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We hypothesized that cardiovascular responses to static muscle contraction are mediated via changes in extracellular concentrations of monoamines (norepinephrine, dopamine and serotonin) following the administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, an AMPA-receptor antagonist) into the rostral (RVLM) or caudal (CVLM) ventrolateral medulla. For the RVLM experiments (n= 8), a 2-min static muscle contraction increased the mean arterial pressure (MAP) and heart rate (HR) by 23 +/- 2 mmHg and 28 +/- 8 bpm, respectively. During this contraction, the concentrations of norepinephrine, dopamine, and serotonin within the RVLM increased by 278 +/- 52%, 213 +/- 23%, and 232 +/- 24%, respectively. Microdialysis of CNQX (1.0 microM) for 30 min into the RVLM attenuated the increases in MAP and HR ( 11 +/- 2 mmHg and 14 +/- 5 bpm) without a change in developed muscle tension. The levels of norepinephrine, dopamine, and serotonin within the RVLM were also attenuated. In contrast, microdialysis of CNQX into the CVLM (n= 8) potentiated the contraction-evoked responses in MAP ( 21 +/- 2 vs 33 +/- 5 mmHg) and HR ( 25 +/- 5 vs 46 +/- 8 bpm) without any effect on the monoamine levels within the CVLM region. These results suggest that AMPA-receptor blockade within the RVLM and CVLM has opposing effects on cardiovascular responses during static muscle contraction. In addition, such receptor blockade modulates extracellular concentrations of monoamines within the RVLM but not in the CVLM. These results provide evidence that AMPA receptors within the ventrolateral medulla play a role in exercise pressor reflex., (Copyright 2001 Academic Press.)

During static muscle contraction, activation of opioid receptors alters the extracellular glutamate concentrations within the rostral ventrolateral medulla (RVLM). In addition, microdialysis of glutamate in the ventrolateral medulla (VLM) increases the release of norepinephrine (NE), dopamine (DA), and serotonin (5-HT). Therefore, we hypothesized that extracellular concentrations of these monoamines as well as cardiovascular responses during static skeletal muscle contraction would be modulated following administration of [D-Ala(2)]methionine enkephalinamide (DAME), an opioid receptor agonist, into the RVLM. Microdialysis of 100 microM DAME into the RVLM of 10 rats significantly (P<0.01) decreased extracellular levels (in pg/10 microl) of NE (from 3.3+/-0.3 to 1.9+/-0.3), DA (from 5.5+/-0.2 to 3.7+/-0.3), and 5-HT (from 6.1+/-0.8 to 3.6+/-0.2) during static exercise. After microdialysis of DAME, the exercise pressor reflex also significantly (P<0.01) decreased mean arterial pressure (MAP) by 13+/-3 mmHg and heart rate (HR) by 16+/-6 bpm, compared with control (MAP=22+/-4 mmHg and HR=31+/-7 bpm). Subsequently, after 30 min microdialysis of naloxone, an opioid receptor antagonist, muscle contraction increased the extracellular monoamine levels (in pg/10 microl, 3.8+/-0.3 NE; 5.2+/-0.3 DA; and 5.5+/-0.4 5-HT) similar to the control groups and evoked a reversal of cardiovascular responses. Similarly, 30 min of microdialyzing naloxone, added to the perfusing medium containing DAME, reversed the attenuating effects of DAME on monoamines, MAP, and HR during a muscle contraction. Furthermore, microdialysis of 100 microM naloxone alone for 30 min potentiated cardiovascular responses and monoamine levels during a muscle contraction. In summary, the present data demonstrates that microdialysis of DAME into RVLM attenuates the exercise pressor reflex mediated increases in MAP, HR and extracellular levels of biogenic monoamines. A subsequent microdialysis of naloxone reversed the effects suggesting that an opioidergic mechanism within RVLM modulates the exercise pressor reflex. Overall, the present study provides further insights into the opioidergic modulation of the exercise pressor reflex.

We previously reported the ability of L-tyrosine (L-TYR) to potentiate the anorectic activity of various mixed-acting sympathomimetics including [R*S*]-(+/-)-norephedrine [phenylpropanolamine (PPA)], [1R,2S]-(-)-ephedrine (EPH), and [S]-(+)-amphetamine (AMPH) in hyperphagic rats. Included in those studies was the attenuation of L-TYR's effect when coadministered with L-valine, a large neutral amino acid that competes with L-TYR for uptake into the brain, suggesting a central locus for the action of L-TYR. Additional studies demonstrated the inability of L-TYR to alter the peripherally mediated PPA-, EPH-, and AMPH-induced increases in gastrointestinal transit time and retention and intrascapular brown adipose tissue thermogenesis. Because the mixed-acting sympathomimetics are known to increase blood pressure, these studies examined the ability of L-TYR to influence the pressor responses to PPA, EPH, and AMPH (0.03-1 mg/kg) in urethane-anesthetized rats. Each of the mixed-acting sympathomimetics significantly increased mean arterial, systolic, and diastolic blood pressures when administered alone, but no potentiation by L-TYR was observed. These results demonstrate the inability of L-TYR to potentiate the peripheral vasopressor effects of PPA, EPH, and AMPH. These data, in conjunction with our previous findings, suggest that the potentiation by L-TYR of the mixed-acting sympathomimetics is largely restricted to centrally mediated responses.

Tyrosine, the amino acid precursor of catecholamines, increases blood pressure (BP) in rats made hypotensive by hemorrhage. Since this amino acid also accelerates catecholamine synthesis in and release from frequently-firing neurons, we tested the hypothesis that tyrosine's pressor action resulted from this mechanism. Male Sprague-Dawley rats (500 g) were anesthetized with chloralose (50 mg/kg) and urethane (500 mg/kg) and tracheostomized. The carotid artery was cannulated allowing BP to be recorded continuously. Blood was removed until systolic BP fell to half of each animal's starting value; 45 min later, animals received tyrosine or other treatments in volumes of 1 ml/kg. Tyrosine (100 mg/kg) increased BP by 58%, while saline caused an insignificant increase. Pretreatment with carbidopa, which inhibits tyrosine's conversion to catecholamines, blocked the amino acid's effect. Tyrosine also failed to increase BP in rats made hypotensive with phentolamine, suggesting that it acts via catecholamine receptors. Adrenal epinephrine significantly (P less than 0.02) and splenic norepinephrine slightly (P less than 0.07) increased in rats receiving tyrosine after 1 h of hypotension when compared with tissue-catecholamine contents in similar rats. These observations show that tyrosine increases BP during hemorrhagic hypotension by accelerating catecholamine synthesis.

This study examines the effects of diazoxide and hydralazine on gastrointestinal and vascular smooth muscle. The effect of the drugs administered individually and in combination was determined on small intestinal transit and blood pressure in adult male Sprague-Dawley rats. Both diazoxide and hydralazine produced dose-dependent decreases in the ratio of intestinal transit to total length. Additionally, combinations of various doses of hydralazine and diazoxide produced a greater than simple summation of the inhibitory effects on intestinal transit. The combination of diazoxide and hydralazine produced only a simple additive effect on mean arterial pressure.

Exogenous tyrosine lowers blood pressure in spontaneously hypertensive rats (SHR). The artificial sweetener aspartame also elevates blood and brain tyrosine levels in rats by being hydrolyzed to phenylalanine, which is then rapidly hydroxylated to tyrosine in the liver. Hence we tested the ability of aspartame; its hydrolytic products phenylalanine, aspartic acid and methanol; and of tyrosine itself to lower blood pressure in SHR. For one week prior to experimentation rats were acclimated to the indirect blood pressure measurement technique; on the day of an experiment they received I.P. injections (mg/kg) of aspartame (12.5-200), tyrosine (25-200) or phenylalanine (100-200), or of aspartic acid or methanol in the doses theoretically contained within 200 mg/kg aspartame. Animals receiving 50, 100 or 200 mg/kg of aspartame exhibited maximum falls in blood pressure of 17.3, 24.2 and 19.3 mmHg, respectively. All changes were significant, as determined by ANOVA and the Newman-Keuls test (p less than 0.05). Tyrosine or phenylalanine also lowered blood pressure, but aspartic acid or methanol produced no significant effects. Co-administration of aspartame with valine, a large neutral amino acid that competes with phenylalanine or tyrosine for brain uptake, attenuated aspartame's hypotensive effect. These observations suggest that the neurochemical changes produced by aspartame lead to predicted tyrosine-induced changes in blood pressure.

Administration of tyrosine, the amino acid precursor of catecholamines, increased blood pressure 38 to 49 percent in rats made acutely hypotensive by hemorrhage; other large neutral amino acids were ineffective. Tyrosine's effect was abolished by adrenalectomy, suggesting that, in hypotensive animals, it acts by accelerating the peripheral synthesis and release of catecholamines.

Various studies have confused the norephedrine and norpseudoephedrine isomers with phenylpropanolamine (PPA, d,l-norephedrine). This confusion has led us to investigate the pharmacological activity of the norephedrine (NOR) and norpseudoephedrine (NORP) isomers in the cardiovascular system of the urethane:chloralose anesthetized rat. Following intravenous administration, in a cumulative-dose fashion, l-NOR and PPA were the most potent compounds at increasing arterial blood pressure, while d-NOR, d-NORP, and l-NORP were relatively inactive at the doses tested (0.31-10 mg/kg). Prior reserpinization did not significantly shift the cumulative dose-response curves for l-NOR and PPA. Repetitive injections of PPA and l-NOR (1 mg/kg, 4 doses at 5-min intervals) failed to produce tachyphylaxis to the pressor response. On the other hand, when d-NORP was administered in a similar fashion, tachyphylaxis to the second and subsequent doses was observed. These studies demonstrate that significant mechanistic differences exist between these norephedrine isomers.

The HEART project was conducted in general practice to determine whether lifestyle strategies, aimed at increasing physical activity and dietary modification, can be substituted for drug therapy in patients who have been well controlled on antihypertensive medication. In addition to blood pressure (BP) and risk factor outcomes, lifestyle behaviours, quality of life of patients, and the acceptability of the approach to both general practitioners (GPs) and patients involved in the trial were assessed. Patients (n = 45) with a history of hypertension and who had been well controlled for at least the past 6 months (BP < 160/95 mmHg) were randomised to a continued medication (C) group (n = 24) or a withdrawal (W) group (n = 21). Subjects had received antihypertensive therapy for an average of 7.8 years (range 1-28 years). Drug therapy in the W group was recommenced if BP exceeded 160/95 mmHg on two consecutive visits. Both groups were counselled regarding lifestyle behaviour change by their GP throughout the study and were provided with specifically developed self-help materials. Subjects were reviewed at least monthly over a 9-month period. Following randomisation, there were no significant differences between the two groups for BP, heart rate, age, duration of therapy, total cholesterol or body mass index. All but three subjects (one from the W and two from the C group) completed 9 months of monitoring following randomisation and there were no cardiovascular events; 71% of subjects remained off drug therapy and were well controlled at the 9-month follow-up (15/21) with mean BP of 141/85 mmHg (W) and 139/86 mmHg (C). Systolic BP tended to increase during the study period in both W and C groups, however, no significant differences were observed in mean systolic or diastolic BP either between the two groups or within each group in comparison to baseline values. Resting heart rate, body mass index and cholesterol levels remained unchanged in both W and C groups after 9 months follow-up. There were no changes attributable to the lifestyle intervention in the subjects continuing drug therapy in BP or lifestyle variables over the study period. However, the group stopping therapy had a 6% reduction in body mass index after 9 months. These data suggest that a proportion of motivated patients willing to trial a lifestyle approach can cease drug therapy and be adequately maintained by the prescription of lifestyle advice via their GP for at least a 9-month period. Cessation of drug therapy may be an important motivating factor to achieve weight loss in this group. [ABSTRACT FROM AUTHOR]