Biomedical subjects

I M Macrae

Publications and source records attributed to I M Macrae.

At least 37 records · Page 2Linked to original sources

PubMed1997

Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus.

Ischaemic stroke is a complex disorder caused by a combination of genetic and environmental factors. Clinical and epidemiological studies have provided strong evidence for genetic influences in the development of human stroke and several mendelian traits featuring stroke have been described. The genetic analysis of the non-mendelian, common ischaemic stroke in humans is hindered by the late onset of the disease and the mode of inheritance, which is complex, polygenic and multifactorial. An important approach to the study of such polygenic diseases is the use of appropriate animal models in which individual contributing factors can be recognized and analysed. The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke characterized by a high frequency of spontaneous strokes as well as an increased sensitivity to experimentally induced focal cerebral ischaemia. Rubattu et al. performed a genomewide screen in an F2 cross obtained by mating SHRSP and SHR, in which latency to stroke on Japanese rat diet was used as a phenotype. This study identified three major quantitative trait loci (QTLs), STR-1-3. Of these, STR-2 and 3 conferred a protective effect against stroke in the presence of SHRSP alleles and STR-2 co-localized with the genes encoding for atrial natriuretic and brain natriuretic factors. Our investigation was designed to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischaemic insult by performance of a genome scan in an F2 cross derived from the SHRSP and the normotensive reference strain, WKY rat. We identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 which accounts for 67% of the total variance, co-localizes with the genes encoding atrial and brain natriuretic factor and is blood pressure independent.

Animals↗

PubMed1997

Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion.

1. The aim of this study was to investigate whether delayed treatment with the anti-oxidant and anti-inflammatory agent ebselen reduces the volume of infarction in a rodent model of permanent focal cerebral ischaemia. 2. Ebselen (10 or 30 mg kg-1) or vehicle was administered by gavage 30 min and 12 h after the induction of cerebral ischaemia by permanent occlusion of the left middle cerebral artery (MCA). Animals were killed 24 h following MCA occlusion, and the volumes of ischaemic damage in the ebselen and control groups were evaluated by quantitative histopathology. 3. Ebselen was quickly absorbed following oral (gavage) administration and reached peak levels in the plasma by 1 h post-administration (plasma selenium level of 0.68 +/- 0.04 and 0.84 +/- 0.1 microgram ml-1 for 10 and 30 mg kg-1, respectively, compared to control level of 0.51 +/- 0.02 microgram kg-1). 4. Treatment with the lower dose of ebselen (10 mg kg-1) significantly (P < 0.01) reduced the volume of infarction in the cerebral hemisphere and cerebral cortex (by 31.8% and 36.7%, respectively compared with the placebo group). 5. The neuroprotective efficacy of the higher dose ebselen (30 mg kg-1) was less than that of the lower dose ebselen (10 mg kg-1). The volume of ischaemic damage in the cerebral hemisphere was reduced by 23.7% (P < 0.02), and cerebral cortex by 27.5% (P < 0.01). 6. Both doses of ebselen (10, 30 mg kg-1) had no therapeutic efficacy on the caudate nucleus, where ischaemia was most severe, in this model. 7. Free radical-mediated injury is normally associated with reperfusion of ischaemic tissue. The present results suggest that oxidative injury is also a significant contributor to brain damage in models of maintained (permanent) ischaemia and that ebselen is effective in attenuating this free radical-induced damage.

Animals↗

PubMed1996

Topographic profile of reperfusion into MCA territory following endothelin-1-induced transient focal cerebral ischaemia.

This study examines the topographic profile of reperfusion into ischaemic tissue following reversible middle cerebral artery (MCA) occlusion. Autoradiographic images of both ischaemia and reperfusion were prepared from brain sections following transient ischaemia induced by endothelin-1 application to the exposed MCA in anaesthetised rats. Blood flow changes were assessed using double tracer autoradiography with 99mTc-exametazime during ischaemia (5 min) and 14C-iodoantipyrine during reperfusion (2 h). Following a significant ischaemic insult, reperfusion was relatively homogeneous within MCA territory but incomplete at 2 h. There was evidence for differential reperfusion in the cortex and caudate nucleus, and increased collateral supply from the anterior cerebral artery.

Animals↗

PubMed1996

Consequences of transient focal cerebral ischaemia for second messenger and neurotransmitter binding in the rat: quantitative autoradiographic analysis of forskolin, dopamine D1 receptor binding and cerebral blood flow changes.

In order to study the consequences of reperfusion for ischaemic brain injury, quantitative ligand binding autoradiography was carried out in a model of reversible focal cerebral ischaemia. Endothelin-1 applied to the abluminal surface of the middle cerebral artery in anaesthetized Sprague-Dawley rats induced severe focal ischaemia and subsequent reperfusion (assessed by blood flow tracers [99mTc]HMPAO and [14C]iodoantipyrine respectively) by 2 h after insult. Ligand binding autoradiography on consecutive sections demonstrated these blood flow changes to be associated with a significant reduction in forskolin binding throughout the middle cerebral artery territory (e.g. 25% in parietal cortex, 11% in dorsolateral caudate nucleus). The most marked losses in forskolin binding were in areas where ischaemia was severe and reperfusion was poor. However, the same changes in cerebral blood flow had no significant effect on D1 dopamine receptor binding (e.g. < 2% reduction in the caudate nucleus). These data demonstrate that ligand binding characteristics are significantly affected as early as 2 h after insult, with evidence of differential sensitivity for forskolin and D1 dopamine binding. With regard to the consequences of reperfusion, comparison with our previous study of 2 h maintained ischaemia demonstrates reperfusion-related salvage of dopamine and forskolin binding in the caudate nucleus but possible exacerbation of forskolin binding loss in the cortex.

Animals↗

PubMed1996

HMPAO as a regional cerebral blood flow tracer at high flow levels.

UNLABELLED: HMPAO is being used extensively to image rCBF during focal seizures in humans. It is, however, theoretically possible that back-diffusion of tracer causes retention to fall as flow rises at high levels. METHODS: We used a double label 99mTc-HMPAO/14C-IAP autoradiographic technique to compare HMPAO retention and regional cerebral blood flow in penicillin induced focal seizures in rats. RESULTS: Using this protocol, flows of up to 717 ml/100 g per min were observed. The same pattern of uptake was seen on IAP and HMPAO autoradiographs, with the exception of relatively high HMPAO uptake in the choroid plexus, in the fissures and, in one animal only, the supramammilary nucleus. Correlation of HMPAO retention and blood flow showed a linear relationship up to 200 ml/100 g per min all animals. HMPAO retention then showed a falloff in its rise with blood flow, but was still increasing, even at the highest flows seen. At 700 ml/100 g/min, HMPAO retention was 20% of that expected from a linear relationship. CONCLUSION: HMPAO is a suitable tracer of rCBF at high flows and is unlikely to produce anomalous images in human focal seizures.

Animals↗

PubMed1995

The neuroprotective efficacy of ebselen (a glutathione peroxidase mimic) on brain damage induced by transient focal cerebral ischaemia in the rat.

The neuroprotective efficacy of the hydroperoxide scavenger ebselen was assessed in a model of transient focal ischaemia that utilises the potent vasoconstrictor peptide endothelin-1 to induce temporary occlusion of the middle cerebral artery (MCA). Pretreatment with ebselen (10 or 30 mg/kg p.o., 40 min pre-MCA occlusion) dose dependently reduced the volume of ischaemic damage assessed 4 h post-endothelin-1 application in the anesthetised rat. The lower dose of ebselen (10 mg/kg) resulted in a non-significant 35% reduction in the total volume of ischaemic damage compared with the vehicle control. In contrast the higher dose of ebselen (30 mg/kg) significantly reduced the volume of ischaemic damage in the cerebral hemisphere and cerebral cortex by 48% and 53%, respectively. The marked reduction in brain damage achieved with ebselen cannot be attributed to drug-induced alterations in blood pressure, body temperature or arterial blood gases since these physiological variables were closely monitored and were not significantly altered by ebselen treatment. Thus ebselen is an effective neuroprotective agent against acute focal ischaemic-reperfusion injury.

Animals↗

PubMed1995

Brain structures involved in the hypotensive effects of rilmenidine: evaluation by [14C]2-deoxyglucose autoradiography.

The centrally acting, antihypertensive drug rilmenidine has activity at both imidazoline-preferring receptors (IPRs) and alpha 2-adrenoceptors: the IPR has been proposed to be the predominant receptor responsible for the hypotensive effects of rilmenidine. In the present study, the neuroanatomic regions of the brain involved in mediating the hypotensive response to rilmenidine were investigated in spontaneously hypertensive rats with the use of [14C]2-deoxyglucose autoradiography. The selective alpha 2-adrenoceptor agonist B-HT 933 was also studied for comparison. Rilmenidine (1 mg/kg s.c.) and B-HT 933 (2 mg/kg s.c.) induced significant and similar reductions in mean arterial pressure (-24 +/- 2 and -18 +/- 5 mm Hg. respectively) and in heart rate (-62 +/- 29 and -69 +/- 14 beats/min. respectively), whereas the vehicle had no significant hemodynamic effects. [14C]2-Deoxyglucose autoradiography revealed significant reductions in glucose use in the following structures of rilmenidine-treated rats: intermediolateral cell column of the thoracic spinal cord, area postrema, ventrolateral medulla, nucleus tractus solitarius, and cuneate nucleus, B-HT 933 did not significantly influence glucose use in any neuroanatomic structure examined. These results provide support for the functional involvement of brainstem cardiovascular control centres and the involvement of IPRs in the hypotensive response to rilmenidine.

Adrenergic alpha-Agonists↗

PubMed1994

Differential patterns of local cerebral glucose utilisation associated with rilmenidine- or B-HT 933-induced hypotension.

The anti-hypertensive drug, rilmenidine, has activity at both imidazoline-preferring receptors (IPRs) and alpha 2-adrenoceptors. However, available evidence suggests that its hypotensive effect is mediated via central IPRs. In the present study, the neuroanatomical regions involved in mediating the hypotensive response to rilmenidine were investigated using the [14C]2-deoxyglucose in vivo autoradiographic technique to map drug-induced changes in glucose utilisation within the CNS of conscious, spontaneously hypertensive rats (SHR). The cerebral metabolic effects of rilmenidine were compared with those of B-HT 933, a selective, alpha 2-adrenoceptor agonist with no selectivity for the IPR. Rilmenidine (1 mg/kg, s.c.) and B-HT 933 (2 mg/kg, s.c.) both elicited a moderate but significant hypotension (-24 +/- 2 and -18 +/- 5 mmHg, resp.) and bradycardia (-62 +/- 19.5 and -69 +/- 14 beats/min, resp.). [14C]2-deoxyglucose autoradiography, initiated after stabilisation of the drug-induced reduction in blood pressure, revealed significant reductions (P < 0.05) in local cerebral glucose utilisation (LCGU) in the intermediolateral cell column of the spinal cord, area postrema, ventrolateral medulla, nucleus tractus solitarius and cuneate nucleus of rilmenidine-treated rats. Rilmenidine did not significantly alter LCGU in a number of structures containing high densities of alpha 2-adrenoceptors such as nucleus accumbens, locus coeruleus, frontal cortex. No significant changes in glucose use were evident in any of the 26 CNS regions examined following B-HT 933 administration. These results provide evidence for the functional involvement of brainstem cardiovascular control centres in the central hypotensive effects of rilmenidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Anti-ischaemic efficacy of a nitric oxide synthase inhibitor and a N-methyl-D-aspartate receptor antagonist in models of transient and permanent focal cerebral ischaemia.

1. We have recently developed a new model of transient focal ischaemia in the rat utilising topical application of endothelin-1 to the left middle cerebral artery (MCA). In order to validate this approach the present study assessed the neuroprotective efficacy of the NMDA receptor antagonist dizocilpine (MK-801) in the endothelin-1 model. The anti-ischaemic efficacy of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was subsequently evaluated, and contrasted with its efficacy against permanent focal ischaemia, to determine the utility of the endothelin-1 model for identification of novel pharmacoprotective agents. 2. MK-801 (0.12 mg kg-1 bolus, 108 micrograms kg-1 h-1 infusion i.v., either 1 or 2.5 h pre-transient MCA occlusion (MCAO)) induced hypotension that persisted for approximately 1.5 h so that mean arterial blood pressure (MABP) at the time of MCAO was significantly lower in the 1 h group compared with control (MABP: 86 +/- 11, 68 +/- 6 and 84 +/- 4 mmHg (mean +/- s.d.) for saline, 1 h MK-801 and 2.5 h MK-801 groups respectively). The 2.5 h pretreatment schedule resulted in significant reduction (71%) in the volume of hemispheric damage (assessed 4 h post onset of ischaemia) while the 1 h pretreatment schedule did not (volumes of hemispheric damage: 59 +/- 38, 51 +/- 51 and 17 +/- 28 mm3 for saline, 1 h and 2.5 h MK-801 groups). 3. Thus the considerable neuroprotective effect of MK-801 in the endothelin-1 model of transient focal cerebral ischaemia was highly sensitive to drug-induced hypotension. This result is in contrast to previous studies of permanent MCAO where MK-801-induced hypotension did not compromise its neuroprotective action.4. L-NAME (3 mg kg-1, i.v. 30 min pre-MCAO) moderately, but significantly, reduced (16%) the volume of ischaemic damage 4 h post-permanent MCA occlusion, whereas the 29% reduction in volume of damage achieved in the model of transient focal ischaemia did not attain significance due to the greater variability associated with this model. L-NAME did not significantly alter MABP in either model.5. The modest neuroprotection achieved with NO synthase inhibition suggests NO is of relatively minor importance as a mediator of neurotoxicity following permanent focal cerebral ischaemia. In addition the comparable efficacy of L-NAME against transient focal ischaemia suggests the presence of reperfusion does not enhance the contribution of NO to neuronal injury in the acute (4 h) phase following a focal ischaemic insult.

Amino Acid Oxidoreductases↗

PubMed1993

Cerebrovascular effects of NG-nitro-L-arginine methylester are conserved under halothane anaesthesia.

The effects of the nitric oxide synthesis inhibitor NG-nitro-L-arginine methylester (L-NAME) on mean arterial blood pressure (MABP) and local cerebral blood flow were determined in conscious and halothane-anaesthetised rats. Thirty minutes post-drug administration in conscious rats L-NAME (30 mg kg-1 i.v.) induced significant hypertension (MABP 132 +/- 2 mmHg and 163 +/- 6 mmHg (means +/- S.D.) for saline and L-NAME groups respectively) and significant hypoperfusion throughout the brain (mean +/- S.D. reduction in cerebral blood flow 27.3 +/- 5.9% compared with controls). In contrast, under halothane anaesthesia, L-NAME did not significantly change MABP but significant reductions in cerebral blood flow (43.2 +/- 3.7%) were observed. Thus the cerebrovascular response to L-NAME is conserved under halothane anaesthesia despite attenuation of the peripheral vasoconstrictive action.

Anesthesia, Inhalation↗

PubMed1993

Neuropeptide Y-induced inositol phospholipid hydrolysis in blood vessels from normotensive and spontaneously hypertensive rats.

1. Neuropeptide Y (NPY) increased inositol phosphate (IP) formation in the femoral artery and vein of adult Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. 2. Noradrenaline (NA, 10(-6) M) induced IP accumulation in both strains of rats. 3. Subthreshold concentrations of NPY (3 x 10(-9) M for femoral vein and 10(-8) M for femoral artery) failed to modify NA (10(-6) M)-induced IP formation in both vessels. 4. These results suggest that the direct contractile effects but not the potentiation of NA-induced contractions may be directly linked to phosphatidylinositol turnover in adult SHR and WKY rats.

Animals↗

PubMed1993

Inhibition of nitric oxide synthesis: effects on cerebral blood flow and glucose utilisation in the rat.

The consequences of inhibition of nitric oxide synthesis on local CBF and glucose utilisation have been studied in the conscious rat using the specific nitric oxide synthase inhibitor Ng-nitro-L-arginine methyl ester (L-NAME; 30 mg kg-1 i.v.). Local CBF and glucose utilisation were assessed with the [14C]iodoantipyrine and the 2-deoxy-D-[14C]glucose autoradiographic techniques, respectively. L-NAME induced prolonged (> 3 h) reductions in local CBF throughout the CNS with concomitant increases in arterial blood pressure. For example, 1 h post L-NAME, CBF dropped from 79 +/- 4 to 45 +/- 1 ml 100 g-1 min-1 in cerebellum, from 76 +/- 4 to 47 +/- 2 ml 100 g-1 min-1 in medulla oblongata, and from 117 +/- 6 to 72 +/- 2 ml 100 g-1 min-1 in cortex. L-NAME produced sustained elevations (e.g., 46 +/- 2 mm Hg at 1 h after bolus administration) in mean arterial blood pressure throughout the period evaluated. Despite evidence implicating nitric oxide in neuronal signalling, L-NAME did not significantly influence CNS functional activity, as measured by local rates of glucose utilisation, in any neuroanatomical region examined. Consequently, the normal ratio of blood flow to glucose use throughout the brain was significantly reduced in the presence of L-NAME, although the hierarchy of blood flow levels in different neuroanatomical regions was preserved. These results are consistent with the involvement of nitric oxide in the tonic control of cerebral tissue perfusion.

Amino Acid Oxidoreductases↗

PubMed1993

Endothelin-1-induced reductions in cerebral blood flow: dose dependency, time course, and neuropathological consequences.

The capacity of endothelin-1 to induce severe reductions in cerebral blood flow and ischaemic neuronal damage was assessed in anaesthetised rats. Endothelin-1 (25 microliters of 10(-7)-10(-4) M) was applied to the adventitial surface of an exposed middle cerebral artery and striatal blood flow assessed by the hydrogen clearance technique. Endothelin-1 induced severe dose-dependent reductions in cerebral blood flow (e.g., minimum CBF at 10(-5) M of 9 +/- 11 ml 100 g-1 min-1 compared to 104 +/- 22 ml 100 g-1 min-1 with vehicle, p < 0.05), which persisted for at least 60 min at each concentration of endothelin-1. Application of endothelin-1 to the middle cerebral artery produced dose-dependent ischaemic brain damage (e.g., volume of damage of 65 +/- 34 mm3 at 10(-5) M compared to 0.22 +/- 0.57 mm3 for vehicle, p < 0.01). These data demonstrate that endothelin-1 is capable of reducing blood flow to pathologically low levels and provide a new model of controlled focal ischaemia followed by reperfusion.

Animals↗

PubMed1992

Inhibition of nitric oxide synthesis does not reduce infarct volume in a rat model of focal cerebral ischaemia.

The effect of the nitric oxide (NO) synthesis inhibitor Ng-nitro-L-arginine methylester (L-NAME) on ischaemic brain damage was determined in a rat model of focal cerebral ischaemia. Ischaemia was induced by permanent occlusion of the left middle cerebral artery (MCA) and infarction assessed 4 h post-occlusion by quantitative histopathology. L-NAME (30 mg/kg s.c.), administered 30 min pre- and 30 min post-MCA occlusion, did not significantly alter the volume of ischaemic damage in the cerebral hemisphere, neocortex or caudate nucleus compared with saline controls. This result provides no support for the view that NO generation is a key component in the post-ischaemic cascade leading to acute neuronal death.

Animals↗

PubMed1992

Autoradiographic evaluation of forskolin and D1 dopamine receptor binding in a rat model of focal cerebral ischaemia.

Post-ischaemic changes in forskolin and D1 dopamine receptor (labelled with SCH23390) binding sites were evaluated in a rat unilateral middle cerebral artery occlusion (MCA) model. The changes in binding were assessed acutely (2 h post-MCA occlusion) in relation to local cerebral blood flow (lCBF) and chronically (24 h post-MCA occlusion) in relation to histopathological alterations. Two hours following occlusion lCBF was significantly reduced throughout the territory of the MCA. Despite the widespread hypoperfusion, significant reductions in binding were only observed in the dorsolateral caudate nucleus--the region with the most profound reduction in blood flow (6% of the control contralateral lCBF value). Forskolin binding sites were reduced to 40% of the contralateral value while D1 binding sites were reduced to 80% of the contralateral value. Analysis of the relationship between forskolin binding and CBF in the caudate nucleus revealed that the ischaemic threshold for alteration in forskolin binding sites 2 h after MCA occlusion was approximately 34 ml/100 g/min. Twenty-four h post-occlusion forskolin binding sites were further reduced in the dorsolateral caudate nucleus (to 6% of contralateral) while D1 binding showed minimal reduction from that observed at 2 h. The areas of reduced binding corresponded to the area of histopathological change in the caudate nucleus and rostral neocortex. In conclusion, reduction in forskolin binding progresses further than reduction in D1 binding within the first 24 h following focal cerebral ischaemia. For both forskolin and D1 binding sites, the areas of reduced binding 24 h post-MCA occlusion predicted the area of histopathological change.

Animals↗

PubMed1992

Central cardiovascular effects of rilmenidine and neuropeptide Y in the conscious spontaneously hypertensive rat: haemodynamic and biochemical evidence for a negative interaction.

The possible cardiovascular and biochemical interactions between the imidazoline ligand rilmenidine, a novel antihypertensive agent, and neuropeptide Y (NPY) were examined in spontaneously hypertensive rats (SHR). Rilmenidine (25-225 micrograms/kg) and NPY (1.7-15 micrograms/kg) both produced a significant, dose-dependent reduction in blood pressure (BP) after intracisternal (i.c.) administration in conscious SHR. When submaximal doses of rilmenidine (25 micrograms/kg) and NPY (1.7 micrograms/kg) were coadministered i.c., the resultant hypotension and bradycardia was less than either individual response and significantly less than the sum of their individual responses, suggesting the existence of an inhibitory interaction between these agents. To determine whether this interaction was evident at the second-messenger level, the effect of these agents on cyclic AMP levels was investigated in slices from the medulla oblongata of SHR. NPY (10(-6) and 10(-7) M) significantly inhibited forskolin-stimulated cyclic AMP production. Rilmenidine (10(-8)-10(-5) M) itself had no significant effect on forskolin-stimulated cyclic AMP levels in this system, but rilmenidine (10(-6) M) attenuated the inhibitory effect of NPY (10(-6) M) on cyclic AMP production. Thus, an inhibitory interaction between rilmenidine and NPY was observed at the hemodynamic and second-messenger level in the SHR.

Adenylyl Cyclases↗

PubMed1991

Reduction in local cerebral blood flow induced by endothelin-1 applied topically to the middle cerebral artery in the rat.

The role of endothelin-1 (ET-1) in cerebral ischemic injury remains the subject of much debate. Vasoconstriction in large conduit vessels may not be associated with reductions in flow at the tissue level. We present two studies examining the effects on local cerebral blood flow of topical application of ET-1 to the surgically exposed middle cerebral artery (MCA) in adult male Sprague-Dawley rats. In the first series using 14C-iodoantipyrine autoradiography, 10 min following application of ET-1 (1 nmol) to the MCA, up to 80% reduction in blood flow in the territory of distribution of the MCA is seen (e.g., dorsolateral caudate nucleus--flow reduced from 131 +/- 3 ml/100 g/min to 29 +/- 25 ml/100 g/min). These levels of flow are comparable with those seen with permanent bipolar diathermy occlusion and division of the proximal MCA--a standard rat model of focal cerebral ischemia. In a second series using hydrogen clearance technique for measurement of local cerebral blood flow in the caudate nucleus, we have shown that flow ipsilateral to application of ET-1 (0.25 nmol) is significantly reduced compared with saline controls for 80 min. Such reduction of flow, at the tissue level, sustained over this duration is consistent with the induction of ischemic cell damage by ET-1.

Administration, Topical↗

PubMed1991

Differences in inositol phosphate production in blood vessels of normotensive and spontaneously hypertensive rats.

1. Total inositol phosphate formation was measured in labelled femoral and iliac arteries and veins of 14 week-old spontaneously hypertensive rats (SHR) and age-matched Wistar Kyoto (WKY) controls, either unstimulated or in the presence of noradrenaline. 2. Basal levels of [3H]-inositol phosphates and [3H]-phosphatidylinositol were significantly enhanced in SHR femoral artery, but not in the other 3 vessels, compared with WKY. 3. Noradrenaline stimulated phosphoinositide hydrolysis in all four vessels of SHR and WKY. Pretreatment with prazosin (10(-7)-10(-6) M) but not with yohimbine (10(-7) M), inhibited the noradrenaline-induced inositol phosphate formation indicating an alpha 1-adrenoceptor-mediated response. 4. In the femoral artery of SHR compared to WKY, [3H]-inositol phosphate accumulation induced by noradrenaline (10(-7)-10(-5) M) was significantly reduced when expressed relative to basal values although the response to higher concentrations (10(-4)-10(-3) M) was not altered. In contrast, a significant reduction of inositol phosphates was seen only with 10(-7) M noradrenaline when absolute values were compared. In the other three vessels, no difference in noradrenaline-induced [3H]-inositol phosphate formation was observed between strains. 5. These data suggest that phosphoinositide hydrolysis-mediated by alpha 1-adrenoceptors may be reduced in some but not all blood vessels of adult SHR.

Animals↗