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1 It has been demonstrated that nerve-evoked contractions of the rat vas deferens involve α1D-adrenoceptors. Definitive evidence for a similar α1D-adrenoceptor-mediated response in mouse vas deferens has been more difficult to obtain. In this study, we have used α1D-adrenoceptor knockout (α1D-KO) mice to aid in the pharmacological characterization. 2 Mouse whole vas deferens was stimulated with a single pulse every 5 min. Once a stable response had been obtained, vehicle or antagonist was administered cumulatively at 5-min intervals and a response to stimulation obtained 5 min later. Cumulative concentration-response curves were also obtained for noradrenaline. 3 In vas deferens from α1D-KO mice, the contractile response to low concentrations of noradrenaline and the contractile response to a single stimulus were significantly reduced as compared to wild type (WT). 4 The α1D-adrenoceptor selective antagonist, BMY 7378, produced a concentration-dependent inhibition of single pulse-evoked contractions of vas deferens from WT and α1D-KO mice. BMY 7378 was significantly less potent in inhibiting stimulation-evoked contractions in vas deferens from α1D-KO mice. 5 It is concluded that α1D-adrenoceptors mediate a component of nerve- and agonist-evoked contractions of the vas deferens of WT mice. [ABSTRACT FROM AUTHOR]

Background and Purpose: We have investigated the ability of alpha(1)-adrenoceptor antagonists to affect the hyperthermia produced by methylenedioxy methamphetamine (MDMA) in conscious mice.Experimental Approach: Mice were implanted with temperature probes under ether anaesthesia and allowed 2 weeks recovery. MDMA (20 mg kg(-1)) was administered subcutaneously 30 min after vehicle or test antagonist or combination of antagonists and effects on body temperature monitored.Key Results: Following vehicle, MDMA produced a hyperthermia, reaching a maximum increase of 1.8 degrees C at 140 min. Prazosin (0.1 mg kg(-1)) revealed an early significant hypothermia to MDMA of -1.94 degrees C. The alpha(1A)-adrenoceptor antagonist RS 100329 (0.1 mg kg(-1)), or the alpha(1D)-adrenoceptor antagonist BMY 7378 (0.5 mg kg(-1)) given alone, did not reveal a hypothermia to MDMA, but the combination of the two antagonists revealed a significant hypothermia to MDMA. The putative alpha(1B)-adrenoceptor antagonist cyclazosin (1 mg kg(-1)) also revealed a significant hypothermia to MDMA, but actions of cyclazosin at the other alpha(1)-adrenoceptor subtypes cannot be excluded.Conclusions and Implications: More than one subtype of alpha(1)-adrenoceptor is involved in a component of the hyperthermic response to MDMA in mouse, probably both alpha(1A)- and alpha(1D)-adrenoceptors, and removal of this alpha(1)-adrenoceptor-mediated component reveals an initial hypothermia. [ABSTRACT FROM AUTHOR]

Background and purpose:We have investigated the ability of α1-adrenoceptor antagonists to affect the hyperthermia produced by methylenedioxy methamphetamine (MDMA) in conscious mice.Experimental approach:Mice were implanted with temperature probes under ether anaesthesia and allowed 2 weeks recovery. MDMA (20 mg kg−1) was administered subcutaneously 30 min after vehicle or test antagonist or combination of antagonists and effects on body temperature monitored.Key results:Following vehicle, MDMA produced a hyperthermia, reaching a maximum increase of 1.8 °C at 140 min. Prazosin (0.1 mg kg−1) revealed an early significant hypothermia to MDMA of −1.94 °C. The α1A-adrenoceptor antagonist RS 100329 (0.1 mg kg−1), or the α1D-adrenoceptor antagonist BMY 7378 (0.5 mg kg−1) given alone, did not reveal a hypothermia to MDMA, but the combination of the two antagonists revealed a significant hypothermia to MDMA. The putative α1B-adrenoceptor anatagonist cyclazosin (1 mg kg−1) also revealed a significant hypothermia to MDMA, but actions of cyclazosin at the other α1-adrenoceptor subtypes cannot be excluded.Conclusions and implications:More than one subtype of α1-adrenoceptor is involved in a component of the hyperthermic response to MDMA in mouse, probably both α1A- and α1D-adrenoceptors, and removal of this α1-adrenoceptor-mediated component reveals an initial hypothermia.British Journal of Pharmacology (2008) 153, 591–597; doi:10.1038/sj.bjp.0707590; published online 26 November 2007 [ABSTRACT FROM AUTHOR]

1 We have investigated the actions of the α1D-adrenoceptor selective antagonist BMY 7378 in comparison with yohimbine at α1- and α2-adrenoceptors. 2 In rat aorta ( α1D-adrenoceptor), BMY 7378 (p A2 of 8.67) was about 100 times more potent than yohimbine (p A2 of 6.62) at antagonizing the contractile response to noradrenaline. 3 In human saphenous vein ( α2C-adrenoceptor), BMY 7378 (p A2 of 6.48) was approximately 10 times less potent than yohimbine (p A2 of 7.56) at antagonizing the contractile response to noradrenaline. 4 In prostatic portions of rat vas deferens, BMY 7378 (10 μ m) did not significantly affect the concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions by xylazine (an action at prejunctional α2D-adrenoceptors). 5 In ligand-binding studies, BMY 7378 showed 10-fold selectivity for α2C-adrenoceptors (p Ki of 6.54) over other α2-adrenoceptors. 6 It is concluded that BMY 7378, in addition to α1D-adrenoceptor selectivity in terms of α1-adrenoceptors, shows selectivity for α2C-adrenoceptors in terms of α2-adrenoceptors. [ABSTRACT FROM AUTHOR]

We have investigated the cardiovascular actions of thalidomide in vivo and in vitro. Blood pressure was recorded in pentobarbitone anaesthetized rats. Isometric contractions were examined in rings of rat tail artery and aorta. Radioligand binding studies of alpha(1A)- and alpha(1B)-adrenoceptor sites were carried out in membranes of rat submandibular gland and spleen, respectively. In pentobarbitone anaesthetized rats, thalidomide and the T-type calcium channel blocker NNC55-0396 (both 1mg/kg, i.v.) significantly reduced blood pressure. In rat tail artery, thalidomide (10-100 microM) produced relaxations of phenylephrine (1 microM) induced contractions. Also in tail artery, thalidomide (100 microM) significantly reduced the contraction to phenylephrine (1 microM), but not KCl (40mM), produced by calcium restoration, and NNC55-0396 (100 microM) had similar actions to thalidomide. Glibenclamide (10 microM), calphostin C (1 microM) or SB203580 (1 microM) failed to affect the inhibitory actions of thalidomide, and thalidomide did not affect contractions to caffeine (10mM). Ligand binding studies found no evidence for alpha(1A)- or alpha(1B)-adrenoceptor affinity of thalidomide, and functional studies in rat aorta found no evidence for alpha(1D)-adrenoceptor affinity. It is concluded that thalidomide has previously unreported vascular relaxant actions. Relaxant actions in vitro do not seem to involve alpha(1)-adrenoceptors, caffeine sensitive calcium stores, glibenclamide sensitive potassium channels, protein kinase C (PKC) or P38 mitogen activated protein kinase (P38 MAP kinase). However, actions of thalidomide resembled those of the T-type calcium channel blocker NNC 55-0396. Further study is necessary to establish the mode of action of thalidomide in causing relaxations., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background and Purpose: We have investigated the ability of the beta(3)-adrenoceptor antagonist 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4,-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride (SR59230A) to affect the hyperthermia produced by methylenedioxymethamphetamine (MDMA) in conscious mice and whether alpha(1)-adrenoceptor antagonist actions are involved., Experimental Approach: Mice were implanted with temperature probes under anaesthesia, and allowed 2 week recovery. MDMA (20 mg x kg(-1)) was administered subcutaneously 30 min after vehicle or test antagonist and effects on body temperature monitored by telemetry., Key Results: Following vehicle, MDMA produced a slowly developing hyperthermia, reaching a maximum increase of 1.8 degrees C at 130 min post injection. A low concentration of SR59230A (0.5 mg x kg(-1)) produced a small but significant attenuation of the slowly developing hyperthermia to MDMA. A high concentration of SR59230A (5 mg x kg(-1)) revealed a significant and marked early hypothermic reaction to MDMA, an effect that was mimicked by the alpha(1)-adrenoceptor antagonist prazosin. Functional and ligand binding studies revealed actions of SR59230A at alpha(1)-adrenoceptors., Conclusions and Implications: 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4,-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride in high concentrations modulates the hyperthermic actions of MDMA in mice in two ways: by blocking an early alpha(1)-adrenoceptor-mediated component to reveal a hypothermia, and by a small attenuation of the later hyperthermic component which may possibly be beta(3)-adrenoceptor-mediated (this seen with the low concentration of SR59230A). Hence, the major actions of SR59230A in modulating the actions of MDMA on temperature involve alpha(1)-adrenoceptor antagonism.

We have investigated the actions of the postacyclin receptor antagonist BAY 73-1449 on shunt vessel development and shunt flow in the portal vein ligated portal hypertensive Wistar rat in vivo. BAY 73-1449 (0.1-1 mg/kg), given intravenously, did not significantly reduce mesenteric inflow, but significantly reduced splenic shunt vessel outflow, compared to the effects of vehicle, in anaesthetized portal vein ligated rats as measured by shunt vessel conductance. There were no differences between portal vein ligated animals treated, beginning just before portal vein ligation, with vehicle for 7 days and animals treated for 7 days with BAY 73-1449 (1-5 mg/kg, s.c.) in the degree of porto-systemic shunting, as measured by the radioactive microsphere technique in anaesthetized rats. Portal pressure was similar in animals treated with vehicle or BAY 73-1449. It is concluded that the prostacyclin receptor antagonist BAY 73-1449 can acutely reduce shunt vessel blood flow in portal hypertensive rats.

We have investigated the role of nitric oxide (NO) in relaxations to beta-adrenoceptor agonists in mesenteric artery from wild-type (WT) and NO synthase-3 knockout (NOS-3-KO) mice. Isoprenaline, formoterol and BRL 37344 ((R(),R())-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid) were chosen as non-selective and beta(2)- and beta(3)-adrenoceptor agonists, respectively. Atenolol, ICI 118,551 ((+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) and SR59230A (1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol hydrochloride) were chosen as selective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonists, respectively. Experiments employing isoprenaline were carried out in the presence of prazosin (0.1 microM). Isoprenaline produced relaxations with a potency of 5.68+/-0.36 (-log M, n=6) in WT mice. Relaxations to isoprenaline were blocked by atenolol (10 microM) and were absent in vessels from NOS-3-KO animals. Formoterol produced relaxations with two components. ICI 118,551 (1 microM) abolished relaxations to low concentrations of formoterol (0.1-10 microM), but failed to affect relaxations to formoterol (100 microM). In NOS-3-KO mice only the highest concentration of formoterol (100 microM) produced relaxations: the relaxation was resistant to all of the beta-adrenoceptor antagonists employed. BRL 37344 (5.75+/-0.28, n=9) was approximately equipotent with isoprenaline but produced a smaller degree of relaxation, in WT mice. SR59230A (1 microM) abolished relaxations to BRL 37344 in WT mice. In NOS-3-KO mice, BRL 37344 produced concentration-dependent relaxations which were abolished by SR59230A. It is concluded that the predominant beta-adrenoceptor mediating relaxations in mouse mesenteric artery is beta(1), and relaxations involve NOS-3. In addition, beta(3)-adrenoceptors mediate smaller relaxations at least partly independent of NOS-3, and beta(2)-adrenoceptors may mediate smaller relaxations dependent on NOS-3.

The effects of injection of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and N-ethyl-3,4-methylenedioxyamphetamine (MDEA) (all 20 mg kg(-1)) on blood pressure, heart rate, core body temperature and locomotor activity in conscious rats were investigated using radiotelemetry. MDMA and MDA produced a prolonged increase in both systolic and diastolic pressures, with MDA causing the most marked rise. MDEA produced a transient but nonsignificant fall in diastolic pressure. The pressor response produced by MDA was accompanied by bradycardia. All three amphetamine derivatives caused an initial hypothermic response; however, MDA also produced a subsequent hyperthermia, and the speed of recovery from hypothermia was MDA>MDMA>MDEA. The alpha2A-adrenoceptor antagonist 2-((4,5-dihydro-1H-imidazol-2-yl)methyl)-2,3-dihydro-1-methyl-1H-isoindole (BRL 44408) (1 mg kg(-1)) prolonged the hypothermic response to MDMA. Only MDA induced locomotor activity when given alone, but in the presence of BRL 44408, MDMA produced increased locomotor activity. The order of potency for producing isometric contractions of rat aorta (alpha1D) and vas deferens (alpha1A) was MDA>MDMA>MDEA, with MDEA acting as an alpha1-adrenoceptor antagonist with a pK(B) of 4.79+/-0.12 (n = 4) in aorta. The order of potency for prejunctional inhibition of stimulation-evoked contractions in rat vas deferens (alpha2A-adrenoceptor mediated) was MDA>MDMA>MDEA. Blood pressure actions of the three amphetamine derivatives may be at least partly due to alpha1-adrenoceptor agonism or antagonism. The reversal of the hypothermic actions are at least partly due to alpha2A-adrenoceptor agonism since the hypothermic response was more prolonged with MDEA which exhibits low alpha2A-adrenoceptor potency, and effects of MDMA after alpha2A-adrenoceptor antagonism were similar to those of MDEA.

1 We have investigated the actions of the alpha(1D)-adrenoceptor selective antagonist BMY 7378 in comparison with yohimbine at alpha(1)- and alpha(2)-adrenoceptors. 2 In rat aorta (alpha(1D)-adrenoceptor), BMY 7378 (pA(2) of 8.67) was about 100 times more potent than yohimbine (pA(2) of 6.62) at antagonizing the contractile response to noradrenaline. 3 In human saphenous vein (alpha(2C)-adrenoceptor), BMY 7378 (pA(2) of 6.48) was approximately 10 times less potent than yohimbine (pA(2) of 7.56) at antagonizing the contractile response to noradrenaline. 4 In prostatic portions of rat vas deferens, BMY 7378 (10 mum) did not significantly affect the concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions by xylazine (an action at prejunctional alpha(2D)-adrenoceptors). 5 In ligand-binding studies, BMY 7378 showed 10-fold selectivity for alpha(2C)-adrenoceptors (pK(i) of 6.54) over other alpha(2)-adrenoceptors. 6 It is concluded that BMY 7378, in addition to alpha(1D)-adrenoceptor selectivity in terms of alpha(1)-adrenoceptors, shows selectivity for alpha(2C)-adrenoceptors in terms of alpha(2)-adrenoceptors.

3,4-Methylenedioxymetamphetamine (MDMA) produces complex effects on body temperature, including hypo- and hyperthermic components that vary with ambient temperature and strain of rat. We have previously reported that MDMA is an alpha(2)-adrenoceptor agonist, and alpha(2)-adrenoceptor agonists such as clonidine produce hypothermia. The purpose of this study was to investigate the effects of MDMA on core body temperature measured by radiotelemetry in conscious wild-type (WT) and alpha(2A)-knockout (alpha(2A)-KO) mice. Clonidine (0.1 mg kg(-1), subcutaneously (s.c.)) produced a hypothermic response in WT mice, but did not significantly affect temperature in alpha(2)-KO mice. MDMA (20 mg kg(-1), s.c.) produced a significant hyperthermia in WT mice beginning at approximately 100 min after injection, recovering by 300 min, but produced a biphasic response, hypothermia followed by hyperthermia, in alpha(2)-KO mice. In WT mice, following the alpha(2A)-adrenoceptor antagonist 2-((4,5-dihydro-1H-imidazol-2-yl)methyl)-2,3-dihydro-1-methyl-1H-isoindole (1 mg kg(-1), s.c.), MDMA (20 mg kg(-1)) produced an initial hypothermia. Hence, alpha(2)-adrenoceptor agonist actions of MDMA contribute to its effects on body temperature, but in a surprising way. Although selective alpha(2A)-adrenoceptor agonism produces hypothermia, the alpha(2A)-adrenoceptor actions of MDMA alter the body temperature response to MDMA from biphasic (hypothermia followed by hyperthermia) to monophasic hyperthemia.

It has been recently reported that the oestrogen receptor alpha agonist PPT (4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl) tris-phenol) is more potent than the oestrogen receptor beta agonist DPN (2,3-bis(4-hydroxyphenyl)-propionitrile) at producing relaxations in rat mesenteric artery. We have investigated the relaxant actions of PPT and DPN in rat and mouse aorta and mesenteric artery. In rat aortic rings contracted with KCl (40 mM), the oestrogen receptor beta agonist DPN produced significantly greater relaxations than the oestrogen receptor alpha agonist PPT. In wild-type (WT) mouse aorta, the same result was found, but in WT mouse mesenteric artery, as in rat mesenteric artery, DPN was significantly less potent than PPT in females but had similar potency to PPT in males. Relaxations to DPN also occurred in aorta from nitric oxide synthase-3-knockout (NOS-3-KO) mice, and in denuded aorta from both mouse and rat. Hence, in the mouse mesenteric artery, as in the rat mesenteric artery, PPT is at least as potent as DPN at producing relaxations; however, DPN was much more potent than PPT in the rat and mouse aorta. Effects of oestrogen receptor subtype selective agonists are tissue dependent. In addition, actions are largely endothelium-independent.

We have previously demonstrated that contractions of rat vas deferens to exogenous noradrenaline involve predominantly alpha(1A)-adrenoceptors, but that contractions to endogenous noradrenaline involve predominantly alpha(1D)-adrenoceptors. In this study, we have examined the effects of sympathectomy on the subtypes of alpha(1)-adrenoceptor in rat vas deferens in radioligand binding and functional studies. In vehicle-treated tissues, antagonist displacement of [(3)H]prazosin binding to alpha(1)-adrenoceptors was consistent with a single population of alpha(1)-adrenoceptors. Binding affinities for a range of alpha(1)-adrenoceptor antagonists were expressed as pK(i) values and correlated with known affinities for alpha(1)-adrenoceptor subtypes. The correlation was significant only with alpha(1A)-adrenoceptors. In tissues from rats sympathectomised with 6-hydroxy-dopamine (2 x 100 mg kg(-1) i.p.), binding affinity for the alpha(1D)-adrenoceptor antagonist BMY 7378 fitted best with a two-site model. In functional studies, the potency of noradrenaline at producing total (phasic plus tonic) but not tonic contractions was increased in tissues from sympathectomised rats. Results obtained from sympathectomised rats suggest that phasic contractions are mainly alpha(1D)-adrenoceptor mediated, whereas tonic contractions are mainly alpha(1A)-adrenoceptor mediated, based on the effects of BMY 7378 and the alpha(1A)-adrenoceptor antagonist RS 100329. It is concluded that the predominant alpha(1)-adrenoceptor in vehicle-treated rat vas deferens is the alpha(1A)-adrenoceptor, both in terms of ligand binding and contractions to exogenous agonists. The alpha(1D)-adrenoceptor is only detectable by ligand binding following chemical sympathectomy, but is involved in noradrenaline-evoked contractions, particularly phasic contractions, of rat vas deferens., (British Journal of Pharmacology (2004).)

The effects of pre-hepatic portal hypertension were examined on the responsiveness of aorta and mesenteric artery from wild-type, inducible nitric oxide synthase knockout (iNOS-KO) and endothelial nitric oxide synthase knockout (eNOS-KO) mice. Mice were sham-operated or made portal hypertensive by creating a calibrated portal vein stenosis. Acetylcholine produced marked relaxations in phenylephrine (10 microM) contracted aorta and mesenteric artery from wild-type and iNOS-KO, both sham and portal hypertensive, but relaxations were abolished in vessels from eNOS-KO mice. There were no significant differences between sham and portal hypertensive animals within groups in the effects of acetylcholine. The potency of KCl was significantly increased in aorta and mesenteric artery from eNOS-KO mice. The maximum contraction to the alpha(1)-adrenoceptor agonist phenylephrine was significantly increased in aorta from eNOS-KO, as compared with wild-type mice. There were no significant differences between sham and portal hypertensive animals within each group in contractions of aorta to KCl or phenylephrine. However, in mesenteric artery, although portal hypertension did not change responsiveness in wild-type or eNOS-KO as compared to sham animals, the potency of phenylephrine was significantly reduced in portal hypertensive iNOS-KO mice as compared to shams. Hence, portal hypertension as compared to sham operation did not affect responses to vasoconstrictors in mouse aorta, but in mouse mesenteric artery portal hypertension affected vascular responses in iNOS-KO mice, suggesting that iNOS is involved in the mesenteric vascular response to portal vein ligation.

A number of deaths have been attributed to severe hyperthermia resulting from the ingestion of 3,4-methylenedioxymethamphetamine (MDMA). The mechanisms underlying these events are unclear. In an attempt to further advance our understanding of these mechanism the present study investigated the effects of the selective GABA(A) agonist muscimol and the GABA(B) agonist baclofen on MDMA-induced responses in the rat. Baclofen at 1 and 3 mg/kg and muscimol at 0.3 and 1 mg/kg administered alone had no effect on heart rate, core body temperature or spontaneous locomotor activity as measured by radiotelemetry. MDMA at 15 mg/kg produced a significant increase in heart rate, body temperature and locomotor activity (P < 0.005) which were unaffected by prior treatment with muscimol. In contrast, prior treatment with baclofen (3 mg/kg) resulted in MDMA causing a sustained lowering of body temperature (P < 0.05), with no effect on heart rate and a small transient delay in the increase in locomotor activity. Baclofen pretreatment (3 mg/kg) not only prolonged the time taken for animals to reach a core body temperature of 40 degrees C (P < 0.001), but also reduced the percentage of rats attaining a core body temperature of 40 degrees C. These data suggest that stimulation of GABA(B) receptors may provide a mechanism for the treatment of MDMA-induced hyperthermia.

The effect of dietary fish oils on development of hypertension and vascular response in vitro were studied in rats and a primate. Dietary fish oils (MaxEPA and an n-3 ethyl ester concentrate of higher EPA and DHA content) were administered to spontaneously hypertensive (SHR), stroke-prone spontaneously hypertensive (SHR-SP) and a backcross of SHR and Wistar Kyoto (SHR/WKY) rats from 4-16 weeks of age. Blood pressure was monitored during the feeding period and vascular responses measured in the aorta and mesenteric vascular bed in vitro. Depending on the strain of rat used and the composition of the fish oil the attenuation in blood pressure was 10-26 mmHg. Fish oils attenuated the response mediated by sympathetic nerve stimulation or intralumenal norepinephrine in the perfused mesenteric vascular bed preparation from the SHR. This attenuation was more pronounced for fish oils enriched with eicosapentaenoic acid and docosahexaenoic acid and was more prominent in the SHR and SHR/WKY backcross than it was in the SHR-SP. Prostanoid synthesis or nitric oxide modulation of alpha-adrenoceptor responses were shown not to be involved in the attenuation of vascular responses produced by fish oil. The maximum contraction of aortic ring preparations in response to norepinephrine (NE) was significantly smaller in SHR than WKY rats fed olive oil and for SHR rats maintained on fish oils the contraction was close to WKY olive oil values. Evidence was obtained also for a modulation of vasoconstrictor responses by dietary fish oils in the perfused mesenteric bed of the marmoset monkey.

We have previously shown cheek cell Na+/H+ antiporter activity to be reduced in human hypertensives. We have now examined the relationship between abnormal antiporter activity and a variety of salivary factors. Total protein concentration and amylase activity were higher in hypertensives, but salivary flow rate and epidermal growth factor, transforming growth factor-alpha, calcium, and magnesium concentrations were not significantly different between hypertensives and normotensives. The lowered cheek cell Na+/H+ antiporter activity in those hypertensives with diastolic BP greater than 95 mmHg was accompanied by lowered salivary Na+/H+ ratios. In borderline hypertensives (diastolic BP between 90 and 95 mmHg), the Na+/H+ ratio was reduced to a similar extent to that seen in those hypertensives with a diastolic BP above 95 mmHg, however the cheek cell antiporter activity was not reduced, suggesting that these two differences are not related in a simple fashion in all hypertensives. It is concluded that it is unlikely that differences in salivary growth factors explain the lowered cheek cell Na+/H+ antiporter activity observed in human hypertension. Our findings indicate that salivary electrolyte composition may be related to cheek cell Na+/H+ antiporter activity and these parameters may be altered in hypertension.

In the present study, we compared the blood pressure in the SHR-SP and in the spontaneously hypertensive rat (SHR) after dietary administration of fish oil from 4 to 17 weeks of age. The retarding influence of dietary fish oils on the development of hypertension was prominent in the SHR (26 mmHg) and not evident in the SHR-SP (8 mmHg). The enhanced development of blood pressure in both the SHR and the SHR-SP is characterised by an elevated maximum contraction in the mesenteric vascular bed to sympathetic nerve stimulation and to injected noradrenaline. In SHR, but not SHR-SP, this maximum contraction was significantly attenuated by dietary fish oil. Likewise, acetylcholine mediated relaxation of the isolated aorta was enhanced in preparations from the SHR but not the SHR-SP. These physiological changes were also associated with a change in the total n-3 polyunsaturated fatty acids (PUFAs) content in vascular tissue, which were inversely proportional to the prevailing blood pressure values seen in all three strains of rat receiving dietary fish oils. Platelet activated thromboxane production was equally depressed in WKY (Wistar Kyoto), SHR and SHR-SP rats. The results indicate that the blood pressure lowering effect of fish oil when administered during the period of development of hypertension is much greater in the SHR than it is in the SHR-SP. Furthermore the lowering of blood pressure by fish oil administration is related to a restoration of normal vascular contraction and normal vascular relaxation, but not related to a suppression of serum thromboxane production.

Aortic ring preparations from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated with N omega-nitro-L-arginine (NOLA, 10(-4) M). This produced a sustained contraction in preparations from SHR but not WKY rats. A similar contraction in aortic ring preparations from the SHR was produced with methylene blue (10(-5) M) and NG-monomethyl-L-arginine (10(-5) M). The NOLA-induced contraction was reversed with indomethacin (8 x 10(-6) M), ridogrel (10(-5) M) and SQ 29548 (10(-6) M) thus confirming the involvement of thromboxane A2/prostaglandin H2 processes. Subsequent experiments demonstrated that the thromboxane-like contraction was not dependent upon the presence of endothelial cells and occurred in preparations from young, prehypertensive (5 week) and older (17 week) SHRs. The thromboxane-like contraction was markedly suppressed with chronic captopril treatment and reinstated 4 weeks after withdrawal from captopril. The addition of saralasin (10(-6) M) or captopril (10(-6) M) to aortic ring preparations did not suppress the thromboxane-like contractions. The foregoing findings support the presence of a nonendothelial cell thromboxane-like constrictor agent in the aorta of the SHR that is revealed after impairment of nitric oxide production. The activity of the thromboxane-like constrictor process is not tightly linked to prevailing blood pressure, but is reduced with chronic in vivo inhibition of the angiotensin-converting enzyme.

An influence of fish oils (rich in eicosapentaenoic acid, EPA) in modulating (a) the development of hypertension in the stroke prone spontaneously hypertensive rat (SHRSP) and (b) vascular neuroeffector mechanisms in the SHRSP was explored. Rats (SHRSP) were placed on a series of diets for a period of 13 weeks from 4 weeks of age. The fatty acid composition of the diets was derived from fish oil, olive oil, safflower oil or beef fat. After 13 weeks, rats fed diets containing fish oil (at a total dietary fat level of either 5% or 15%) had mean blood pressures approximately 20-25 mmHg lower than other SHRSP rats maintained on diets containing either olive oil, safflower oil or beef fat. The dietary schedules providing fish oil depressed the contractile responses mediated by sympathetic nerve stimulation in the mesenteric vascular bed preparation. The results suggest that the n-3 polyunsaturated fatty acids retard the development of hypertension in the SHRSP rat and modulate the contractile responses of blood vessels mediated by sympathetic nerves in the isolated perfused mesenteric vascular bed preparation.