Increase in G(i alpha) protein accompanies progression of post-infarction remodeling in hypertensive cardiomyopathy

Hypertensive cardiac hypertrophy and myocardial infarction (MI) are clinically relevant risk factors for heart failure. There is no specific information addressing signaling alterations in the sequence of hypertrophy and post-MI remodeling. To investigate alterations in beta-adrenergic receptor G-protein signaling in ventricular remodeling with pre-existing hypertrophy, MI was induced by coronary artery ligation in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Ten weeks after the induction of MI, the progression of left ventricular dysfunction and increases in plasma atrial natriuretic peptide (ANP) and cardiac ANP mRNA were more pronounced in SHR than WKY. In addition, the impaired contractile response to beta-adrenergic stimulation was observed in the noninfarcted papillary muscle isolated from SHR. Immunochemical G(s alpha) protein and beta-adrenoceptor density were not significantly altered by MI in both strains. However, immunochemical G(i alpha) was increased (1.5-fold) in the noninfarcted left ventricle of the SHR in which infarction had been induced when compared with that in SHR that underwent sham operation. This increase was observed especially in rats with a high plasma ANP level. Furthermore, there was a positive correlation between G(i alpha) and the extent of post-MI remodeling in WKY. A similar correlation between G(i alpha) and the extent of hypertensive hypertrophy was observed in SHR. In conclusion, the vulnerability of hypertrophied hearts to ischemic damage is greater than that of normotensive hearts. An increase in G(i alpha) could be one mechanism involved in the transition from cardiac hypertrophy to cardiac failure when chronic pressure overload and loss of contractile mass from ischemic heart disease coexist.     

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)     

Effect of Nicorandil on Cardiac Dysfunction During Reperfusion in Normotensive and Spontaneously Hypertensive Rats

The cardioprotective effect of nicorandil, an opener of ATP-sensitive potassium channels, was studied in the isolated perfused hearts of the spontaneously hypertensive rat (SHR) and normotensive Wistar-Kyoto (WKY) rat. The hearts were subjected to 30 min of global ischemia followed by 30 min of reperfusion. Controls received no drug. In the nicorandil group, the hearts were treated with 0.03 to 0.3 mmol/L nicorandil for 15 min before ischemia. Left ventricular developed pressure (LVDP and end diastolic pressure (LVEDP) at 30 min of reperfusion were significantly lower and larger, respectively, in SHR than in WKY rats. Nicorandil improved LVDP and decreased LVEDP at 30 min of reperfusion in both SHR and WKY rats dose-dependently. The hypertensive heart in the early stage is already susceptible to reperfusion-cardiac dysfunction. Nicorandil has a beneficial effect on the post-ischemic dysfunction in both SHR and WKY rats.     

Functional and metabolic properties in hearts from aged spontaneously hypertensive rats

The effect of long-term pressure overload on myocardial functional and metabolic alterations was investigated in hearts from spontaneously hypertensive rats of 16 weeks (young SHR) and 44 weeks (aged SHR) and age matched normotensive Wistar Kyoto strain rats (young WKY, aged WKY). The hearts were perfused by working heart mode and whole heart ischemia was induced by one-way valve. Following 20 min of ischemia, the hearts were reperfused for 30 min. The heart-body weight ratio in both SHR groups was significantly higher than in the respective age-matched WKY groups. Coronary flow relative to heart weight in both SHR groups was significantly lower than that of the respective age-matched WKY during both preischemic and reperfused periods. There was no significant difference in the recovery rate of cardiac output between young and aged WKY, whereas the young and aged SHR revealed significantly less recovery than their respective age-matched WKY. Tissue creatine phosphate and energy charge in both aged groups were significantly lower than in the young groups. These results indicate that long-term pressure overload increases susceptibility to ischemia and decreases the myocardial reserve presumably resulting from relative ischemia, whereas deterioration was minimal in the normotensive aged rat heart.     

Effect of noise stress and ethanol intake on hearts of spontaneously hypertensive rats

Summary The pathogenesis and progression of hypertensive heart disease are unclear; however, both involve a genetic predisposition and environmental influences. To test the role of exogenous factors, we examined the hearts of spontaneously hypertensive rats (SHR) exposed to noise stress and ethanol intake. Twenty-two SHR and nine normotensive Wistar rats (NWR) were continuously exposed to a 65 db, 4 and 250 Hz tone for 52 weeks. Twelve of these SHR aged 20–22 weeks were concomitantly given 20% ethanol in their drinking water up to week 52. Eight SHR and 12 NWR served as controls. We examined hemodynamic parameters, the cardiac configuration, the cardiac microvasculature, interstitial tissue, and ischemic myocardial lesions. We found that noise stress significantly increased the microvessel wall area, the number of microvessels with an outer diameter >19 m, the degree of cardiac fibrosis, and the extent of ischemic myocardial lesions in SHR, but not in NWR. These effects were all ameliorated and the diastolic blood pressure was lowered by the ingestion of ethanol. Cardiac weights and dimensions, heart rate and dp/dt_max were not influenced by either noise or ethanol intake. These results suggest that hypertensive heart disease in SHR can be aggravated by noise stress. Ethanol ameliorates these changes by mechanisms which remain to be explored.     

Influence of long-term antihypertensive therapy on cardiac function, coronary flow and myocardial oxygen consumption in spontaneously hypertensive rats

The relationships between cardiac performance, coronary flow, coronary vascular resistance at maximal vasodilatation and myocardial oxygen consumption were determined in isolated hearts from spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY) and from SHR given metoprolol (beta 1-selective blocker) and felodipine (selective calcium antagonist) for 35 weeks. A working heart perfusion system was used. An oxygen electrode allowed continuous measurement of oxygen tension in the venous coronary effluent. Blood pressure was reduced close to normal levels in treated SHR. Treatment also caused a substantial reduction of left ventricular weight. In both treated and untreated SHR, maximal cardiac performance, expressed as peak stroke volume, was enhanced above that of WKY at high perfusion pressures, while performance at low perfusion pressures was clearly reduced in the former groups. At a given workload, myocardial oxygen consumption (mmol O2/min per g) was reduced in both groups of SHR. This suggests a physiological structural adaptation to an elevated cardiac load in hypertension, where more myofibrils contribute to produce a given amount of work and therefore less oxygen is consumed per unit muscle mass. Coronary flow was reduced at any given perfusion pressure and oxygen extraction was increased in untreated SHR versus WKY. By causing regression of hypertensive structural vascular changes, treatment markedly increased coronary flow and correspondingly decreased oxygen extraction. Thus, by enhancing the myocardial nutritional supply with antihypertensive treatment, the reduced cardiac function at low perfusion pressure in untreated SHR was almost normalized.     

Altered calcium sequestration by subcellular fractions of vascular smooth muscle from spontaneously hypertensive rats.

The calcium sequestration characteristics of microsomal and mitochondrial fractions prepared from aortae of spontaneously hypertensive (SHR), Kyoto Wistar normotensive (NWR), and normotensive Sprague-Dawley (NSDR) rats were studied. Calcium uptake by the microsomal vesicles of SHR was significantly lower as compared to NWR and NSDR. However, mitochondria isolated from SHR aortae did not differ from NWR in their calcium uptake characteristics. Microsomal vesicles of NSDR aortae accumulated consistently more calcium than NWR. These findings illustrate the significance of relevant controls for SHR. Calcium-dependent ATPase activity in the microsomal fraction was significantly increased in SHR as compared to NWR. This may indicate a compensatory phenomenon on the part of the smooth muscle cell to increase Ca²⁺ uptake by the microsomal vesicles. These results suggest that a decreased ability to sequester calcium by the microsomal fraction of vascular smooth muscle of SHR may result in altered calcium distribution in the muscle cell.     

Modulation of endothelin-1 coronary vasoconstriction in spontaneously hypertensive rats by the nitric oxide system

To determine whether nitric oxide contributes to the augmented vasoconstrictive response to endothelin-1 (ET-1) in coronary vessels of hypertensive hearts, and also whether l-arginine administration can inhibit the augmented response to ET-1, we designed experiments to measure coronary perfusion resistance in isolated hearts of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) with or without l-arginine administration (0.5 g/L) for 2 weeks. The hearts were paced at a constant rate and perfused by the Langendorff technique at constant pressure (75 mm Hg). Perfusion flow and pressure were monitored, and coronary vascular resistance (CVR) was calculated. ET-1 infusion elicited dose-dependent increases in CVR in both WKY and SHR. At an ET-1 concentration of 1.5 × 10⁻⁹ mol/L, the response was significantly greater in SHR. In L-NAME–treated WKY and SHR, responses to ET-1 were augmented, compared with those of nontreated rats, and this augmentation was greater in WKY. l-arginine administration reduced the CVR response to ET-1 in SHR, whereas it did not change responses to ET-1 in WKY. These findings suggest that the augmented vasoconstriction of the coronary artery induced by ET-1 in hypertensive hearts was due to a reduction in nitric oxide release in coronary vessels and that l-arginine can partially inhibit the vasoconstrictive response of the coronary artery.     

Streptozotocin-Induced Diabetes Mellitus Lowers Blood Pressure in Spontaneously Hypertensive Rat

There are conflicting reports showing that alloxan or streptozotocin-induced diabetes in rat increases, decreases or does not alter blood prassure. Since hypertension influences organ-specific diabetic complications, this study was designed to examine the effects of streptozotocin-induced diabetes on blood pressure (BP), hemodynamics and heart weight in spontaneously hypertensive (SHR) and normotensive Wistar (NWR) rats. In order to control the influence of weight loss on BP affected by diabetes, we have examined the effect of weight loss without diabetes on BP, hemodynamics and heart weight in SHR. Weight loss parallel to that in diabetic SHR was induced in a group of SHR by food restriction (fasting). Significant (P< .05) decreases in systolic and direct BP were observed in diabetic SHR. This hypotensive effect was accompanied by a significant (P < .05) decrease in total peripheral resistance, but no change in cardiac output. These blood pressure and hemodynamic findings in diabetic SHR were complimented by a significant (P < .05) reduction in left ventricular weight to body weight ratio. On the contrary, fasting SHR with weight loss equivalent to that in diabetic SHR showed no change in BP or total peripheral resistance. Further, fasting SHR revealed a significant (P < .05) increase in heart weight to body weight ratio. The weight loss of equal magnitude induced by streptozotocin-induced diabetes in NWR did not have any effect on BP or hemodynamics. In addition, like fasting SHR, diabetic NWR showed a significant (P < .05) increase in left ventricular weight to body weight ratio. This study concludes that streptozotocin-induced diabetes significantly reduces BP independent of weight loss in SHR, and that the hypotensive effect is the result of peripheral vasodilatation.     

Impaired inotropic response to alpha 1- but not to beta-adrenoceptor stimulation in isolated hearts from spontaneously hypertensive rats.

OBJECTIVES: Hypertension in humans and experimental animals is known to be associated with an increase in left ventricular myocardial mass. The development of cardiac hypertrophy is not caused by increased blood pressure alone; the autonomic nervous system may also play an important role. DESIGN: The functional responses to the beta-adrenoceptor agonists isoprenaline, dobutamine, salbutamol and terbutaline, and the alpha 1-adrenoceptor agonists methoxamine, cirazoline and phenylephrine were studied in isolated (Langendorff) hearts from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) controls. The results were compared with data from radioligand binding experiments. RESULTS: There was no significant difference in the increase of left ventricular pressure induced by all beta-adrenoceptor agonists studied in SHR and WKY rat hearts. Although there was no significant difference in the response to phenylephrine, the inotropic responses to cirazoline and methoxamine proved to be significantly weaker in hearts from SHR than in those from WKY rats. Binding experiments with 3H-prazosin revealed no differences in density or affinity for cardiac tissues from SHR and WKY rats. CONCLUSIONS: Long-standing hypertension leads to an impaired response of the isolated heart to alpha 1-adrenoceptor stimulation, without changes in alpha 1-receptor density or affinity. It seems likely that changes in postreceptor events are responsible for the impaired inotropic response to alpha 1-adrenoceptor agonists in hearts from SHR.     

Hemodynamic consequences of left ventricular hypertrophy in spontaneously hypertensive rats.

Compared with hearts from normotensive rats isolated, perfused hearts from spontaneously hypertensive rats exhibit a rightward shift of the Frank-Starling curve in the lower range of filling pressures, that is, up to 10 mm Hg. The extent of this shift is proportional to the degree of left ventricular hypertrophy. This is suggested to be a consequence of an altered relation between end-diastolic pressure and end-diastolic tension of the progressively more thick-walled left ventricle. Furthermore, the cardiac function curves revealed that maximal cardiac performance is apparently better in spontaneously hypertensive rats than in normotensive rats at increased levels of afterload. Therefore, left ventricular hypertrophy in established hypertension seems to contribute to adjustment of cardiac performance to the enhanced pressure work in hypertension; however, this occurs at the expense of a rightward shift of the Frank-Starling curve. In spontaneously hypertensive rats studied in vitro, coronary vascular resistance per unit weight of tissue was increased at maximal dilation, as was maximal pressor response. This may reflect the same type of structural vascular adaptation that occurs in most systemic vascular beds in hypertension and that contributes to maintenance of increased vascular reactivity and flow resistance in both hypertensive patients and spontaneously hypertensive rats. Apparently as a consequence of this adaptation, splanchnic nerve stimulation at an increasing rate caused exaggerated increases in resistance in anesthetized hypertensive rats by comparison with findings in normotensive rats. However, the effect of capacitance vessel constriction on stroke volume caused by splanchnic nerve stimulation was less pronounced in hypertensive rats. This relative “hyporeactivity” of the capacitance vessels also suggests an altered relation between cardiac filling pressure and stroke volume of the hypertrophied left ventricle in the spontaneously hypertensive rat.     

Abnormal renal vascular responses to dipyridamole-induced vasodilation in spontaneously hypertensive rats

The objective of this study was to determine whether there were differences in hemodynamic responses of different vascular beds to systemic administration of dipyridamole between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. To this end, systemic hemodynamics and organ blood flows (using labeled microspheres) were determined in conscious rats before and 10 minutes after dipyridamole (4 mg. kg(-1). min(-1)) infusion. In both the normotensive and hypertensive rats, the dipyridamole infusion reduced arterial pressure by approximately 20 mm Hg, associated with a decreased total peripheral resistance and an increased cardiac output. Renal blood flow decreased significantly in SHR after dipyridamole but remained unchanged or increased slightly in the WKY rats. There were no other differences in regional hemodynamics, including those of brain, liver, skin, and muscle, between the WKY and SHR. Antihypertensive treatment completely restored normal renal vascular response to dipyridamole. Previous reports had demonstrated an abnormal coronary hemodynamic response of the SHR. Our data demonstrate that, as with coronary hemodynamics, hypertension selectively induced alterations in renal vasculature. These findings may be of importance in identifying the earliest hemodynamic evidence of developing hypertensive nephrosclerosis.     

Isoprenaline-induced myocardial infarction in spontaneously hypertensive rats.

Spontaneously hypertensive rats were subjected to massive myocardial infarction. The pathophysiological changes were similar to those of normotensive rats but the spontaneously hypertensive rats developed congestive heart failure during myocardial repair rather than during the necrosis phase and survived in superior numbers. Blood pressure fell despite maximally increased corticosterone levels. Atrial and ventricular thromboses and left ventricular aneurysm formation were frequent.     

Impaired cardiac ischemic tolerance in spontaneously hypertensive rats is attenuated by adaptation to chronic and acute stress

Chronic hypertension may have a negative impact on the myocardial response to ischemia. On the other hand, intrinsic ischemic tolerance may persist even in the pathologically altered hearts of hypertensive animals, and may be modified by short- or long-term adaptation to different stressful conditions. The effects of long-term limitation of living space (ie, crowding stress [CS]) and brief ischemia-induced stress on cardiac response to ischemia/reperfusion (I/R) injury are not yet fully characterized in hypertensive subjects. The present study was designed to test the influence of chronic and acute stress on the myocardial response to I/R in spontaneously hypertensive rats (SHR) compared with their effects in normotensive counterparts. In both groups, chronic, eight-week CS was induced by caging five rats per cage in cages designed for two rats (200 cm²/rat), while controls (C) were housed four to a cage in cages designed for six animals (480 cm²/rat). Acute stress was evoked by one cycle of I/R (5 min each, ischemic preconditioning) before sustained I/R in isolated Langendorff-perfused hearts of normotensive and SHR rats. At baseline conditions, the effects of CS were manifested only as a further increase in blood pressure in SHR, and by marked limitation of coronary perfusion in normotensive animals, while no changes in heart mechanical function were observed in any of the groups. Postischemic recovery of contractile function, severity of ventricular arrhythmias and lethal injury (infarction size) were worsened in the hypertrophied hearts of C-SHR compared with normotensive C. However, myo-cardial stunning and reperfusion-induced ventricular arrhythmias were attenuated by CS in SHR, which was different from deterioration of I/R injury in the hearts of normotensive animals. In contrast, ischemic preconditioning conferred an effective protection against I/R in both groups, although the extent of anti-infarct and anti-arrhythmic effects was lower in SHR. Both forms of stress may improve the altered response to ischemia in hypertensive subjects. In contrast to short-term preconditioning stress, chronic psychosocial stress was associated with a higher risk of lethal arrhythmias and contractile failure in normotensive animals exposed to an acute ischemic challenge.     

Changes in Creatine Kinase Expression Induced by Exercise in Borderline Hypertensive Rat Hearts

Hypertrophy in hypertensive hearts is associated with increased risk of cardiac morbidity and mortality that is not characteristic of exercised hearts. This study was done to determine whether exercise training of normotensive and borderline hypertensive rats induces the increased myocardial expression of BB and MB isoforms of creatine kinase (CK) that characterizes hypertensive hypertrophy. Spontaneously hypertensive (SHR), borderline hypertensive (BHR), and normotensive Wistar-Kyoto (WKY) rats were subjected to either an 8% sodium chloride diet or swim training to produce myocardial hypertrophy. Both exercise and a high salt diet induced an increase in the combined expression of CK-MB and CK-BB in SHR after 2 months. However, since swimming also exacerbated hypertension in SHR, exercise induced effects on CK were not distinguishable from those of hypertension. In WKY, neither exercise nor a high salt diet induced significant changes in CK isozyme expression. In BHR fed a high sodium chloride diet, significant increases in mean arterial pressure and left ventricular weight to body weight were not associated with changes in CK expression. In contrast, following 10 months of swim training BHR exhibited mild hypertrophy, decreased resting heart rates, and an increase in the combined expression of CK-MB and CK-BB. Therefore, exercise associated with a cardiac training effect in BHR induced changes in CK isozyme expression similar to those in hypertensive hearts.     

Effects of inhibition of nitric oxide formation on regional blood flow in experimental myocardial infarction.

BACKGROUND. Large myocardial infarction is associated with reactive hypertrophy and dilation of the left ventricle, depressed coronary flow reserve, and the development of heart failure including systemic vasoconstriction. We hypothetized that changes in endothelial function, e.g., in the synthesis or action of nitric oxide in the coronary and peripheral vasculatures, might be involved in the depressed coronary flow reserve and increased systemic vascular resistance observed in postinfarction myocardial hypertrophy and failure. METHODS AND RESULTS. The regional blood flow changes that occur as a result of inhibiting the basal release of nitric oxide with NG-monomethyl-L-arginine (L-NMMA) and how this regional pattern may be altered in large MI (infarct size, 30-51% of left ventricle) were examined. Measurements were made 24 hours and 8 weeks after myocardial infarction or sham operation in conscious rats. The left ventricular end-diastolic pressure and effects of L-NMMA on left ventricular end-diastolic pressure was similar 24 hours and 8 weeks after myocardial infarction. The effects of L-NMMA (30 mg/kg i.v.) on heart rate and blood pressure were similar in infarcted and sham animals. L-NMMA exerted a marked vasoconstriction in the renal, splanchnic, cutaneous, and cerebral circulations of similar magnitude in sham-operated rats and animals with myocardial infarction. The coronary vasoconstrictor effect of L-NMMA was attenuated significantly in the hypertrophied right and noninfarcted left ventricle of 8-week-old infarcted rats (p less than 0.01 versus sham-operated animals) but not 24 hours after induction of myocardial infarction when cardiac hypertrophy has not yet developed. The increase in left ventricular coronary resistance in 8-week-old infarcted animals was inversely related to infarct size (r = -0.787, p = 0.012, n = 9). Nitroglycerin exerted similar increases in coronary blood flow in rats with chronic myocardial infarction and sham-operated animals, arguing against a reduced vascular responsiveness to nitric oxide. Transmission electron microscopy of coronary resistance vessels in 8-week-old infarcted animals did not reveal endothelial abnormalities. CONCLUSIONS. These data suggest that the basal release of nitric oxide in the renal, intestinal, and cutaneous circulations is not affected adversely in this model of myocardial infarction and failure. However, the blunted coronary vasoconstrictor effect of L-NMMA late after large myocardial infarction supports the view that the basal release of nitric oxide is impaired in postinfarction reactive cardiac hypertrophy.     

Effects of spontaneously hypertensive rat plasma on blood pressure and tail artery calcium uptake in normotensive rats

Previous studies have described the presence of humoral hypertensive factors in spontaneously hypertensive rats (SHR). Other studies have described factors that increase calcium uptake in vascular tissue. In this study, we attempted to confirm, and thereby correlate, the presence of both types of factors in SHR plasma. Intravenous infusion or bolus administration of dialyzed SHR plasma consistently induced an increase in blood pressure in normotensive rats. This hypertensive response was somewhat delayed, with peak blood pressures occurring 45 minutes after bolus administration and 90 minutes after infusion of SHR plasma. Spontaneously hypertensive rat plasma also increased 45Ca uptake in isolated normotensive rat tail arteries in a dose-dependent manner, with a time course similar to that for the hypertensive response to bolus administration. These findings suggest, therefore, that a substance exists in SHR plasma that can increase intracellular calcium in vascular tissues and thereby increase blood pressure.     

A treatment with rosuvastatin induced a reduction of arterial pressure and a decrease of oxidative stress in spontaneously hypertensive rats

The aim of this study was to appreciate consequences of rosuvastatin administration on hemodynamic function, vascular oxidative stress and ischemia/reperfusion disorders in normotensive and hypertensive rats. At 10 weeks of age, spontaneously hypertensive rats (SHR, n=20) and normotensive Wistar Kyoto male rats (WKY, n=20) were divided into four groups and given, either vehicle or 10 mg/kg/day of rosuvastatin by gavage for 3 weeks. Systolic blood pressure was assessed every week. At the end of these treatments, vascular NADPH oxidase activity was evaluated by chemiluminescence (lucigenin 0.5 microM). Hearts were isolated and perfused according to the Langendorff method and were subjected to 30 min of global ischemia. Reactive oxygen species (ROS) produced during reperfusion were quantified by electron spin resonance (ESR) spectroscopy using a spin probe (CP-H, 1 mM). After one week of treatment, rosuvastatin reduced the arterial pressure in SHR rats (180.3 +/- 2.1, SHR vs 169.7 +/- 2.3 mmHg, SHR+rosuvastatin; p < 0.01), without lowering plasma cholesterol levels; these effects were not observed in WKY. NADPH activity was 25% higher in control SHR rat aortas compared to control WKY, and was reduced by rosuvastatin in SHR rats. In isolated rat hearts subjected to ischemia/reperfusion sequences, there was a deterioration in functional parameters in control SHR compared to control WKY hearts. Rosuvastatin decreased post-ischemic contracture in WKY hearts by 50% (41.5 +/- 7.5, WKY control vs 18.4 +/- 4.6 mmHg, WKY+rosuvastatin; p < 0.01) and increased left ventricular developed pressure. This beneficial effect was accompanied by a decrease in ROS detected by ESR during reperfusion (312.5 +/- 45.3, WKY control; vs 219.3 +/- 22.9 AUC/mL, WKY+rosuvastatin; p < 0.05). In conclusion, these results are in accordance with the hypothesis that oxidative stress plays a crucial role in the pathogenesis of cardiovascular diseases including hypertension, and demonstrate the beneficial effects of rosuvastatin.     

Cardiac aging, calcium overload, and arrhythmias

The effect of aging was tested on experimental ventricular arrhythmias in isolated heart preparations from normal Wistar rats (NWR), Wistar Kyoto rats (WKY), and spontaneously hypertensive rats (SHR). Delayed afterdepolarizations and triggered activity induced by high-calcium perfusion (16 mM) in isolated papillary muscles were more frequent in the 24-month-old than in 6-month-old NWR. Reperfusion-VA were more severe in 14-month-old SHR than in WKY. The authors have previously shown that: (1) reperfusion- and reoxygenation-induced VA, in the isolated Langendorff perfused heart, were significantly more severe and frequent in 24-month-old than in 6-month-old NWR; (2) no age-related difference in the incidence of programmed electrical stimulation (PES, train of stimuli + 1 or 2 extrastimuli)-induced VA was observed in isolated NWR hearts during control perfusion, after coronary artery ligation or during hypoxia; (3) on the contrary, the incidence of PES-induced VA was significantly higher in isolated hearts from 14-month-old SHR than from 3-month-old SHR, and 3-month-old and 14-month-old WKY. It was concluded that "physiological" aging is associated with a higher propensity to calcium-related VA, while "pathological" aging characterized by hypertension of long duration increases the incidence of PES-induced VA, probably caused by myocardial fibrosis, which could facilitate reentry.     

Effects of hypertension on cardiac performance in rats with myocardial infarction

To determine the effects of hypertension and myocardial infarction on cardiac performance, hemodynamic studies were performed on etheranesthetized, female spontaneously hypertensive rats and on two strains of normotensive rats, Wistar-Kyoto and American Wistar, 26 days after coronary arterial ligation. Baseline measurements of ventricular and arterial pressures and cardiac output (electromagnetic flowmeter) were obtained. Peak cardiac pumping and pressure-generating capacities were determined during a volume load and aortic occlusion, respectively. Infarct size was determined by planimetry. There was a progressive reduction in mean arterial pressure in relation to infarct size in both hypertensive and normotensive rats, but this reduction was twice as great in spontaneously hypertensive rats as in the normotensive rats, such that the arterial pressure of hypertensive rats with a moderate or large infarction decreased to within the “normotensive range.” However, spontaneously hypertensive rats still maintained significantly higher arterial pressures than did normotensive rats at comparable infarct sizes. There was also a progressive reduction in the peak pressure developed during an afterload stress, and this reduction was greater in hypertensive rats than in normotensive rats with a large infarct. Maximal flow-generating capacity was similarly altered in rats with infarction: Peak stroke volume index varied inversely with infarct size and the reduction in this index was significantly greater in spontaneously hypertensive rats than in normotensive rats with a large infarct. Moreover, peak stroke work index was reduced to a greater extent in spontaneously hypertensive rats than in both normotensive strains of rats at any infarct size. Thus, after myocardial infarction, greater reductions in both pressure and flow-generating capacities occurred in hypertensive rats than in normotensive rats.