The effect of branded versus standardized e-cigarette packaging and device designs: an experimental study of youth interest in vaping products.

OBJECTIVES: Standardized ('plain') packaging is effective in reducing the appeal of cigarettes among young people. This study examined the impact of plain packaging and brand imagery on interest in trying e-cigarettes among youth. STUDY DESIGN: Experimental design. METHODS: Two online experiments were conducted in February 2020 as part of the ITC Youth Tobacco & Vaping Survey, conducted with 13,624 16- to 19-year-olds in Canada, England, and the USA. In the between-group Experiment 1, participants were randomized to view a set of 3 e-cigarette brands, in either their original external packaging ('branded' condition) or standardized olive-green packaging ('standardized' condition), and asked to select the product they would be most interested in trying. The within-group Experiment 2 examined brand imagery directly on devices, including potential differences in appeal among subgroups. Each participant viewed 4 pod-style e-cigarette devices: one 'plain' and 3 in colourful 'skins'. Logistic regression models were conducted to test the effect of condition, adjusting for demographics, smoking and vaping status. RESULTS: In Experiment 1, participants in the 'standardized' packaging condition were significantly more likely to indicate 'I have no interest in trying any of these products' (72.3%) than those in the 'branded' condition (66.9%, AOR 1.45, 95% CI 1.33-1.59). Experiment 2 results indicated differences in e-cigarette appeal by sex in the selection of male- and female-oriented designs, and by cannabis use for a Rastafarian-themed design. CONCLUSIONS: Brand imagery on e-cigarettes can target products to specific subgroups. Removal of imagery, in the form of standardized packaging, has the potential to reduce interest in trying e-cigarettes among young people.

Coaching to enhance qualified surgeons' non-technical skills: a systematic review.

INTRODUCTION: The lack of an effective continuing professional development programme for qualified surgeons, specifically one that enhances non-technical skills (NTS), is an issue receiving increased attention. Peer-based coaching, used in multiple professions, is a proposed method to deliver this. The aim of this study was to undertake a systematic review of the literature to summarize the quantity and quality of studies involving surgical coaching of NTS in qualified surgeons. METHODS: A systematic search of the literature was performed through MEDLINE, EMBASE, Cochrane Collaboration and PsychINFO. Studies were selected based on predefined inclusion and exclusion criteria. Data for the included studies was independently extracted by two reviewers and the quality of the studies evaluated using the Medical Education and Research Study Quality Instrument (MERSQI). RESULTS: Some 4319 articles were screened from which 19 met the inclusion criteria. Ten studies involved coaching of individual surgeons and nine looked at group coaching of surgeons as part of a team. Group coaching studies used non-surgeons as coaches, included objective assessment of NTS, and were of a higher quality (average MERSQI 13.58). Individual coaching studies focused on learner perception, used experienced surgeons as coaches and were of a lower quality (average MERSQI 11.58). Individual coaching did not show an objective improvement in NTS for qualified surgeons in any study. CONCLUSION: Surgical coaching of qualified surgeons' NTS in a group setting was found to be effective. Coaching of individual surgeons revealed an overall positive learner perception but did not show an objective improvement in NTS for qualified surgeons.

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.

Losartan, an orally active angiotensin (AT1) receptor antagonist: a review of its efficacy and safety in essential hypertension.

Losartan potassium, an angiotensin II receptor antagonist, is the first of a new class of agents to be introduced for the treatment of hypertension. In this review, we describe the clinical pharmacology of losartan, including its pharmacokinetics in healthy, male volunteers and special patient groups, such as the elderly, patients with liver disease and patients with renal impairment. We also review its pharmacodynamics, including safety and tolerability; specificity of action; and the effect of salt depletion. We then review the studies examining clinical efficacy and safety in hypertension.

A postsynaptic location of alpha 2 adrenoceptors in vascular smooth muscle: in vivo studies in the conscious rabbit.

The rise in blood pressure after intravenous administration of a range of alpha-adrenoceptor agonists and the effect of alpha adrenoceptor antagonists was studied in groups of conscious rabbits. Phentolamine was equally effective at blocking the pressor response to the alpha 1 adrenoceptor agonist phenylephrine and the mixed alpha 1/alpha 2 adrenoceptor agonist noradrenaline. Phenoxybenzamine which acts preferentially on alpha 1 adrenoceptors and the more specific alpha 1 adrenoceptor antagonist prazosin were more effective against phenylephrine induced rises in pressure, while yohimbine and alpha yohimbine which preferentially act on alpha 2 adrenoceptors were more effective against noradrenaline. The immediate pressor response to intravenous injections of the alpha 2 adrenoceptor agonists clonidine and guanabenz was blocked more effectively by phentolamine than prazosin when doses which gave a postsynaptic location of both alpha 1 and alpha 2 adrenoceptors both of which mediate vasoconstrictor responses in vascular smooth muscle.

Pharmacological characterisation of endothelium-dependent relaxation in human radial artery: comparison with internal thoracic artery.

OBJECTIVE: The aim of this study was to investigate the contribution of nitric oxide/prostanoid-independent pathways to endothelium-dependent vasorelaxation in human conduit arteries. METHODS: Rings of internal thoracic artery (ITA) and radial artery (RA) taken from patients undergoing coronary artery bypass graft surgery were suspended in 10-ml organ baths and relaxation to carbachol and bradykinin studied in the presence and absence of nitric oxide synthase (NOS) inhibitors and potassium channel blockers. RESULTS: No significant relaxation to carbachol or bradykinin was observed in ITA after NOS inhibition. In contrast, in RA less than 40% attenuation of relaxation to carbachol or bradykinin was achieved with any of the NOS inhibitors. In the presence of 20 mM K+ relaxation to carbachol and bradykinin was inhibited by 28 +/- 9% and 42 +/- 9% while in the presence of L-NAME 200 microM + 20 mM K+ relaxation was inhibited by 66 +/- 6% and 70 +/- 4% respectively in this artery. Tetraethylammonium, glibenclamide, apamin and iberiotoxin had little effect on relaxation to carbachol but charybdotoxin alone and charybdotoxin plus apamin attenuated relaxation to carbachol by 23 +/- 4% and 49 +/- 9% in RA. In the presence of L-NAME 200 microM attenuation of these relaxations were increased to 60 +/- 4% and 78 +/- 4%. CONCLUSION: In ITA relaxations to carbachol and bradykinin were mediated via nitric oxide. In contrast in RA, a conduit vessel of similar diameter, both nitric oxide-dependent and independent pathways appeared to contribute to vascular relaxation. This nitric oxide-independent relaxation involved opening of Ca2+ activated potassium channel(s). The existence of alternative pathways mediating endothelium-independent relaxation could be important under pathological conditions and may contribute to the long term survival of radial artery grafts.

Alpha adrenoceptors and autonomic mechanisms in perinephritis hypertension in the rabbit.

Increased pressor responses to norepinephrine and other pressor agents have been reported to occur in human essential hypertension and in several animal models of experimental hypertension. These increased responses might be related to the development of hypertension or could be a secondary consequence of the elevation in blood pressure. We have examined pressor responses to alpha-adrenoceptor agonists and to angiotensin II in male New Zealand White rabbits with perinephritic hypertension. Increased pressor responses were observed for the alpha 1 adrenoceptor agonist phenylephrine and the mixed alpha 1/alpha 2-adrenoceptor agonist norepinephrine but not for the alpha 2 adrenoceptor selective agonist guanabenz or angiotensin II. The increase occurred within 7 days of surgery and in some animals was observed when mean arterial pressure was not significantly elevated. It could not readily be attributed to intimal thickening or hypertrophy of the arterial wall, altered basal levels of norepinephrine or epinephrine, changes in norepinephrine clearance, beta-adrenoceptor interactions, or decreased baroreceptor sensitivity. However, the possibility that vascular hypertrophy and decreased baroreflex sensitivity may contribute to the increase at later times cannot be excluded. In all tissues examined, specific prazosin binding was decreased in the older animals and specific clonidine binding was decreased in forebrain. However, these changes were observed in both hypertensive and sham-operated animals and were probably age-related. We believe the increased response to alpha 1-adrenoceptor agonists may be related to changes at a postreceptor site in the coupling of receptor activation to smooth muscle contraction.

Concentration-effect analysis of antihypertensive drug responses.

It is now widely recognized that a rigid stepped-care approach to antihypertensive therapy is not universally appropriate. Individualized treatment may result in good or better blood pressure control and a simpler regimen without troublesome side effects. Successful development of such a strategy depends on accurate characterization of a dose-response relation and quantitative assessment of the response in each individual. In the past such relations have proved to be hard to identify for antihypertensive drugs, often because of inappropriate study design during drug development. Despite failure of earlier studies to identify drug concentration-antihypertensive response relations, use of concentration-effect modeling, which recognizes and characterizes the temporal discrepancy between drug concentration and effect, has proved more successful. By using such approach, it has been possible to characterize the concentration-effect relations after acute and steady-state antihypertensive therapy with prazosin, doxazosin, nifedipine, verapamil, and enalapril. With enalapril and nifedipine, it has been demonstrated that the mathematical parameters of effect derived from the first dose can predict the response to these drugs after 4-6 weeks of treatment. These findings suggest that the definition of individual concentration-effect relations may be of value in the rational choice of antihypertensive drug therapy and optimization of dose and dose frequency. In particular, the approach can provide valuable information on dose-effect relations and should optimize choice of dose intervals in drug development and practice.

Opiate analogs, substance P, and baroreceptor reflexes in the rabbit.

The putative transmitters, enkephalins and substance P, and their binding sites have been identified in the nucleus of the solitary tract. Their role in the modulation of baroreceptor reflex activity is the subject of this study in the rabbit. A stable decarboxy analog of leu-enkephalin, RX 783016, which has mu receptor specificity, was used to attenuate the baroreflex sensitivity to intravenous phenylephrine. RX 783016, 50 micrograms/kg intracisternally, did not alter resting heart rate of blood pressure. Intravenous administration of the opiate receptor antagonist, naloxone, prevented the effects of RX 783016. Naloxone given alone significantly increased reflex sensitivity. Substance P given intracisternally in low doses (1 to 10 ng/kg) caused a dose-dependent pressor response, which was reduced by pretreatment with morphine and enhanced by naloxone. Bilateral sinoaortic denervation also enhanced the pressor response to substance P, but after deafferentation, naloxone had no further effect. It is proposed that enkephalin-containing neurons, acting through mu receptors, and substance P neurons influence baroreceptor reflex activity by modulating respectively the primary and second order neurons of the baroreceptor reflex.

Endogenous opioids and baroreflex control in humans.

We describe two studies designed to elucidate the role of endogenous opioids in blood pressure control in humans. In the first study, nine normal subjects received infusions of DAMME (a metenkephalin analog), naloxone, or saline, and blood pressure, heart rate, and plasma norepinephrine concentration were determined supine and following 5 minutes of 70 degrees head-up tilt at intervals for 6 hours. Blood pressure following tilt was significantly decreased by DAMME but not influenced by naloxone, the effect being most marked at 3 hours (placebo = 110 +/- 6/78 +/- 7 mm Hg; naloxone = 106 +/- 10/79 +/- 5 mm Hg; DAMME = 96 +/- 16/67 +/- 8 mm Hg (p less than 0.01). However, heart rate and plasma norepinephrine did not rise in response to this hypotension. Heart rates at 3 hours were: placebo = 87 +/- 16 bpm; naloxone = 88 +/- 19 bpm; DAMME = 89 +/- 23 bpm. Plasma norepinephrine levels (nmol/liter) at 3 hours were: placebo = 6.0 +/- 2.2; naloxone = 5.8 +/- 1.9; DAMME = 6.0 +/- 1.9. In the second study, seven normal subjects had blood pressure reduced by incremental infusions of sodium nitroprusside, and the effects of placebo, naloxone, and DAMME on the slope of the heart period/blood pressure relationship investigated. Naloxone significantly increased the slope by 90% and DAMME significantly reduced the slope by 30%. It is concluded that endogenous opioids modulate the baroreflex control of blood pressure in normal humans.

Kinetic-dynamic relations and individual responses to enalapril.

Pharmacokinetic and pharmacodynamic variability largely account for interindividual differences in the response to antihypertensive drugs including angiotensin converting enzyme inhibitors. The factors determining the response to enalapril have been investigated in a placebo-controlled study in essential hypertension. The effects of placebo, the initial dose of enalapril, and long-term (1 and 6 weeks) treatment with enalapril were studied in 13 subjects. By using an integrated kinetic-dynamic model that incorporates a parameter for saturable protein binding, individual responses for blood pressure reduction and angiotensin converting enzyme inhibition were characterized in terms of the maximum effect (Emax) and the drug concentration required to produce 50% of Emax (Ce50). In individual subjects, plasma enalaprilat concentrations could be correlated with falls in blood pressure and changes in plasma angiotensin converting enzyme activity. For the group, Emax was -46.1 +/- 16.5 and -19.7 +/- 3.8 mm Hg for systolic and diastolic blood pressure, respectively, and the corresponding Ce50 values were 66.1 +/- 20.2 and 61.6 +/- 22.5 ng/ml. For angiotensin converting enzyme inhibition, Emax (%) and Ce50 (ng/ml) were, respectively, 102.4 +/- 5 and 19.8 +/- 13 after the first dose, 103 +/- 5 and 33.4 +/- 20.3 after 1 week, and 101.3 +/- 2.2 and 31.3 +/- 18.9 after 6 weeks. There was no relation between the responsiveness to enalapril (Emax or Ce50) and patient age or plasma renin activity, but there was a significant positive correlation between Emax and the pretreatment blood pressure. In individual subjects, Emax (first dose) was directly correlated with Emax after 1 and 6 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Withdrawal reactions following cessation of central alpha-adrenergic receptor agonists.

Interruption of long-term treatment with alpha 2-adrenergic receptor agonists may be associated with reversal of their hemodynamic effects, clinical and biochemical evidence of increased peripheral sympathetic activity, and behavioral responses similar to those seen after narcotic or alcohol withdrawal. Reactions are most commonly observed after short-acting imidazoline drugs such as clonidine and tiamenidine. Reactions are less common after longer acting agents such as guanfacine. A new management approach to withdrawal has been evaluated, which uses a combination of alpha 1-blockade (prazosin) and cardioselective beta-blockade (atenolol) together with a benzodiazepine (chlordiazepoxide). Withdrawal reactions were not observed in eight patients in whom clonidine was withdrawn under cover of these agents. The mechanism of the withdrawal reaction may involve agonist-induced down regulation of alpha 2-adrenergic receptor affinity, number, or both. Experimental studies with the irreversible alpha-antagonist phenoxybenzamine on the turnover of alpha 2-receptors suggest that recovery of receptor number may be much slower in the brain than in the periphery.

Sex differences in the abundance of endothelial nitric oxide in a model of genetic hypertension.

A deficiency of nitric oxide may be responsible for the increased vascular resistance associated with human essential hypertension and that seen in animal models of hypertension. Premenopausal females are relatively protected from hypertension and cardiovascular complications. Levels of superoxide can influence the availability of nitric oxide. We hypothesize that there are differences in nitric oxide availability between stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) and that superoxide may be responsible for at least some of these differences. We studied vascular reactivity in endothelium-intact aortic rings from WKY and SHRSP. We measured nitric oxide synthase activity in endothelial cells removed from aortas and also measured circulating nitrite/nitrate levels. We found the response to N(G)-nitro-L-arginine methyl ester to be significantly greater in WKY compared with SHRSP (95% CI: 20 to 174; P=.015) and in females compared with males in WKY (95% CI: 143 to 333; P=.00004) and SHRSP (95% CI: 70 to 224; P=.0006). Endothelial nitric oxide synthase activity was significantly greater in SHRSP compared with WKY (95% CI: 2.3 to 17.6; P=.016). The EC50 for relaxation to carbachol was significantly greater in male rats compared with female rats (95% CI: -1.1 to -0.2; P=.003) within the SHRSP strain. The maximum relaxation to carbachol was significantly attenuated in stroke prone spontaneously hypertensive compared with Wistar-Kyoto rats (95% CI: 1.7 to 14.4; P=.015). Diethyldithiocarbamate had a significantly greater effect on the stroke prone spontaneously hypertensive rats' carbachol response than that of Wistar-Kyoto rats (95% CI: 14.3 to 47.0; P=.0008). We conclude that superoxide may be responsible for strain differences in vascular reactivity, whereas nitric oxide availability may be responsible for sex differences independently of endothelial nitric oxide synthase activity and superoxide.

Nifedipine: individual responses and concentration-effect relationships.

Dynamic and kinetic variability account for the large intersubject differences in the antihypertensive response to nifedipine, and a clear concentration-effect relationship has not been established. The effects of placebo, first dose, and chronic (1 and 6 weeks) treatment with nifedipine were studied in 14 subjects with essential hypertension using an integrated kinetic-dynamic model to calculate individual subject responsiveness in terms of fall in blood pressure per unit change in drug concentration. Nifedipine concentrations were well correlated with the fall in systolic blood pressure in individual subjects, and the mean responsiveness was -0.48 mm Hg/ng/ml after the first dose, -0.45 mm Hg/ng/ml after 1 week, and -0.49 mm Hg/ng/ml after 6 weeks. The responsiveness to the first dose of nifedipine was significantly correlated with the responsiveness after 1 (r = 0.83) and 6 weeks (r = 0.78) of therapy and with the height of the pretreatment blood pressure (r = 0.6). This study incorporated kinetic as well as dynamic information to characterize the antihypertensive response to nifedipine and identify nifedipine concentration-effect relationships in individual hypertensive subjects.

DNA synthesis and apoptosis in smooth muscle cells from a model of genetic hypertension.

The present study was designed to assess vascular smooth muscle cell (VSMC) proliferation and apoptosis in primary cultured VSMCs prepared from the aortic tunica media of adult (4 to 5 months old) age- and gender-matched groups of stroke-prone spontaneously hypertensive rats (SHRSP) and the normotensive reference strain, Wistar-Kyoto (WKY) rats. In the present study, VSMC proliferation was assessed with measurement of DNA synthesis in response to stimulation of G(0)/G(1) arrested VSMCs with 10% serum, whereas apoptosis was measured in response to serum deprivation. Apoptosis in aortic VSMCs was assessed in vitro with the technique of Annexin V binding in combination with propidium iodide exclusion with bivariate flow cytometric analysis. The percentage of necrotic VSMCs in the cell populations was assessed simultaneously. The light-scattering properties of the cells were assessed to provide further information on cell shrinkage and chromatin condensation. Results of the present study have shown enhanced DNA synthesis in VSMCs from SHRSP (n=10; 5.2+/-0.9 cpmx10(3)/mg protein) compared with WKY (n=12; 2.4+/-0.7 cpmx10(3) /mg protein; P<0.05, 95% CI, -5271 to -296). In addition, the results of the present study have demonstrated the role of serum in the survival of VSMCs in vitro, because SHRSP VSMCs underwent significantly more apoptosis in response to insult by serum deprivation (n=13; 10.21+/-1.8%) than WKY VSMCs (n=7; 3.44+/-1.4%; P<0.01, 95% CI, -11.5 to -2.0). Thus, it appears that both proliferation and apoptosis are enhanced in synthetic phenotype aortic medial VSMCs from the SHRSP in vitro.

Bradykinin B(2) receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men.

The physiological effects of angiotensin-converting enzyme (ACE) inhibition may be in part mediated by bradykinin. We investigated the effect of coadministration of the specific bradykinin B(2) receptor antagonist icatibant on hemodynamic and neurohormonal responses to acute intravenous ACE inhibition in normal men on a normal sodium diet. We performed a 4-phase, double-blind, double-dummy, placebo-controlled study in 12 male volunteers. The bradykinin antagonist icatibant (10 mg IV) was coadministered over the first 15 minutes of a 2-hour infusion of the ACE inhibitor perindoprilat (1.5 mg IV). Perindoprilat inhibited ACE activity and elicited the expected changes in active renin concentration and angiotensin peptides. Over the 3 hours after the start of drug infusion, perindoprilat lowered and icatibant increased mean arterial blood pressure (each P<0.0005 versus placebo). Coadministration of icatibant attenuated the mean arterial blood pressure response to perindoprilat (P<0.0005) but had no effect on neurohormonal responses to perindoprilat. Our study indicates that the bradykinin B(2) receptor antagonist icatibant attenuates the short-term blood pressure-lowering effect of acute ACE inhibition in normal men on a normal sodium diet. Bradykinin B(2) receptor antagonism alone increases resting blood pressure. Bradykinin may be involved in the control of blood pressure in the resting state in humans.

Changes in plasma norepinephrine, blood pressure and heart rate during physical activity in hypertensive man.

We have investigated the changes in plasma norepinephrine and blood pressure and heart rate during a range of physical activities in eight hypertensive subjects in order to determine whether changes in plasma norepinephrine reflect changes in sympathetic activity. Blood pressure was recorded over 24 hours from an intra-arterial cannula. Plasma norepinephrine, measured by a sensitive radioenzymatic method, increased progressively with increasing levels of physical activity. In each subject a statistically significant linear relationship was observed between the logarithm of plasma norepinephrine and systolic blood pressure. Analysis of variance showed that 66% of the variance of plasma norepinephrine was associated with changes in blood pressure and heart rate. These observations support the hypothesis that plasma norepinephrine reflects short-term changes in sympathetic activity. Use of the quantitative relationship described, in conjunction with measurements of norepinephrine metabolism, may help to determine the significance of increased levels of plasma norepinephrine observed in some hypertensive patients.

Calcium antagonists and hormone release: effect of nifedipine on luteinizing hormone-releasing hormone and thyrotropin-releasing hormone-induced pituitary hormone release.

In vitro evidence suggests that calcium is involved in the release of anterior pituitary hormones. Therefore, we studied the effect of the slow calcium channel blocker or calcium antagonist nifedipine on the FSH and LH responses to LRH and the TSH and PRL responses to TRH in vivo. Nine normal male subjects were studied on two occasions, and nifedipine (20 mg, by mouth, or matching placebo) was administered in a randomized single blind manner. Blood pressure and heart rate were measured at 0 and 30 min. The patients then received TRH (200 micrograms) and LRH (100 micrograms) iv. Blood levels of FSH, LH, TSH, and PRL were measured by RIA at 0, 30, 50, 60, and 120 min. Nifedipine lowered diastolic blood pressure significantly (--12 +/- 8 mm Hg; P less than 0.005) and increased heart rate (+ 17 /*- 10 beats/min; P less than 0.005), but had no effect on either baseline hormone levels or the incremental response of any hormone to its secretagogue. In contrast to the results of previous studies with verapamil, nifedipine does not inhibit the release of pituitary hormones. More information is required on the precise intracellular actions of these drugs before they can be used to study the role of calcium in hormone release. Nifedipine, however, may be less likely to influence pituitary function than verapamil.

Superoxide anion production is increased in a model of genetic hypertension: role of the endothelium.

The hypothesis that the decreased nitric oxide (NO) availability observed in spontaneously hypertensive stroke-prone rats (SHRSP) is due to excess superoxide (O2-) was examined. O2- generation, measured by lucigenin chemiluminescence, was studied in 12- to 16-week male and female Wistar-Kyoto rats (WKY) and SHRSP. In addition, expression of the gene encoding endothelial NO synthase, the enzyme involved in NO generation, was investigated. O2- generation was increased in male and female SHRSP (4.11+/-0.24 and 3. 84+/-0.28 nmol O2-. min-1. mg-1 respectively) compared with their WKY counterparts and was significantly higher in male than female WKY (1.22+/-0.08 in males and 0.8+/-0.08 nmol O2-. min-1. mg-1 respectively) (SHRSP versus WKY P<0.0001, 95% CI -3.39, -2.51; male versus female WKY P=0.0029, 95% CI -0.67, -0.17). Removal of the endothelium by rubbing or addition of NO synthase inhibitors attenuated O2- generation in SHRSP but not WKY. In males, removal of the endothelium reduced O2- generation from 3.86+/-0.12 to 1.35+/-0. 08 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.29, 2.81), whereas addition of L-NAME caused a reduction from 4.13+/-0.17 to 1.32+/-0.16 nmol. min-1. mg-1 (P<0.0001, 95% CI 2.36, 2.83). Similar reductions were observed in females. L-arginine had no significant effect, but tetrahydrobiopterin significantly decreased O2- generation in SHRSP from 4.04+/-0.11 to 2.36+/-0.40 nmol. min-1. mg-1 (P=0.0026, 95% CI 0.89, 2.44). Endothelial NO synthase mRNA expression was significantly greater in SHRSP than in WKY and in WKY males than in WKY females. These results show that O2- generation is increased in SHRSP and that the tissue and enzymatic sources of this excess O2- appear to be the endothelium and eNOS, respectively. The increase in O2- generation could explain the decreased availability of basal NO observed in this model of genetic hypertension.

Blood pressure in genetically hypertensive rats. Influence of the Y chromosome.

We used a cross between the stroke-prone spontaneously hypertensive rat (SHRSP) strain and the Wistar-Kyoto (WKY) normotensive strain to elucidate the genetic basis of hypertension. Previous studies have reported conflicting evidence for the contribution of the Y chromosome to hypertension in these models. To investigate further the role of the Y chromosome in hypertension, we performed two large reciprocal crosses: one with the SHRSP as a male progenitor of the cross, yielding 60 F2 rats, and another with the WKY as a male progenitor, yielding 83 F2 rats. The resulting F2 hybrids were phenotyped with the use of a radiotelemetry system (Data Sciences) for measurement of systolic, diastolic, and mean arterial pressures as well as heart rate and motor activity continuously for 96 hours at baseline and after 1% NaCl was added to the rats' drinking water for 12 days. Male F2 hybrids with the SHRSP grandfather had significantly higher average systolic, diastolic, and mean arterial pressures at baseline compared with male F2 hybrids with the WKY grandfather (188.7 +/- 18.1 versus 168.9 +/- 11.5, 130.3 +/- 14 versus 115.7 +/- 7.3, and 159.1 +/- 15.8 versus 141.5 +/- 9.4 mm Hg, respectively). These differences were also observed after salt loading (197.9 +/- 22.1 versus 176.8 +/- 11.7, 136.5 +/- 17.3 versus 120.7 +/- 7.6, and 166.7 +/- 19.5 versus 148 +/- 9.7 mm Hg, respectively; P < .0001 for each comparison). These results suggest that the SHRSP Y chromosome contains a locus or loci that contribute to hypertension in SHRSP/WKY F2 hybrids.