R Fiocchi

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

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.

Antihypertensive action and serotonin-induced platelet aggregation during long-term ketanserin treatment in hypertensive patients

Ketanserin (3 × 40 mg daily) was administered during 6 weeks in 14 patients with mild to moderate essential hypertension using a double-blind, placebo-controlled, crossover design. Ketanserin decreased (p < 0.01) the recumbent blood pressure from 159/104 to 153/97 mm Hg and the recumbent heart rate from 75 to 72 beats/min. Platelet aggregation induced by 5-hy-droxytryptamine (5-HT), whether or not amplified by threshold doses of collagen, was not inhibited; however, it was reduced in 10 normal volunteers after a single oral dose of 40 mg ketanserin. The results suggest that long-term treatment with ketanserin reduces blood pressure; whereas 5-HT receptor inhibition could not be demonstrated when assessed by platelet aggregation.

The nature of opioid involvement in the hemodynamic respiratory and humoral responses to exercise.

After 30 min rest in the lying position, 12 healthy male volunteers (average age 22 years) received, in a randomized double-blind cross-over protocol, either saline or naloxone (10 mg iv followed by a continuous infusion of 10 mg/hr). Thereafter they rested for a further 30 min in the recumbent position and for 15 min sitting on a bicycle ergometer; they then exercised to exhaustion. At rest plasma levels of adrenocorticotropin (ACTH), cortisol, and aldosterone increased during infusion of naloxone, while body temperature decreased. During exercise the difference in plasma ACTH between naloxone and saline periods was abolished, while the differences in plasma cortisol and aldosterone lost statistical significance. Intra-arterial pressure, heart rate, ventilation, O2 uptake, and CO2 output were continuously monitored throughout the experiment and were not affected by naloxone. This was also the case for several hormonal and biochemical measurements, including those of plasma renin, angiotensin II, norepinephrine, 13,14-dihydro-15-keto-prostaglandin F2 alpha, glucose and lactate, and serum insulin and growth hormone. Exercise performance was not changed by naloxone. In conclusion (1) during exhaustive graded exercise of short duration opioidergic inhibition of the pituitary-adrenocortical axis is probably not sustained, (2) apart from the latter mechanism, the present study does not support the hypothesis that endogenous opioids are involved in various hemodynamic, respiratory, and hormonal responses to this type of exercise.

Progressive attenuation of the carotid baroreflex control of blood pressure and heart rate during exercise.

With the use of a variable pressure neck chamber, the effect of supine bicycle exercise on the carotid baroreceptor reflex was investigated in 10 normal volunteers who were studied at rest and during moderate and severe exercise, i.e., at 33% and 66% of their previously determined maximal exercise capacity. Deactivation of the carotid baroreceptors by a decrease in carotid transmural pressure produced a greater (p less than 0.001) increase in mean intra-arterial pressure at rest (+11.2 +/- 0.2 [SE] mm Hg) than during moderate (+9.0 +/- 0.2 mm Hg) and severe (+6.1 +/- 0.1 mm Hg) exercise. Heart interval decreased less (p less than 0.005) at rest (-73 +/- 3.2 msec) than during exercise (-0.7 +/- 0.7 msec and -4.6 +/- 0.2 msec, respectively). Furthermore, activation of the carotid baroreceptors by an increase in carotid transmural pressure provoked a greater (p less than 0.005) reduction in mean intra-arterial pressure at rest (-11.5 +/- 0.2 mm Hg) than during exercise (-9.8 +/- 0.1 mm Hg and -7.5 +/- 0.1 mm Hg, respectively), while the lengthening of heart interval was also more (p less than 0.005) pronounced at rest (+97 +/- 4.3 msec) than during moderate (+44 +/- 1.2 msec) and severe (+7.6 +/- 0.3 msec) exercise. Finally, carotid baroreceptor sensitivity was defined as the slope of the changes in blood pressure and heart interval that occurred with increasing (baroreceptor deactivation) and decreasing (activation) neck tissue pressure. On average, baroreceptor sensitivity was consistently smaller (p less than 0.05) during exercise, as compared to rest.(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind comparison of ketanserin with propranolol in hypertensive patients: interim report.

This double-blind study, which is still in progress, aims to compare ketanserin (K) and propranolol (P) during long-term treatment of hypertensive patients in general practice. After a run-in period on placebo, active treatment was initiated with 20 mg K or 40 mg P, b.i.d., during a 2-week period, whereafter the daily dose of either drug was doubled. Presently, 331 patients have been randomized, two-thirds to the K group (n = 221) and one-third to the P group (n = 110). Both groups were similar at randomization, with blood pressure (BP) averaging 171/105 mm Hg. The presently available data concerning the initial 3 months of the trial show that up to the 2nd month after randomization, systolic BP was significantly (p less than 0.05) higher in the K than in the P group, whereas the differences in diastolic BP were mostly not significant. The change in BP after 3 months on K treatment was positively and independently related to both the initial BP and the concurrent changes in body weight. Heart rate was lower (p less than 0.001) during P, whereas body weight was not statistically different between both groups. Differences in complaints between the K and P group were small. However, in the K group dry mouth was transiently more frequently reported at 1 month (p = 0.02) and multiple complaints at 3 months (p = 0.03).

Differentiation of exercise-induced metabolic responses during selective beta 1- and beta 2-antagonism.

The effect of beta 1- or beta 2-antagonism on the plasma levels of glucose, lactate, triglycerides, and free fatty acids was studied in seventeen normal male volunteers. All subjects performed three graded and uninterrupted exercise tests until exhaustion. Prior to each exercise test they received in a randomized order during three consecutive days either placebo or a predominant beta 1-blocker (atenolol, 50 mg once per day) or a predominant beta 2-blocker (ICI 118,551, 20 mg t.i.d.), according to a double-blind cross-over study design. Atenolol increased the plasma level of glucose at rest but did not influence the rise in plasma glucose during exercise. ICI 118,551 did not change the resting plasma glucose level, but it prevented the exercise-induced rise in plasma glucose, observed during placebo. During beta 1-antagonism the plasma lactate concentration at rest and during or after exercise was not different from placebo. During beta 2-blockade the exercise-induced rise in plasma lactate tended to be suppressed, and during recovery the plasma lactate levels were significantly lower than during placebo. The serum triglycerides concentration at rest and exercise was not altered, either by beta 1- or by beta 2-antagonism. Atenolol and ICI 118,551 did not affect the serum level of free fatty acids at rest, but at moderate exercise the serum free fatty acids concentration was lower during beta 1-blockade than during placebo. Our results provide further evidence that beta 2-adrenergic receptors are involved in the regulation of the plasma levels of glucose and lactate during exercise.

Carotid baroreflex sensitivity and physical fitness in cycling tourists

SummaryCarotid baroreceptors were stimulated with neck suction in 47 healthy subjects. Pulse interval lengthening was measured and the time course of the response was evaluated. Eight intensities of neck chamber suction were applied to select a criterion for computing the “RR response” that gives a significant linear relationship with the magnitude of the stimuli in the highest number of individuals. The best criterion was the maximal RR prolongation within 5 seconds after the onset of the stimulus. The slope of this relationship was defined as baroreflex sensitivity.The effect of physical fitness on baroreceptor function was investigated in 24 cycling tourists with a wide range of peak oxygen uptake and training characteristics. Baroreflex sensitivity averaged 7.3±0.8 msec · mm Hg−1 and was not significantly related to age, weight, basal heart rate, peak oxygen uptake and ventilation and other training characteristics.The results suggest that in man the so defined sensitivity of the carotid baroreflex control of heart rate is not influenced by the level of physical fitness and therefore the measurement of these characteristics can be neglected in evaluating baroreflex sensitivity.

Erythrocyte 2,3-diphosphoglycerate and serum enzyme concentrations in trained and sedentary men

The acute effect of exercise on the intraerythrocyte 2,3-diphosphoglycerate concentration and on various serum enzymes and some related variables was investigated in 14 male athletes before and after a 50-min cross-country run and compared at rest to 15 sedentary subjects. Compared to the sedentary subjects, the athletes had higher resting levels of serum creatine phosphokinase, plasma myoglobin, and renin substrate but had a lower plasma renin activity. The red blood cell 2,3-diphosphoglycerate concentration increased after exercise in the runners and was not different at rest between the athletes and the sedentary subjects. Our data therefore suggest that the resting plasma renin activity is reduced in athletes when compared to sedentary subjects. Training seems however not to alter the resting level of 2,3-diphosphoglycerate in the red blood cells.

Erythrocyte cations and Na+,K+-ATPase pump activity in athletes and sedentary subjects

SummaryThe chronic effect of training on intraerythrocyte cationic concentrations and on red cell Na+,K+-ATPase pump activity was studied by comparing well-trained athletes with sedentary subjects at rest. Also the acute effect of a 50-min cross-country run on these erythrocyte measurements was studied in the athletes. At rest the intraerythrocyte potassium concentration was increased (P<0.01) in the athletes compared to that of the control subjects. The intraerythrocyte concentrations of sodium and magnesium and red cell Na+, K+-ATPase pump activity were, however, similar in the trained and the untrained subjects.As compared with the resting condition, the intraerythrocyte potassium concentration was decreased (P<0.05) after exercise in the athletes, and this was accompanied by a minor increase in the intraerythrocyte sodium concentration. Red cell Na+,K+-ATPase pump activity was slightly increased (P<0.05) after exercise.

Ketanserin: a new hypotensive drug?

The possible use of ketanserin for the chronic treatment of patients with essential hypertension was discussed based on the data exposed at this symposium. Its hypotensive effect is established during placebo controlled trials, but more data are needed to determine its relative potency compared to standard hypotensive drugs. The drug seems to act by reducing systemic vascular resistance, but the relative role of the serotonin and alpha inhibition in the chronic hypotensive effect in man is not yet known. Subjective side effects occur after the first dose, but seem to be less frequent during chronic treatment; organ toxicity has not been reported in the therapeutic doses. The drug could be particularly indicated in elderly hypertensive patients, especially in those with peripheral vascular disease. The influence on morbidity and mortality is not yet known.