Clinical and experimental hypertension. Part A, Theory and practice最新文献

The antihypertensive effects of lisinopril 10-20 mg once daily and felodipine (extended release formulation) 5-10 mg once daily were compared in a double-blind, parallel group study of eight weeks duration involving 219 patients with mild to moderate hypertension. On lisinopril treatment sitting blood pressure fell from 166.3/102.9 +/- 17.5/5.8 mmHg to 146.7/89.7 +/- 19.5/8.7 mmHg and on felodipine blood pressure fell from 166.7/103.3 +/- 18.3/5.4 mmHg to 153.6/92.3 +/- 15.9/7.9 mmHg. The decreases in sitting systolic and diastolic blood pressures were significantly greater on lisinopril than on felodipine treatment (p = 0.019 and p = 0.033). A subgroup analysis in elderly patients (age > or = 65 years) showed that lisinopril and felodipine were equally effective in reducing blood pressure. In young subjects (age < 65 years) felodipine treatment lowered systolic blood pressure less than did lisinopril treatment (p = 0.001). Lisinopril was better tolerated than felodipine. On lisinopril treatment, reports of headache and dizziness were reduced while that of cough increased. On felodipine treatment, dizziness was reduced but reports of flushing and oedema were increased. The results show a better antihypertensive effect and better tolerability for lisinopril compared with extended release felodipine.

Common carotid blood flow and cold pressor test were evaluated in 16 patients with sustained essential hypertension before and after 30 days treatment with the converting enzyme inhibitor Enalapril (20 mg). Enalapril decreased blood pressure and carotid vascular resistance with no significant change in heart rate. After treatment, despite a wide range of the responses, the changes in systolic blood pressure to cold test were significantly attenuated, whereas the heart rate responses were not. Acute random and double blind administration of either Cadralazine or Nitrendipine, two vasodilating drugs which are known to cause an activation of the autonomic nervous system, were performed before and after long term treatment by Enalapril. Whereas the blood pressure and heart rate responses to cold test was unmodified by these compounds before Enalapril treatment, significant changes were observed after converting enzyme inhibition: Cadralazine reduced the heart rate response whereas Nitrendipine increased it significantly. The study provides evidence that converting enzyme inhibition causes sympatho-inhibitory influences which are principally observed in stress conditions, with heterogeneous responses depending on the nature and the type of stimulation.

The question whether there is a level of diastolic pressure during treatment below which further reduction of pressure may be harmful rather than beneficial is of great interest. If, as the proponents of this hypothesis maintain, death from CHD among treated hypertensives becomes more rather than less common at very low diastolic pressure, this might explain at least in part why most primary prevention trials of hypertension have failed to show a reduction in CHD mortality. However, as the sceptics have pointed out, the evidence that drug induced lowering of blood pressure is harmful is not of the highest quality, and alternative explanations for excess cardiovascular mortality at low diastolic pressure exist. In the following review of this hotly contested debate it is concluded that both proponents and sceptics may be correct, but that the presence of a J curve should not divert attention from the main benefit of treating hypertension which is a reduction in the risk of fatal and non fatal stroke.

Sodium (Na+)-dependent hypertension was studied in hypoxia in an effort to determine the basis for hypoxia-mediated attenuation of hypertension. Hypoxia attenuated spontaneous hypertension while Na+ increased blood pressure in SHR. A lack of interaction between the effects of hypoxia and Na+ indicated additivity of effects. As a result, hypoxia-exposed, Na(+)-supplemented SHR had similar blood pressure as did normoxic, nonsupplemented SHR although both groups had lower blood pressure than normoxic, Na(+)-supplemented SHR. Hypoxia decreased serotonin turnover (5-HIAA/5-HT) in the brain stem of SHR while supplemental Na+ had no influence on this measurement. Hypoxic exposure in DOCA-treated rats failed to prevent the development of hypertension although hypoxia decreased 5-HIAA/5-HT in the brain stem of hypoxic rats, irrespective of DOCA treatment. The finding in SHR that Na+ counteracts the protection of hypoxia could be argued to support a similar mechanism of action for hypoxia and sodium. However, the results with DOCA treatment clearly refute such an interpretation. Our findings indicate that the pressor influence of Na+ does not occur through the modulation of brain stem 5-HIAA/5-HT.

Endogenous dopamine (DA) selectively contributes to the natriuresis (UNaV) produced by infusion and dietary consumption of sodium chloride. The present study in anesthetized rats determined whether DA has a role in the natriuresis produced by small (2.0 +/- 0.11% increase in body weight) and large (17.9 +/- 0.58% increase in body weight) increments in extracellular fluid volume with iso-osmotic saline. Small volume expansion increased urine flow (V) by 59 +/- 15%, UNaV by 155 +/- 31%, and dopamine excretion by 25 +/- 9%. DA1-receptor blockade with SCH 23390 (SCH, 1.0 microgram/kg/min), attenuated the natriuresis; an increase in UNaV of only 69 +/- 15%. Large volume expansion increased V by 1,026 +/- 215% and UNaV by 2,735 +/- 899%, without affecting dopamine excretion. Increments in V and UNaV were unaffected by increasing doses of SCH (1.0 microgram/kg/min; 10 micrograms/kg/min; and 50 micrograms/kg bolus, followed by 10 micrograms/kg/min). Adequacy of DA1-receptor blockade was demonstrated by the fact that SCH (1.0 microgram/kg/min) attenuated the natriuresis produced by the DA1-receptor agonist, fenoldopam (0.1 micrograms/kg/min ia). We conclude that endogenous DA contributes to the natriuresis produced by small, but not large, increases in extracellular fluid volume with iso-osmotic saline.

Vascular smooth muscle cells from spontaneously hypertensive rats (SHR) were growth stimulated when cocultured with bovine aortic endothelial cells whereas myocytes from normotensive, Wistar Kyoto rats (WKY) were growth inhibited. The responsiveness of cells from the two rat sources to the two homodimeric forms of platelet-derived growth factor (PDGF-AA or -BB) was different; SHR-derived cells responding equally well to both PDGF forms whereas cells from WKY responded to the B-chain homodimer only. The responses measured included S6 kinase activation, phospholipase C mediated phosphoinositide catabolism and cell growth. Saturation binding experiments using [125I]-labelled PDGF homodimers (AA or BB) indicated that smooth muscle cells from hypertensive rats possess similar numbers of cell-surface A-chain receptors (alpha subunits) as Swiss 3T3 cells which have been used to characterize the mitogenic effects of the two PDGF homodimeric forms. The differences in responsiveness of SHR vs WKY cells to PDGF-AA and to the influence of endothelial cells may reside in their differential expression of PDGF receptors.

Local cerebral glucose utilization (LCGU) was decreased in SHRSP with stroke compared with normotensive Wistar rats. The decrement of LCGU was less in Solcoseryl-treated SHRSP with stroke than that in saline-treated SHRSP with stroke and these brain areas where LCGU was less damaged, in Solcoseryl-treated SHRSP were consistent with the important functioning sites of emotion, motor movement and memory. The result suggests that Solcoseryl may be useful for metabolic improvement of the brain damage after stroke.

Spontaneously hypertensive rats (SHRs) were compared to Wistar-Kyoto (WKY) and Wistar (WIS) rats on 18 behaviors to determine strain differences while undisturbed and when being restrained by a jacket and tether system often used for monitoring blood pressure chronically. Male SHRs unrestrained in the home cage initially exhibited greater magnitudes of body grooming, quadrant changes, turning, sniffing and rearing than WKYs, whose behavioral levels remained low throughout the entire session. SHRs and WISs gradually declined in behavioral levels within the sessions. The effects of restraint significantly decreased the exploratory/activity behaviors of nose poking, rearing and quadrant changes, with SHRs showing a greater decrement as a result of the restraint. Because of this differential effect of restraint on behaviors distinguishing SHRs and WKYs, studies simultaneously measuring behavior and blood pressure should be interpreted with caution, especially when comparing strains. The hypoactivity of the WKY would suggest the use of an additional control strain in behavioral studies.

Two inbred strains have been developed from a cross between SHR and WKY. WK-HTs are hypertensive but not hyperactive, and WK-HAs are hyperactive but normotensive. Together with SHR (that express both traits) and WKY (expressing neither trait) we used four strains to follow correlations of biological changes with the expression of hyperactivity or hypertension. We show that the well known sympathetic hyperreactivity of SHRs to acute stress is associated with the hyperactivity trait and not the hypertension among the four strains. Similarly, the well known ventricular hypertrophy in SHRs is more prominent among the hyperactive strains than the hypertensives. Examination of regional brain amine levels revealed an imbalance in forebrain serotonin transmission in the hyperactive strains, and no significant correlations with hypertension. On the other hand, neuropeptides in brainstem and spinal cord revealed a decrease, in hypertension, in neuropeptide Y and PNMT content of terminals of C1 fibers that innervate the spinal cord sympathetic outflow. Also, the two hypertensive strains showed increased TRH-and proctolin-like immunoreactivity in fibers that innervate the C1 cells in the rostral ventrolateral medulla. These findings illustrate the unique advantage provided by WK-HA and WK-HT strains as additional controls for SHRs in studying hypertension and hyperactivity.