Spontaneously Hypertensive Rats Hearts Research Articles

Lack of vasodilatory response in skeletal muscle blood vessels of aged spontaneously hypertensive rats.

Regional hemodynamic responses to the vasodilators, hydralazine (1 mg/kg, i.v.) and verapamil (0.1 mg/kg/min, i.v.), were examined in conscious Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), 15 and 50 weeks of age, using the radioactive microsphere method. The flow rates of heart and skeletal muscle in SHR were higher than those in WKY, and the flow rates of liver, kidney, intestines, and skin in SHR were lower than those in WKY. These differences between the regional blood flow in WKY and SHR were observed in both aged and young rats. The changes in organ blood flow induced by hydralazine and verapamil were similar for WKY and SHR in most organs. Both drugs increased the skeletal muscle blood flow in WKY and young SHR, but not in aged SHR, that is, the skeletal muscle blood vessels in aged SHR lost their vasodilatory response. These results suggest that, although a lack of vasodilatory responses in the skeletal muscle vasculature of aged SHR may be triggered by persistent hypertension, the vital organ vasculature maintains its normal vasodilating capacity.

Alterations in tissue concentration and gene expression of adrenomedullin in spontaneously hypertensive rats

In order to elucidate the role of adrenomedullin in hypertension, we have compared concentrations of immunoreactive rat adrenomedullin and adrenomedullin messenger RNA levels in tissues of 8-week-old spontaneously hypertensive rats (SHR) with those of age-matched Wistar-Kyoto rats (WKY). The adrenomedullin immunoreactivity concentrations in adrenal gland and cardiac atrium were significantly higher in SHR than in WKY. The adrenomedullin content of cardiac ventricle was also significantly higher in SHR than in WKY. The rat adrenomedullin messenger RNA levels in adrenal gland and heart of SHR were also higher than those of WKY. These results suggest that adrenomedullin participates in the mechanism to counteract the blood pressure elevation in SHR.

Decreased GLUT-4 mRNA content and insulin-sensitive deoxyglucose uptake show insulin resistance in the hypertensive rat heart

Insulin resistance in skeletal muscle and adipose tissue often accompanies hypertension; however, it has not been shown that heart muscle is similarly affected. The aims of this study were to determine whether basal and insulin-stimulated glucose transport and glucose transporter mRNA content are altered in the spontaneously hypertensive rat (SHR) heart. Hearts from 16-18-month-old SHRs were compared to their normotensive (WKY) controls. The accumulation of 2-deoxyglucose-6-phosphate (2DG6P), detected using 31P nuclear magnetic resonance spectroscopy, was used to assess glucose uptake before and during insulin stimulation in the isolated perfused heart. The mRNA levels of both the insulin-sensitive glucose transporter (GLUT-4) and the transporter responsible for basal glucose uptake (GLUT-1) were quantified by Northern blot analysis. The hypertensive rat hearts exhibited hypertrophy in that the heart/body weight ratio was increased by 59%. In these hearts, the basal rate of glucose uptake was 3-fold greater and hexokinase activity was 1.6 fold greater than that of the control rat hearts. On exposure to insulin, accumulation of 2DG6P increased 5-fold in the control hearts, but only 1.4-fold in the SHR hearts. Thus, in the presence of insulin, the rate of glucose uptake by the hypertensive rat heart was significantly (P < 0.05) reduced, being 82% of control. GLUT-4 mRNA content was decreased was no significant difference in the GLUT-1 mRNA content. We have demonstrated insulin resistance in the hypertrophied heart of the hypertensive rat that may have a molecular basis in a lower GLUT-4 content.

Altered Na +-H +-exchange activity in the spontaneously hypertensive perfused rat heart

Intracellular pH (pHi) and developed pressure during hypercapnic acidosis were studied in the spontaneously hypertensive rat (SHR) heart and Wistar-Kyoto controls. Developed pressure was determined using a modified Langendorff isovolumic perfusion technique and 31P magnetic resonance spectroscopy was used to determine pHi. In response to acidosis, both developed pressure and pHi first decreased and then partially recovered. In the SHR group, pHi during the early periods of acidosis was significantly higher than in the control group while there was no significant difference in the steady-state pHi. The addition of 5-(N,N)-hexamethylene-amiloride (HMA), a specific inhibitor of Na(+)-H+ exchange, abolished these difference. Furthermore, HMA was found to inhibit recovery in pHi and developed pressure during acidosis in both groups. These results demonstrate that Na(+)-H(+)-exchange in the rat heart plays a major role in pHi regulation and contributes to functional recovery during acidosis. In addition, Na(+)-H(+)-exchange activity, as previously found in other tissues in hypertension, is increased in the SHR heart.

4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion injury of the myocardium

4-Hydroxynonenal (HNE) has been proposed as an important marker of radical-induced lipid peroxidation (LPO) during postischemic reperfusion injury of the myocardium. Therefore, the liberation of HNE into the effluent of isolated perfused rat hearts was investigated. For the first time, the formation of the aldehyde is demonstrated in myocardium. During control perfusion, 1.28 +/- 0.33 pmol HNE.min-1.mg protein-1 were formed by the hearts of 18-mo-old Wistar-Kyoto (WKY) rats and 2.74 +/- 1.12 pmol.min-1.mg protein-1 by those of 18-mo-old spontaneously hypertensive (SHR) rats, respectively. In the WKY group, HNE release increased to 3.35 +/- 1.13 pmol.min-1.mg protein-1 2 min after the onset of reperfusion following 30 min of total and global ischemia compared with the preischemic control period (P < 0.05). In the SHR group, HNE liberation was higher during reperfusion (8.66 +/- 1.33 pmol.min-1.mg protein-1, maximum at 2 min reperfusion) compared with both the respective preischemic control and the respective reperfusion interval of the WKY group (P < 0.05 each). The SHR rats showed signs of congestive cardiac failure of a decompensated hypertrophy in comparison to the normotensive WKY rats. Moreover, the SHR rat hearts exhibited a lower release of adenine nucleotide degradation products (adenine, inosine, hypoxanthine plus uric acid: 48.1 +/- 10.2 nmol.30 min-1.mg protein-1; P < 0.05) and a diminished functional recovery (left ventricular developed pressure, 32 +/- 16 mmHg; P < 0.05) during 30 min of reperfusion compared with the WKY group (77.9 +/- 14.4 nmol.30 min-1.mg protein-1; 90 +/- 21 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Quantification of Myotrophin From Spontaneously Hypertensive and Normal Rat Hearts

A novel peptide, myotrophin, has been isolated, purified, cloned, and sequenced from the hearts of spontaneously hypertensive rats (SHR) and from dilated cardiomyopathic human heart tissue. Myotrophin accelerates myocyte growth by stimulating protein synthesis (not by altering myocardial cell division). Our successive studies were conducted to evaluate the pathophysiological significance of myotrophin; a solid-phase radioimmunoassay technique was developed for quantifying the protein in hypertrophied and normal hearts. Specific antipeptide antibody was raised in rabbits against a peptide that represents a selected amino acid sequence of a 17-amino acid myotrophin segment by using the multiple antigenic peptide technique. The specificity of the antibody was evaluated by determining the affinity constant after constructing the Scatchard plot obtained from the ratio of bound to free myotrophin against bound myotrophin. The value obtained was 2.61 x 10(7) L/mol. The specificity was further demonstrated by Western blot analysis, in which a single protein band was obtained in the region of 12 kD. Pretreatment of the antibody with myotrophin completely blocked the binding sites, because no protein band was detected on the immunoblot. The antibody prevented the myocardial protein synthesis induced by myotrophin as revealed by the blockage of the stimulation of [3H]leucine incorporation into myocyte protein. Quantification of myotrophin from different heart tissues was achieved by Western blot and dot blot analyses. Amounts of myotrophin present in different dots were determined by using a video image analyzer. The level of myotrophin in the embryonic tissue was found to be similar in male normal and SHR hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased activity of constitutive nitric oxide synthase in cardiac endothelium in spontaneous hypertension.

We analyzed the activity of nitric oxide synthase in the rat heart to study whether this activity is affected by high blood pressure. Hearts from young (3 to 4 weeks old) and adult (15 to 25 weeks old) Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were excised and frozen in liquid nitrogen. The activities of Ca(2+)-dependent (cNOS) and Ca(2+)-independent (iNOS) were determined in homogenized tissues by measuring the conversion of [14C]-L-arginine to [14C]-L-citrulline in the presence or absence of either EGTA (1 mmol/L) or EGTA plus NG-nitro-L-arginine methyl ester (L-NAME, 1 mmol/L each). Arterial pressure was higher in adult SHR than in young SHR and WKY rats of both ages (P < .01). The cNOS activity was two to three times higher in hypertensive than in normotensive hearts (P = .01 to P = .04). No significant activity of iNOS was detected in any tissue. Studies of the right and left ventricles demonstrated a higher cNOS activity in the left sides of the hearts of adult SHR (P < .05). No differences were found in hearts from WKY rats. Selective removal of endocardial or coronary endothelial cells in hearts of SHR and WKY rats substantially reduced cNOS activity (P < .01). The cNOS activity is upregulated in cardiac endothelial cells of genetically hypertensive rats. The high activity of cardiac cNOS is related to increased arterial pressure of these animals. We propose that in the heart, endothelial cells respond with a higher production of nitric oxide as a compensatory mechanism against high blood pressure and its damaging effects in this organ.

Wall stress induced arrhythmia is enhanced by low potassium and early left ventricular hypertrophy in the working rat heart

The aim was to investigate the effect of lowering external potassium on the sensitivity of the normal and hypertrophied rat heart to arrhythmias induced by increases in ventricular wall stress. The isolated working heart model was used to compare hypertrophied hearts from the spontaneously hypertensive rat (SHR) with hearts from normotensive control rats (NCR) from the Wistar and Wistar-Kyoto strains. Young animals [131.5(SEM 0.64) days] were used to ensure uncomplicated left ventricular hypertrophy. Arrhythmias were induced by 20 s increases in ventricular wall stress. The ECG was recorded and the arrhythmic response of each heart was compared during perfusion with Tyrode solutions containing [K] 6, 4.8, 3.6, and 2.4 mM. Hypertrophied SHR hearts showed a significantly greater arrhythmic response than control hearts at all levels of afterload increase when perfused with [K] 3.6 and 2.4 mM (t test P < 0.05 and P < 0.01). Both the number and complexity of arrhythmias were increased in the SHR hearts; ventricular tachycardia occurred in 10/12 compared with 4/12 control hearts whereas ventricular fibrillation occurred in 5/12 hearts but in none of the control hearts. At higher levels of [K] the sensitivity of SHR and normal hearts to wall stress induced arrhythmias is similar. However, as [K] is lowered to 3.6 mM or below, hypertrophied hearts show a greatly enhanced response to increases in ventricular wall stress. They develop a larger number of ventricular ectopics and more complex ventricular arrhythmias when compared to normal hearts. This may be of relevance to arrhythmic sudden death in hypertensive patients in whom left ventricular hypertrophy, potassium depletion, and blood pressure lability is common. Excessive fluctuations in systolic pressure and therefore ventricular wall stress could provide a powerful arrhythmic stimulus in hypertensive patients with left ventricular hypertrophy, even before ischaemia, cardiac failure, or extensive extracellular fibrosis have developed.

Effects of a synthetic rat adrenomedullin on regional hemodynamics in rats

The effects of rat adrenomedullin, a novel vasorelaxant peptide, on systemic and regional hemodynamics were examined in conscious Sprague Dawley (SD) rats and spontaneously hypertensive rats (SHR). The intravenous infusion of adrenomedullin at rates of 1.67 and 5 μg/kg per min decreased the mean arterial pressure in a dose-dependent fashion in both types of rats. Adrenomedullin at a rate of 5 μg/kg per min increased the heart rate and cardiac output. As a result, the total peripheral resistance significantly decreased. With regards to the regional hemodynamics, adrenomedullin significantly increased the flow rates in the lungs, heart, spleen, kidneys, adrenal glands and small intestine of SHR. The flow rates in the brain and skin did not change and the flow rates in the skeletal muscle and testis were decreased. These regional hemodynamic changes were also observed in SD rats and there was no qualitative difference in the regional responses to adrenomedullin between SHR and SD rats. Thus, adrenomedullin predominantly increased the flow rates in organs in which adrenomedullin gene was highly expressed. It therefore seems that adrenomedullin may act as a local vasodilatory hormone rather than as a circulatory hormone.

Cardiac hypertrophy-related gene expression in spontaneously hypertensive rats: crucial role of angiotensin AT1 receptor.

Angiotensin converting-enzyme inhibitors (alacepril and imidapril) or an AT1-receptor antagonist (SC-52458) was administered to 10-week-old spontaneously hypertensive rats (SHR) for 7 days, and cardiac mRNA levels for contractile proteins and atrial natriuretic polypeptide (ANP) were comprehensively measured. The expression of skeletal alpha-actin and ANP was selectively enhanced in the heart of vehicle-treated SHR compared with Wistar-Kyoto rats (WKY), thereby suggesting that the phenotypic modulation of myocytes occurred at the early stage of hypertension. The above-mentioned three drugs similarly suppressed these enhanced gene expressions, nearly to the control levels. In contrast, although the treatment with hydralazine lowered the blood pressure of SHR similarly, hydralazine did not suppress ANP expression at all and only partially suppressed skeletal alpha-actin. Moreover, alacepril did not affect these gene expressions in WKY. Thus, AT1 receptor may be crucial for phenotypic modulation in the heart of SHR.

ボピンドロール投与による高血圧自然発症ラット(SHR)の心筋&amp;alpha;&lt;SUB&gt;1&lt;/SUB&gt;-及び&amp;beta;-受容体の性状変化に関する研究

We investigated the effects of chronic administration of bopindolol in the heart of spontaneously hypertensive rats (SHR) The values of Kd and Bmax of α1 and β-adrenoceptors in the heart of SHR were calculated by Scatchard analysis used 3H-prazosin and 3H-CGP 12177 binding. In addition, their blood pressure was also determined and these effects of bopindolol were compared with those of other β-blockers. SHR were given bopindolol (1 mg/kg and 3 mg/kg), atenolol (50 mg/kg), propranolol (60 mg/kg) in drinking water during 12 weeks. The systolic blood pressure of SHR was lowered by chronic administration of bopindolol, dose-dependently observed. The chronic administration of bopindolol (3 mg/kg) to SHRs increased the Kd and Bmax values of the a lx-adrenoceptors (high affinity binding sites for 3H-prazosin). On the other hand, the administration of bopindolol (1 mg/kg and 3 mg/kg) decreased the Bmax values of the β-adrenoceptor. These findings suggest that chronic administration of bopindolol had a beneficial effect on the blood pressure and had a dose-dependent effect on the α1- and β-adrenoceptors in the heart. These effects of bopindolol maybe involved in the inhibition of the development of hypertension.

Monocyte infiltration and c-fms expression in hearts of spontaneously hypertensive rats.

To elucidate mechanisms of myocardial hypertrophy in spontaneously hypertensive rats (SHR), we examined by Northern blotting the expression of the proto-oncogenes c-myc, c-fos, c-sis, and c-fms in the hearts of 4- and 14-week-old SHR and normotensive Wistar-Kyoto (WKY) rats. No difference in c-myc or c-fos expression could be found between SHR and WKY rats. In SHR, c-sis gave a weak and c-fms a very strong signal at 14 weeks, whereas no signal for these oncogenes was found in either WKY rats or Sprague-Dawley controls. Since c-fms codes for the receptor of monocyte colony-stimulating factor, we next used in situ hybridization to localize the presence of c-fms in hearts of SHR at 14 weeks. We found strong signals for c-fms around small blood vessels and between cardiac myocytes in 14-week-old SHR but none in WKY rats. Immunohistochemical staining corroborated the presence of clusters of monocyte infiltration at these same perivascular sites in significantly greater numbers in SHR than in WKY rats. We conclude that c-fms expression and macrophage infiltration are increased in the perivascular space of hypertrophied hearts from SHR. We suggest that mononuclear cell recruitment and induction of c-fms may play a role in the development of hypertension-associated myocardial hypertrophy.

Cilazapril treatment depresses ventricular function in spontaneously hypertensive rats

The purpose of this study was to characterize the effect of chronic treatment with an angiotensin-converting enzyme (ACE) inhibitor on left ventricular function in spontaneously hypertensive rats (SHR). Cilazapril (5 mg/kg) was administered in the drinking water continuously for 11 wk, beginning at 4 wk of age. Systolic arterial pressure (SAP) was monitored weekly. At the end of the 11-wk period, left ventricular function was quantified using the perfused working heart preparation. Cilazapril exerted a rapid, complete, and persistent antihypertensive effect in the SHR in vivo but had no effect on SAP in the normotensive Sprague-Dawley (S-D) group. Nevertheless, the drug reduced left ventricular weight to the same extent in both strains. Function of untreated SHR hearts was not different from that of the untreated S-D hearts. Cilazapril treatment depressed heart performance (28-35%) in SHR but had no effect in the S-D group. The decline in pump performance in SHR hearts was associated with diminished tension development and velocity of shortening of papillary muscles. These results demonstrate that an ACE inhibitor, administered to young SHR, produces a reduction in left ventricular contractile function, which may be due to a decline in muscle contractility and which cannot be explained exclusively by the reduction in left ventricular mass.

Hypertension, aging, and myocardial synthesis of heat-shock protein 72.

We determined the temperature-induced synthesis of the 72-kD heat-shock protein (hsp72) in hearts of normotensive and spontaneously hypertensive rats (SHR) subjected to whole-body hyperthermia (42.0 +/- 0.5 degrees C for 15 minutes). The animals were studied at three different ages: young (2 months), adult (6 months), and old (18 months). The hsp72 was determined by Western blot analysis using a monoclonal antibody. The results were calculated densitometrically as a percentage of a commercial standard. Young SHR responded to hyperthermic stress with increased synthesis of hsp72 compared with age-matched normotensive rats (298.8 +/- 70.0% versus 88.3 +/- 25.5%). This trend was maintained in adult rats (118.1 +/- 31.0% versus 54.8 +/- 21.3%) but not in old rats (65.3 +/- 29.4% versus 43.6 +/- 15.1%). Aging caused a reduction of hsp72 expression in response to hyperthermic stress in both SHR (4.6-fold) and normotensive rats (twofold). These data show that hearts of young and adult SHR respond to heat shock with enhanced synthesis of hsp72. This abnormal response, attenuated by aging, is independent of the presence and degree of hypertension or hypertrophy and is potentially linked to the genetic determination of the disease.

Altered Glucose and Fatty Acid Oxidation in Hearts of the Spontaneously Hypertensive Rat

Metabolic fuel oxidation may be altered in left ventricular hypertrophy (LVH), but detailed characterizations are lacking. Although the spontaneously hypertensive rat (SHR) is a widely used experimental model of LVH, its myocardial fuel oxidation rates are unknown. The purpose of this study was to directly measure glucose and fatty acid (FA) oxidation in the SHR heart ex vivo under controlled loading conditions. Hearts from 15-weeks-old SHR and Sprague Dawley (SD) rats were perfused in a recirculating system and indices of cardiac performance were continuously monitored. The oxidation of glucose and palmitate were determined simultaneously at low and high workloads by the addition of U- 14 C-glucose and 9.10- 3H-palmitate to the recirculating perfusate. The results demonstrate that FA oxidation of SHR hearts is profoundly suppressed (60-80%) relative to that of the normotensive SD strain, particularly at high workloads. Glucose oxidation is also moderately elevated, yielding a marked (four-to-five-fold) increase in the ratio of glucose/FA oxidation rates in the SHR hearts. Since more ATP in generated per mole of oxygen consumed when glucose is the fuel scource, these results are consistent with the hypothesis that a shift away from FA use toward glucose contributes to the preservation of energetic economy in stable, concentric LVH.

Ionic basis of action potential prolongation of hypertrophied cardiac myocytes isolated from hypertensive rats of different ages

The aim was to determine the ionic basis of action potential lengthening associated with cardiac hypertrophy. Action potentials and ionic currents of left ventricular myocytes isolated from normal and hypertrophied hearts were recorded with patch pipettes. Since cardiac hypertrophy is a time dependent process, myocytes isolated from hearts of spontaneously hypertensive rats (SHR) of different ages (3 and 18 months old) were compared with those of age matched normotensive controls (Wistar Kyoto rats, WKY). Membrane capacitance, an index of cell size, was significantly higher in SHR than WKY. The degree of action potential prolongation was independently correlated with hypertension and its duration, resulting in a statistically significant lengthening of action potential in 18 month old SHR compared to age matched WKY and to 3 month old SHR. ICa,L density was not significantly modified in hypertrophied myocytes compared to normal controls. Depolarising steps positive to -40 mV activated an outward current, which was composed of both transient (ItO) and maintained components (Ilate) and played a major role in controlling repolarisation in rat ventricular myocytes. Ito density was significantly reduced in SHR myocytes compared to age matched WKY and was also smaller in 18 month old compared to 3 month old SHR. Ilate was not statistically different in 3 and 18 month old SHR and WKY. Current-voltage relationships for IK1 were completely superimposable in all groups. Prolongation of action potential in the hypertrophied heart of SHR is due to specific alterations in the repolarising potassium current Ito. The phenomenon is directly related to the duration of hypertension.

Age-Related Increase in Sensitivity for Ischemic ATP Breakdown in Hypertrophic Hearts of SHR Normalized by Enalapril

We evaluated, firstly, the sensitivity to cardiac ischemic ATP breakdown during the development of hypertension and cardiac hypertrophy in Spontaneously Hypertensive Rats (SHR) v Wistar Kyoto (WKY) controls, and secondly, the effects of short-term (8 days) and prolonged (3 months) antihypertensive treatment with the angiotensin enzyme inhibitor enalapril on hypertrophy and sensitivity to global ischemia. In isolated perfused hearts, ischemia was induced by a stepwise lowering of the perfusion pressure and the appearance of the ATP breakdown products (purines) in the coronary effluent was assessed as a measure of ischemia. Hearts from 2.5- and 4-month-old SHR started to release purines at a higher perfusion pressure than hearts of WKY, associated with a higher maximum concentration in the coronary effluent. This increased ischemic ATP breakdown in 2.5- and 4-month-old SHR could be attributed to a decreased flow at a given perfusion pressure, because of a two-fold increase in coronary vascular resistance (CVR). In contrast, the maximal purine concentration in the coronary effluent in hearts of 7-month-old SHR was reduced compared to the younger SHR and only slightly higher than 7-month-old WKY, despite a persistent increase in CVR. Enalapril normalized the blood pressure, but only prolonged treatment, significantly prevented and regressed cardiac hypertrophy, and reduced CVR. Whereas enalapril did not influence ATP breakdown in WKY, in SHR both short- and long-term treatment normalized it to the pattern observed in WKY. We conclude that during the early phase of cardiac hypertrophy the hearts of SHR become more sensitive to ischemic ATP breakdown solely because of an increase in CVR, whereas during the established hypertrophic phase, the hearts appear to adapt metabolically, resulting in normalized purine release. Enalapril normalized the transient increase in sensitivity to ischemic ATP breakdown during the development of hypertension in SHR, independent of effects on cardiac hypertrophy, apparently by improving coronary flow at low perfusion pressures.

Nuclear magnetic resonance measurement of intracellular sodium in the perfused normotensive and spontaneously hypertensive rat heart.

We have used 23Na nuclear magnetic resonance spectroscopy to examine the relationship between intracellular sodium and cardiac muscle alterations in genetic hypertension. In the spontaneously hypertensive rat (SHR) compared with the normotensive Wistar-Kyoto rat (WKY) (aged 15 to 19 weeks), mean systolic blood pressures (measured using the tail-cuff method) were significantly (P < .05) different (WKY: 118 +/- 8 mm Hg, n = 5; SHR: 185 +/- 9 mm Hg, n = 5). Heart weights were also increased significantly (P < .05) in SHR (grams dry heart to kilograms body weight ratio was 0.73 +/- 0.04, n = 5, for SHR and 0.55 +/- 0.02, n = 5, for WKY). Intracellular sodium levels, measured using shift-reagent-aided and triple quantum filtered (TQF) nuclear magnetic resonance techniques, were significantly increased (P < .05) in the isolated Langendorff perfused hypertensive rat hearts (17.3 +/- 3.6 mmol/L, n = 5) compared with normotensive rat hearts (8.4 +/- 2.3 mmol/L, n = 5). These data demonstrate increased sodium in cardiac muscle in essential hypertension. We also investigated the effect of pacing on cardiac TQF 23Na nuclear magnetic resonance and found an increase in TQF Na+ content in both WKY and SHR hearts on stepped up pacing. These results support the existence of sodium pump lag in the rat heart perfused at physiologic Ca2+ concentration and suggest that the hypertensive rat heart has adapted to compensate for increased basal intracellular Na+ and maintain a normal response to increased heart rate. Our data appear to suggest an ionic contribution to the cardiac hypertrophy of genetic hypertension in the rat.

Function and energy metabolism of isolated hearts obtained from hyperthyroid spontaneously hypertensive rats (SHR). A 31P-nuclear magnetic resonance study.

It was the aim of this study to evaluate the effects of hyperthyroidism on heart function and cardiac energy metabolism of spontaneously hypertensive (SHR) rats. Hyperthyroidism was induced by daily injections of T3 (0.2 mg/kg s.c.) for 14 days. The hearts were then isolated and perfused in the Langendorff mode. ATP, phosphocreatine (PCr), and inorganic phosphate (Pi) were measured continuously by means of 31P-nuclear magnetic resonance (NMR) spectroscopy. Work load was altered by varying stepwise the Ca++ concentration in the perfusion fluid from 0.5 to 1.0, 1.5, and 2.0 mM, respectively. At every elevation of the Ca++ concentration, the increase in left ventricular developed pressure (LVDP) was higher in the hyperthyroid SHR than in the untreated SHR hearts. The ATP and PCr concentrations were lower in the hyperthyroid SHR compared to the untreated SHR hearts throughout the perfusion period. PCr decreased at every Ca++ elevation in both the untreated and hyperthyroid SHR hearts. The PCr/ATP ratio was not altered at any Ca++ concentration neither in the untreated SHR nor in the hyperthyroid SHR hearts. The Ca(++)-induced stepwise elevation in LVDP was higher at any given PCr/Pi ratio in the hyperthyroid SHR than in the untreated SHR hearts. Thus, the Ca(++)-inducible contractile reserve was greater in the hyperthyroid SHR heart.

Altered Na, K-ATPase mRNA Expression in Spontaneously Hypertensive Rats.

We investigated the expression of Na, K-ATPase α and β isoform mRNAs in spontaneously hypertensive rat (SHR) hearts, aortae and kidneys, compared with findings in normotensive Wistar-Kyoto rat (WKY), to obtain insight into the role of these isoforms in the development of hypertension in SHR. We used 4-, 8-, and 16-week-old SHR and WKY. Systolic blood pressure was recorded by tail sphygmomanometry. The expression of Na, K-ATPase α and β isoform mRNAs was analyzed by Northern blot hybridization, using isoform specific cDNA probes. In the ventricles, pre-hypertensive 4-week-old SHR showed a significant 3 to 4-fold increase in the α1 and α2 isoform mRNA accumulation compared with age-matched WKY. The α3 isoform mRNA expression was detected only in 4-week-old SHR hearts. The pattern of β1 mRNA expression resembled that of α1 or α2 mRNAs, and a significant 7-fold increase was observed in 4-week-old SHR compared with age-matched WKY. In the aortae, the α1 and α2 isoform mRNAs were expressed, and 4-week-old SHR exhibited a significant 5-fold increase in the α1 and α2 isoform mRNA levels compared with age-matched WKY. In the kidneys, only the α1 isoform mRNA was expressed, and that of SHR showed a significant 2-fold increase compared with age-matched WKY. We conclude that the expression of Na, K-ATPase α and β isoform mRNAs is significantly increased in the hearts, aortae and kidneys of SHR before the onset of hypertension. These findings suggest that, in this model, the altered expression of Na, K-ATPase gene is an early, if not a primary, event in the development of hypertension. (Hypertension Res 1993; 16: 269-274)