A major controversy about the safety of calcium channel blockers (CCBs) has arisen since the publication of a case-control study showing that hypertensives who suffered an acute myocardial infarction (MI) were more likely than hypertensives who had not had an MI to be taking one of these (short-acting) agents than other antihypertensive agents. This study was accompanied by a republication of older studies showing that large doses of short-acting nifedipine given to post-MI patients increased their mortality rate. The danger of massive doses of short-acting nifedipine in a post-MI patient is real but irrelevant to current practice. On the other hand, the putative dangers of short-acting CCBs in the treatment of hypertension do not apply to the current use of long-acting CCBs. Therefore the scare over their use is both irrational and unfortunate. (Hypertens Res 1996; 19: 57-64)

View full abstract

Dahl salt sensitive rats (DS) developed severe hypertension on four weeks of high salt feeding while the Dahl salt resistant rats (DR) remained normotensive under the same conditions. The specific maximal binding of epidermal growth factor (EGF) in the freshly prepared kidney membranes of high salt fed DS rats was higher than those from DR rats (5.3±1.9 vs. 1.6±0.62fmoles/mg protein, p<0.001). Scatchard analysis of EGF binding in the kidney showed one class of receptors in the DR (K_d=0.75±0.05 nM) as well as in the DS rats (K_d=0.69±0.06nM). The EGF binding in the aortic membranes of DS rats was also high compared to DR rats (24.98±5.52 vs). 13.20±4.10 (moles/mg protein, p< 0.001). Scatchard analysis of EGF binding in the aorta showed one class of receptors in the DR aorta with a K_d of 0.70±0.06nM. On the other hand, in the DS rat aorta two classes of receptors, a high affinity form (K_d=0.05±0.01nM) and a low affinity form (K_d=3.5±0.3nM) were noted. The induction of a high affinity species of EGF receptors in the aorta, appears to be a mechanism unique to the salt fed DS rats. (Hypertens Res 1996; 19: 65-68)

View full abstract

Noradrenergic (NA) nerve fiber density was investigated in the subepicardium and myocardium of ventricles in stroke-prone spontaneously hypertensive rats (SHRSP) and was compared with that of normotensive Wistar Kyoto (WKY) rats. Fluorescent NA nerve fibers in the subepicardium of the right and left ventricles of both strains at the ages of 10, 30, 60, 90, and 180 days were examined by the glyoxylic acid method. NA nerve fibers in the myocardium of the right and left ventricles and the ventricular septum of both strains at the ages of 30, 90, and 180 days were also examined in a similar manner. The density of NA nerve fibers was measured by quantitative image analysis. The distribution pattern of NA nerve fibers in the entire subepicardium of ventricles of both strains showed a meshwork pattern throughout the examination period. In sections of the myocardium, NA nerve fibers were distributed between heart muscle cells and around blood vessels in both strains at all ages examined. The densities of NA nerve fibers in the subepicardium of the ventricles of SHRSP were significantly higher than those of WKY rats at all ages examined except for the subepicardium of the left ventricle at 90 days of age. The densities in the myocardium of the right ventricle in 30- and 90-day-old SHRSP were significantly higher than those in WKY rats. The ratios of NA nerve fiber density of SHRSP to that of WKY rats were greater in the subepicardium of the right and left ventricles, except at 90 days of age, and in the myocardium of the right ventricle of younger animals as compared with older ones. NA hyperinnervation in the subepicardium and myocardium of the ventricles of SHRSP may be a primary change of the heart before the onset of hypertension and may be caused by hyperfunction of the stellate ganglia. (Hypertens Res 1996; 19: 69-73)

View full abstract

Antihypertensive effects of an angiotensin (Ang) II receptor antagonist, candesartan cilexetil (TCV-116), were compared with those of an angiotensin converting enzyme (ACE) inhibitor, enalapril, in spontaneously hypertensive rats (SHR), 2-kidney, 1-clip hypertensive rats (2K, 1C-HR) and 1-kidney, 1-clip hypertensive rats (1K, 1C-HR). CV-11974, the active form of TCV-116, had no inhibitory activity for plasma ACE. In rats, TCV-116 inhibited the pressor responses to Ang I, Ang II, and Ang III without an effect on the bradykinin (BK)-induced depressor response. Enalapril inhibited only the Ang I-response and potentiated the BK-response. In SHR, the antihypertensive effect of TCV-116 (10mg/kg) was larger than the maximum antihypertensive effect of enalapril and was not intensified by combination with enalapril. Administration of CV-11974 potentiated the maximum antihypertensive effect of enalapril. Although both agents reduced blood pressure in 2K, 1C-HR, only TCV-116 had a marked antihypertensive effect in 1K, 1C-HR. These findings indicate that TCV-116 is more effective than enalapril in reducing blood pressure in SHR and 1K, 1C-HR, and that the BK- and/or prostaglandin-potentiating effect of enalapril contributes little to its antihypertensive mechanism in SHR. (Hypertens Res 1996; 19: 75-81)

View full abstract

Male Dahl salt-sensitive hypertensive (S) rats develop hypertension faster than females. We measured renal α₂-adrenergic receptor density of inbred Dahl salt-sensitive (SS/JR) and salt-resistant (SR/JR) rats, using [³H]-rauwolscine saturation binding studies. Male and female SS/JR rats were gonadectomized or sham-operated at 6 weeks of age and fed a high salt diet for 4 weeks. Additional intact SS/JR and SR/JR rats of both sexes were fed the high salt diet for a longer period of time (7 weeks instead of 4 weeks). Both blood pressure and renal α₂-adrenergic receptor density were significantly higher in male than female SS/JR rats on high salt diet for 4 weeks. Gonadectomy did not change blood pressure nor did it change renal α₂-adrenergic receptor density measured at the 4th week of high salt feeding in either male or female SS/JR rats. When the SS/JR rats were fed high salt diet for a longer period (for 7 weeks), blood pressure of female SS/JR reached the level of males, but the density of renal α₂-adrenergic receptors was still significantly lower than that of males. Both renal α₂-adrenergic receptor density and blood pressure were higher in male than female SR/JR. We conclude that higher blood pressure in male Dahl SS/JR and SR/JR rats is associated with higher renal α₂-adrenergic receptor density compared with their female counterparts. (Hypertens Res 1996; 19: 83-89)

View full abstract

To assess the effect of recombinant human erythropoietin (EPO) on the factors regulating blood pressure (BP), we determined the hemoglobin level (Hgb), blood viscosity (BV), plasma renin activity (PRA), plasma concentrations of aldosterone (PAC), adrenaline (Ad), noradrenaline (NAd), and atrial natriuretic peptide (ANP), and serum and intracellular concentrations of cations before and after 3 months of EPO treatment (40units/kg/week of EPO intravenously after each hemodialysis session) in 11 patients undergoing maintenance hemodialysis. Intracellular sodium concentration ([Na⁺]_i) was measured using erythrocytes with flame photometry. EPO treatment was associated with significant increases in Hgb (7.1±1.4 to 8.4±1.8g/dl, p<0.01), mean BP (103±11.4 to 116±19.9mmHg, p<0.01), [Na⁺]_i (4.99± 0.78 to 6.22±0.96mmol/l, p<0.01) and BV (1.39±0.14 to 1.53±0.18 c.p., p<0.05), but no significant alteration in PRA, PAC, Ad, NAd, ANP, or in the serum concentration of Na⁺, K⁺, and Ca²⁺. The changes in mean BP (ΔMBP) were significantly correlated with Δ[Na⁺]_i (R=0.676, p=0.022) and ΔBV (R=0.668, p=0.034), but not with ΔHgb. By multiple regression analysis, Δ[Na⁺]_i and ΔBV independently contributed to ΔMBP; ΔMBP=2.27×Δ[Na⁺]_i+32.2×ΔBV+3.37 (R=0.695). These data suggest that intracellular sodium accumulation as well as increased blood viscosity may be independently involved in the blood pressure elevation after EPO treatment in patients under maintenance hemodialysis. We found no evidence supporting a role of circulating hormonal factors, such as the renin-angiotensin system, adrenaline, or ANP, in the change in blood pressure. (Hypertens Res 1996; 19: 91-95)

View full abstract

We investigated the potential role of increased plasma adrenomedullin and brain natriuretic peptide (BNP) levels in a patient with malignant hypertension. A 51-year-old man was admitted to our hospital with a chief complaint of visual disturbance. His blood pressure was 270/160mmHg on admission. Papillary edema associated with retinal bleeding was observed. Echocardiography revealed marked concentric left ventricular hypertrophy with mild systolic dysfunction. Plasma levels of adrenomedullin and BNP were markedly elevated. Antihypertensive therapy reduced the plasma levels of adrenomedullin in association with a concomitant decrease in blood pressure. The plasma level of BNP also decreased and regression of left ventricular hypertrophy and normalization of left ventricular systolic function were observed. Our findings suggest that adrenomedullin may be involved in the defense mechanism against further elevations in blood pressure in patients with hypertension and that the plasma level of BNP may reflect left ventricular systolic dysfunction, left ventricular hypertrophy, or both, in patients with severe hypertension. (Hypertens Res 1996; 19: 97-101)

View full abstract

Strips of tail artery from stroke-prone spontaneously hypertensive rats (SHRSP), but not from normotensive Wistar Kyoto (WKY) rats, exhibit oscillatory activity after stimulation with norepinephrine. In addition, oscillatory activity is observed in response to tetraethylammonium (TEA) in vessels from both SHRSP and WKY rats. Mechanistically, the oscillatory contractions are associated with calcium (Ca²⁺)-driven action potentials. We have tested the hypothesis that intracellular Ca²⁺ stores participate in the generation of norepinephrine-induced oscillatory contractions in tail arteries from SHRSP. Additionally, the role of intracellular Ca²⁺ stores on TEA-induced contractions were evaluated. Contractile force in strips of tail artery from SHRSP and WKY rats was measured, using standard muscle bath procedures, and the effect of interventions that affect the storage of intracellular Ca²⁺ on the oscillatory contractions was evaluated. Depletion of intracellular Ca²⁺ stores, with ryanodine, or inhibition of Ca²⁺ uptake into the sarcoplasmic reticulum (SR), with thapsigargin and cyclopiazonic acid (CPA), did not inhibit oscillatory contractions induced by norepinephrine in SHRSP vessels. However, these agents inhibited the amplitude of TEA-induced contractions in WKY strips. Bay K 8644 and A23187 inhibited TEA-induced oscillatory contractions in WKY vessels. In SHRSP tail artery Bay K 8644 inhibited both norepinephrine and TEA-induced contractions, while A23187 did not have any effect. The phospholipase C inhibitor, NCDC (3×10^-5M), blocked oscillatory activity induced by norepinephrine in SHRSP tail artery and TEA-induced oscillations both in SHRSP and WKY vessels. These observations suggest that Ca²⁺ release and Ca²⁺ uptake into intracellular Ca²⁺ stores are not involved in the contraction-relaxation cycles that characterize norepinephrine-induced oscillatory activity in SHRSP tail artery. Similarly, SR Ca²⁺ stores may modulate but are not essential for TEA-induced oscillatory contractions. (Hypertens Res 1996; 19: 103-111)

View full abstract

The present study was undertaken to determine whether adrenomedullin modulates the arginine vasopressin (AVP)-activated mitogen-activated protein (MAP) kinase in cultured rat glomerular mesangial cells. AVP dose-dependently increased cellular free calcium, and this increase was unaffected by adrenomedullin. Adrenomedullin increased cellular cAMP production in a dose-dependent manner and AVP activated MAP kinase in a dose-dependent manner. When cells were preincubated for 15min with adrenomedullin at concentrations of 1×10^-8M or higher, the AVP-activated MAP kinase was significantly reduced. In addition, the activation of MAP kinase by phorbol-12-myristate-13-acetate (PMA) was significantly inhibited by adrenomedullin. Similarly, forskolin also diminished the activation of MAP kinase by AVP and PMA. The inhibition by adrenomedullin or forskolin of AVP-activated MAP kinase disappeared when cells were preexposed to H-89, an inhibitor of protein kinase A. These results indicate that adrenomedullin inhibits the AVP activation of MAP kinase mediated through cAMP in glomerular mesangial cells and that the site of action of adrenomedullin is behind the site of activation of protein kinase C. (Hypertens Res 1996; 19: 113-119)

View full abstract

To examine potential intracellular signalling abnormalities of endothelin-1 (ET-1) and vasopressin (AVP) which may contribute to blood pressure elevation, contractility and inositol phosphate levels in intact arteries and calcium transients in vascular smooth muscle cells were investigated after stimulation with these peptides in pre-hypertensive 5 week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats. Contractility of aorta in response to ET-1, AVP and norepinephrine (NE) was blunted in SHR relative to WKY. Contraction of mesenteric resistance arteries induced by ET-1 was similar in both groups, whereas sensitivity in response to NE and AVP was greater in SHR. Basal inositol phosphate in aorta and mesenteric arteries was elevated in SHR, but ET-1 and AVP-stimulated inositol phosphate responses were similar in both groups. Calcium transients induced by ET-1 and AVP in vascular smooth muscle cells were similar in young SHR and WKY. In contrast, in adult rats inositol phosphate responses to ET-1 were blunted in aorta of SHR, but were normal in mesenteric arteries. Inositol phosphate responses to AVP were similar in both rat strains of rats both in aorta and mesenteric arteries except for accumulation of inositol trisphosphate, which was enhanced in mesenteric arteries of SHR. Calcium mobilization in vascular smooth muscle cells from adult SHR also exhibited enhanced responses to AVP. In conclusion, in young SHR, blunted ET-1 and AVP-induced contraction in aorta and enhanced AVP-induced mesenteric artery contraction are associated with normal inositol phosphate production and calcium mobilization. Signal transduction in response to ET-1 and AVP is depressed in aorta of pre-hypertensive SHR after the step of inositol phosphate generation and calcium mobilization. Resistance vessel reactivity to AVP is enhanced in young SHR at steps following inositol phosphate generation and calcium mobilization. These results argue against a role of ET-1, but suggest the possible involvement of AVP in the development of this model of genetic hypertension. (Hypertens Res 1996; 19: 121-132)

View full abstract

We investigated the relation between pressor responses to laboratory stressors and 24-hour blood pressure (BP) variability or left ventricular mass. Mental arithmetic tests, isometric hand grip exercise, and bicycle ergometer exercise were carried out in middle-aged normotensive subjects (n=10) and in age-matched WHO stage I (n=23) and stage II (n=11) patients with essential hypertension. Mental arithmetic was associated with a greater rate of increase in plasma epinephrine than in norepinephrine, and handgrip exercise was associated with a greater rate of increase in plasma norepinephrine than in epinephrine in all three groups. Bicycle ergometer exercise caused a remarkable increase in plasma norepinephrine and a mild increase in plasma epinephrine in all three groups. In mental arithmetic tests, pressor responses of hypertensive patients were significantly greater than those of normotensives. The pressor response during mental tests was significantly correlated with the value of 24-hour BP variability in all subjects (r=0.56, p<0.01). The pressor response to handgrip increased with the stage of hypertension. A good correlation existed between the pressor response to handgrip and the left ventricular mass index in the subjects (r=0.73, p<0.001). There was no difference in the pressor response to ergometer exercise between any of the groups. The findings suggest that the pressor response to mental stress reflects BP variability and that the response to handgrip is correlated with target-organ disease associated with hypertension, especially the degree of cardiac hypertrophy. (Hypertens Res 1996; 19: 133-137)

View full abstract