G P Hodsman

Neurohumoral responses to chronic myocardial infarction in rats.

In chronic cardiac failure, various neurohumoral mechanisms are activated to sustain blood volume, blood pressure, and organ perfusion. Using the coronary artery ligation model of heart failure in the rat, we have measured changes in vasoactive hormone secretion and related these changes to salt and water status during a 1-month period. When compared with controls, rats with infarction had a marked rise in plasma atrial natriuretic peptide (294 +/- 59 vs. 79 +/- 10 pg/ml, p less than 0.001) although there was no increase in total exchangeable body sodium. Plasma renin activity and plasma aldosterone concentrations were the same for both rats with infarction and controls. Similarly, there were no significant differences in plasma arginine vasopressin, plasma osmolality, or plasma sodium concentration in rats with infarction. Ventricular norepinephrine levels were reduced in animals with infarction (p less than 0.01). Plasma atrial natriuretic peptide levels were raised in this model of chronic left ventricular failure. However, there was no salt retention and little stimulation of the renin-angiotensin-aldosterone system or vasopressin. The results suggest that high circulating atrial natriuretic peptide levels may prevent or limit salt and water retention, either directly or indirectly, by inhibiting the renin-angiotensin-aldosterone system.

Atrial natriuretic peptide in chronic heart failure in the rat: a correlation with ventricular dysfunction.

To assess the relation between atrial natriuretic peptide and ventricular dysfunction, we simultaneously measured both atrial and plasma immunoreactive atrial natriuretic peptide concentrations in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. When compared to controls (n = 39), rats with infarction (n = 16) had markedly elevated plasma immunoreactive atrial natriuretic peptide concentrations (1205.8 ± 180.9 vs. 126.7 ± 8.9 pg/ml, p < 0.001) and reduced immunoreactive atrial natriuretic peptide concentrations in right and left atria (31.4 ± 4.6 vs. 61.2 ± 3.2 ng/mg, p < 0.001; 14.9 ± 2.2 vs. 32.7 ± 2.4 ng/mg, p < 0.001, respectively). Right ventricular weight increased in proportion to infarct size, and both were correlated with plasma immunoreactive atrial natriuretic peptide levels (r = 0.825, p < 0.001 and r = 0.816, p < 0.001, respectively). Right atrial immunoreactive atrial natriuretic peptide content was significantly higher than left in both controls and rats with infarction. Both right and left atrial immunoreactive atrial natriuretic peptide concentrations were negatively correlated with both right ventricular weight as well as plasma imunoreactive atrial natriuretic peptide concentrations (right atrium: r = −0.816, p < 0.001, r = −0.708, p < 0.01; left atrium: r = −0.687, p<0.01, r = −0.644, p < 0.01, respectively). These results suggest that chronic stimulation of atrial natriuretic peptide release from both atria is associated with increased turnover and depleted stores of atrial natriuretic peptide in atria in proportion to the severity of heart failure. It also suggests that plasma atrial natriuretic peptide levels may be used as a reliable index of cardiac decompensation in chronic heart failure.

Decreased Atrial Natriuretic Peptide Binding in Renal Medulla in Rats With Chronic Heart Failure

The relations between atrial natriuretic peptide (ANP) binding sites in the renal medulla, plasma ANP concentration, and ventricular dysfunction have been studied in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. Plasma ANP concentration was measured by radioimmunoassay, and quantitation of receptors was performed by computerized in vitro autoradiography with 125I-labeled α-rat ANP (1-28) as the radioligand. When compared with controls, rats with myocardial infarction had markedly elevated plasma immunoreactive ANP concentrations (462 ± 82 versus 124 ± pg/ml, /K0.01) and reduced densities of ANP binding in the inner renal medulla (2.93 ±0.19 versus 3.53 ±0.22 fmol/mg protein, p < 0.01). Extensive myocardial infarction was associated with a significant decrease in receptor numbers in the inner medulla (33.6 ±5.7 versus 95.6 ±9.6 fmol/mg protein, p < 0.01) without significantly altering the affinity constant (1.76 ±0.51 versus 1.03 ± 0.15 ± 109 M-1, p > 0.05). Right ventricular weight increased in proportion to infarct size(r = 0.71, p < 0.01), and both were correlated with plasma immunoreactive ANP levels (r = 0.74, p < 0.01 and r = 0.75, p < .01, respectively). Binding densities in the inner medulla of rats with infarcts were negatively correlated with right ventricular weight, plasma immunoreactive ANP concentrations, and also with infarct size (r = −0.92, p < 0.001;r= −0.78, p < 0.001; r= −0.77, p < 0.01, respectively). These results suggest that specific binding sites of ANP in the inner medulla decrease in proportion to the elevation in circulating ANP levels, which in turn are related to infarct size and degree of ventricular dysfunction. Decreased ANP binding sites in the kidney may contribute to the blunted natriuretic response to infused ANP in heart failure and may be responsible in part for the impaired sodium and water excretion in chronic heart failure.

Plasma atrial natriuretic peptide in patients with acute myocardial infarction: effects of streptokinase.

Plasma concentrations of immunoreactive atrial natriuretic peptide (mean (SEM] were measured in 135 patients admitted to two coronary care units with myocardial infarction, ischaemic chest pain, or non-ischaemic chest pain. Concentrations were significantly higher in patients with acute myocardial infarction not treated with systemic thrombolysis (60.4 (14.3) pg/ml) than in patients with non-ischaemic chest pain (21.1 (4.3) pg/ml). Patients with ischaemic chest pain had intermediate values (39.3 (7.1) pg/ml). Patients with acute myocardial infarction treated with intravenous streptokinase had normal concentrations of plasma atrial natriuretic peptide (20.2 (3.6) pg/mg), which were significantly lower than those in patients with myocardial infarction not given streptokinase. These changes could not be explained by factors such as age, pre-existing hypertension, renal dysfunction, or cardiac failure, nor treatment other than streptokinase. Raised plasma concentrations of atrial natriuretic peptide in acute myocardial infarction may be a homoeostatic response acting to reduce atrial pressures by natriuresis, diuresis, and venodilatation. The lower concentrations of atrial natriuretic peptide in patients with acute myocardial infarction treated with streptokinase may reflect a short term beneficial haemodynamic effect of streptokinase.

Cardiac hypertrophy and salt status in chronic myocardial infarction in the rat: effects of enalapril versus salt restriction

The effects of salt restriction and the ACE inhibitor enalapril were compared in a model of chronic myocardial infarction in the rat. Total exchangeable sodium was measured by an isotopic dilution technique to quantitate the effects of the low salt diet and ACE inhibitor on body sodium and extracellular fluid. Rats with infarction developed a marked increase in cardiac weight (4.29 ± 0.18 mg/g body weight) compared with control rats (3.64 ± 0.08 mg/g, p < 0.01). There was hypertrophy of both left and right ventricles. Salt restricted rats with infarction developed identical cardiomegaly (4.30 ± 0.11 mg/g), although total exchangeable body sodium fell by 10% (p < 0.001). In contrast, rats with infarction receiving enalapril developed significantly less cardiomegaly (3.97 ± 0.10 mg/g) while body sodium remained unchanged. Rats with infarction had a significant increase in lung weight which was not changed by salt restriction but which was abolished by enalapril. These results suggest that salt restriction does not prevent the progression of cardiomegaly in chronic left heart failure. In contrast our results confirm the ability of ACE inhibitors to prevent progressive cardiomegaly and left heart failure without affecting long-term changes in sodium balance.

Atrial natriuretic factor in chronic renal failure: studies in man and the rat.

1. Plasma concentration and atrial content of atrial natriuretic factor (ANF) were measured in rats with chronic renal failure induced by subtotal nephrectomy.

Comparative effects of angiotensin converting enzyme inhibition (perindopril) or diuretic therapy on cardiac hypertrophy and sympathetic activity following myocardial infarction in rats

SummaryThe long-term effects of perindopril or chlorothiazide therapy were studied in rats after the induction of myocardial infarction by coronary artery ligation. Rats with infarction developed marked cardiomegaly, indicating the presence of chronic left ventricular dysfunction. The ratio of the norepinephrine metabolite, 3,4-dihydroxyphenylethylene glycol (DHPG) to norepinephrine (NE) was elevated in the right ventricle of rats with infarction, suggesting a chronic increase in cardiac sympathetic activity. Perindopril therapy commenced either immediately following infarction or 4 weeks following infarction reduced DHPG/NE ratios toward normal levels, and prevented or reversed cardiac hypertrophy. In contrast, chlorothiazide therapy significantly reduced DHPG/NE ratios but did not decrease cardiac hypertrophy. Perindopril reverses or prevents cardiac hypertrophy and chronic cardiac sympathetic hyperactivity following myocardial infarction, while chlorothiazide reduces cardiac sympathetic activity without influencing cardiomegaly.

Cardiac 3,4-dihydroxyphenylethylene glycol (DHPG) and catecholamine levels in a rat model of left ventricular failure.

Cardiac norepinephrine (NE), dopamine (DA), epinephrine (Epi), and dihydroxyphenylethylene glycol (DHPG) (a major neuronal metabolite of NE) content were measured in rats with cardiac failure resulting from left ventricular myocardial infarction (LVMI) induced by coronary ligation. The ratio of DHPG/NE was significantly higher in both the right ventricle and interventricular septum of rats with LVMI compared with controls, reflecting a tendency for cardiac DHPG content to rise and NE content to fall during cardiac failure. Cardiac DA and Epi content did not significantly differ between rats with LVMI and controls. Elevated DHPG/NE ratios apparently reflected the increase in NE turnover that accompanies elevated sympathetic activity in heart failure more precisely than changes in NE levels or DHPG levels alone. Furthermore, DHPG/NE ratios are not influenced by increases in cardiac weight due to cardiac hypertrophy. The DHPG/NE ratios may be a useful index of cardiac sympathetic activity for future studies of the effects of drug treatment of cardiac failure in this animal model.

Atrial natriuretic peptide infusion in chronic heart failure in the rat.

Summary: The natriuretic, diuretic, and hypotensive responses to infused atrial natriuretic peptide (ANP) were measured in rats 4 weeks after myocardial infarction induced by coronary artery ligation. Rat [1‐28]‐ANP was infused intravenously in doses of 0.1, 0.3, and 1.0 μg/kg/min for 30 min each under pentobarbital anesthesia. There was a marked natriuresis, diuresis, and fall in blood pressure in rats with infarction but each response was significantly attenuated when compared with sham‐operated controls (ANOVA: p < 0.01, p < 0.05, and p < 0.01, respectively). Urinary cyclic guanosine monophosphate (cGMP) excretion in rats with infarction was higher than that of controls but rose to the same absolute level in both groups in response to ANP infusion (0.3 μg/kg/min). Reduced ANP responsiveness may result from impaired postreceptor mechanisms or from physiological antagonism by angiotensin II. Reduced ANP responsiveness may partly explain impaired salt handling in heart failure.

EFFECT OF GLYCAEMIC CONTROL ON GLOMERULAR FILTRATION RATE IN THE STREPTOZOTOCIN DIABETIC RAT

1. Diabetes was induced in 32 adult Wistar‐Kyoto rats with streptozotocin (60 mg/kg). Fourteen rats remained untreated, 10 received insulin three times per week, and eight received insulin daily. Fourteen non‐diabetic rats served as controls.