micrograms/kg s.c. Prominent hyperventilation and salivation accompanied this response. A still higher dose (250 micrograms/kg s.c.) induced tremor, signs of anxiety and occasional vomiting in addition to the hyperventilation and salivation. Paradoxically, no cardiovascular activity was noted at this dose.