Polyamines and noradrenaline following myocardial hypertrophy

The aliphatic amines, spermine and spermidine, and amino-oxidase activity were evaluated in hypertrophic rabbit heart obtained following aortic arch constriction. The polyamines were determined early after surgery (at 1, 2, 4, 8 h), during the first 10 days (at 1, 2, 5, 6, 10 days) and during the following 6 months (at 1, 2, 4, 6 months) after surgery. The pattern showed a rapid increase of spermine that reached a peak at 5 days after surgery (+146%). The changes of the enzymic activity are in accordance with the behaviour of polyamines. Under the same experimental conditions the myocardial concentrations of noradrenaline were evaluated. This chemical mediator rapidly increased 1 h after aortic stenosis. The results suggest that biogenic amines are related to the metabolic phenomena at the early stages of cardiac hypertrophy, and in particular to protein synthesis.     

Early prevention of experimental left ventricular hypertrophy in experimental hypertension and angiotensin II levels]

INTRODUCTION: Angiotensin II levels can be partially inhibited during chronic administration of angiotensin converting enzyme (ACE) inhibitors, limiting from a clinical point of view its efficacy in the treatment of hypertension. There are few studies relating ACE activity directly with early prevention of left ventricular hypertrophy (LVH) in systemic hypertension during the administration of an ACE inhibitor (ACEI). AIM: To evaluate the effects of early ACE inhibition with perindopril on the development of hypertension, LVH and levels of angiotensin II (Ang II) in plasma as well as in LV in the rat Goldblatt model (Gb; 2 kidneys-1 clip), 2 weeks after surgery. RESULTS: Systolic blood pressure and relative LV mass increased by 42% and 20% respectively, in the Gb group (p < 0.001). Plasma and LV ACE activities were significantly higher in the Gb rats compared with the control rats. Plasma and LV Ang II levels also increased by 129% and 800%, respectively. Perindorpil prevented hypertension and LVH development by inhibiting plasma ACE (and also LV ACE), and also circulation Ang II in plasma and in the LV. CONCLUSIONS: In this experimental model of hypertensive LVH, there is an early activation of plasma and cardiac ACE. Early administration of an ACE inhibitor prevents the development of hypertension and LVH by inhibiting the increases of plasma and LV Ang II.     

Morphometry of cardiac hypertrophy induced by experimental renal hypertension.

A method for determining the mean volume of cells within a tissue has been applied to the measurement of endocardial and epicardial myocytes in the left ventricle of normal and hypertensive rats. The technique is based on nuclear counts per unit area in tissue slices of different known thicknesses. It measures the mean cell volume per nucleus and has been combined with electron microscopic morphometry. Compared with the epicardial regions, the normal endocardial regions contained 30 percent more myocytes, 27 percent less interstitial space, 48 percent less capillary volume, 17 percent less capillary surface and the same capillary length per unit of tissue volume. In terms of both the relative and absolute volumes and surface areas of their organelles, the cytoplasmic composition of normal endocardial and epicardial myocytes was nearly identical.After 1 to 4 weeks of hypertension induced by renal arterial constriction, endocardial myocytes enlarged from 10,370 ± 410 to 12,520 ± 490 μ m³ whereas epicardial myocytes enlarged from 12,600 ± 1,600 to 17,300 ± 1, 100 μm³. The number of myocytes and the total length of capillaries remained constant. The epicardial region enlarged 37 percent with proportional increases of myocyte and interstitial volumes. In contrast, the endocardial enlargement was only 26 percent, consisting of 21 percent hypertrophy of myocytes and a 55 percent increase in interstitial components. Expansion of capillary lumens accounted for much of the interstitial enlargement throughout the myocardium. Hypertrophy of myocytes in the epicardial region was accompanied by a reduced mitochondria to myofibril ratio and disproportionately large increases (two- to three-fold) in both smooth endoplasmic reticulum and T system volume and surface area. On a cell basis the morphometric characteristics of myocytes from hypertensive rats are significantly different from normal, and significant differences occur between the inner and outer layers of the myocardium for practically every cytoplasmic component.     

Cardiac hypertrophy in hypertension

The time course of regression of left ventricular hypertrophy and changes in left ventricular function were followed in 52 middle-aged hypertensive patients divided into two groups: 30 treated with betablockers and 22 with methyldopa. In case of inadequate blood pressure control, diuretics and/or vasodilators were added in both groups. Blood pressure decreased significantly over a three-year follow-up period. The decrease was most pronounced during the first three months. The biggest decrease in posterior wall and interventricular septum thickness was detected by echocardiography also within the first three months. While complete regression of posterior wall hypertrophy was noted within the next three months, interventricular septum thickness decreased steadily over a period of two years. No significant change was seen in the septum in the third year of follow-up. Complete regression of hypertrophy was found in 30 (57.7%) of probands, with no change altogether observed in as few as two patients. Regression was incomplete in 20 (38.4%) obese patients with manifest hypertrophy at the start of the study. Regression of hypertrophy was not associated with left ventricular function deterioration and was observed even after vasodilator administration. There were no differences between the two groups of patients.     

Polyamines and epidermal growth factor in monocrotaline-induced pulmonary hypertension

Multiple lines of evidence suggest that the polyamines, a family of low-molecular-weight organic cations with documented regulatory note in cell growth and differentiation, are involved with hyperplastic and hypertrophic responses of lung cells underlying hypertensive pulmonary vascular disease. Little is known, however, of the factor(s) initiating polyamine synthesis in pulmonary hypertension. This study tested the key aspects of the hypothesis that augmented polyamine synthesis, and attendent vascular structural alterations in monocrotaline (MCT)-treated rats can be ascribed to elaboration of an epidermal growth factor (EGF)-like mitogen. In lungs of rats treated 4 days previously with 60 mg/kg, EGF-like immunoreactivity was detected diffusely throughout perivascular regions. Intravenous administration of human recombinant EGF (125 pg/h) to rats for 1 wk was associated with medial thickening in pulmonary arteries between 100 and 200 microns in diameter, significant increases in lung polyamine contents, and a moderate elevation in mean pulmonary arterial pressure. These observations indicate that EGF can be detected in the lungs of MCT-treated rats and that exogenous EGF mimics some of the action of MCT on the rat lung. It is thus reasonable to speculate that an EGF-like mitogen may participate in the response to MCT in part through a polyamine-dependent mechanism.     

Prevention of angiotensin II-induced hypertension, cardiovascular hypertrophy and oxidative stress by acetylsalicylic acid in rats

BACKGROUND: Angiotensin II (Ang II)-induced oxidative stress has been suspected to play an important part in the pathogenesis of many cardiovascular diseases. Our previous study demonstrated that acetylsalicylic acid (ASA) possesses potent antioxidative properties. OBJECTIVE: To evaluate the pathogenetic role of oxidative stress in Ang II-induced hypertension and cardiovascular hypertrophy. METHODS AND RESULTS: Chronic infusion of Ang II (200 ng/kg per min for 12 days) increased the aortic and cardiac tissue production of superoxide anion (O2) (lucigenin-enhanced chemiluminescence method) by 77 and 35%, respectively. These effects were associated with progressive increases in systolic blood pressure (from 135 to 194 mmHg) and heart/body weight ratio (from 2.25 to 2.69). Chronic treatment with oral ASA alone (100 mg/kg per day for 12 days) significantly reduced aortic and cardiac production of O2 (by 31 and 33%, respectively), without alteration in blood pressure and heart/body weight ratio in control normotensive animals. However, concurrent treatment with ASA in Ang II-infused rats completely prevented the Ang II-induced production of O2, in addition to hypertension and cardiac hypertrophy. Similar protective effects were observed in cultured aortic smooth muscle cells, in which increases in O2 production and [H]leucine incorporation (221 and 38%, respectively) induced by Ang II (10 mol/l) were totally prevented by concurrent incubation with ASA (10 mol/l). Losartan, but not PD 123319, also blocked the Ang II-induced oxidative and hypertrophic effects in those cells. Other anti-inflammatory drugs, such as salicylic acid, indomethacin and ibuprofen, did not show similar anti-Ang II and antioxidative effects in vivo. CONCLUSIONS: Oxidative stress plays a major part in chronic Ang II-induced hypertension and cardiovascular hypertrophy. Chronic concurrent treatment with ASA was found to prevent those Ang II-induced effects on the cardiovascular system, presumably through its antioxidative properties.     

Cardiac hypertrophy in experimental hypertension: interaction of the sodium ion, blood pressure and lisinopril

The interaction of blood pressure, salt intake and the inhibition of angiotensin converting enzyme activity with cardiac hypertrophy were examined in the Dahl rat model. Eight-week-old salt sensitive and salt resistant rats were each separated into two colonies, one of which was maintained on a low salt and the other on a high salt diet for three weeks, at the end of which time both salt sensitive colonies were hypertensive. Each colony was then separated into two groups, one received no medication the other was given lisinopril until normotension was achieved. After 11 weeks of therapy, intra-arterial blood pressures and heart rates were recorded. The rats were sacrificed and heart weight to body weight ratios were determined. Both untreated salt sensitive groups displayed marked cardiac hypertrophy which correlated well with diastolic blood pressure irrespective of salt intake. Lisinopril therapy lowered blood pressures to normotensive levels in all groups except for salt sensitive rats ingesting a high salt diet where, despite a 10-fold increase in drug dose, normotension was not achieved. Significant cardiac regression accompanied lisinopril therapy in rats receiving low salt diets but high salt intake severely attenuated regression in both strains. There was no significant correlation between heart weight and blood pressure in the treated groups. The results suggest that cardiac regression appears to be mediated by other factors besides ventricular afterload pressure and that high salt intake adversely affects blood pressure and heart weight response to lisinopril therapy.     

Renal hypertrophy in experimental diabetes

Summary Renal hypertrophy in rats with streptozotocin diabetes or after unilateral nephrectomy was studied by sterological techniques. — After 4 days of diabetes total glomerular volume had increased by 30%, and after 47 days by 43%. Glomerular growth was more pronounced than whole kidney growth during the first 4 days, but subsequently whole kidney growth exceeded glomerular growth. In control rats glomerular volume was 4.9% of total kidney volume; after 4 days of diabetes it was 5.4% and after 47 days 4.1%. — Proximal tubule length increased from 366 m/kidney in control rats to 447 m/kidney after 47 days of diabetes; tubular luminal diameter increased from 26.8 m to 31.4 m in the same rats. Tubular length and luminal diameter were, however, not increased after 4 days of diabetes. — In unilaterally nephrectomised rats there was no early rapid glomerular growth. Glomerular fractional volume was 4.9% in controls, 4.4% at four days, and 4.2% at 24 days after nephrectomy. — The results indicate a disturbed glomerulo-tubular balance in the early phases of diabetic renal hypertrophy.     

Polyamines, vascular smooth muscle, and deoxycorticosterone acetate-salt hypertension

This study was performed to determine if an alteration in vascular polyamine contents is associated with the development of deoxycorticosterone acetate-salt hypertension. The effects of chronic administration of alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase and thus polyamine biosynthesis, on vascular polyamine contents, structure, and function as well as the development of hypertension was studied. Control and deoxycorticosterone acetate-salt rats received either tap water or a drinking solution containing alpha-difluoromethylornithine for 6 weeks, during which period systolic blood pressures were recorded. Vascular reactivity studies were performed on rings of aorta and tail artery. Medial thickness, vessel weight, and vascular polyamine contents were also assessed in these arteries. alpha-difluoromethylornithine treatment had no significant effect on either systolic blood pressure or vascular structure, function, and polyamine contents of control animals. The elevation in blood pressure and the increase in medial thickness, ring weight, and vascular polyamine contents as well as altered vascular reactivity observed in deoxycorticosterone acetate-salt rats was significantly attenuated by alpha-difluoromethylornithine treatment. These results are the first to demonstrate that vascular polyamine contents are elevated in the deoxycorticosterone acetate-salt rat and that chronic alpha-difluoromethylornithine treatment prevents the rise in vascular polyamines as well as the elevation in blood pressure and attendant changes in the vasculature. Thus, the increase in vascular polyamines may comprise a critical link between the initiating stimuli and the alterations in vascular structure and function implicated in the pathogenesis of deoxycorticosterone acetate-salt hypertension.     

Cardiac hypertrophy in early hypertension.

Studies of cardiac hypertrophy in spontaneously hypertensive rats have indicated that left ventricular hypertrophy occurred even in the prehypertensive stage. These findings suggested that other factors besides blood pressure levels, and including possibly a genetic predisposition to myocardial hypertrophy, could play a role in structural cardiovascular alterations in spontaneously hypertensive rats. More recent studies have confirmed these anatomic results; left ventricular hypertrophy was vectorcardiographically detected even in the prehypertensive stage in voth young stroke-prone rats and stroke-resistant spontaneously hypertensive rats. Further, a close relation was found between degree of left ventricular hypertrophy and vascular hypertrophy or hyperplasia; this suggests that early detection of left ventricular hypertrophy may be a useful indicator of the incipient stage of structural vascular changes in genetic hypertension.     

Development of heart hypertrophy in hypertension

A total of 120 patients with essential hypertension, stage I and II, were examined, using radio- and electrocardiography, before and after a hypotensive treatment. Two mechanisms: excessive volume (in patients with hyperkinetic circulation) and excessive pressure (in those with normo- and hypokinetic circulation) were found to form the basis of the formation of left-ventricular muscular hypertrophy. Antihypertensive effect of treatment reducing electrocardiographic signs of left-ventricular muscular hypertrophy was shown to be related to improved arterial pressure control and lesser adrenergic influence on the heart.     

Effect of diltiazem and ibuprofen on right ventricular hypertrophy in an experimental model of hypoxic pulmonary hypertension

The effectiveness of diltiazem, a slow channel calcium blocker, ibuprofen, a nonselective inhibitor of prostanoid synthesis, and the selective inhibition of thromboxane A2 with imidazole and UK-38,485 in retarding the development of right ventricular (RV) hypertrophy was assessed in a rat model of chronic hypoxic pulmonary hypertension. Both ibuprofen and diltiazem significantly reduced RV hypertrophy in the chronically hypoxic rat. In contrast, selective inhibition of thromboxane A2 was ineffective in reducing RV hypertrophy. The beneficial effect of ibuprofen was unrelated to inhibition of thromboxane A2. Furthermore, thromboxane A2 did not appear to be involved in the development of RV hypertrophy in this experimental model of hypoxic pulmonary hypertension.     

Cardiac hypertrophy and arterial distensibility in essential hypertension

Echocardiographic determinations, left ventricular mass-volume ratio (M/V), left ventricular end-systolic stress (ESS), carotidofemoral pulse wave velocity (PWV), and brachial artery compliance (BAC), deduced from pulsed Doppler measurements and from the Bramwell-Hill equation, were evaluated in 20 patients with sustained essential hypertension in comparison with 20 control subjects of the same age and sex. In hypertensive patients, M/V ratio, ESS, and PWV were significantly increased while BAC was reduced. In the overall population, ESS was directly correlated with PWV (r = 0.73), and M/V ratio was significantly correlated with PWV (r = 0.60), BAC (r = -0.70), and systolic arterial pressure (r = 0.71). No comparable results were observed with diastolic arterial pressure. PWV was unchanged after cadralazine, a dihydralazine-like substance, and was decreased with the same blood pressure reduction following nitrendipine, a new calcium-blocking agent. These results suggest that: (1) the distensibility of large arteries plays an important role in the maintenance of cardiac hypertrophy in hypertension, and (2) antihypertensive drugs may act differently on arterial distensibility with possible consequences on ESS and reversion of left ventricular hypertrophy.     

Metabolic syndrome and biventricular hypertrophy in essential hypertension

The metabolic syndrome (MS) is associated with structural and functional alterations of the left ventricle (LV); no evidence is available on the impact of the MS on the right ventricle (RV). To assess whether MS, as defined by the ATP III report, is associated with biventricular hypertrophy, a total of 286 hypertensive subjects (mean age 58.7+/-12.2 years) attending our outpatient clinic underwent the following procedures: (1) physical examination and standard clinic blood pressure (BP) measurement; (2) routine laboratory investigations; (3) M-mode, two-dimensional and Doppler echocardiography. LV hypertrophy (LVH) was defined by LM mass index>or=51/47 g m(-2.7) in men and women, respectively. Right-sided chambers were measured in parasternal long axis at the outflow tract and subcostal view; RV hypertrophy (RVH) was defined by anterior RV wall thickness>or=6.0/5.5 mm in men and women, respectively. Filling velocities of both ventricles were assessed by pulsed Doppler echocardiography. Structural cardiac alterations were more pronounced in hypertensive men and women with MS than in their non-MS counterparts and involved both ventricles as shown by the differences in continuous variables as well as in prevalence rates of LVH (58 and 48% vs 28 and 30%, respectively, P<0.01) and RVH (48 and 54% vs 25 and 35%, respectively, P<0.01). Both LV and RV filling in MS hypertensives were more dependent on the atrial systole. Our study shows that in human hypertension, structural and functional cardiac changes induced by MS are not limited to the LV but also involve the right one.     

Effects of verapamil and aspirin on experimental chronic hypoxic pulmonary hypertension and right ventricular hypertrophy in rats.

Rats made hypoxic by confinement in hypoxic cages for 4 weeks developed pulmonary hypertension and right ventricular hypertrophy. Treatment with Verapamil or aspirin reduced both chronic hypoxic pulmonary hypertension and the hypertrophy of the right ventricle. The antihypertensive effect of Verapamil is explained by the involvement of the transmembrane calcium flux in pulmonary vascular smooth muscle in the hypoxic vasoconstrictory response. Part of the antihypertensive effect of inhibition of prostaglandin synthesis is attributed to a decrease in packed cell volume produced in hypoxic, aspirin treated rats.