S100B interaction with the receptor for advanced glycation end products (RAGE): a novel receptor-mediated mechanism for myocyte apoptosis postinfarction.

RATIONALE: Post-myocardial infarction ventricular remodeling is associated with the expression of a variety of factors including S100B that can potentially modulate myocyte apoptosis. OBJECTIVE: This study was undertaken to investigate the expression and function of S100B and its receptor, the receptor for advanced glycation end products (RAGE) in both postinfarction myocardium and in a rat neonatal myocyte culture model. METHODS AND RESULTS: In a rat model of myocardial infarction following coronary artery ligation, we demonstrate in periinfarct myocytes, upregulation of RAGE, induction of S100B, and release into plasma with consequent myocyte apoptosis. Using a coimmunoprecipitation strategy, we demonstrate a direct interaction between S100B and RAGE. In rat neonatal cardiac myocyte cultures, S100B at concentrations > or = 50 nmol/L induced myocyte apoptosis, as evidenced by increased terminal DNA fragmentation, TUNEL, cytochrome c release from mitochondria to cytoplasm, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p53, increased expression and activity of proapoptotic caspase-3, and decreased expression of antiapoptotic Bcl-2. Transfection of a full-length cDNA of RAGE or a dominant-negative mutant of RAGE resulted in increased or attenuated S100B-induced myocyte apoptosis, respectively. Inhibition of ERK1/2 by U0126/PD-98059 or overexpression of a dominant negative p53 comparably inhibited S100B-induced myocyte apoptosis. CONCLUSIONS: These results suggest that interaction of RAGE and its ligand S100B after myocardial infarction may play a role in myocyte apoptosis by activating ERK1/2 and p53 signaling. This receptor-mediated mechanism is uniquely amenable to therapeutic intervention.

Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat.

OBJECTIVE: Diabetic cardiomyopathy is an increasingly recognized cause of cardiac failure despite preserved left ventricular systolic function. Given the over-expression of angiotensin II in human diabetic cardiomyopathy, we hypothesized that combining hyperglycaemia with an enhanced tissue renin-angiotensin system would lead to the development of diastolic dysfunction with adverse remodeling in a rodent model. METHODS: Homozygous (mRen-2)27 rats and non-transgenic Sprague Dawley (SD) rats were randomized to receive streptozotocin (diabetic) or vehicle (non-diabetic) and followed for 6 weeks. Prior to tissue collection, animals underwent pressure-volume loop acquisition. RESULTS: Diabetic Ren-2 rats developed impairment of both active and passive phases of diastole, accompanied by reductions in SERCA-2a ATPase and phospholamban along with activation of the fetal gene program. Structural features of diabetic cardiomyopathy in the Ren-2 rat included interstitial fibrosis, cardiac myocyte hypertrophy and apoptosis in conjunction with increased activity of transforming growth factor-beta (p<0.01 compared with non-diabetic Ren-2 rats for all parameters). No significant functional or structural derangements were observed in non-transgenic, SD diabetic rats. CONCLUSION: These findings indicate that the combination of enhanced tissue renin-angiotensin system and hyperglycaemia lead to the development of diabetic cardiomyopathy. Fibrosis, and myocyte hypertrophy, a prominent feature of this model, may be a consequence of activation of the pro-sclerotic cytokine, transforming growth factor-beta, by the diabetic state.

Inhibition of norepinephrine-induced cardiac hypertrophy in s100beta transgenic mice.

We have recently reported that the Ca2+-binding protein S100beta was induced in rat heart after infarction and forced expression of S100beta in neonatal rat cardiac myocyte cultures inhibited alpha1-adrenergic induction of beta myosin heavy chain (MHC) and skeletal alpha-actin (skACT). We now extend this work by showing that S100beta is induced in hearts of human subjects after myocardial infarction. Furthermore, to determine whether overexpression of S100beta was sufficient to inhibit in vivo hypertrophy, transgenic mice containing multiple copies of the human gene under the control of its own promoter, and CD1 control mice were treated with norepinephrine (NE) (1.5 mg/kg) or vehicle, intraperitoneally twice daily for 15 d. In CD1, NE produced an increase in left ventricular/body weight ratio, ventricular wall thickness, induction of skACT, atrial natriuretic factor, betaMHC, and downregulation of alphaMHC. In transgenic mice, NE induced S100beta transgene mRNA and protein, but provoked neither hypertrophy nor regulated cardiac-specific gene expression. NE induced hypertrophy in cultured CD1 but not S100beta transgenic myocytes, confirming that the effects of S100beta on cardiac mass reflected myocyte-specific responses. These transgenic studies complement in vitro data and support the hypothesis that S100beta acts as an intrinsic negative regulator of the myocardial hypertrophic response.

miRNAs and their role in the correlation between schizophrenia and cancer (Review).

Schizophrenia (SZ) and cancer (Ca) have a broad spectrum of clinical phenotypes and a complex biological background, implicating a large number of genetic and epigenetic factors. SZ is a chronic neurodevelopmental disorder signified by an increase in the expression of apoptotic molecular signals, whereas Ca is conversely characterized by an increase in appropriate molecular signaling that stimulates uncontrolled cell proliferation. The rather low risk of developing Ca in patients suffering from SZ is a hypothesis that is still under debate. Recent evidence has indicated that microRNAs (miRNAs or miRs), a large group of small non­coding oligonoucleotides, may play a significant role in the development of Ca and major psychiatric disorders, such as SZ, bipolar disorder, autism spectrum disorders, suicidality and depression, through their interference with the expression of multiple genes. For instance, the possible role of let­7, miR­98 and miR­183 as biomarkers for Ca and SZ was investigated in our previous research studies. Therefore, further investigations on the expression profiles of these regulatory, small RNA molecules and the molecular pathways through which they exert their control may provide a plausible explanation as to whether there is a correlation between psychiatric disorders and low risk of developing Ca.

The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure.

Action potential prolongation is a common finding in human heart failure and in animal models of cardiac hypertrophy. The mechanism of action potential prolongation involves altered expression of a variety of depolarising and hyperpolarising currents in the myocardium. In particular, decreased density of the transient outward potassium current seems to play a prominent role, regardless of species, precipitating factors or the severity of hypertrophy. The decreased density of the transient outward current appears to be caused by reduced transcription of Kv4.2 and Kv4.3 and may be caused in part by an inhibitory effect of alpha-adrenoceptor stimulation. During the early stage of the disease process, action potential prolongation may increase the amplitude of the intracellular calcium transient, causing positive inotropy. We argue therefore, that action prolongation may be a compensatory response which may acutely support the compromised cardiac output. In severe hypertrophy and end-stage heart failure however, despite continued action potential prolongation, the amplitude of the calcium transient becomes severely reduced. The mechanism underlying this event appears to involve reduced expression of calcium handling proteins, and these late events may herald the onset of failure. At present the events leading to the late changes in calcium handling are poorly understood. However, chronic activation of compensatory mechanisms including action potential prolongation may trigger these late events. In the present article we outline a hypothesis which describes a potential role for action potential prolongation, and the associated elevation in the levels of intracellular calcium, in maladaptive gene expression and the progression toward cardiac failure.

Effects of arterial vasodilators on cardiac hypertrophy and sympathetic activity in rats.

In spontaneously hypertensive rats (SHR), the progression (or absence of regression) of cardiac hypertrophy despite adequate blood pressure (BP) control by arterial vasodilators has been attributed to increased cardiac sympathetic activity. We evaluated changes in indices of general and cardiac sympathetic tone in relation to changes in cardiac anatomy during treatment of normotensive rats and SHR with hydralazine, 120 mg/L, or minoxidil, 120 mg/L of drinking water. In SHR, both vasodilators reduced BP rapidly and consistently. Significant increases in heart rate and plasma norepinephrine were observed only in the initial 2 days of arterial vasodilator treatment. After 5 weeks of treatment, marked increases in left and right ventricular sympathetic activity (as assessed by norepinephrine turnover rates) were present, but no increase was seen in heart rate and plasma norepinephrine. Intravascular volume expansion was observed on Day 14 of minoxidil and Day 35 of hydralazine treatment. Prolonged treatment with minoxidil induced significant increases in left ventricular internal diameter, as well as in left and right ventricular weights, but not in the wall thickness of the left ventricle. Treatment with hydralazine did not affect left ventricular weight and caused a small increase in the weight of the right ventricle. In normotensive rats, both vasodilators initially decreased BP, but tolerance developed within 1 to 2 weeks of treatment. Plasma norepinephrine and heart rate showed increases only at Day 1 of either treatment, whereas cardiac sympathetic hyperactivity persisted at 2 and 5 weeks of treatment. Changes in cardiac anatomy were qualitatively similar to those observed in SHR. We conclude that, during treatment of normotensive rats and SHR with arterial vasodilators, cardiac sympathetic hyperactivity persists and may be involved in the cardiac effects of arterial vasodilators. However, other mechanisms, such as chronic cardiac volume overload, may also play an important role, particularly with minoxidil.

Prevention of hypertension and vascular changes by captopril treatment.

Treatment of female spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats with captopril was carried out by the addition of the drug in the drinking water throughout pregnancy and lactation and after weaning. At 28 weeks of age, average systolic blood pressure of treated SHR was 113 +/- 3 mm Hg, which was below that of control SHR (188 +/- 3 mm Hg) and WKY rats (124 +/- 3 mm Hg). Body weight and heart rate of the SHR were not affected by the treatment. Tissue level of catecholamines was increased by captopril treatment in the superior cervical ganglia but remained unchanged in the plasma, heart, mesenteric arteries, and the adrenal glands of both SHR and WKY rats. Left ventricular weight, wall thickness, and internal diameter of the left ventricle in the SHR were reduced by the treatment. Morphometric measurements of the mesenteric arteries showed that vascular alterations present in the control SHR were prevented by the treatment. In the superior mesenteric artery and large mesenteric artery, smaller lumen size at maximal relaxation found in the control SHR was normalized to the level of the WKY rats. Hypertrophy of the medial wall in the superior mesenteric, large and small mesenteric arteries, and an increase in the number of smooth muscle cell layers in the large mesenteric artery of the SHR were prevented by the treatment. Perfusion study of the mesenteric vascular bed showed that reactivity of these vessels to norepinephrine was reduced, and sensitivity to norepinephrine (as determined by the effective dose that causes 50% of maximal response) was increased in the SHR by captopril treatment. Sensitivity of the tail artery in response to norepinephrine was not altered by the treatment. We conclude that long-term treatment with captopril of SHR before and after birth prevented the development of hypertension, structural and functional alterations of the mesenteric arteries, and cardiac hypertrophy.

Effects of the arterial vasodilator minoxidil on cardiovascular structure and sympathetic activity in spontaneously hypertensive rats.

OBJECTIVE AND DESIGN: In spontaneously hypertensive rats (SHR) arterial vasodilators do not cause regression and might cause further progression of cardiac hypertrophy. To assess whether these effects extend to the vasculature, and to examine the possible mechanisms involved, cardiac and mesenteric arterial structure was evaluated with respect to changes in cardiac volume load and cardiac and arterial sympathetic activity during long-term (5- and 10-week) treatment of 16-week-old SHR with the arterial vasodilator minoxidil, alone or in combination with the diuretic hydrochlorothiazide. RESULTS: Despite causing a persistent decrease in blood pressure in SHR, minoxidil further increased left and right ventricular weights and left ventricular internal diameter. In combination with hydrochlorothiazide, minoxidil caused concentric, rather than eccentric, left ventricular hypertrophy. In the mesenteric arterial bed of SHR, minoxidil increased the lumen of the superior mesenteric artery, and prevented further increases in the medial area of the large and small mesenteric arteries. The increase in lumen size of the superior mesenteric artery by minoxidil was abolished when hydrochlorothiazide was added to the treatment. After 10 weeks' treatment with minoxidil, noradrenaline turnover rates were still significantly increased in the left ventricle but were decreased in the mesenteric arteries in the SHR. Minoxidil increased plasma and blood volumes, the increases being largely prevented by concomitant diuretic treatment. CONCLUSIONS: We conclude that there are regional differences in the response of the cardiovascular system to minoxidil in SHR. Some of these differences may be related to differences in regional sympathetic activity, whereas volume load appears to play a modulatory role.

Arterial hypertrophy and pressor responsiveness during development of hypertension in spontaneously hypertensive rats.

BACKGROUND: In contrast to studies in isolated blood vessels, results from whole-animal studies are ambiguous regarding differences in pressor responsiveness between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, possibly related to the measurement of blood pressure instead of total peripheral resistance (TPR) and to differences in compensatory mechanisms. OBJECTIVE AND DESIGN: We evaluated responses of blood pressure and TPR to two doses of the alpha 1-agonist phenylephrine during the development of hypertension and cardiovascular hypertrophy in SHR aged 8-26 weeks compared with age-matched WKY rats before and after ganglionic blockade. At 16 weeks of age more-complete dose-response curves to the alpha 1-agonist methoxamine were also constructed. RESULTS: Over the age range studied, the SHR developed marked hypertension, related to a significant rise in TPR, and concomitantly significant cardiac hypertrophy, as well as hypertrophy of the mesenteric arterial bed. The blood pressure responses to phenylephrine were diminished in the SHR compared with the WKY rats at all ages studied, but this effect was significant only in the absence of ganglionic blockade. TPR responses were significantly less in the SHR than in the WKY rats, both with and without concomitant ganglionic blockade. In contrast, both blood pressure and TPR responses to low doses, but not higher doses, of methoxamine were enhanced in the SHR compared with the WKY rats. CONCLUSION: These results indicate that the development of hypertension in SHR in vivo is associated with variable changes in blood pressure and TPR responses to alpha 1-receptor stimulation, depending on the alpha 1-agonist employed.

S100A6 is a negative regulator of the induction of cardiac genes by trophic stimuli in cultured rat myocytes.

S100A6 (calcyclin), a member of the S100 family of EF-hand Ca2+ binding proteins, has been implicated in the regulation of cell growth and proliferation. We have previously shown that S100B, another member of the S100 family, is induced postinfarction and limits the hypertrophic response of surviving cardiac myocytes. We presently report that S100A6 expression is also increased in the periinfarct zone of rat heart postinfarction and in cultured neonatal rat myocytes by treatment with several trophic agents, including platelet-derived growth factor (PDGF), the alpha1-adrenergic agonist phenylephrine (PE), and angiotensin II (AII). Cotransfection of S100A6 in cultured neonatal rat cardiac myocytes inhibits induction of the cardiac fetal gene promoters skeletal alpha-actin (skACT) and beta-myosin heavy chain (beta-MHC) by PDGF, PE, AII, and the prostaglandin F2alpha (PGF2alpha), induction of the S100B promoter by PE, and induction of the alpha-MHC promoter by triiodothyronine (T3). By contrast, S100B cotransfection selectively inhibited only PE induction of skACT and beta-MHC promoters. Fluorescence microscopy demonstrated overlapping intracellular distribution of S100B and S100A6 in transfected myocytes and in postinfarct myocardium but heterodimerization of the two proteins could not be detected by co-immunoprecipitation. We conclude that S100A6 may function as a global negative modulator of differentiated cardiac gene expression comparable to its putative role in cell cycle progression of dividing cells.

Enhancement by glutathione of the inotropic actions of catecholamines and glucagon.

We have previously shown that cardiostimulation produced by catecholamines, glucagon, tachycardia or CaCl2, resulted in a metabolically induced increase in coronary flow [9, 11, 12]. Slow infusion of prostaglandin E2 (PGE2) or its precursor, arachidonic acid, inhibited the development of metabolic coronary dilatation without major alterations of the effects of the cardiostimulating agents on the cardiac activity [9, 11, 12]. Since PGE2 synthesis is known to be enhanced by glutathione we thought that its addition to the perfused heart would intensify the inhibition of the metabolic coronary dilatation produced by arachidonic acid. While testing the influence of noradrenaline in the isolated perfused heart, we found that the inotropic action and the resulting coronary dilatation were markedly increased during glutathione administration. We diverted the investigation from its original purpose to further study this novel action of glutathione and we report here that catecholamines and glucagon inotropic effects, and resulting metabolic coronary dilatation are enhanced by glutathione. Neither the CaCl2 nor the coronary dilatations due to reactive hyperaemia or adenosine were altered by glutathione.

Effects of hydralazine on blood pressure, pressor mechanisms, and cardiac hypertrophy in two-kidney, one-clip hypertensive rats.

In 2-kidney, 1-clip hypertensive rats, the time course of changes in blood pressure (BP), heart rate, activity of the sympathetic nervous system and the renin-angiotensin system, plasma and blood volumes, left ventricular (LV) and right ventricular (RV) weight, and LV dimensions were evaluated during treatment with hydralazine 80 and 120 mg/L drinking water for 2 days or 1, 2, 3, 5, and 8 weeks. Hydralazine induced initially a clear antihypertensive effect (mean BP from 170-180 down to 135-145 mmHg (1 mmHg = 133.32 Pa], subsequently tolerance developed. Heart rate, plasma catecholamines, and the blood pressure response to hexamethonium were not affected by treatment. Significant increases in plasma renin activity occurred during the initial 1-3 weeks of treatment. Plasma and blood volumes showed only small increases with prolonged treatment. RV weight and LV internal diameter showed significant increases at 3, 5, and 8 weeks of treatment, LV weight at 5 and 8 weeks. LV wall thickness did not change significantly. Thus, treatment with the arterial vasodilator hydralazine causes both RV hypertrophy and eccentric LV hypertrophy. Intravascular volume expansion, associated possibly with redistribution of blood volume to the central compartment, may play a major role in these cardiac effects. Increased renin release but not a generalized increase in sympathetic tone may play a role in the development of tolerance to the antihypertensive effect.

Cardiac volume load as a determinant of the response of cardiac mass to antihypertensive therapy.

Whereas chronic pressure overload induces left ventricular hypertrophy in a predictable way, the same lowering of systolic blood pressure by different antihypertensive drug classes is not associated with the same regression of LV mass. In particular, arterial vasodilators may not induce regression or even cause progression despite persistent decreases in blood pressure. It has been commonly assumed that different activation of non-haemodynamic mechanisms may explain such a dissociation. However, different effects on the other haemodynamic determinant of cardiac mass, cardiac volume overload, have not been taken into account. Our results in normotensive and hypertensive humans and rats indicate that arterial vasodilators induce a pattern of changes in cardiac anatomy, compatible with cardiac volume overload being a major contributor to these changes. Cardiac sympathetic hyperactivity may also contribute, possibly more in hypertension than in normotension.

Reduced glutathione modulates the arachidonic acid induced coronary reactions.

Coronary flow was recorded from spontaneously beating isolated perfused hearts of rats and guinea pigs. Arachidonic acid (AA), in single bolus doses, produced a fast short lasting coronary constriction followed by a slow developing but persisting vasodilation. These reactions (biphasic type) were characteristic of the guinea pig heart. In about 50% of the rat hearts the vasoconstrictor action predominated while the biphasic response was obtained in the rest of the experiments. Pretreatment of rats with aspirin prevented the responses to AA in the isolated heart. The administration of reduced glutathione (GSH) (about 1 mM to the rat or 0.5-0.75 mM to the guinea pig hearts) produced a marked development and (or) enhancement of the vasodilator action of AA. Repeated or single large doses of AA produced a change of pattern of responses from biphasic to constrictor type; the addition of GSH restored the vasodilator phase. Since GSH directs the endoperoxide metabolism towards the synthesis of prostaglandin E2 (PGE2), we postulate that the coronary dilatation of resistance vessels produced by AA would be due to a great extent to PGE2.

Contrasting effects of calcium antagonists vs. arterial vasodilators on cardiac anatomy and sympathetic activity in spontaneously hypertensive rats.

In spontaneously hypertensive rats (SHRs) we evaluated the effects of 35 and 70 days of treatment with nisoldipine (2 mg/g of food) vs. minoxidil (120 mg/L of drinking water) on cardiac anatomy [i.e., left ventricular (LV) and right ventricular (RV) weights and LV internal diameter and wall thickness] and cardiac sympathetic activity assessed by the norepinephrine turnover rate. The minoxidil-induced antihypertensive response was associated with a marked increase in cardiac sympathetic activity, potentiation of RV hypertrophy (RVH), and the development of eccentric LV hypertrophy (LVH). Nisoldipine decreased both blood pressure (BP) and cardiac sympathetic activity, but caused only small decreases in LV weight and LV wall thickness and no change in RV weight. With regard to minoxidil, the increase in sympathetic activity may contribute to the minoxidil-induced potentiation of cardiac mass. Nisoldipine, despite decreasing BP as well as cardiac sympathetic activity, unexpectedly resulted in only a small decrease in cardiac mass, suggesting that additional mechanisms may play a role in the effects of calcium antagonists on cardiac mass.

Influence of chronic nadolol treatment on blood pressure and vascular changes in spontaneously hypertensive rats.

Chronic treatment of spontaneously hypertensive rats (SHR) and Kyoto-Wistar normotensive rats (WKY) with nadolol was carried out from gestation until 28 weeks of age. Nadolol treatment caused some lowering of blood pressure but did not prevent the development of hypertension or cardiac hypertrophy in the SHR, in spite of significant beta-blockade. The lumen of large mesenteric arteries from control SHR was smaller than from WKY, and nadolol treatment increased the lumen size in the SHR. An increased number of smooth muscle cell layers present in the control SHR as compared with WKY was reduced slightly by nadolol treatment. However, the changes produced by nadolol did not reach the levels of control and treated WKY. In the aorta, the incidence of polyploid smooth muscle cells was higher in the SHR than the WKY in the control group. Nadolol treatment reduced the percentage of polyploid cells in both SHR and WKY, so that the difference between these two groups of animals was eliminated in the treated groups. The tissue level of norepinephrine in the plasma, heart, mesenteric arteries, and adrenal glands in the SHR and WKY was not affected by the treatment. We suggest that the ineffectiveness of nadolol in preventing hypertension development may be due to its lack of effect in preventing primary changes in the resistance arteries, and that the development of polyploidy of smooth muscle cells may be mediated by beta-receptors.

Induction of S100b in myocardium: an intrinsic inhibitor of cardiac hypertrophy.

Cardiac hypertrophy induced by pressure overload and following myocardial infarction entails regulation of myocardial gene expression, recapitulating an embryonic phenotype, including activation of fetal beta-myosin heavy chain and skeletal alpha-actin. Progressive hypertrophy and alterations in gene expression may contribute to myocardial failure. Although signaling pathways that contribute to hypertrophy development have been identified, intrinsic cardiac regulators that limit hypertrophic response have not been determined. The beta subunit of S100 protein is induced in the myocardium of human subjects and an experimental rat model following myocardial infarction. Forced S100 beta expression in neonatal rat cardiac myocyte cultures and high level expression of S100 beta in transgenic mice hearts inhibit cardiac hypertrophy and the associated phenotype by modulating protein kinase C-dependent pathways. S100 beta expression is probably a component of the myocyte response to trophic stimulation that serves as a negative feedback mechanism to limit cellular growth and the associated alterations in gene expression.

Arterial vasodilators, cardiac volume load, and cardiac hypertrophy in normotensive rats.

To assess a possible involvement of cardiac volume overload in the development of cardiac hypertrophy during chronic arterial vasodilator treatment, changes in indexes of cardiac volume load in relation to changes in cardiac anatomy were evaluated during treatment of normotensive rats with 120 mg/l hydralazine or 120 mg/l minoxidil, with drinking water. Long-term treatment with hydralazine, but not minoxidil, caused small decreases in systolic blood pressure; neither vasodilator affected heart rate with chronic treatment. Arterial vasodilator treatment for 2 wk or more resulted in increases in plasma and blood volumes by 10-20%. Both arterial vasodilators increased right atrial pressure and left ventricular end-diastolic pressure in the initial weeks of treatment. Only the minoxidil group showed a persistent increase in right atrial pressure throughout the treatment period. These hemodynamic changes were associated with increases in left ventricular (LV) internal diameter and right ventricular (RV) weight, and with minoxidil these changes were also associated with increased LV weight. LV wall thickness did not increase. Cardiac volume overload therefore indeed occurs during treatment with arterial vasodilators and may contribute to their effects on cardiac anatomy (i.e., development of RV hypertrophy and, in the case of minoxidil, also, eccentric LV hypertrophy), which are consistent with cardiac volume overload.

Differential effects of the calcium antagonist, nisoldipine, versus the arterial vasodilator, minoxidil, on ventricular anatomy, intravascular volume, and sympathetic activity in rats.

Opposite effects on cardiac volume load or sympathetic activity by calcium-antagonists versus classical arterial vasodilators may be responsible for their different effects on ventricular anatomy, [i.e., left ventricular (LV) and right ventricular (RV) weights and LV internal diameter and wall thickness.] Therefore, we evaluated the time course of changes in intravascular volume and ventricular anatomy in unanesthetized normotensive rats, following treatment for 1, 2, 14, 35, or 70 days with minoxidil (120 mg/L drinking water) or nisoldipine (0.3 and 1.0 mg/g food). Tissue-specific sympathetic activity was assessed by the norepinephrine turnover rate (NE TR) after 14 and 35 days of treatment. Minoxidil produced RV hypertrophy and eccentric LV hypertrophy (i.e., increased LV diameter with unchanged wall thickness) and increased intravascular volume. Nisoldipine did not alter LV anatomy, but the high dose produced a small, significant increase in RV weight, associated with a tendency (p less than 0.1) to increase blood volume. Minoxidil increased NE TR in the LV (after 14 and 35 days), in the RV (after 14 days), as well as in the superior mesenteric artery (after 14 and 35 days), but not in the kidney. Nisoldipine decreased cardiac NE TR, but did not affect NE TR in the other tissues, suggesting a central effect of nisoldipine. We conclude that an increase in blood volume caused by arterial vasodilators may contribute to cardiac volume overload resulting in cardiac hypertrophy. These volume and cardiac changes are largely absent during treatment with calcium-antagonists. Changes in cardiac sympathetic activity possibly modulate (i.e., potentiate or blunt) the extent of cardiac hypertrophy induced by cardiac overload.

Combined effect of neonatal sympathectomy and adrenal demedullation on blood pressure and vascular changes in spontaneously hypertensive rats.

Neonatal sympathectomy using a combined treatment with antiserum to nerve growth factor and guanethidine during the first 4 weeks after birth was carried out in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Bilateral adrenal demedullation was performed in 4-week-old sympathectomized SHR and WKY rats. The development of hypertension in SHR was prevented by sympathectomy, but the blood pressure (BP) was still higher than in age-matched WKY rats. Demedullation reduced the BP of sympathectomized SHR to the same level as that of WKY rats. Heart rates of SHR and WKY rats were not affected by the treatments. Morphometric measurements of the mesenteric arteries showed that sympathectomy significantly reduced the medial mass in the mesenteric arteries of SHR, mainly through a reduction in the number of smooth muscle cell layers. In sympathectomized SHR, demedullation increased the lumen size of muscular arteries under maximally relaxed conditions, which might explain the further reduction in BP in these animals. Demedullation in sympathectomized SHR and WKY rats caused a decrease in smooth muscle cell layers in the superior mesenteric artery, but the same treatment resulted in a slight increase in the number of smooth muscle cell layers in the large and small mesenteric arteries of SHR and WKY rats. Adventitial area was increased in some mesenteric arteries of SHR and WKY rats by sympathectomy, and demedullation caused a further increase in the size of adventitia in WKY rats. Heart weight in SHR was normalized to the level found in WKY rats by sympathectomy and demedullation. We conclude that in sympathectomized SHR, the elevated BP was maintained by the adrenal medulla.