The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

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Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial

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

Purpose Physical activity has been associated with reduced blood pressure in observational epidemiologic studies and individual clinical trials. This meta-analysis of randomized, controlled trials was conducted to determine the effect of aerobic exercise on blood pressure. Data sources English-language articles published before September 2001. Study selection 54 randomized, controlled trials (2419 participants) whose intervention and control groups differed only in aerobic exercise. Data extraction Using a standardized protocol and data extraction form, three of the investigators independently abstracted data on study design, sample size, participant characteristics, type of intervention, follow-up duration, and treatment outcomes. Data synthesis In a random-effects model, data from each trial were pooled and weighted by the inverse of the total variance. Aerobic exercise was associated with a significant reduction in mean systolic and diastolic blood pressure (-3.84 mm Hg [95% CI, -4.97 to -2.72 mm Hg] and -2.58 mm Hg [CI, -3.35 to -1.81 mm Hg], respectively). A reduction in blood pressure was associated with aerobic exercise in hypertensive participants and normotensive participants and in overweight participants and normal-weight participants. Conclusions Aerobic exercise reduces blood pressure in both hypertensive and normotensive persons. An increase in aerobic physical activity should be considered an important component of lifestyle modification for prevention and treatment of high blood pressure.

Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials.

Exercise reduces blood pressure in both hypertensive and normotensive persons. An increase in aerobic physical activity should be considered an important component of lifestyle modification for pre...

Effect of Aerobic Exercise on Blood Pressure

The analysis of plasma kinetics of the sympathetic neurotransmitter norepinephrine can be used to estimate sympathetic nervous "activity" (integrated nerve firing rate) for the body as a whole and for individual organs. In 12 patients with cardiac failure (left ventricular ejection fraction 10% to 39%), the mean arterial plasma norepinephrine concentration was 557 +/- 68 pg/ml (mean +/- SE) compared with 211 +/- 21 pg/ml in 15 subjects without heart failure (p less than .002). The difference was due to both increased release of norepinephrine to plasma (indicating increased "total" sympathetic activity) and reduced clearance of norepinephrine from plasma. The increase in sympathetic activity did not involve all organs equally. Cardiac (32 +/- 9 vs 5 +/- 1 ng/min; p less than .002) and renal (202 +/- 45 vs 66 +/- 9 ng/min; p = .002) norepinephrine spillover were increased by 540% and 206%, respectively, but norepinephrine spillover from the lungs was normal. Adrenomedullary activity was also increased in the patients with heart failure, whose mean arterial plasma epinephrine concentration was 181 +/- 38 pg/ml compared with 71 +/- 12 pg/ml in control subjects (p less than .02). There is marked regional variation, inapparent from measurements of plasma norepinephrine concentration, in sympathetic nerve activity in patients with congestive heart failure. The finding of increased cardiorenal norepinephrine spillover has important pathophysiologic and therapeutic implications.

Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.

Determination of norepinephrine apparent release rate and clearance in humans.

SUMMARY 1. Rises and falls in mean arterial (MAP) and pulse (PP) pressures from the resting value were evoked by intravenous injections of phenylephrine and glyceryl trinitrate, and were related to the reflexly evoked changes in heart period (HP; pulse interval).



2. The steady-state properties of the baroreceptor-heart rate reflex were examined by deriving MAP-HP curves in a group of twenty-three healthy normotensive subjects, and in two groups of sixteen and eight subjects with essential hypertension of different severity. Each group was subdivided into two subgroups according to age: (i) 18–30 years; (ii) 33–57 years. The MAP-HP curves are sigmoid and each is characterized by its median blood pressure (BP50), average gain (Ḡ1) and heart period range (HPR).



3. In a given age group, the curves are ‘reset’ about a higher BP50 with increasing severity of hypertension. There is progressive reduction in HPR (to 80–55% of normotensive HPR) due to lowering of the upper HP plateau, which probably indicates impairment of function of the vagal component of the reflex. In three out of four hypertensive groups, Ḡ is also significantly reduced to between 60 and 30% of Ḡ of normotensive subjects of the same age.



4. The effect of age on the curve parameters is independent of the effects due to hypertension. For a given MAP, Ḡ and HPR are lower in older than in younger subjects.

‘Steady-state’ properties of the baroreceptor-heart rate reflex in essential hypertension in man

In 17 normal subjects we studied the changes evoked by five levels of expiratory pressure (EP) ranging from 2.5 to 30 mmHg in a number of circulatory variables during the last 10 s of a 30-s Valsal...

Reflex and mechanical circulatory effects of graded Valsalva maneuvers in normal man

Curves relating renal sympathetic nerve activity and mean arterial pressure were derived in conscious rabbits during ramp changes in mean arterial pressure, elicited by perivascular balloon inflation. The renal sympathetic nerve activity-mean arterial pressure relationship consisted of a high-gain sigmoidal region about resting, where renal sympathetic nerve activity rose or fell in response to moderate falls and rises of mean arterial pressure. With larger pressure rises, renal sympathetic nerve activity first fell to a lower plateau and then reversed at even higher mean arterial pressure. When mean arterial pressure was lowered below resting, renal sympathetic nerve activity rose to an upper plateau and then reversed abruptly toward resting at low mean arterial pressure. Both arterial and cardiac baroreceptors exerted substantial inhibitory influences on renal sympathetic nerve activity at all pressure levels. These effects appeared additive over the central high gain region of the curve, but beyond this region there were non-additive interactions. The latter were affected considerably by alfathesin anesthesia. In other experiments, we studied the effects of sustained alterations in resting mean arterial pressure induced by infusing nitroprusside and phenylephrine, which produced rapid resetting of the renal baroreflex. The latter could be accounted for, in part, by resetting of the threshold of the arterial baroreceptors and in part by contributions from other afferents, probably the cardiac receptors. During resetting associated with nitroprusside-induced falls in resting blood pressure, high-gain reflex adjustments in renal sympathetic nerve activity to moderate changes in mean arterial pressure were preserved, but during resetting associated with phenylephrine-induced rises in resting mean mean arterial pressure, the resting renal sympathetic nerve activity lay on the lower curve plateau, resulting in reduction in the apparent gain of the reflex renal sympathetic nerve activity response to moderate changes in mean arterial pressure.

Paul I. Korner

Papers

Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity.

Determination of norepinephrine apparent release rate and clearance in humans.

‘Steady-state’ properties of the baroreceptor-heart rate reflex in essential hypertension in man

Reflex and mechanical circulatory effects of graded Valsalva maneuvers in normal man

The renal sympathetic baroreflex in the rabbit. Arterial and cardiac baroreceptor influences, resetting, and effect of anesthesia.