Effects of depleting central and peripheral adrenaline stores on blood pressure in stroke-prone spontaneously hypertensive rats

The potential role of adrenaline, both circulating and in the central nervous system, in the maintenance of high blood pressure was examined in stroke-prone spontaneously hypertensive rats (SHRSP). alpha-Monofluoromethyldopa, a long-lasting inhibitor of dopa decarboxylase, was used to induce rapid depletion of central and peripheral catecholamine stores. Subsequent inhibition of phenylethanolamine-N-methyltransferase (PNMT) allowed the gradual restoration of dopamine and noradrenaline but not adrenaline, resulting in a greater relative depletion of adrenaline. Adrenaline was almost totally depleted in the circulation and peripheral tissues. The resting level of blood pressure, however, was unaffected, excepting after administration of a vasopressin (AVP) antagonist. Moreover, there was no reduction in the magnitude of acute pressor responses to electrical stimulation of the rostral ventrolateral medulla oblongata (C1 area), despite extensive loss of adrenaline from the brainstem and spinal cord. The results suggest that adrenaline contributes to the resting level of blood pressure but that its loss can be offset by the pressor activity of AVP. Thus neither central nor peripheral adrenaline stores appear to be essential for the maintenance of hypertension or for centrally-evoked vasoconstriction in adult SHRSP.     

Exercise metabolism during 1 hour of treadmill walking while taking high and low doses of propranolol,metoprolol, or placebo

Aerobic exercise and beta-blocking drugs are regularly prescribed as treatment for hypertension and as a prophylactic for patients at risk from coronary heart disease and for those recovering from an infarct. Some beta blockers, particularly non-beta₁-selective drugs, may make exercise more difficult, possibly by interfering with substrate metabolism during exercise. This study examined the effects of low and high doses of a beta₁-selective blocker, metoprolol, and a nonselective beta blocker, propranolol, on exercise metabolism. The study involved 20 healthy subjects (10 men, 10 women) who walked on a treadmill at 50% of their maximal oxygen uptake for 1 h on five occasions, separated by 7 days. On each of the five occasions they received one of the following treatments, given in random order: placebo, metoprolol 50 mg, metoprolol 100 mg, propranolol 40 mg, or propranolol 80 mg, all taken twice daily. Fat oxidation, expressed as a percentage of total energy expenditure, was significantly lower than with placebo for all of the active treatments except metoprolol 50 mg (placebo: 42.7 ± 11.6%; metoprolol 50 mg: 38.7 ± 14.1%, p = NS; metoprolol 100 mg: 36.3 ± 13.7%, p = 0.05; propranolol 40 mg: 31.2 ± 9.3%, p = 0.01; propranolol 80 mg: 29.5 ± 10.9%, p = 0.01); and significantly lower with propranolol than with metoprolol (propranolol 40 mg: p = 0.0036; propranolol 80 mg: p = 0.01). Plasma ammonia concentration was significantly higher than with placebo with propranolol 40 mg, propranolol 80 mg, and metoprolol 100 mg (p = 0.01 for all); with metoprolol 50 mg, there was no difference from placebo (p = NS). Both beta blockers in this study reduced fat metabolism and increased perceived exertion to some degree. Additional inhibition of fat oxidation occurred with the nonselective drug, probably in intramuscular rather than adipose lipolysis, and was probably beta₂ mediated. The results of this study suggest that a selective beta blocker has less of an adverse effect on substrate metabolism than does a nonselective beta blocker. Beta₁-selective drugs may offer advantages in patients who undertake regular aerobic exercise.     

Importance of spinal noradrenergic pathways in cardiovascular reflexes and central actions of clonidine and alpha-methyldopa in the rabbit

We have examined in conscious rabbits the chronic effects of 6-hydroxydopamine (6-OHDA)-induced local lesions of the spinal noradrenaline (NA) pathways on (i) resting mean arterial pressure (MAP) and heart rate (HR), (ii) the nasopharyngeal pressor response, (iii) the sympathetic component of the baroreceptor-heart rate reflex (iv) the acute responses to intracisternal (i.c.) clonidine and alpha-methyldopa (alpha-MD), and (v) the acute NA release response produced by i.e. 6-OHDA. One month after injection of 6-OHDA (40 nmol in 4 microliters) into the first cervical spinal cord segment (C1), the NA content was reduced to 29% in C2, 45% in T4 and 61% in L3 with little non-specific damage. Basal MAP was 14% higher (P less than 0.05) than in sham-operated rabbits suggesting increased vasoconstrictor tone. Basal cardiac sympathetic tone was enhanced, but a corresponding increase in cardiac vagal tone resulted in little net effect on resting HR in the spinal NA-depleted group. Spinal NA lesions attenuated the nasopharyngeal pressor reflex by 27% in baroreceptor-intact rabbits and by 38% in sino-aortically denervated (SAD) animals. The lesion did not affect HR range, gain and BP50 of the sympathetic baroreflex. In SAD rabbits, the acute MAP responses to i.c. 6-OHDA (early hypotension, late hypertension) were not affected by spinal NA depletion, but the early fall in HR (cardiac sympathetic inhibition) was abolished. The hypotension produced by i.c. clonidine or alpha-MD was not affected by the lesion, probably because many of the NA terminals in the lower thoracic and upper lumbar cord were still intact. Our results suggest that intraspinal NA fibers have a tonic inhibitory action on spinal preganglionic vasoconstrictor and cardiac motoneurons. The spinal NA neurons affecting vasomotor tone (but not cardiac sympathetic tone) are in turn inhibited by higher vasomotor centers receiving projections from the arterial and trigeminal afferents and thereby participate in vasoconstrictor reflexes.     

Exercise metabolism in healthy volunteers taking celiprolol, atenolol, and placebo.

OBJECTIVE: Previous studies have shown that beta 1 selective agents have fewer adverse effects on exercise metabolism than nonselective beta blockers, and this has been attributed to their reduced blockade of beta 2 receptors. This study aimed at determining whether a beta blocker with partial agonist activity at beta 1 and beta 2 receptors (celiprolol) was better than a conventional beta 1 receptor-blocker (atenolol) in prolonging exercise capabilities. METHODS: After four days of treatment with celiprolol 200 mg, atenolol 50 mg, or placebo, 22 healthy volunteers exercised on a treadmill for two hours at 50% of their maximal oxygen uptake. Resting heart rate and blood pressure were recorded before and after exercise. During exercise, fat oxidation, plasma free fatty acids, glycerol, glucose, and ammonia were measured together with heart rate and perceived exertion. RESULTS: Mean exercising heart rate was significantly lower in those taking either of the beta blockers than in those taking placebo, and significantly lower for those taking atenolol rather than celiprolol. Fat oxidation was significantly lower for those taking celiprolol (38.8 (SD 12.2)%, P < 0.01) and atenolol (36.6 (15.9)%, P < 0.01) compared with placebo (45.6 (14.1)%). For the first 15 minutes of exercise, fat oxidation was significantly lower for those taking atenolol (24.6 (12.8)%, P < 0.01) than celiprolol (29.6 (14.3)%). The rise in plasma free fatty acids and glycerol during exercise was also significantly attenuated by both beta blockers in comparison with the rise in those taking placebo (P < 0.01). CONCLUSIONS: Both celiprolol and atenolol reduced fat oxidation compared with placebo. For the first 15 minutes of exercise fat oxidation was preserved by celiprolol, but not atenolol. This preservation of fat oxidation during the early part of exercise may confer some small benefit to patients who take beta blockers and intend to exercise regularly. However, we did not detect significant differences between atenolol and celiprolol in overall mean fat oxidation or perceived exertion in this study.     

Stereotaxic needle localization and biopsy of occult breast lesions: first year's experience.

During a 12-month period 115 patients with abnormal mammograms had stereotaxic needle localization and biopsy of nonpalpable breast lesions. The procedure was performed on a Fischer Mammotest II machine (Fischer Imaging; Denver, CO) and the biopsies were taken with a #18 gauge Bard biopsy needle using a Bard biopty gun (distributed by Bard Urological; Covington, GA; manufactured by Radiplast; Uppsala, Sweden). Mammographic lesions were suspicious matrix densities (85), clustered microcalcifications (22), or a combination of both (8). The pathologist recommended open biopsy in 16 per cent (18/115) of the patients. Pathology on the 18 open biopsies revealed that 11 (9 matrix densities and 2 calcifications) were carcinomas and true positives, whereas the other 7 (all matrix densities) were benign mastopathies and false positives. Further analysis of the pathologic data showed that there were three possible diagnoses from the needle biopsies on the patients that later went to open biopsy: cancer (6), very suspicious lesion (9), and slightly suspicious lesion without atypical hyperplasia (3). All 6 cancers were confirmed by open biopsy; about half (5/9) of the very suspicious lesions were cancer and none (0/3) of the slightly suspicious lesions were cancer. More cases, followed by open biopsy, are needed to refine the selection procedure for open biopsy and careful follow-up of the patients who did not have open biopsy will also be needed to determine the false negative rate. Excellent patient acceptance was found and the test was easy to perform in the office without serious complications. Furthermore, the test was cost effective because it avoided open biopsy in 97 patients.     

Chronic captopril treatment reverses the enhanced vascular concentrations of 3-methylhistidine in the spontaneously hypertensive rat.

Morphometric studies conducted on the blood vessels of the spontaneously hypertensive rat have provided evidence that medial hypertrophy is a key characteristic of the vascular change which occurs in hypertension. In the present study, we determined whether 3-methylhistidine (3MH), a post-translationally modified amino acid which is found uniquely in the actin and myosin of muscle, could provide a biochemical marker of such change. Our results indicated that the concentrations of 3MH were selectively elevated in the blood vessels from the spontaneously hypertensive rat, when compared with concentrations in vascular tissues from the Wistar-Kyoto rat. The concentrations of 3MH in non-vascular tissues were similar in the two strains. Chronic captopril treatment prevented the development of hypertension in the spontaneously hypertensive rat and was associated with a reduction of the vascular concentrations of 3MH. We therefore conclude that blood vessel concentrations of 3MH are a useful biochemical index of the changes in vascular smooth muscle contractile protein which occur during the development of hypertension in the spontaneously hypertensive rat.     

Hypernoradrenergic innervation and vascular smooth muscle hyperplastic change

Two distinguishing features of the vasculature of the spontaneously hypertensive rat (SHR) are an increased sympathetic innervation and vascular smooth muscle hyperplasia. Evidence supporting the existence of hypernoradrenergic innervation and vascular smooth muscle cell hyperplasia is presented with emphasis upon the possible interrelationships between the two events. The results of experiments designed to explore this relationship are presented and include the determination of the role of endogenous nerve growth factor (NGF) and the influence of exogenous NGF on the development of sympathetic innervation of blood vessels and blood pressure change. Attention is focused upon elevated levels of 3-methylhistidine (a biochemical marker for contractile proteins) in the mesenteric vasculature of the SHR. The potential relationships between hypernoradrenergic innervation and increased concentrations of 3-methylhistidine are explored.