The effect of prolonged administration of CGS 10078B on systemic and regional haemodynamics in normotensive and spontaneously hypertensive rats

The effects of 3 weeks treatment with CGS 10078B (30 mg/kg orally) on systemic and regional haemodynamics and cardiac mass were studied in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The significant decrease in mean arterial pressure (MAP) (174 +/- 3 versus 156 +/- 4 mmHg, P less than 0.002) in SHR was associated with a significantly slower heart rate. No significant alteration in systemic haemodynamics was observed in WKY rats. The reduced MAP in SHR was related to the preserved blood flow to the vital organs, and therefore reduced renal and cerebrovascular resistances. Left ventricular mass index was reduced in both rat strains of treated animals. Therefore, the reduced MAP and heart rate in the SHR without haemodynamic changes in the WKY indicates that CGS 10078B was an effective antihypertensive agent that decreased cardiac mass in rats through mechanisms that may be dissociated from their haemodynamic effects.     

Immediate Hemodynamic Changes Produced by Urapidil in Normotensive and Spontaneously Hypertensive Rats

The immediate effects on regional and systemic hemodynamics of urapidil (1 mg/kg IV), a recently synthesized vasodilator with a possible combined central and peripheral action, were studied in spontaneously hypertensive (SHR) and normotensive (WKY) rats. Maximal decrease in mean arterial pressure was achieved within the first minute after injection (154 ± 4 vs 113 ± 6 mm Hg in SHR and 111 ± 4 vs 82 ± 4 mm Hg in WKY, p < 0.01). This effect was accompanied by a transient (10 min) significant increase in heart rate in both strains. There was a significant fall in total peripheral resistance (0.43 ± 0.02 vs 0.30 ± 0.02 U/kg in WKY and 0.62 ± 0.03 vs 0.43 ± 0.03 U/kg in SHR, p < 0.01) and rise in cardiac index 15 min after drug injection (371 ± 9 vs 425 ± 12 m1/min/kg in WKY and 395 ± 8 vs 432 ± 12 ml/min/kg in SHR, p < 0.01). Organ vascular resistance decreased significantly in all the organs of WKY and most of the organs of SHR rats. However, a significant increase in blood flow was observed only in skeletal muscle. The data indicate that urapidil is a potent hypotensive agent. The pressure fall is mediated through a decreased total peripheral resistance that is distributed through all circulations. The increased cardiac output and heart rate are most likely reflexly induced.     

DOCA-salt induced malignant hypertension in spontaneously hypertensive rats

DOCA-salt hypertension was produced in 10 male 10-week-old normotensive Wistar-Kyoto (WKY) rats receiving deoxycorticosterone acetate (DOCA; 100 mg/kg, subcutaneous pellet) and 1% NaCl drinking water and was compared with data from 10 age- and sex-matched WKY receiving normal tap water (C). These data were also compared with spontaneously hypertensive (SHR) rats similarly treated. After 10 weeks on these programmes, systemic and regional haemodynamics were determined in conscious rats using microsphere techniques. DOCA-salt treatment increased mean arterial pressure (MAP), total peripheral resistance index (TPRI), cardiac and renal weights in both WKY and SHR. In contrast to SHR (C), the SHR (DOCA) demonstrated more severe MAP elevation (204 +/- 4 versus 185 +/- mmHg; P less than 0.01), more severe systemic and regional (especially renal) vasoconstriction, and malignant vasculitis associated with azotaemia and hyperuricaemia. The hyperuricaemia was related inversely to renal blood flow (r = -0.74; P less than 0.01) and directly to renal vasoconstriction (r = 0.65; P less than 0.05) in SHR (DOCA). These data suggest that in both WKY and SHR, DOCA and salt produced marked cardiovascular changes and SHR rats developed malignant hypertension.     

L-arginine reverses severe nephrosclerosis in aged spontaneously hypertensive rats

OBJECTIVE: Acute and prolonged effects of L-arginine on systemic and renal hemodynamics and on renal pathological changes were examined in 85-week-old spontaneously hypertensive rats (SHR). RESULTS: After 3 weeks of L-arginine administration (n = 9; 2 g/l in drinking water), mean arterial pressure remained unchanged, although the cardiac index increased (187 +/- 26 versus 263 +/- 15 ml/min per kg; P < 0.05) and total peripheral resistance decreased (1.15 +/- 0.18 versus 0.67 +/- 0.06 AU; P < 0.05); the glomerular filtration rate increased (0.41 +/- 0.07 versus 0.79 +/- 0.07 ml/min; P < 0.01). Control untreated, aged SHR (n = 10) demonstrated severe nephrosclerosis histologically, but those treated with L-arginine demonstrated a markedly reduced glomerular injury score (164 +/- 22 versus 83 +/- 9; P < 0.005), and their urinary protein excretion (39 +/- 5 versus 19 +/- 5 mg/100 g body weight per day; P < 0.05) and serum creatinine concentration (1.4 +/- 0.1 versus 0.9 +/- 0.1 mg/dl; P < 0.05) diminished. Intravenous L-arginine (300 mg/kg body weight) given to untreated SHR reduced mean arterial pressure, increased the cardiac index (+98 versus +1%; P < 0.05) and decreased total peripheral resistance (+56 versus +13%, P < 0.005); however, these variables remained unchanged after 3 weeks of L-arginine treatment. CONCLUSIONS: Three weeks of treatment with L-arginine improved systemic hemodynamics, renal function and renal histologic changes in aged SHR with naturally occurring nephrosclerosis. These data provide an important insight into the pathophysiology of nephrosclerosis in hypertension and with aging, which is seen clinically.     

Cardiovascular mass and ventricular function after celiprolol in Wistar-Kyoto and spontaneously hypertensive rats.

OBJECTIVE: The effects of a new beta 1 adrenergic receptor blocking agent with beta 2 receptor agonistic properties on cardiovascular mass, left ventricular function, and aortic distensibility were studied in Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. METHODS: 20 male SHR and 20 male WKY rats (10 treated and 10 untreated) aged 22 weeks were studied after three weeks of treatment. Cardiovascular mass was measured and left ventricular function was assessed using electromagnetic flowmetry while rapidly infusing whole blood at pharmacologically reduced mean arterial pressure and at pretreatment arterial pressure levels. Aortic distensibility was assessed by obtaining pressure-volume relationships in isolated aortic segments. RESULTS: Mean arterial pressure was reduced without changing cardiac output in SHR (p less than 0.01); it remained unchanged in WKY despite reduced cardiac output. Most noteworthy, and like no other agent studied to date, celiprolol significantly reduced both left and right ventricular as well as aortic mass in both WKY and SHR. Despite these similar mass reductions, celiprolol improved left ventricular function (p less than 0.01) and aortic distensibility (p less than 0.05) only in the SHR, a function maintained even when mean arterial pressure was increased abruptly to pretreatment levels. CONCLUSIONS: Unlike other beta receptor blockers (or any other agent studied in the SHR), celiprolol was effective in reducing mass of right and left ventricles and of aorta; decreasing mean arterial pressure through a fall in total peripheral resistance; and improving left ventricular function and aortic distensibility in the SHR. In contrast, while these structural changes were also produced in WKY, they were not associated with similar functional responses. These findings provide further support for the thesis of a structural and haemodynamic dissociation in antihypertensive therapy.     

Increased systolic performance with diastolic dysfunction in adult spontaneously hypertensive rats

Hypertensive heart disease is characterized by early development of hypertrophy and fibrosis that leads to heart failure (HF). HF develops in spontaneously hypertensive rats (SHR) after 18 months; however, it is not clear whether hypertrophy leads to altered cardiac performance at an earlier age in these rats. We studied cardiac performance in 10- to 11-month-old SHR and age-matched Wistar-Kyoto rats (WKY), using presssure-volume (PV) conductance catheter system to evaluate systolic and diastolic function in vivo at different preloads, including preload recruitable stroke work (PRSW), +dP/dt, and its relation to end-diastolic volume (+dP/dt-EDV) and preload-adjusted maximal power (PWR(max)-EDV(2)) as well as the time constant of left ventricular pressure decay, tau (tau), as an index of relaxation. The slope of the end-diastolic pressure-volume relation (EDPVR) and the ex vivo PV relation, both indexes of stiffness, were also calculated for each heart, and the Doppler E/A ratio was determined. In addition, plasma samples were obtained to assess B-type natriuretic peptide levels (BNP). We found that PRSW was higher in SHR than in WKY (174.5+/-15.6 versus 92.6+/-18.9 mm Hg; P<0.01). +dP/dt and +dP/dt-EDV were also enhanced in SHR versus WKY (9125+/-662 versus 6633+/-392 mm Hg/sec, P<0.01, and 28.14+/-4.35 versus 12.7+/-2.8 mm Hg/s per micro L, P<0.02). In addition, PWR-EDV(2) was elevated in SHR (7.3+/-1.5 versus 3.1+/-0.6 mW/ micro L(2)). Tau was prolonged in SHR (14.5+/-1 ms versus 10.8+/-0.8 for WKY, P<0.02) and EDPVR was significantly greater in SHR than in WKY (0.01+/-0.005 versus 0.004+/-0.001, P<0.05). The ex vivo pressure-volume relation was also steeper for SHR and the E/A ratio was 2.53+/-0.15 for SHR versus 1.67+/-0.08 for WKY (P<0.02). BNP was 45+/-2.5 pg/mL for SHR and 33.3+/-1.8 pg/mL for WKY (P<0.02). Taken together, these data suggest that at 10 to 11 months of age, before HF develops, SHR have increased systolic performance accompanied by delayed relaxation and increased diastolic stiffness.     

Hemodynamic effects of a new alpha- and beta-adrenergic receptor inhibitor with calcium entry blocking effects (CGS 10078B) in WKY and SHR rats

The immediate acute hemodynamic effects of CGS 10078B, a new agent with combined alpha- and beta-adrenergic antagonist with slow channel calcium entry blocking effects, were studied in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), total peripheral resistance index (TPRI), and regional hemodynamic measurements were determined before and two hours after its administration (10 mg/kg, gavage) using the combined radioactive reference sample and microsphere techniques (85SR and 141Ce). The agent significantly reduced MAP (168 +/- 5 to 158 +/- 5 mm Hg; p less than 0.02) after 20 minutes without changing HR in SHR. After two hours MAP, HR, and Cl were significantly reduced without change in TPRI. Only Cl decreased (p less than 0.05) in WKY, presumably from its beta receptor antagonist effects. Blood flow to the major organs (eg, heart, brain, and kidneys) was maintained in both groups of rats. These hemodynamic effects reflect the combined actions of this new agent and suggest its potential value for the treatment of hypertension.     

Immediate hemodynamic effects of urapidil in patients with essential hypertension

Systemic, renal and splanchnic hemodynamics and certain reflex and endocrine responses were determined in 10 patients with essential hypertension before and after intravenous administration of urapidil, a new antihypertensive agent that acts through both central and peripheral alpha-adrenergic inhibitory mechanisms. The reduction in mean arterial pressure by 12% (103 +/- 3 vs 91 +/- 6 mm Hg, p less than 0.05) was mediated through a decreased total peripheral resistance index (from 34 +/- 2 to 25 +/- 3 U/m2, p less than 0.01), which was associated with a significant reflexive increase in cardiac index, heart rate and serum norepinephrine level. This hypotensive effect was also associated with blunted Valsalva overshoot and orthostatic hypotension, suggesting peripheral arteriolar and venular dilation. Renal and splanchnic blood flows increased (p less than 0.05), resistances in these vascular beds decreased (p less than 0.01) and there were no changes in creatinine clearance or glomerular filtration fraction. Thus, intravenous urapidil reduced arterial pressure by decreasing total peripheral, renal and splanchnic resistances associated with maintained organ flows and increased heart rate and cardiac index.     

Potentiation of the baroreceptor-heart rate reflex by sympathectomy in conscious rats

In both animals and humans, stimuli leading to sympathetic activation are accompanied by an impairment of the baroreceptor-heart rate reflex. To determine whether sympathetic activity normally interferes with this reflex function we examined in conscious Wistar-Kyoto (WKY) rats the effect of chemical sympathectomy by 6-hydroxydopamine on the bradycardic response to baroreceptor stimulation induced by raising blood pressure via intravenous phenylephrine boluses; control rats received vehicle. Spontaneously hypertensive rats were also studied because in these animals there is both a baroreceptor reflex impairment and a sympathetic overactivity. Baroreceptor reflex sensitivity, calculated as the ratio of the peak increase in pulse interval to the peak increase in mean arterial pressure, was 75% greater in sympathectomized WKY rats than in control WKY rats (1.28 +/- 0.15 versus 0.73 +/- 0.10 msec/mm Hg, mean +/- SEM; p less than 0.01). The sympathectomy-induced increase in sensitivity was even larger in spontaneously hypertensive rats (SHR) (1.26 +/- 0.12 versus 0.44 +/- 0.06 msec/mm Hg in sympathectomized SHR versus control SHR, +186%; p less than 0.01) so that the impaired baroreceptor reflex sensitivity observed in control SHR as compared with control WKY rats (-40%, p less than 0.01) was no longer detectable in the sympathectomized groups. To establish whether the sympathectomy-induced potentiation of the reflex was due to an increase in cardiac responsiveness to vagal stimuli, we subjected separate groups of anesthetized, vagotomized SHR and WKY rats to graded electrical stimulation of the right efferent vagus. The bradycardic effects of vagal stimulation, however, were similar in sympathectomized and control animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional and metabolic responses to ischemia in the perfused heart isolated from normotensive and spontaneously hypertensive rats

The difference between normotensive rats (WKY) and spontaneously hypertensive rats (SHR) in functional and metabolic responses to ischemia was studied. Systolic arterial blood pressure of SHR (171.2 +/- 2.9 mmHg) was significantly higher than that of WKY (135.3 +/- 1.2 mmHg), and the left ventricular mass of SHR was larger than that of WKY. Hearts isolated from either WKY or SHR were perfused by the working heart technique. Ischemia was induced by lowering the afterload pressure of the working heart. Ischemia produced cardiac arrest, and decreased the tissue levels of adenosine triphosphate and creatine phosphate in both WKY and SHR. Recovery of mechanical function of the heart during reperfusion following ischemia in SHR was better than that in WKY, while recovery of the high-energy phosphates level in SHR was less prominent than in WKY. It is postulated that hypertension has a deleterious effect on myocardial energy metabolism in ischemic heart, even when cardiac mechanical function is maintained.     

Ventricular performance in spontaneously hypertensive rats (SHR) with reduced cardiac mass

Summary This study was designed to investigate the effect of 4 weeks of captopril treatment on cardiac mass and performance in spontaneously hypertensive rats (SHR). Left (LV) and right (RV) ventricular mass of SHR and normotensive WKY rats was reduced (p<0.01). Mean arterial pressure (MAP) and total peripheral resistance index (TPRI) in the treated SHR and WKY were reduced; cardiac (CI) and stroke (SI) indices remained unaltered in SHR but increased in WKY. Ventricular performance (i.e., cardiac pumping ability), assessed by rapid blood infusion, did not differ between untreated SHR and WKY, and between treated and untreated WKY rats. However, the ventricular performance curves for the treated SHR shifted down and to the right from the untreated SHR (p<0.01). Moreover, when MAP of treated SHR (with regressed LV mass) was elevated to their pretreatment levels, cardiac performance curves shifted further rightward and downward. In contrast, the performance curves of treated WKY whose MAP was also elevated to the level of untreated WKY were no different from those of untreated WKY. These data demonstrate that captopril treatment (at doses used in this study) reduced MAP in SHR through decreased TPRI while decreasing biventricular mass. Furthermore, the cardiac-pumping ability of previously hypertrophied SHR hearts was reduced, suggesting that certain antihypertensive agents that diminish cardiac mass could produce impaired cardiac function when called upon to increase performance (e.g., when MAP is suddenly raised).     

Hypertension in obese subjects: distinct hypertensive subgroup

Obesity and hypertension are two closely associated conditions and obesity probably predisposes to hypertension. In this investigation we evaluated central, systemic haemodynamic and intravascular volume characteristics of 51 established hypertensive obese subjects subgrouped for degree of obesity. Subgrouping according to body mass index (BMI) was as follows: lean hypertensives, 17 subjects (BMI 23.00 +/- 0.45 Kg/m2); moderately obese, 19 subjects (BMI 26.92 +/- 0.30 Kg/m2); severely obese, 15 subjects (BMI 32.78 +/- 0.45 Kg/m2). Obese hypertensives were characterised by significantly increased cardiac output and total plasma volume (P less than 0.05) and by decreased total peripheral resistance (not significantly) and left ventricular ejection fraction (P less than 0.01). These changes appear to be related to the degree of obesity. Significant correlation coefficients between body mass index and cardiac output, total blood volume, total peripheral resistance and ejection fraction were also observed. In conclusion, established hypertension in the severely obese patient appears to be a separate haemodynamic entity.     

The effects of urapidil therapy on hemodynamics and gas exchange in exercising patients with chronic obstructive pulmonary disease and pulmonary hypertension

To examine the hemodynamic changes induced by vasodilator therapy with urapidil during exercise in patients with chronic obstructive pulmonary disease (COPD) and their potential impact on symptom-limited maximal oxygen consumption, we studied 12 clinically stable patients using a randomized, crossover design. Placebo or urapidil (60 mg orally thrice a day) was given during 48 h preceding each incremental maximal exercise testing. Urapidil compared to placebo consistently lowered the pulmonary artery pressure either at rest from 29 +/- 2.5 to 24 +/- 1.5 mm Hg (p less than 0.001) or during exercise from 55 +/- 3 to 46 +/- 2 mm Hg (p less than 0.01). At rest, the systemic arterial pressure was reduced from 97.5 +/- 4 to 88.5 +/- 3 mm Hg (p less than 0.001) with no significant difference in heart rate or cardiac index. During exercise, systemic arterial pressure decreased from 135 +/- 4 to 119 +/- 3 mm Hg (p less than 0.001). As compared to placebo, urapidil tended to increase the cardiac index from 6.1 +/- 0.4 to 6.6 +/- 0.4 L/min.m2 (NS) and to decrease heart rate, from 122 to 116 beats/min (NS); the resulting stroke volume index increased with urapidil from 49 +/- 3 to 57 +/- 4 ml/m2 (p less than 0.01); at rest, urapidil did not induce alteration in gas exchange, while during exercise, C(a-v)O2 decreased from 8.6 +/- 0.5 to 7.7 +/- 0.4 vol% (p less than 0.01), SVO2 increased from 39.5 +/- 2 to 44.5 +/- 1.5% (p less than 0.01), and SaO2 from 82 +/- 2 to 85 +/- 2% (p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cilnidipine improves spontaneously hypertensive rat coronary hemodynamics without altering cardiovascular mass and collagen

OBJECTIVE : The present study was designed to determine the effects of prolonged treatment with cilnidipine, a novel dihydropyridine calcium antagonist which blocks both L-type and N-type calcium channels, on systemic, regional and coronary hemodynamics, cardiovascular mass and collagen content in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. METHODS : Male 23-week-old WKY and SHR rats were divided into two groups for each strain. One group received cilnidipine (10 mg/kg per day), whereas their respective controls were given no therapy. Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular and aortic mass, and hydroxyproline concentration were determined after 12 weeks treatment. RESULTS : The data demonstrated that cilnidipine neither affected systemic hemodynamics nor cardiovascular mass and collagen content in WKY rats. The same treatment in the SHR reduced arterial pressure and total peripheral resistance without changes in heart rate and cardiac index. Ventricular and aortic mass indices as well as ventricular collagen content remained unchanged. There were no differences in organ blood flows between two SHR groups, whereas renal, liver and left ventricular coronary vascular resistances were reduced by cilnidipine. After dipyridamole infusion left ventricular minimal coronary vascular resistance decreased further in cilnidipine-treated SHR as compared with control SHR rats. CONCLUSION : These data suggest that cilnidipine, an L- and N- type calcium channel antagonist, exerted beneficial effects on coronary hemodynamics without altering cardiovascular mass or collagen content in SHR.     

Vascular remodeling and improvement of coronary reserve after hydralazine treatment in spontaneously hypertensive rats

The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial and coronary vascular function and structure. Twelve-month-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with and without 12 weeks of vasodilator antihypertensive treatment (hydralazine) were studied using an isolated perfused rat heart model. Hydralazine treatment normalized blood pressure in SHR but did not cause regression of cardiac hypertrophy (heart weight to body weight ratio of SHR + hydralazine 4.33 +/- 0.098 vs. SHR 4.66 +/- 0.091; WKY 3.21 +/- 0.092 and WKY + hydralazine 3.38 +/- 0.152; mean +/- SEM). Coronary flow reserve, elicited by adenosine vasodilation in the perfused heart, was decreased in SHR (29%) compared with WKY (105%) and WKY + hydralazine (100%) and was significantly improved in SHR + hydralazine (75%). Morphometric evaluation of perfusion-fixed coronary arteries and arterioles (30-400 microns diameter) demonstrated a significant increase in the slope of the regression line comparing the square root of medial area versus outer diameter in SHR (0.444) compared with WKY (0.335) and WKY + hydralazine (0.336, p less than 0.05). Blood vessels from SHR + hydralazine were not different from control (0.338). Cardiac oxygen consumption was decreased in SHR (10.9 +/- 0.74 mumols oxygen/min/g/60 mm Hg left ventricular pressure) compared with WKY (22.4 +/- 1.47) and WKY + hydralazine (23.4 +/- 1.90; p less than 0.01), while SHR + hydralazine was intermediate (16.0 +/- 1.60). These studies suggest that significant alterations in myocardial and coronary vascular structure and function occur in hypertension-induced cardiac hypertrophy. The coronary vasculature is responsive to blood pressure, independent of cardiac hypertrophy, although moderate coronary deficits do remain after chronic antihypertensive therapy.     

Compensated function in hypertrophied ventricles of Wistar Kyoto and spontaneously hypertensive rats

STUDY OBJECTIVE--The aim of the study was to compare the compensatory nature of left ventricular hypertrophy in models of normal and increased peripheral resistance. DESIGN--Peak left ventricular performance was compared in normotensive Wistar Kyoto (WKY) rats, in a subset of this strain with biventricular hypertrophy associated with volume overload (WKY-CH), and in spontaneously hypertensive rats (SHR), all studied at one year of age (ie, long term hypertrophy). SUBJECTS--8 WKY-CH rats with biventricular hypertrophy were compared with 8 WKY (normal right and left ventricular weights). These groups were then compared with 9 SHR rats. All were maintained under identical conditions. MEASUREMENTS AND MAIN RESULTS--Left ventricular to body weight ratios (mg:g) were as follows: WKY-CH 2.78(SEM 0.09); SHR 2.90(0.09); WKY 2.10(0.09). Systolic blood pressures (mm Hg) were normal in WKY-CH [104(9)] and WKY [111(9)], but raised in SHR [163(8)]. Left ventricles from WKY and WKY-CH had normal histology and no fibre disorientation, fibrosis, or other morphological abnormalities. Peak cardiac index (ml.min-1.body weight-1) measured during rapid volume expansion with Tyrode's solution was higher in WKY-CH [427(33)] than in WKY [315(33)] and SHR [349(31)] (p less than 0.05). When peak stroke volume was expressed per mg left ventricular weight there were no significant differences between the groups. Peripheral resistance (mean arterial pressure divided by cardiac output) at peak cardiac output was higher in SHR [1.20(0.12)] than in either WKY-CH [0.57(0.08)] or WKY [0.74(0.08)]. CONCLUSIONS--These data show that both types of hypertrophy enhance peak left ventricular performance. In WKY-CH, which have normal peripheral resistance, the larger ventricle allows a higher peak cardiac index compared to WKY with no left ventricular hypertrophy. In SHR, the higher left ventricular mass is used to overcome an increased peripheral resistance and thereby provide a normal peak cardiac index.     

Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension

Enalapril, a new angiotensin-converting enzyme inhibitor, is an effective antihypertensive agent for both renovascular and essential hypertension. It is structurally different from captopril in that it does not possess a sulfhydryl group. The systemic and renal hemodynamic, biochemical and cardiac adaptive changes induced by enalapril were studied in 8 patients with essential hypertension before and after 12 weeks of therapy. Mean arterial pressure decreased from 110 to 90 mm Hg (p less than 0.01), and this was mediated through a decrease in total peripheral resistance from 42 +/- 3 to 32 +/- 3 U (p less than 0.01). Cardiac index and heart rate did not change. Renal plasma flow was increased in 6 of 8 patients and renal vascular resistance decreased from 123 +/- 6 to 91 +/- 7 U (p less than 0.001). Left ventricular mass index decreased from a mean of 166 +/- 29 to 117 +/- 8 g/m2 (p less than 0.05) without impaired myocardial contractility. Thus, enalapril lowers arterial pressure by reducing total peripheral resistance without reflexive cardiac effects. It also has favorable hemodynamic effects on the kidney. This is the first report of regression of LV mass with this agent in man.     

Prevention of coronary vasodilator reserve decrement in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) demonstrate an elevated minimal coronary vascular resistance by the seventh month of age. In an attempt to determine the role of long-standing hypertension in the etiological process of the elevated minimal coronary vascular resistance, we treated SHR and normotensive Wistar-Kyoto rats (WKY) with the vasodilator hydralazine from the time of weaning (1 month) until they were 7 to 8 months of age. The animals were instrumented 24 hours after their last drug dose and then studied on the following day. Using microspheres we measured myocardial perfusion in conscious rats at rest and during maximal coronary dilation induced with dipyridamole infusion. Hydralazine maintained arterial blood pressures in the normotensive range throughout the experimental period, but had little effect on left ventricular weight/body weight ratios (control SHR = 2.95 +/- 0.07, treated SHR = 2.73 +/- 0.08, control WKY = 2.39 +/- 0.09, mean +/- SEM). In treated SHR, left ventricular minimal coronary vascular resistance (per 100 g of tissue) was markedly lower (0.10 +/- 0.01) than in the controls (0.16 +/- 0.01) and not significantly different from that of WKY (0.11 +/- 0.01). Similar differences were noted in the nonhypertrophic right ventricle (treated SHR = 0.08 +/- 0.01, control SHR = 0.16 +/- 0.01, control WKY = 0.10 +/- 0.01). Total minimal coronary vascular resistance was also lower in both ventricles of the treated SHR compared with their nontreated controls. In WKY, hydralazine treatment significantly reduced blood pressure and total minimal coronary vascular resistance (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic Effects of Prolonged Treatment with Diltiazem in Conscious Normotensive and Spontaneously Hypertensive Rats

To determine systemic and regional hemodynamic effects of prolonged treatment with the calcium antagonist diltiazem (30 mg/kg twice daily by gastric gavage, for 3 weeks), data from 12 Wistar-Kyoto (WKY) and 10 spontaneously hypertensive (SHR) rats were compared with those obtained from 11 WKY and 10 SHR controls treated with the vehicle. Systemic and regional hemodynamics were determined in the conscious, unrestrained state using the reference sample microsphere method. Mean arterial pressure (MAP) decreased in SHR by 9% (183±4 to 167±4 mmHg; p < 0.05) but remained unchanged in WKY, while cardiac index (CI) tended to decrease in both strains; heart rate fell by 15% only in WKY (481·;10 to 354·13 beats/min; p < 0.05). Total peripheral resistance index (TPRI) tended to decrease in SHR but to increase in WKY. Organ blood flow in SHR decreased in skin and splanchnic organs, while organ vascular resistance decreased in brain and increased in splanchnic organs. In contrast, organ blood flow increased in heart and decreased in kidneys and skin of the WKY, while organ vascular resistance decreased in heart and increased in kidneys and skin. Thus, diltiazem produced nonuniform and different hemodynamic effects in the two strains. Further, diltiazem did not alter the cardiac mass in either rat strain. We therefore conclude that diltiazem demonstrated a mild hypotensive effect in SHR that was associated with slight reductions in CI and TPRI, the latter being non-uniformly distributed in the component organ circulations.     

Systemic and Regional Hemodynamics in Normotensive and Spontaneously Hypertensive Rats after Slow-Channel Calcium Blocker Nitrendipine

To determine the effects of the recently synthesized slow channel calcium blocker nitrendipine on systemic and regional hemodynamics, mean arterial pressure, heart rate, cardiac index and organ blood flow distribution were measured with the combined radioactive reference sample and microsphere techniques before and one hour after its oral administration (1 mg or 10 mg/kg). Twenty-week-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) conscious male rats were studied. At the 10 mg dose, nitrendipine exerted a hypotensive effect within 15 minutes, and this effect persisted throughout the study. After one hour, mean arterial pressure fell by 14 percent of pretreatment levels in WKY controls; it fell by 25 percent in SHR (p < 0.001). This action was mediated by a fall in total peripheral resistance index (p < 0.01) that was nonuniformly distributed to the organ circulations since blood flow was maintained or increased to brain, heart, kidneys, lungs, and adrenals, but decreased to skin. No change in cardiac index was observed.