Alterations in the regional beta adrenergic system in experimental left ventricular hypertrophy.

STUDY OBJECTIVE - The aim of the study was to determine the changes in the beta adrenergic system induced by cardiac hypertrophy due to valvular aortic stenosis. DESIGN - Density of beta adrenoceptors, cardiac tissue noradrenalime concentrations, coronary blood flow (using radioactive microspheres), and haemodynamic variables were compared in a model of experimental aortic valve stenosis of 6 month's duration and in sham operated controls. SUBJECTS - 14 mongrel dogs with aortic stenosis and eight sham operated litter mates were used in the studies. MEASUREMENTS and RESULTS - Heart weight to body weight ratio was 33% greater in dogs with aortic valve stenosis than in controls. There were no haemodynamic differences except for a left ventricular to aortic systolic pressure gradient of 38 (SD 22) mm Hg in the aortic stenosis group. Response of left ventricular dP/dtmax to dopamine was similar in the two groups, as was coronary flow. Density of beta adrenoceptors (Bmax) as measured by (125I)-iodopindolol binding was reduced in ventricles from the aortic stenosis group compared to control: 41.2(13.3) v 59.1(8.1) fmol.mg-1 protein, p less than 0.005. Affinity of receptor for ligand (Kd) was not affected by cardiac hypertrophy. Tissue noradrenaline concentration was reduced in the hypertrophy group: 1108(402) (control) v 438(13) ng.g-1 initial wet weight (aortic stenosis), p less than 0.05. There were no significant subepicardial v subendocardial differences in any variable. CONCLUSIONS - Cardiac hypertrophy induced by aortic valve stenosis over a 6 month period is accompanied by a decrease in the density of ventricular beta adrenoceptors per gram and a decrease in ventricular noradrenaline concentration, though responsiveness of the whole heart is maintained.

Myocardial O2 supply and consumption in early cardiac hypertrophy of renal hypertensive rabbits.

This study examined myocardial O2 supply and O2 consumption in hypertension-induced myocardial hypertrophy. New Zealand white rabbits prepared as uninephrectomized (sham) controls (n = 7), or one kidney/one clip (1K1C) hypertensive rabbits (n = 7) were examined four weeks after surgery. A group of renally intact "true" controls (n = 4) was also examined. Coronary blood flow (CBF) was measured with radioactive microspheres in anesthetized open chest animals during baseline and vasodilated conditions (adenosine, 0.4 mg/kg/min). Microvascular O2 saturations were determined by microspectrophotometry. Myocardial oxygen consumption (MVO2) was calculated. Mean pressure was elevated in hypertensive animals (121 +/- 7 mmHg, means +/- SE) compared to uninephrectomized controls (74 +/- 7 mmHg). Hypertrophy was indicated by a 30% increase in heart weight to body weight ratio in the 1K1C animals. The average MVO2 was elevated in hypertrophy (12.4 +/- 0.9 vs. 9.6 +/- 0.8 ml O2/min/100 g). Baseline CBF was higher in cardiac hypertrophy (227 +/- 21 ml/min/100 g) compared to sham controls (169 +/- 14 ml/min/100 g). In hypertrophy the percent increase in CBF during adenosine infusion was reduced and the minimal vascular resistance was higher. No difference in microvascular O2 saturations was observed between groups, thus O2 extraction was similar. No subepicardial vs. subendocardial difference occurred within either the sham controls or the 1K1C animals in any parameter. Therefore, an overall increased MVO2 resulted in increased CBF and reduced coronary flow reserve in short-term renovascular hypertension-induced cardiac hypertrophy in rabbits.

Relationship between beta-adrenoceptors and coronary blood flow heterogeneity.

The purpose of this study was to investigate the hypothesis that the heterogeneous distribution of beta adrenoceptors contributes to the control of flow heterogeneity in the canine myocardium. beta adrenoceptor density and affinity were measured simultaneously with coronary blood flow in multiple sections of the left ventricle of 14 anesthetized open chest dogs. Radioactive microspheres were used for the measurement of blood flow. The left ventricle was cut into 15 subepicardial (EPI) and 15 subendocardial (ENDO) sections. Receptor density (Bmax) and dissociation constant (Kd) were measured using [125I]-iodopindolol. The average control myocardial blood flow (MBF) was 86 +/- 15 ml/min/100 g. Isoproterenol (0.5 micrograms/kg/min) increased MBF by 82%, whereas propranolol (2 mg/kg) reduced MBF by 13%. The mean value for Bmax was unaltered by either treatment. Under control conditions, a significant positive correlation (r = 0.26, p less than 0.0001) was observed between Bmax and blood flow. In the isoproterenol treatment group, this correlation was enhanced (r = 0.49, p less than 0.0001). Beta adrenoceptor blockade led to a negative correlation. Kd showed no overall correlation with blood flow. Kd but not Bmax was significantly higher in the EPI than in the ENDO and in the base compared to the apex. There appears to be a direct linear relationship between the distribution of beta adrenoceptors and MBF distribution which is enhanced under conditions of high beta adrenergic activity. There is a correlation between beta adrenoceptor activity and blood flow distribution in the canine myocardium.

Effect of reperfusion on O2 supply/consumption balance in ischemic canine left ventricle.

This study was designed to assess the effects of reperfusion on regional O2 supply and O2 consumption of ischemic areas of the myocardium in 15 anesthetized open-chested dogs. The left anterior descending coronary artery (LAD) was occluded for 6 h (n = 8), 2 h (n = 5), 2-h occlusion followed by 4-h period of reperfusion (n = 7), and 10-min occlusion followed by 90-min period of reperfusion (n = 3). Small artery and vein O2 saturations obtained microspectrophotometrically were combined with regional flow measurements using radioactive microspheres to determine regional myocardial O2 consumption. Coronary occlusion for 2 or 6 h significantly reduced mean flow to 15 +/- 8 and 13 +/- 14 ml/min/100 g (mean +/- SD), respectively, in the affected LAD areas as compared to 128 +/- 26 and 113 +/- 46 ml/min/100 g in the non-ischemic areas. In the 4-h reperfusion group, reperfusion increased the average flow (60 +/- 42 ml/min/100 g). O2 extraction was greater in the ischemic area than in the unaffected area after both occlusion and 4-h reperfusion. In the affected area, O2 consumption was reduced by 84% after 6-h occlusion. Reperfusion for 4 h increased O2 consumption toward normal values. Coronary artery occlusion produced an increase in the number of arteries and veins with reduced O2 saturations and this was not affected by reperfusion. Short-term occlusion had no significant O2 supply effects after 90 min of reperfusion. It can be concluded that even though there was an increased O2 consumption as a consequence of reperfusion, O2 consumption still appeared to be flow-limited as indicated by the microregions of low O2 supply and/or high O2 extraction.

Effects of propranolol on regional O2 supply and O2 consumption in reperfused dog myocardium.

This study was designed to assess whether propranolol would improve the relationship between O2 supply and O2 consumption in the reperfused ischemic dog myocardium. In 14 dogs, the left anterior descending coronary artery was occluded for 2 hr, followed by a 4-hr period of reperfusion. In 7 of the 14 dogs, 1 mg/kg of propranolol was administered 10 min before and again 2 hr after reperfusion. Small artery and vein O2 saturations obtained microspectrophotometrically were combined with regional blood flow measurements using radioactive microspheres to determine regional myocardial O2 consumption. In both groups, 2 hr of occlusion lowered the regional flow to a similar level. In the control group, 4 hr of reperfusion returned the blood flow toward normal levels, from 17 +/- 20 ml/min/100 g (mean +/- S.D.) at the end of occlusion to 60 +/- 42 ml/min/100 g in the affected area compared with 84 +/- 28 ml/min/100 g in the nonischemic area. In the propranolol-treated animals, the flow increase with reperfusion was not significant (25 +/- 30 ml/min/100 g to 45 +/- 26 ml/min/100 g). O2 extraction was greater in the ischemic than in the unaffected area in both groups. However, ischemic region O2 extraction was lower in the propranolol-treated group than in the control group. There were a greater number of arteries and veins with reduced O2 saturations in the control group reperfused area compared with the nonischemic area. Propranolol decreased the number of low O2 saturation vessels in the ischemic area.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenergic receptors in rat myocardium during the development and reversal of hypertrophy and following chronic infusions of angiotensin II and epinephrine.

The effect of cardiac hypertrophy on beta-adrenergic receptor density and affinity was studied under 4 experimental conditions: in the spontaneously hypertensive rat (SHR), in the 2K-1C renal hypertensive rat (RHR), and following subcutaneous infusions of 2 pressor agents; epinephrine (E) and angiotensin II(AII). Using the antagonist 3H-dihydroalprenolol [( 3H]-DHA), the number of binding sites was shown to significantly decrease at both 13 and 24 weeks of age in the SHR when compared to age-matched WKY, with no change in affinity. In the RHR a significant increase in binding sites was observed at both 6 and 10 weeks after clipping, returning towards normal levels following removal of the clipped kidney. Cardiac hypertrophy and hypertension were induced by subcutaneous infusions for up to 2 weeks of both E and AII. E caused an alteration in receptor density, causing a significant decrease with no change in affinity. In contradistinction, although the degree of hypertrophy was the same following AII, no changes in receptor density or affinity were seen. These present experiments confirm our hypothesis that different models of hypertensive hypertrophy are associated with varying changes in beta-adrenergic receptors. This suggests that any consequential changes in myocardial function may be a result of other post receptor mechanisms.

Excitation-contraction coupling in hypertrophied myocardium.

In hypertensive cardiac hypertrophy, inotropic responsiveness of alpha and beta adrenergic stimuli is reduced. We have previously shown that hearts from two-kidney, one-clip renal hypertensive rats (RHR) have increased beta-adrenergic receptor density and a defect in the guanine nucleotide regulatory protein, leading to decreased adenylate cyclase activity. In spontaneously hypertensive rats (SHR), beta-receptor density was decreased with no change in adenylate cyclase. In these present experiments, we have shown that the alpha 1-adrenergic receptor changes are in the opposite direction, decreasing in RHR and increasing in SHR. All these changes are reversible within 4 weeks following removal of the clipped kidney in RHR, at which time blood pressure and heart weight have also returned towards normal. Further studies on the excitation-contraction pathway have indicated that c-AMP-stimulated protein kinase is decreased in SHR with no changes seen in RHR. Subcutaneous infusion of epinephrine leads to some increase of cardiac mass associated with decreased beta-adrenergic receptors element and decreased adenylate cyclase activity. However, following angiotensin II infusion, even though hypertrophy is more pronounced, no changes in receptors or cyclase are detected. We conclude that different models of hypertensive cardiac hypertrophy associated with different biochemical defects in the adrenergic excitation response pathway, and that if some of these changes become irreversible, further cardiac deterioration and even heart failure may ensue.

Biochemical alterations in cardiac hypertrophy.

In both two-kidney, one clip renal hypertensive rats (RHR) and spontaneously hypertensive rats (SHR) with myocardial hypertrophy, inotropic responsiveness to adenylate cyclase mediated agonists, such as isoproterenol and glucagon is decreased, as is the responsiveness to phenylephrine acting via alpha 1 adrenergic receptors. However, defects in the excitation response pathway differ in the two hypertensive models. In SHR beta-adrenergic receptors are decreased, alpha 1 receptors increased, cyclase activity is unchanged but c-AMP stimulated protein kinase is decreased. In RHR beta-receptors are increased, alpha 1 receptors decreased, adenylate cyclase activity decreased due to decreased nucleotide regulatory protein activity, and microsomal cAMP stimulated protein kinase is increased. We conclude that, although functional changes in hypertensive cardiac hypertrophy are similar, the underlying biochemical alterations are different. The shift in balance between alpha- and beta-adrenergic pathways may be a compensatory mechanism and play a role in the pathophysiology of cardiac hypertrophy.

Beta adrenergic receptor response coupling in hypertrophied hearts.

Reports in the literature have indicated that inotropic responsiveness to isoproterenol (ISO) of hypertrophied rat myocardium is decreased. We have studied possible biochemical mechanisms to explain this. Adenylate cyclase activity in myocardial membranes from 13-week-old spontaneously hypertensive rats (SHR) was unchanged compared to enzyme activity in Wystar-Kyoto (WKY) when measured under basal conditions or following NaF, a guanosine triphosphate analog, MnCl2, or forskolin stimulation. However, ISO-stimulated cyclase activity was decreased as were beta-adrenergic receptor density with no change in receptor affinity. On the other hand, hearts from two-kidney, one clip renal hypertensive rats 6 weeks after initiation of hypertension showed decreased basal, ISO, NaF, and GTP analog-stimulated cyclase activity with no change in Mn++ or forskolin-stimulated activity. In this model, receptor density increased. When the clipped kidney was removed, these changes returned toward normal as did the blood pressure and heart weight. We interpret these data to indicate that in SHR the biochemical defect leading to decreased inotropic responsiveness of hypertrophied hearts is due to decreased beta-adrenergic receptor density, leading to decreased ISO-stimulated cyclase activity. The nucleotide regulatory protein component (N) and the catalytic subunit (C) are not changed. In the renal hypertensive rat, on the other hand, although the C is unchanged, there is a decrease in the activity of N, and this is probably the primary reason why inotropic responsiveness to ISO is decreased. Increases in receptor density seen in this model may possibly be compensatory.

Effect of chemical sympathectomy and ganglion blockade on angiotensin-stimulated fluid absorption in the rat jejunum.

A study has been made of the effects of chemical sympathectomy and ganglion blockade on the responses of rat jejunum in vivo to intravenous doses of angiotension and noradrenaline capable of stimulating fluid transport. Pretreatment with 6-hydroxydopamine (chemical sympathectomy) or pentolinium tartrate (ganglion blockade) abolished the stimulatory actions of angiotensin II but left the responses to noradrenaline unimpaired. Dopamine, like noradrenaline, stimulated fluid transport but this response required very high dopamine infusion rates, was refractory to the dopamine antagonist sulpiride and was inhibited by the alpha- blocker phentolamine. The possible interaction between angiotensin and the intestinal sympathetics is discussed with reference to control in extracellular fluid volume.