SUMMARY Hypertension (HTN), one of the most common medical disorders, is associated with an increased incidence of all-cause and cardiovascular disease (CVD) mortality. Lifestyle modifications are advocated for the prevention, treatment, and control of HTN, with exercise being an integral component. Exercise programs that primarily involve endurance activity prevent the development of HTN and lower blood pressure (BP) in adults with normal BP and those with HTN. The BP lowering effects of exercise are most pronounced in people with HTN who engage in endurance exercise with BP decreasing approximately 5–7 mm Hg after an isolated exercise session (acute) or following exercise training (chronic). Moreover, BP is reduced for up to 22 h after an endurance exercise bout (e.g., postexercise hypotension), with the greatest decreases among those with the highest baseline BP. The proposed mechanisms for the BP lowering effects of exercise include neurohumoral, vascular, and structural adaptations. Decreases in catecholamines and total peripheral resistance, improved insulin sensitivity, and alterations in vasodilators and vasoconstrictors are some of the postulated explanations for the antihypertensive effects of exercise. Emerging data suggest genetic links to the BP reductions associated with acute and chronic endurance exercise. Nonetheless, definitive conclusions regarding the mechanisms for the BP reductions following endurance exercise cannot be made at this time. Individuals with controlled HTN and no CVD or renal complications may participate in an exercise program or competitive athletics, but should be evaluated, treated, and monitored closely. Preliminary peak or symptom-limited exercise testing may be warranted, especially for men over 45 and women over 55 yr planning a vigorous exercise program (i.e., 60% u VO2R, oxygen uptake reserve). In the interim, while formal evaluation and management are taking place, it is reasonable for the majority of patients to begin moderate intensity exercise training (40 –60% u VO2R) such as walking. When pharmacologic therapy is indicated in physically active people it should, ideally: a) lower BP at rest and during exertion; b) decrease total peripheral resistance; and, c) not adversely affect exercise capacity. For these reasons, angiotensin converting enzyme (ACE) inhibitors (or angiotensin II receptor blockers in case of ACE inhibitor intolerance) and calcium channel blockers are currently the drugs of choice for recreational exercisers and athletes who have HTN. Exercise remains a cornerstone therapy for the primary prevention, treatment, and control of HTN. The optimal training frequency, intensity, time, and type (FITT) need to be better defined to optimize the BP lowering capacities of exercise, particularly in children, women, older adults, and

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Exercise and Hypertension

Regulation of noradrenaline release by presynaptic receptor systems.

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that pre-diet PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, ∼80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately $US5000 for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.

Clinical significance of the cytochrome P450 2C19 genetic polymorphism.

The overall scheme for control is as follows: central command sets basic patterns of cardiovascular effector activity, which is modulated via muscle chemo- and mechanoreflexes and arterial mechanoreflexes (baroreflexes) as appropriate error signals develop. A key question is whether the primary error corrected is a mismatch between blood flow and metabolism (a flow error that accumulates muscle metabolites that activate group III and IV chemosensitive muscle afferents) or a mismatch between cardiac output (CO) and vascular conductance [a blood pressure (BP) error] that activates the arterial baroreflex and raises BP. Reduction in muscle blood flow to a threshold for the muscle chemoreflex raises muscle metabolite concentration and reflexly raises BP by activating chemosensitive muscle afferents. In isometric exercise, sympathetic nervous activity (SNA) is increased mainly by muscle chemoreflex whereas central command raises heart rate (HR) and CO by vagal withdrawal. Cardiovascular control changes for dynamic exercise with large muscles. At exercise onset, central command increases HR by vagal withdrawal and "resets" the baroreflex to a higher BP. As long as vagal withdrawal can raise HR and CO rapidly so that BP rises quickly to its higher operating point, there is no mismatch between CO and vascular conductance (no BP error) and SNA does not increase. Increased SNA occurs at whatever HR (depending on species) exceeds the range of vagal withdrawal; the additional sympathetically mediated rise in CO needed to raise BP to its new operating point is slower and leads to a BP error. Sympathetic vasoconstriction is needed to complete the rise in BP. The baroreflex is essential for BP elevation at onset of exercise and for BP stabilization during mild exercise (subthreshold for chemoreflex), and it can oppose or magnify the chemoreflex when it is activated at higher work rates. Ultimately, when vascular conductance exceeds cardiac pumping capacity in the most severe exercise both chemoreflex and baroreflex must maintain BP by vasoconstricting active muscle.

Reflex control of the circulation during exercise: chemoreflexes and mechanoreflexes

The chromogranins A and B: The first 25 years and future perspectives

Two proteins present in noradrenergic vesicles of the splenic nerve (dopamine beta-hydroxylase and chromogranin A) are released into the perfusate from the spleen when the splenic nerve is stimulated. Experiments in which drugs were added to the perfusion fluid showed that the proteins were released from terminals of the splenic nerve. There was a correlation between the amounts of the proteins released and the quantity of noradrenaline released; and the release process was dependent upon calcium. It is suggested that the proteins are released from the large dense-cored vesicles present in the terminals of the splenic nerve, and that secretion from these vesicles occurs by exocytosis.

Release of dopamine β-hydroxylase and chromogranin A upon stimulation of the splenic nerve

The possible influence of long-term treatment with lansoprazole on the single-dose pharmacokinetics of diazepam was investigated in 12 healthy male volunteers. In this double-blind randomized crossover study, 60 mg lansoprazole or placebo was administered once daily for 10 days. One hour after administration on day 7, 0.1 mg/kg diazepam was administered intravenously, and blood was collected up to 96 hours after the injection for plasma diazepam and desmethyldiazepam measurement. During the placebo session, the plasma elimination half-life, clearance, and volume of distribution of diazepam were 26.0 +/- 1.6 hours, 22.5 +/- 1.1 ml/hr/kg, and 0.82 +/- 0.04 L/kg, respectively. These parameters were not significantly different during the lansoprazole session. The mean plasma concentrations of desmethyldiazepam were similar in both sessions. These findings illustrate that long-term treatment with a therapeutic dose of lansoprazole does not interfere with the metabolism of diazepam.

Influence of lansoprazole treatment on diazepam plasma concentrations

Ketanserin (120 mg/day) or placebo was given orally to 14 patients with mild to moderate essential hypertension according to a double blind crossover protocol, each treatment period lasting six weeks. Resting intra-arterial pressure in the recumbent position was reduced from 150/84 to 141/77 mm Hg; the hypotensive effect persisted throughout an uninterrupted graded exercise test to the point of exhaustion. The haemodynamic effects were similar at rest and during exercise. Overall, systemic vascular resistance decreased by 14%, heart rate fell by 5%, but stroke volume and cardiac output increased. Mean pulmonary arterial pressure and capillary wedge pressure were not significantly affected, but pulmonary vascular resistance decreased by 15%. The pressor response to methoxamine was significantly reduced by ketanserin. Both plasma noradrenaline and adrenaline concentrations increased, plasma renin activity and angiotensin II concentration decreased, and plasma aldosterone concentration was unchanged. The data indicate that ketanserin induces arteriolar dilatation, possibly related to an alpha-1-antagonistic action and to a reduced circulating angiotensin II concentration. The haemodynamic response is complex, and an increase in cardiac output limits the hypotensive effect. There is no firm evidence of an effect on venous tone as cardiac filling pressures do not change.

https://heart.bmj.com/content/heartjnl/51/2/149.full.pdf

Haemodynamic and humoral responses to chronic ketanserin treatment in essential hypertension.

The effect of physical endurance training on the plasma renin-angiotensin-aldosterone system was studied in 27 normal sedentary volunteers aged between 20 and 55 years, using a randomized two-period cross-over study design. After 4 months of training (2.5 h/week), peak oxygen uptake and physical working capacity at a heart rate of 130 beats/min were increased by 16% (P less than 0.01) and 29% (P less than 0.001) respectively, whereas resting heart rate was decreased by 15% (P less than 0.001). The plasma noradrenaline concentration and haematocrit were both decreased (P less than 0.01) after training. For the total group of subjects, the small decreases in plasma renin activity (PRA) and in the plasma concentrations of angiotensin-I, angiotensin-II and aldosterone were not statistically significant. However, the change in PRA during the training period was negatively correlated with the increase in physical working capacity (r = -0.49, P less than 0.01), suggesting that PRA decreased only in those subjects with the greatest increase in exercise capacity. Also, the change in plasma aldosterone during training was negatively related to the rise in physical working capacity (r = -0.57, P less than 0.01). Furthermore, the changes in plasma angiotensin-I (r = 0.75), angiotensin-II (r = 0.49) and aldosterone (r = 0.43) during the training period correlated positively with the change in PRA. It is concluded that physical endurance training, leading to a substantial gain of physical working capacity, suppresses the plasma renin-angiotensin-aldosterone system in normal man.

Effects of physical endurance training on the plasma renin-angiotensin-aldosterone system in normal man.

1 beta-adrenoceptor blockade with metoprolol provoked, both at rest and during exercise, a decrease of 'active' renin and angiotensin II together with an increase of 'inactive' renin and unchanged 'total' renin. The significant exercise-provoked increases in angiotensin II, plasma renin activity and 'active', 'inactive' and 'total' renin when on placebo, were reduced by metoprolol. 2 No significant change in serum sodium and potassium and in plasma aldosterone was found during beta-adrenoceptor blockade at rest. During exercise plasma aldosterone dropped significantly without any change in serum sodium or potassium. 3 Plasma noradrenaline increased significantly at rest on metoprolol. The increase in plasma noradrenaline and adrenaline during exercise was similar on placebo and on metoprolol.

E Moerman

Papers

Release of dopamine β-hydroxylase and chromogranin A upon stimulation of the splenic nerve

Influence of lansoprazole treatment on diazepam plasma concentrations

Haemodynamic and humoral responses to chronic ketanserin treatment in essential hypertension.

Effects of physical endurance training on the plasma renin-angiotensin-aldosterone system in normal man.

The effects of beta‐adrenoceptor blockade on renin, angiotensin, aldosterone and catecholamines at rest and during exercise.