Functional and metabolic responses to ischemia in the perfused heart isolated from normotensive and spontaneously hypertensive rats

The difference between normotensive rats (WKY) and spontaneously hypertensive rats (SHR) in functional and metabolic responses to ischemia was studied. Systolic arterial blood pressure of SHR (171.2 +/- 2.9 mmHg) was significantly higher than that of WKY (135.3 +/- 1.2 mmHg), and the left ventricular mass of SHR was larger than that of WKY. Hearts isolated from either WKY or SHR were perfused by the working heart technique. Ischemia was induced by lowering the afterload pressure of the working heart. Ischemia produced cardiac arrest, and decreased the tissue levels of adenosine triphosphate and creatine phosphate in both WKY and SHR. Recovery of mechanical function of the heart during reperfusion following ischemia in SHR was better than that in WKY, while recovery of the high-energy phosphates level in SHR was less prominent than in WKY. It is postulated that hypertension has a deleterious effect on myocardial energy metabolism in ischemic heart, even when cardiac mechanical function is maintained.     

Cardiac mechanical dysfunction induced by ischemia-reperfusion in perfused heart isolated from stroke-prone spontaneously hypertensive rats

We investigated the difference in mechanical function after ischemia and reperfusion between Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) or stroke-prone SHR (SHRSP) using the isolated working heart model, in order to examine postischemic mechanical dysfunction in the severely hypertrophied heart. Systolic blood pressure of SHRSP was higher than that of SHR and WKY, and the left ventricular wall in SHRSP was thicker than in WKY. Mechanical dysfunction of the heart during reperfusion following ischemia (11 min) in SHRSP was severer than that in SHR and WKY, and recovery of the cardiac energy charge potential (ECP) level in SHRSP was lower than that in SHR and WKY. Twenty-five, 12 and 11 min-ischemia in WKY, SHR and SHRSP, respectively, caused a similar level of cardiac mechanical damage. Also, the ECP levels were almost equivalent among them at the end of 20 min reperfusion following each time of ischemia. Under each ischemic condition, a Ca2+-channel blocker, diltiazem, and an adenosine potentiator, dilazep, produced a beneficial effect on the post-ischemic dysfunction in SHR and WKY. However, neither cardioprotective drug led to recovery of the mechanical dysfunction of the heart during reperfusion following ischemia in SHRSP. Thus, the severely hypertrophied heart such as that in SHRSP was more susceptible to cardiac reperfusion dysfunction, than the moderately hypertrophied heart such as that in SHR. These results suggest that the cardioprotective effects of drugs may be deteriorated in severe hypertrophied hearts.     

Effects of low-dose chronic diltiazem treatment on hemodynamic changes in spontaneously hypertensive rats

The effects of long-term diltiazem treatment on hemodynamic and cardiovascular characteristics were investigated in young spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY) and their respective untreated controls. The drug was administered to treated rats over a period of 24 weeks. Body weight, left ventricular weight, mean arterial pressure (MAP), heart rate, max dp/dt or maximum velocity of the contractile element (Vmax) were not significantly different in diltiazem-treated SHR and untreated SHR. In diltiazem-treated SHR, cardiac index (CI) and stroke volume index (SI) were significantly increased and total peripheral resistance and the index of left ventricular compliance (delta P/delta V) were significantly decreased compared with untreated SHR. Left ventricular pumping ability in treated SHR was higher than that in untreated SHR, despite the low dose of diltiazem given. However, there was no significant difference between treated and untreated WKY. Long-term diltiazem treatment did not affect left ventricular function or biochemical properties in SHR and WKY. These data suggest that long-term diltiazem treatment improves pump function in SHR without changing blood pressure.     

Development of blood pressure in spontaneously hypertensive rats after withdrawal of long-term treatment related to vascular structure

We have studied the effects of long-term treatment with different antihypertensive drugs on blood pressure and mesenteric resistance vessel structure of spontaneously hypertensive rats (SHR), both during treatment and after withdrawal of treatment. Young SHR were treated from 4 to 24 weeks with five different drugs: perindopril (1.5 mg/kg per day), captopril (60 mg/kg per day), hydralazine (25 mg/kg per day), isradipine (42 mg/kg per day) and metoprolol (130 mg/kg per day). At 24 weeks, 24-h mean blood pressures (MBP), measured invasively, were 121 mmHg (perindopril), 137 mmHg (captopril), 140 mmHg (hydralazine), 149 mmHg (isradipine) and 146 mmHg (metoprolol), compared to control values of 177 mmHg (SHR) and 132 mmHg (Wistar-Kyoto rats, WKY). Mesenteric resistance vessel structure, measured as media:lumen ratio (m:l), was also reduced to different extents: to WKY-level by perindopril (m:l = 4.4%), to midway between SHR- and WKY-levels by captopril, hydralazine and isradipine (m:l = 5.9%), and not at all by metoprolol (m:l = 6.8%). When treatment was discontinued, low MBP (ca 151 mmHg) persisted for 12 weeks in rats treated with the angiotensin converting enzyme inhibitors (perindopril and captopril), but rose rapidly in rats which had received the other treatments. At 3-12 weeks after withdrawal of treatment vascular structure was closely correlated with the blood pressure expected from the SHR- and WKY-control values, as were the left ventricle: body weight ratios. The results suggest that the ability of a drug to control vascular structure during treatment is not in itself a predictor of a persistent effect on blood pressure after withdrawal of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced spontaneous calcium efflux and decrease of calcium-dependent calcium release from the isolated perfused heart of spontaneously hypertensive rats.

OBJECTIVE: The aim of this study was to clarify the further details of calcium handling in hypertension. DESIGN: By preserving the physiological environment of cell membrane, whole hearts were used for comparison of calcium flux between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. METHODS: Hearts from SHR and WKY rats were perfused with Krebs-Henseleit solution under constant flow and the effluent collected. RESULTS: After labelling of the heart with 45Ca2+ (100 mumol/l), 45Ca2+ binding was found to be saturated, and washing with calcium-free perfusion solution showed two exponential curves for calcium dissociation, indicating a fast (alpha-) and slow (beta-) phase. The half-lives of the beta-phase for both 4- and 8-week-old SHR were significantly shorter than those for age-matched WKY. Also in this phase, infusion of non-radioactive Ca2+ caused a transient dose-dependent release of 45Ca2+. A significant reduction in the amount of 45Ca2+ release induced by 2 mmol/l Ca2+ was observed in both 4- and 8-week-old SHR compared with age-matched WKY rats. Infusion of lanthanum, caffeine, ionomycin (calcium ionophore) and treatment of the hearts with ethyleneglycol-bis-(beta-aminoethylether)-N,N,N,',N'-tetraac etic acid did not alter 45Ca2+ release by non-radioactive Ca2+. From these observations, 45Ca2+ is presumably released from the intracellular calcium pool, and not from extracellular binding sites or sarcoplasmic reticulum. CONCLUSIONS: These findings suggest that an abnormal calcium-handling defect (enhanced calcium efflux and reduction of membrane-bound Ca2+) exists under physiological conditions before and after the onset of hypertension, and that this may be a primary characteristic of SHR.     

Altered energy supply to the pump function of the isolated heart of spontaneously hypertensive rats

OBJECTIVE:

The reasons for the development of cardiac insufficiency after a prolonged period of compensation accompanying myocardial hypertrophy are still uncertain and a disturbance in the energy metabolism of cardiomyocytes may serve as an underlying cause. The goal of the present work was to study functional and energetic correlates of the isolated heart of spontaneously hypertensive rats (SHR) at the stage of compensation.

METHODS:

Isolated hearts of SHR and normotensive age-matched Wistar-Kyoto (WKY) rats were subjected to volume and resistance loads. The myocardial content of high-energy phosphates and creatine was determined both before and after the functional loads.

RESULTS:

The contractile performances of the SHR hearts was significantly higher than those of the WKY hearts, the maximal cardiac output during volume load was higher by 36% and the maximal cardiac work index at complete aortic clamping was 68% higher. However, because the dry weight of SHR hearts was 48% higher, the normalized functional indices did not differ significantly between the groups. The ATP-to-ADP ratio and the total creatine level were significantly lower by 10% to 13% in the SHR group before and after the functional loads. In addition, the total adenine nucleotide pool and ATP content were 17% to 20% lower in SHR hearts after the functional loads. The content of high-energy phosphates correlated with contractile indices in the WKY group but not in the SHR group.

CONCLUSIONS:

The results showed that the SHR hearts were better adapted to increased loads than the WKY hearts; however, this advantage combines with an altered interrelation between myocardial energy state and its function.     

Norepinephrine overflow in perfused mesenteric arteries of spontaneously hypertensive rats

We examined the overflow of endogenous norepinephrine with electrical stimulation, the associated pressor response, and rate of initial neuronal uptake of [3H]norepinephrine in perfused mesenteric arteries of 7- and 13-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. The tissues of two rats, a spontaneously hypertensive and a WKY control rat, were simultaneously processed and subjected to the same electrical stimulation. Both absolute and fractional overflow of endogenous norepinephrine during periarterial nerve stimulation (5 and 10 Hz for 1 minute) in the tissue of 7-week-old SHR was significantly greater whereas overflow of 13-week-old SHR was equivalent as compared with that of the age-matched WKY rats. The tissue content of norepinephrine was 20-25% higher in SHR of both ages. There was significantly enhanced [3H]norepinephrine uptake in the tissues of young SHR, but no difference was observed in the older SHR. The pressor response to periarterial nerve stimulation was significantly enhanced in 7-week-old SHR and much more so at the older age as compared with the WKY control rats. Exogenous norepinephrine dose-response curves in the tissues of 7-week-old SHR exhibited a parallel leftward shift, characteristic of a change in sensitivity, whereas that of 13-week-old SHR showed a much steeper slope as compared with the respective WKY control rats. This finding suggests that in addition to smooth muscle supersensitivity, structural alterations had occurred in vasculature of 13-week-old SHR. These data indicate that in SHR both the exocytotic release of norepinephrine and the responsiveness of the vascular smooth muscle cells are enhanced in the developmental stage of hypertension whereas smooth muscle supersensitivity to norepinephrine and nonspecific structural alterations primarily contribute to the maintenance of hypertension at 13 weeks of age.     

Enhanced neuroinhibitory effect of diltiazem in blood vessels of spontaneously hypertensive rats

This study investigated the effects of diltiazem (a Ca2(+)-entry blocker) on neuromuscular junctions of blood vessels in hypertension. In isolated perfused mesenteric vasculatures prepared from spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY), the effects of diltiazem on norepinephrine release from vascular adrenergic neurons and pressor responses were examined. The influences of extracellular Ca2(+)-reduction on these responses were also studied. Stimulation evoked pressor responses and norepinephrine release were significantly greater in the mesenteric vasculatures of SHR than in those of WKY. Diltiazem inhibited both pressor responses and norepinephrine release during electrical nerve stimulation in a dose-dependent manner. The suppression of these responses was more pronounced in SHR than in WKY. Reduction of extracellular Ca2(+)-concentration also decreased the responses in SHR and WKY, and the inhibitory degree was significantly greater in SHR than in WKY. These results demonstrate that diltiazem affected the presynaptic site of the mesenteric vasculatures and decreased the stimulation-evoked norepinephrine release from vascular adrenergic neurons with a concomitant reduction of pressor responses of the preparation. Furthermore, the marked inhibition of pressor responses and norepinephrine release by diltiazem or Ca2(+)-depletion in SHR may suggest the increased Ca2(+)-dependency in vascular neurotransmission in this model of hypertension.     

Effects of PAF on cardiac function and eicosanoid release in the isolated perfused rat heart: comparison between normotensive and spontaneously hypertensive rats

The aim of this study was (a) in isolated perfused rat heart to characterize the effects of platelet-activating factor (PAF) on coronary flow, ventricular contractility, and eicosanoid release and (b) to determine whether PAF effects are altered in hearts from spontaneously hypertensive rats (SHR). PAF (10^–10–10^–7 mol) dose-dependently decreased coronary flow and ventricular contractility; concomitantly, coronary effluent concentrations of thromboxane (TX)B₂ and prostaglandin F₂ (PGF₂) were elevated but not those of prostacyclin. The PAF receptor antagonist WEB 2086 (10^–7–10^–5 mol/l) concentration-dependently antagonized these PAF effects. In addition, the cyclo-oxygenase inhibitor indomethacin (5×10^–5 mol/l) prevented PAF (10^–9–10^–7 mol) induced eicosanoid release; in the presence of indomethacin PAF caused coronary constriction and ventricular depression only at the highest dose (10^–7 mol) but had no effect at 10^–9 or 10^–8 mol. Moreover, the TXA₂ antagonist SQ 29,548 (10^–6 mol/l) completely inhibited 10^–8 mol PAF induced ventricular depression but did not effect coronary constriction. In SHR PAF (10^–9–10^–7 mol) evoked decreases in coronary flow and ventricular contractility did not differ from those in normotensive Wistar-Kyoto rats while PAF induced TXA₂ and PGF₂ release was markedly enhanced. In addition, decreases in coronary flow and ventricular contractility induced by the TXA₂ agonist U 46619 (10^–7 mol/l) were markedly depressed in SHR. We conclude that in isolated perfused rat heart PAF causes coronary constriction and depression of ventricular function mainly indirectly through released TXA₂ and/or PGF₂. Moreover, the fact that in SHR the PAF effects on coronary flow and ventricular function are not altered despite markedly enhanced TXA₂ and PGF₂ release supports the view that in the SHR the receptors mediating TXA₂ and/or PGF₂ effects are desensitized.     

Brain ischemia and gastric mucosal damage in spontaneously hypertensive rats

Brain ischemia is often accompanied by acute gastric lesions. To clarify the underlying mechanism, the influence of acute ischemic insult to the brain on gastric hemodynamics and mucosal integrity was examined in spontaneously hypertensive rats. One hour after brain ischemia, gastric mucosal blood flow decreased to 71% of the preischemic levels in the control rats but was preserved significantly better, at 94 and 108%, in the prazosin-treated and guanethidine-treated rats, respectively. Vagotomy almost abolished the decrease in gastric mucosal blood flow during cerebral ischemia. Intragastric 0.6 N hydrochloric acid administered just after reperfusion induced more severe hemorrhagic ulcers in the control than in the prazosin-treated and vagotomized groups. These results suggest that noradrenergic neurons acting through ₁-adrenoceptors contributes to the decrease in gastric mucosal blood flow, and the subsequent disturbed integrity of the gastric mucosa, through the vagal adrenergic pathway during brain ischemia in spontaneously hypertensive rats.     

Cardiovascular effects of nebivolol in spontaneously hypertensive rats persist after treatment withdrawal

OBJECTIVES: We observed previously that nebivolol treatment for 2 months reduced cardiovascular lesions in spontaneously hypertensive rats (SHR). Therefore, we investigated whether this beneficial effect is increased with a longer treatment, and its persistence after withdrawal. METHODS: Male SHR were treated with 8 mg/kg per day of nebivolol (N-SHR) for 6 months. A separate group was also given identical treatment but they were then monitored for a further 3 months after drug withdrawal. SHR and Wistar-Kyoto rats (WKY) receiving vehicle were used as controls. Systolic blood pressure and heart rate were measured using the tail-cuff method. Left ventricular weight/body weight ratio was calculated as the hypertrophy index. Cardiac and vascular fibrosis was evaluated on sections stained with sirious red. Vascular reactivity was evaluated on aortic rings through acetylcholine and sodium nitroprusside responses. The effect of treatment on vascular structure was assessed by lumen diameter, wall thickness and medial cross-sectional area determination. RESULTS: Blood pressure was reduced in N-SHR. After withdrawal it increased progressively, without reaching the values of the hypertensive controls. Cardiac hypertrophy and collagen content both in heart and aorta were significantly reduced, and these changes persisted after nebivolol suppression. Acetylcholine-induced relaxant response was improved by nebivolol and maintained after withdrawal. Medial thickness and cross-sectional area were significantly reduced in both conductance and resistance arteries, and these effects persisted after withdrawal. CONCLUSION: The nebivolol antihypertensive effect was accompanied by an important reduction of hypertrophy and collagen deposition in both vascular and left ventricle tissue, which was maintained after a long period of therapy withdrawal.     

The response to ischemia in blood perfused vs. crystalloid perfused isolated rat heart preparations.

With a research hypothesis that the behavior of blood perfused hearts was different from that of crystalloid perfused hearts, we tested the null hypothesis that the functional and metabolic status of blood-perfused (paracorporeal oxygenation) and Krebs-Henseleit (bubble oxygenation) perfused Langendorff isolated rat hearts is the same before, during and after global myocardial ischemia. Thirty isolated rat hearts were studied under identical conditions except that in equal numbers they were randomly assigned to either blood or crystalloid perfusion. In the blood perfused and crystalloid perfused hearts subjected to 22 min of normothermic ischemia and 30 min of reperfusion, mean systolic recovery was 72 +/- 3.9% (S.E.) and 20 +/- 10% (P = 0.001), respectively; coronary resistance increased 21 +/- 16% and 158 +/- 27% (P = 0.0003) (unadjusted for viscosity); mean water content after reperfusion was 82.0 +/- 0.43% and 86.7 +/- 0.42% (P < 0.0001), ATP content was 8.4 +/- 1.9 and 4.3 +/- 0.5 mumol/g dry wt (P = 0.08), and energy charge was 0.74 +/- 0.114 and 0.59 +/- 0.048 (P = 0.3). A major qualitative difference during reperfusion was spontaneous relaxation of contracture and rapid resumption of sinus rhythm in blood perfused hearts, in contrast to continued contracture and rise in intraventricular pressure in 9 of 10 crystalloid perfused hearts. One crystalloid perfused heart did not develop contracture, and its phenomena during reperfusion were similar to those of blood perfused hearts. The data support the research hypothesis, and suggest caution in extrapolating to blood perfused systems inferences from crystalloid perfused models. Better preservation of reactive hyperemia early in reperfusion may explain the better performance of blood perfused hearts.     

Myocardial protection during ischemia in the isolated perfused rabbit heart

Although many studies of the protective effects of cardioplegic solutions using hypothermia have been conducted, it is also necessary to examine their protective effects under normothermia as regional increases in myocardial temperature during hypothermic arrest are often reported. For this purpose myocardial protection was investigated in the isolated perfused rabbit heart exposed to 60 minutes of normothermic global ischemia during which Krebs-Henseleit, blood with heparin, Tyers', and St. Thomas' Hospital solutions were infused at 0.2 mL/min. Percent functional recovery dP/dtmax (mm hg/sec) at 5 minutes relative to pre-ischemic values using Tyers' (12 +/- 5)% was significantly less (p less than 0.05) than recovery using Krebs-Henseleit (57 +/- 13)% and St. Thomas' Hospital solution (47 +/- 5)%. Recovery using blood (79 +/- 7)% was significantly better than all other solutions. Following 25 minutes reperfusion, 4/6 hearts perfused with Tyers' experienced left ventricular fibrillation, while recovery of developed pressure with Krebs-Henseleit (74 +/- 5.8)%, St. Thomas' Hospital (66 +/- 3.4)% and blood (98 +/- 2.9)% was again significantly improved relative to Tyers', (p less than 0.05). Time to develop 5 mm contracture during the ischemic period was significantly shorter using Tyers' than with the other solutions. Using these indices of function, whereas Tyers' solution provided poor protection, blood provided excellent protection in rabbit hearts under normothermic conditions.     

Hemodynamic comparison of diltiazem and TA-3090 in spontaneously hypertensive and normal Wistar-Kyoto rats

Systemic and regional hemodynamic effects of 2 benzothiazepine derivatives, diltiazem and its congener TA-3090, were studied both acutely and chronically in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. All hemodynamic data were obtained in the conscious state using the reference sample radiomicrosphere method. Mean arterial pressure was reduced significantly with both immediate and more long-term treatment with both drugs in the SHR. The hypotensive action of TA-3090 was about 3 times as potent as diltiazem. The pressure reduction with both drugs was associated with a decrease in total peripheral resistance. TA-3090 seemed to have lesser effect on heart rate than diltiazem, although its net effect on cardiac output was similar, remaining unchanged in each study group. After intravenous injection, both diltiazem and TA-3090 significantly reduced vascular resistances of the major target organs of hypertension: heart, brain and kidneys in SHR. However, with prolonged treatment, organ vascular resistances seemed to be nonuniformly distributed. Intrarenal hemodynamics revealed significant differences between SHR and WKY rats after intravenous diltiazem and prolonged treatment with TA-3090. Thus, efferent as well as afferent arteriolar resistance decreased and therefore calculated glomerular capillary hydrostatic pressure decreased in SHR; however, efferent resistance and glomerular pressure remained unchanged in WKY rats. In contrast, intravenous TA-3090 evoked no such differences. Thus, diltiazem as well as TA-3090 dilated efferent as well as afferent arterioles in the SHR but not in the WKY rats. This effect was associated with a reduction in glomerular capillary pressure, preventing glomerular hyperfiltration through efferent arteriolar dilation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improved myocardial efficiency in the working perfused heart of the spontaneously hypertensive rat

We assessed the relationship between determinants of myocardial oxygen demand--wall stress, peak rate of change of pressure and heart rate--and measured myocardial oxygen consumption over a range of loading conditions in the perfused, working heart of 6-month-old spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY). Two isolated heart preparations, an aortic-ejecting heart and an isovolumically contracting preparation with and without isoproterenol (10(-7)M) added, were employed. Under a constant perfusion pressure of 110 mm Hg, the heart rate, developed wall stress, and peak rate of change of pressure were not different between the two groups, but coronary flow and myocardial oxygen consumption were significantly lower in the SHR. Systolic values of myocardial high energy phosphate compounds (adenosine 5'-triphosphate, phosphocreatine) and myocardial lactate in the two preparations were not significantly different between SHR and WKY. Following adenosine infusion at maximum developed pressure (isovolumic preparation), both SHR and WKY demonstrated preservation of coronary reserve. These results indicate that cardiac hypertrophy represents a compensatory adaptation with improved mechanical efficiency in the 6-month-old SHR when maximally stressed and may be related to the shift from V1 to V2 and V3 isomyosin phenotypes that was observed in the hypertensive animals.     

Myocardial stretch induced by increased left ventricular diastolic pressure preconditions isolated perfused hearts of normotensive and spontaneously hypertensive rats

Objective: The aim of our study was to determine whether myocardial stretch (non-ischemic stress) could precondition isolated perfused hearts of both normotensive Wister-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).Methods: The perfused hearts in Langendorff mode were subjected to 30 min of global no-flow ischemia followed by 30 min of reperfusion. Left ventricular developed pressure (LVDP) and end-diastolic pressure (LVEDP) were measured. In the control group, LVEDP was set at 10 mmHg. In the stretch group, LVEDP was increased to 30 or 60 mmHg for 5 min before 30 min of ischemia. In the ischemic preconditioning group, the hearts were exposed to two cycles of a 5-min period of ischemia before 30 min of ischemia. Myocardial lactate contents were measured at the baseline and at the end of the 60 mmHg stretch.Results: Hemodynamic parameters of LVDP and LVEDP at 30 min of reperfusion improved in the stretch group (LVEDP at 60 mmHg) and the ischemic preconditioning group. Coronary flow did not decrease during the stretch. Recovery of the coronary flow during reperfusion was better in the stretch and ischemic preconditioning groups. Postischemic contractile function was better in WKY rats than in SHR. Myocardial lactate contents at the end of 60 mmHg stretch were negligible. Conclusions: Myocardial stretch induced by increasing LVEDP preconditioned isolated perfused hearts of both WKY rats and SHR, via mechanisms not involving myocardial ischemia during stretch.     

Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term

Our study examines the long-term cardiovascular effects after a brief period of angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR). SHR were treated with perindopril (3 mg/kg/day) by gavage from 2 to 6, from 6 to 10, or from 2 to 10 weeks of age. Systolic blood pressure was measured in the tail weekly until 25 weeks of age. Corresponding control groups received distilled water for the same periods. In each treatment group blood pressure was reduced significantly during treatment, rose when treatment stopped, but plateaued significantly below control SHR thereafter. This difference in blood pressure at 25 weeks of age was due to reduced total peripheral resistance as determined by microsphere methods, but plasma renin activity and angiotensin II concentrations were not different. Cardiac hypertrophy was also reduced in treated SHR. In a separate experiment, perindopril treatment from 6 to 10 weeks of age resulted in a significant reduction in the media/lumen ratios of mesenteric resistance vessels at 32 weeks of age. Concomitant administration of angiotensin II with perindopril from 6 to 10 weeks of age not only prevented the long-term effects on blood pressure seen with perindopril treatment alone but was associated with cardiovascular hypertrophy in excess of untreated control SHR. Finally, perindopril given for a shorter period (6 to 7 weeks) or later in life (20 to 24 weeks) had no significant long-term effects on blood pressure. These results demonstrate that a 4-week period of ACE inhibitor treatment in young SHR is sufficient to prevent the full expression of genetic hypertension and cardiovascular hypertrophy and that angiotensin II might be important in the development of hypertension in this model, its role in later life being less important.     

Insulin resistance in adipocytes from spontaneously hypertensive rats: effect of long-term treatment with enalapril and losartan.

Insulin responsiveness was studied in isolated adipocytes from the normotensive Wistar Kyoto (WKY) rat and the spontaneously hypertensive rat (SHR). The effect of insulin (0.1 to 5 nmol/L) on glucose uptake (glucose transport and lipogenesis) was measured, and the maximal effect of insulin (Emax) and the dose of insulin required to elicit 50% of the maximal response (EC50) were calculated. A diminished Emax on lipogenesis without changes in the EC50 was detected in SHRs. The Emax was 0.49 +/- 0.09 (SHR) and 1.16 +/- 0.14 (WKY) micromol/10(5) cells (P < .05), and the EC50 was 0.13 +/- 0.03 and 0.11 +/- 0.02 nmol/L for WKY and SHR, respectively. Similar results were obtained when measuring insulin-stimulated glucose transport. A 30-day long-term treatment with enalapril (20 mg/kg/d) normalized insulin responsiveness in adipocytes from SHRs. The effect of enalapril was suppressed when SHRs were pretreated with enalapril and 150 microg/kg/d of the bradykinin (BK) B2-receptor blocker Hoe 140. Pretreatment with losartan (40 mg/kg/d) did not improve insulin action in the SHR. Since these results were obtained with isolated cells in which glucose availability was not a function of blood flow, and the effect of insulin in the SHR was improved by pretreatment with an angiotensin-converting enzyme (ACE) inhibitor but not with the AT1-receptor blocker, it appears that the insulin resistance linked to the hypertension is not related to changes in blood flow.     

Malignant hypertensive retinopathy in spontaneously hypertensive stroke-prone rats. Effect of treatment with cicletanine

Stroke-Prone spontaneously hypertensive rat strain (SHR-SP) always develops hypertensive retinopathy. The aim of the present work was to study the activity of a new antihypertensive drug, a synthetic furopyridine: cicletanine, in retinal hypertensive morphological lesions. The experiment was performed in 39 rats SHR-SP/A3N Iffa Credo, 11 weeks old, divided into 3 groups: group 1 was the control group, groups 2 and 3 were orally treated with cicletanine (respectively 100 and 150 mg/kg). All the rats had free access to tap water containing 1 p. 100 NaCl. During 6 weeks, blood pressure, body weight and survival were recorded, then all the rats were sacrificed. The eyes were removed, the posterior pole collected and fixed with Trump liquid for transmission election microscopy. In the SHR-SP control group, each layer showed neural body and/or process lesions: in the ganglion cell layer, some ganglion cells realized cytoid bodies corresponding to a lysed cell with nucleus degeneration, most of the axons were destroyed. In the inner and outer plexiform layers, most of the contacts between processes were lost because of fibrinous deposits. Numerous synapses were destroyed in the outer plexiform layer. These findings might explain the numerous dense bodies in the inner rod segment and the vesiculation of the rod outer segment. The capillaries showed markedly hypertensive lesions. Whereas, in both treated groups, rare and animal lesions were observed. The fact that these lesions were so few and so unimportant after 6 weeks of treatment, as well as for the photoreceptors which remained unimpaired, is closely related to cicletanine therapy, since it was so even though the treatment had been started with an already high blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)