Altered heart and kidney phospholipid fatty acid composition are associated with cardiac hypertrophy in hypertensive rats

Objective

We examined the association of cardiac hypertrophy or fibrosis with the phospholipid fatty acid (FA) composition of heart and kidney in hypertensive rats.

Design and methods

Eight-week-old spontaneously hypertensive rats (SHRs) (n = 8) and Wistar Kyoto rats (WKYs, n = 8) as a normotensive control, were fed ad libitum for 6 weeks with regular AIN-76 diet. Phospholipid FA compositions in the left ventricle and kidney were measured and histological analyses were performed.

Results

Compared with WKYs, SHRs had lower proportions of γ-linolenic acid, α-linolenic acid, eicosadienoic acid, eicosatrienoic acid, dihomo-γ-linoleic acid, docosadienoic acid and nervonic acid in heart, and stearic acid (SA), γ-linolenic acid, and eicosapentaenoic acid (EPA) in kidney. After adjusting for food intake, SHRs still maintained higher proportions of SA, and total saturated FAs in the heart and a lower proportion of eicosapentaenoic acid in the kidney. Additionally, compared with WKYs, SHRs showed larger cardiomyocyte diameters in the left ventricles, indicating cardiac hypertrophy and interstitial fibrosis. Cardiomyocyte diameters also positively correlated with cardiac SA (r = 0.550, p < 0.05) and negatively with kidney EPA (r = − 0.575, p < 0.05).

Conclusion

Tissue FA compositions were associated with cardiac hypertrophy in a hypertensive setting, implicating the pathogenic role of tissue FAs in hypertension and related complications.     

Diabetic cardiomyopathy

The purpose of this article was to review the clinical and experimental features of diabetic cardiomyopathy, with particular relevance to the Black population. One hundred thirty-seven studies were identified, of which 57 were selected as references for this article. Diabetes is associated with the development of cardiomyopathy, independent of coronary atherosclerosis. Pathological studies show myocardial hypertrophy and fibrosis; microvascular pathology is also present, but all of these pathological findings have an uncertain relationship to myocardial failure. Hemodynamic findings of both congestive and restrictive cardiomyopathy have been described. Noninvasive studies revealed abnormal systolic and diastolic function in many diabetic subjects, particularly in the presence of diabetic complications and/or hypertension. Experimental studies have focused on the mildly diabetic dog and the severely diabetic rat. One year of diabetes in dogs resulted in decreased left ventricular compliance and increased interstitial connective tissue. Studies in the diabetic rat showed a marked slowing of contraction and relaxation. Chronic insulin therapy reversed the changes in the rat model. Combining hypertension with diabetes in the rat resulted in increased myocardial and coronary microvascular pathology and greater changes in isolated muscle function, electrophysiology, and contractile protein biochemistry. Many hypertensive diabetic rats died spontaneously, showing signs of congestive heart failure. Diabetic cardiomyopathy is a significant cause of heart failure in diabetic subjects and occurs more frequently in those with microvascular complications and/or hypertension. Clinical studies are needed to clarify the natural history of this disorder, focusing on the benefits of tight control of hyperglycemia and treatment of associated hypertension. Experimental studies will clarify the pathophysiology and contribute to improved therapy. The high prevalence of diabetes and hypertension in Blacks makes these considerations especially relevant to this population.     

The Effect of Hypertension on Uncontrolled Hemorrhage in a Rodent Model

Patients with essential hypertension (EH) have higher mortality rates from hemorrhage. How the complex physiologic changes seen in EH affect the response to uncontrolled hemorrhage has yet to be adequately described. OBJECTIVE: To test the null hypothesis that there would be no difference in the hemorrhage volumes and hemodynamic responses to uncontrolled hemorrhage between hypertensive rats (SHRs) and normotensive rats (WKYs). METHODS: Twenty-four adult rats (12 WKYs and 12 SHRs) were anesthetized with althesin via the intra-peritoneal route. The femoral artery was cannulated by cutdown for mean arterial pressure (MAP) measurement and blood gas sampling. Twelve rats (6 WKYs and 6 SHRs) underwent uncontrolled hemorrhage by 50% tail amputation. Twelve rats (6 WKYs and 6 SHRs) served as non-hemorrhage controls. The MAP, base excess (BE), and cumulative blood loss were measured pre-hemorrhage and then every 15 minutes post-hemorrhage for 90 minutes. Data were reported as mean +/- standard error of the mean. Comparisons between control and uncontrolled hemorrhage groups were analyzed by analysis of variance (ANOVA) with repeated-measures post-hoc testing by Bonferroni. Statistical significance was defined by an alpha = 0.05. RESULTS: Mortality rates were significantly higher (p < 0.05) for the SHRs (100%) as compared with the WKYs (33%). Changes in time-averaged MAP post-hemorrhage were significantly greater (p < 0.001) in the SHR group (88 +/- 10 mm Hg) as compared with the WKY group (48 +/- 4 mm Hg). Hemorrhage volume was significantly lower (p = 0.02) in the SHR group (3.7 +/- 0.5 mL) as compared with the WKY group (6.1 +/- 0.7 mL). CONCLUSIONS: Hypertensive rats had a higher mortality rate than normotensives from a comparable vascular injury with lower hemorrhage volumes.     

Endothelial modulation of vascular relaxation to nitrovasodilators in aging and hypertension

Blood vessel responses to relaxant drugs have been reported to change with aging and with the development of hypertension. In view of the requirement of endothelial cells for the activity of many relaxant drugs, we examined the role of the endothelium in the relaxation response of vascular tissue. Aortic and mesenteric ring segments from normotensive and hypertensive rats, ages 5 to 6, 15 to 18 and 30 to 31 weeks, were examined for relaxation to sodium nitroprusside, sodium nitrite, atrial natriuretic factor and 8-bromo-cyclic GMP. Relaxation responses to the nitrovasodilators were reduced progressively with aging in ring segments of Wistar-Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) with intact endothelium; however, intact SHR ring preparations displayed less relaxation to nitrovasodilators at 15 to 18 and 30 to 31 weeks than those of WKYs. Rubbed (endothelium denuded) ring preparations displayed greatest relaxation to nitrovasodilators with no difference being observed between SHR and WKY preparations at any age tested. Relaxation to atrial natriuretic factor and 8-bromo-cyclic GMP was not different between rubbed and unrubbed ring segments or between SHRs and WKYs, indicating no detectable impairment of the overall relaxation response in the vascular smooth muscle of SHRs. These results suggest that the total functional capacity of vascular smooth muscle to relax to nitrovasodilators is not changed with aging or hypertension. However, the endothelial cells exert modulatory influences upon the vascular smooth muscle to reduce overall responsiveness to nitrovasodilators, an effect that is enhanced with aging and the development of genetic hypertension.     

Altered muscarinic receptor properties and function in the heart in diabetes

The cardiac cholinergic system was studied in streptozotocin (STZ)-diabetic and age-matched control rats. STZ-diabetic rats (8-10 weeks) were supersensitive to the negative chronotropic effects of acetylcholine, carbamylcholine and bethanechol; inotropic responses to these muscarinic agonists were unaltered. This phenomenon was associated with a decrease in acetylcholinesterase activity but no change in the rate and extent of neuronal choline uptake. [3H]N-methylscopolamine bound to muscarinic receptors in atria from both groups of rats with the same high affinity. The density of [3H]N-methylscopolamine binding sites, however, was 34% lower in atria from STZ-diabetic rats. Agonist binding affinity was lower in diabetes; carbamylcholine had a lower affinity for both the high- and low-affinity receptors. These results indicate that cardiac cholinergic supersensitivity in right atria in diabetes occurs before the development of autonomic neuropathy insofar as neuronal [3H]choline uptake is unaltered at this stage of STZ diabetes. Changes in agonist binding conformation, without a concomitant change in antagonist binding affinity, suggest that supersensitivity of right atria to muscarinic agonist may be a consequence of altered coupling of muscarinic receptor to transduction mechanisms involved in chronotropism in diabetes.     

Contractile effects of Bay k 8644, a dihydropyridine calcium agonist, on isolated femoral arteries from spontaneously hypertensive rats

Agonist actions of methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate (Bay k 8644) were investigated in femoral and mesenteric arteries from 6-week-old spontaneously hypertensive rats (SHRs), and data compared with findings in normotensive Wistar-Kyoto rats (WKYs). The addition of Bay k 8644 produced a dose-dependent contraction in SHR femoral artery with a pD2 value of 8.55. Maximum contraction induced by this agonist (1 X 10(-7) M) was comparable to the maximum developed by K+-depolarization. Bay k 8644 was much less effective in eliciting the contractile responses on WKY femoral artery. Contractile responses of mesenteric and tail arteries to Bay k 8644 were weak and were not significantly different between SHR and WKY. Thoracic aorta was sensitive to the contractile response to Bay k 8644, but the sensitivity was not significantly different between SHR and WKY. Increased responsiveness to exogenously applied K+ was also observed in SHR femoral artery as compared to WKY. Contractile responses of SHR femoral artery to Bay k 8644 were antagonized competitively by nifedipine (pA2 = 8.36), a dihydropyridine Ca++ antagonist, but noncompetitively by diltiazem, a non-dihydropyridine Ca++ antagonist. When the effect of nifedipine on the dose-response curve for Bay k 8644 was determined in WKY femoral artery, there was a similar extent of rightward displacement of the dose-response curve to that seen in SHR. Nifedipine was less efficacious in relaxing the contractile response to Bay k 8644 compared to the contractile response to K+ in SHRs femoral arteries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Type 1 diabetes-induced hyper-responsiveness to 5-hydroxytryptamine in rat pulmonary arteries via oxidative stress and induction of cyclooxygenase-2

Recent epidemiological data suggest that diabetes is a risk factor for pulmonary arterial hypertension. The aim of the present study was to analyze the link between type 1 diabetes and pulmonary arterial dysfunction in rats. Male Sprague-Dawley rats were randomly divided into a control group (saline) and a diabetic group (70 mg/kg streptozotocin). After 6 weeks, diabetic animals showed a down-regulation of the lung bone morphogenetic protein receptor type 2, up-regulation of 5-hydroxytryptamine (5-HT) 2A receptors and cyclooxygenase-2 (COX-2) proteins as measured by Western blot analysis, and increased contractile responses to 5-HT in isolated intrapulmonary arteries. The hyper-responsiveness to 5-HT was endothelium-independent and unaffected by inhibition of nitric-oxide synthase but prevented by indomethacin, the selective COX-2 inhibitor N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398), superoxide dismutase, and the NADPH oxidase inhibitor apocynin or chronic treatment with insulin. However, diabetic rats at 6 weeks did not develop elevated right ventricular pressure or pulmonary artery muscularization, whereas a longer exposure (4 months) to diabetes induced a modest, but significant, increase in right ventricular systolic pressure. In conclusion, type 1 diabetes mellitus in rats induces a number of changes in lung protein expression and pulmonary vascular reactivity characteristic of clinical and experimental pulmonary arterial hypertension but insufficient to elevate pulmonary pressure. Our results further strengthen the link between diabetes and pulmonary arterial hypertension.     

Regional differences in the responses of guinea-pig cardiac tissue to carbachol and their potentiation by hypothermia

The responses of guinea-pig isolated cardiac tissues to carbachol were examined. Tension responses of paced left atria and right ventricular papillary muscles, rate responses of spontaneously beating right atria and working hearts and contractility (+dP/dt) of paced and unpaced working hearts were obtained at 38 degrees C. Carbachol induced negative inotropic and chronotropic responses of atria, abolishing tension and rate at the maxima. The spontaneously beating heart also exhibited negative chronotropy. The papillary muscles displayed partial inhibition of tension but, in tissues from reserpine-pretreated animals, negative inotropy was absent. Similarly, no reduction of contractility of paced working hearts was obtained. It was concluded that muscarinic receptors mediating a direct inhibition of ventricular muscle are virtually absent and that the small response obtained in untreated tissue may be due either to inhibition of endogenous catecholamine release via presynaptic receptors or to antagonism of released norepinephrine. Lowering the temperature to 30 or 25 degrees C affected resting tension, rate and contractility and the magnitude of carbachol responses. The concentration-response curves, when plotted as a percentage of the maximum, were displaced to the left by cooling of the atria and papillary muscles. The papillary muscles now exhibited a response after reserpine pretreatment. In working hearts, the concentration-response curves for the fall in spontaneous rate were also shifted to the left, but this was not significant, probably because the temperature could be reduced to only 30 degrees C, below which contractions ceased. Cooling of guinea-pig isolated cardiac preparations therefore induced supersensitivity to the muscarinic effects of carbachol.     

超声心动图对早期糖尿病心肌病探讨的实验研究

目的探讨超声心动图对早期糖尿病心肌病变诊断的价值。方法19只Wistar雄性大鼠分为对照组7只,糖尿病组12只,于糖尿病组大鼠模型建立第8周末检测两组大鼠心脏M型、彩色及频谱多普勒超声指标,观察糖尿病心肌病的早期心脏结构及功能改变,并取大鼠心肌进行病理检查。结果与对照组比较,糖尿病组大鼠心率增快,左室收缩末期容积、左室质量增加,E峰减速时间缩短,肺静脉血流反流速度增高,二尖瓣环舒张早期组织运动速度／舒张晚期组织运动速度减小,舒张早期左室内血流传播速度减慢,左室射血分数、短轴缩短率减低,差异均有统计学意义（P〈0．05）。结论超声心动图检查能反映早期糖尿病变心肌病心脏结构和功能的变化,可以作为检测早期糖尿病心肌病变的主要辅助检查。     

NG-monomethyl-L-arginine-induced pressor response at developmental and established stages in spontaneously hypertensive rats

The effect of nitric oxide (NO) pathway inhibitor, NG-monomethyl-L- arginine (L-NMMA), on arterial blood pressure was examined in spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs) to investigate whether the vasodilating effect of basal levels of NO, one of the endothelium-derived relaxing factors, is preserved during the development of hypertension. L-NMMA (1-100 mg/kg i.v.) produced dose-dependent increase in arterial pressure and bradycardia in anesthetized and conscious SHRs and WKYs. L-Arginine, a precursor of NO, inhibited the pressor response to L-NMMA. The L-NMMA-induced increases in arterial pressure in both 5- to 6- and 12- to 13-week (wk)-old anesthetized SHRs were similar to those of age-matched WKY controls; rather, the increase was significantly larger in 53- to 54-wk-old SHRs than in the age-matched WKYs. In conscious SHRs (13-14 wk-old), L-NMMA induced larger hypertensive effect than in the age-matched WKYs. The amplitude of acetylcholine (ACh)-induced hypotension was somewhat larger in 5- to 6- and 12- to 13-wk-old anesthetized SHRs compared with the age-matched WKY controls. The duration of the hypotension in 5- to 6- and 12- to 13-wk-old anesthetized SHRs was similar to the age-matched WKY controls. L-NMMA significantly reduced the duration of the ACh-induced hypotension; an effect which was recovered by L-arginine. However, L-NMMA did not decrease the amplitude of the hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac peroxisome-proliferator-activated receptor expression in hypertension co-existing with diabetes

Hypertension and DM (diabetes mellitus) are common chronic disorders that often co-exist. DM and PPAR (peroxisome-proliferator-activated receptor)-γ agonists may directly impair heart function. However, the effects of DM and PPAR-γ agonists on hypertensive myocardium are not known. Hence the aim of the present study was to investigate whether DM and a PPAR-γ agonist [RGZ (rosiglitazone)] modulated the effects of hypertension on myocardial expression of PPAR isoforms. Cardiac PPAR isoforms, TNF (tumour necrosis factor)-α and IL (interleukin)-6 were evaluated by real-time PCR and Western blotting in SHRs (spontaneously hypertensive rats), diabetic SHRs, diabetic SHRs treated with RGZ (5?mg/kg of body weight) and control WKY (Wistar-Kyoto) rats. Cardiac NADPH oxidase activity was quantified using a SOD (superoxide dismutase)-sensitive cytochrome c reduction assay. When compared with hearts from control WKY rats, hearts from SHRs had decreased PPAR-α and PPAR-δ mRNA and protein levels (39 and 44% respectively for PPAR-α, and 37 and 42% respectively for PPAR-δ), but had increased PPAR-γ mRNA and protein levels (1.9- and 1.4-fold respectively). The hypertension-induced changes in mRNA and protein of cardiac PPAR isoforms were enhanced in diabetic SHRs, which were attenuated in diabetic SHRs treated with RGZ. Cardiac TNF-α and IL-6 protein levels and NADPH oxidase activities were increased in SHRs and were increased further in diabetic SHRs. RGZ treatment decreased TNF-α and IL-6 protein levels and NADPH oxidase activities in hearts from diabetic SHRs. In conclusion, these findings suggest that DM and the PPAR-γ agonist modulated the hypertensive effects on cardiac PPAR isoform expression.     

Cardiac oxidative stress is elevated at the onset of dilated cardiomyopathy in streptozotocin-diabetic rats

The association between nitric oxide synthase (eNOS and iNOS) status, oxidative stress, and cardiac function was evaluated in streptozotocin (STZ)-diabetic rats to understand the etiology of diabetic cardiomyopathy. Cardiac function was determined by echocardiography. eNOS and iNOS status and superoxide production were assessed by immunohistochemistry and chemiluminescence, respectively. In STZ-diabetic rats, stroke volume, cardiac output, and left ventricular ejection fraction were significantly lower than in controls (CT, P < .05), whereas left ventricular end-systolic volume was higher. Cardiac NOS activity increased from 161 +/- 18 cpm/mg tissue in CT rats to 286 +/- 20 cpm/mg tissue (P < .001) in STZ-diabetic rats. Furthermore, superoxide production and cardiac eNOS and iNOS levels were higher in STZ-diabetic rats than in CT rats (P < .05). An increased activation of cardiac eNOS and iNOS is observed concomitantly with decreased cardiac function. Thus, increased oxidative stress in the heart may be implicated in the development of dilated cardiomyopathy in STZ-diabetic rats.     

Whether phenylephrine exerts inotropic effects through α- or β-adrenoceptors depends upon the relative receptor populations

Phenylephrine produced concentration-related positive inotropic responses in isolated left atria and papillary muscles of guinea-pigs and rats. In rat tissues, these responses were unaffected by propranolol but antagonized by prazosin and therefore mediated via alpha 1-adrenoceptors. The alpha 1-adrenoceptor agonist methoxamine also exerted positive inotropic effects in these rat tissues. The maximum alpha-adrenoceptor-mediated effect of methoxamine (relative to the isoprenaline maximum) was greater than that of phenylephrine in left atria (in the presence of propranolol), whereas in papillary muscles phenylephrine exerted the greater maximum. In guinea-pig papillary muscles, the response to phenylephrine was unaffected by prazosin but was antagonized by propranolol and therefore caused by stimulation of beta-adrenoceptors. Methoxamine had no effect in guinea-pig papillary muscles. Guinea-pig left atria produced biphasic concentration-response curves for phenylephrine, the lower portion being antagonized by phentolamine and was therefore alpha-adrenoceptor-mediated, while the upper portion was antagonized by propranolol and therefore beta-adrenoceptor-mediated. Methoxamine exerted a small inotropic response, the maximum of which was similar to that of the first component of the phenylephrine response. Phenylephrine was a partial agonist for the cardiac beta-adrenoceptor. The density of rat ventricular alpha-adrenoceptors was 4 times greater than beta-adrenoceptor density, as measured by [3H]-prazosin and [3H]-dihydroalprenolol binding. This explains why the responses of rat papillary muscles were alpha-adrenoceptor-mediated. In contrast, the density of beta-adrenoceptor binding sites in guinea-pig ventricles was 6 times greater than the alpha-adrenoceptor density. This explains why the phenylephrine responses were beta-adrenoceptor-mediated in guinea-pig papillary muscles. In the left atria of guinea-pigs, which displayed both alpha- and beta-adrenoceptor-mediated responses, the densities of alpha- and beta-adrenoceptor binding sites were similar. Thus, phenylephrine exerts positive inotropic effects through alpha- or beta-adrenoceptors depending upon their relative densities.     

组织多普勒评价2型糖尿病患者左、右心室功能

目的 评价2型糖尿病患者左、右心室的收缩和舒张功能,为糖尿病性心肌病的早期预防和诊断提供可靠依据.方法 通过彩色和组织多普勒对50例2型糖尿病患者和30名正常受试者左、右心室的收缩和舒张功能进行研究.利用相关分析检验左、右室功能之间可能存在的相关性.结果 2型糖尿病患者的左、右心室舒张功能受损,但左、右心室整体收缩功能保留;左心室和右心室功能的参数之间存在显著相关性.结论 2型糖尿病患者在出现心肌收缩功能异常前已有左、右心室舒张功能的损害,这些功能的改变可能与心室的相互依赖和糖尿病对心脏功能的等同作用有关.     

组织多普勒成像评价2型糖尿病患者左心室纵向收缩功能

目的 探讨组织多普勒成像技术(TDI)对评价2型糖尿病患者左心室纵向收缩功能改变的临床应用价值.方法 对42例2型糖尿病患者和25名健康志愿者行组织多普勒超声心动图检查,测量左心室各室壁基底段、中间段、心尖段共18个节段的心肌收缩期峰值运动速度(Sm)、位移值(Dm)及应变率(SRs).结果 两组糖尿病患者心肌收缩期最大位移和峰值应变率均较正常对照组有明显减低(P<0.01);合并高血压组左心室壁中间段心肌收缩期峰值运动速度也较对照组明显减低(P<0.05).结论 TDI技术为糖尿病心脏病变左心室收缩功能的早期检测提供了一种无创方法,局部心肌收缩期最大位移及峰值应变率能够成为检测糖尿病患者左心室收缩功能变化较敏感指标.     

Ultrastructural changes of human cardiac atrial nerve endings in diabetes mellitus

BACKGROUND: Autonomic neuropathy resulting from long-term diabetes mellitus may affect heart innervation. However, so far diabetes induced morphological changes of cardiac nerves are not well-known. In this study human cardiac atrial tissue from diabetic patients was analysed by electron microscopy for structural alterations as a result of diabetic neuropathy. METHODS: In coronary bypass surgery, an edge of the right auricle was routinely resected for reason of extracorporal circulation. Thin cardiac tissue sections of 100 nm were studied by electron microscopy. Atrial tissue samples were collected from 5 patients with long-standing diabetes (for at least 8 years) and compared to atrial tissue samples from 5 patients without diabetes, equally undergoing coronary bypass surgery. RESULTS: In all atria-free nerve endings with unmyelinized, axons were observed. Cross sections of 479 axons from diabetic patients were compared to 419 axons of nondiabetic patients. The number of altered axons was significantly higher in cardiac tissue of diabetic patients (32%) in comparison to normal subjects (17%). In diabetic patients, 20% of the intra-axonal mitochondria were condensed or hydropic, whereas in nondiabetic patients only 4% of the mitochondria were altered. Membrane fragments were present in 21% of the axons in atria of diabetic patients compared to 10% in nondiabetic subjects. Only in cardiac axons from diabetic patients there were lamellar bodies, dissolved axoplasma and junctions between neighbouring axons in a minor number. Few vacuoles were present in axons of both groups. CONCLUSION: In myocardial atrial-free nerve fibre bundles of diabetic patients, the amount of degenerative changes was higher in comparison to atrial cardiac tissue from nondiabetic subjects. These morphological alterations may indicate manifestation of diabetic neuropathy and might contribute to the impairment of autonomic neural control affecting the heart in long-standing diabetes mellitus.     

Altered responsiveness to sympathetic nerve stimulation and agonists of isolated left atria of diabetic rats: no evidence for involvement of hypothyroidism

To clarify the role of hypothyroidism in diabetes-induced sympathetic neuropathy, we examined the responsiveness to sympathetic nerve stimulation and to agonists of the left atria of streptozotocin-induced diabetic rats, and compared it with those in hypothyroid, thyroxine(T4)-treated diabetic or T4-treated hypothyroid rats. Positive inotropic response of isolated left atria to transmural nerve stimulation (TNS) was examined in the presence of atropine. In diabetic rats, plasma triiodothyronine and T4 levels decreased markedly. The responses to TNS and norepinephrine (NE) also decreased. The decrease was greater in response to TNS, which may be due to the reduction of presynaptic NE release. As to the postsynaptic response, the maximal response to NE decreased without any significant change in ED50 value, and a similar decrease in the maximal response to Ca++ was also observed in spite of a slight decrease in the beta receptor density. Therefore, in diabetic rats the decreased response to TNS may result mainly from a decreased NE release from nerve endings and a decreased contractility beyond the adrenoceptor level. In hypothyroid rats, the response to TNS and NE decreased, and the decrease was again greater in response to TNS. The decrease in the NE response was due to the increased ED50 value without any change in the maximal response. Similarly, the maximal response to Ca++ did not change. Thus in the hypothyroid rats, the decreased response to TNS probably results from a decreased NE release from nerve endings as well as a decreased sensitivity to NE.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of contractile function through neuropeptide Y receptors during development of cardiomyocyte hypertrophy

Severity of left ventricular hypertrophy (LVH) correlates with elevated plasma levels of neuropeptide Y (NPY) in hypertension. NPY elicits positive and negative contractile effects in cardiomyocytes through Y(1) and Y(2) receptors, respectively. This study tested the hypothesis that NPY receptor-mediated contraction is altered during progression of LVH. Ventricular cardiomyocytes were isolated from spontaneously hypertensive rats (SHRs) pre-LVH (12 weeks), during development (16 weeks), and at established LVH (20 weeks) and age-matched normotensive Wistar Kyoto (WKY) rats. Electrically stimulated (60 V, 0.5 Hz) cell shortening was measured using edge detection and receptor expression determined at mRNA and protein level. The NPY and Y(1) receptor-selective agonist, Leu(31)Pro(34)NPY, stimulated increases in contractile amplitude, which were abolished by the Y(1) receptor-selective antagonist, BIBP3226 [R-N(2)-(diphenyl-acetyl)-N-(4-hydroxyphenyl)methyl-argininamide)], confirming Y(1) receptor involvement. Potencies of both agonists were enhanced in SHR cardiomyocytes at 20 weeks (2300- and 380-fold versus controls). Maximal responses were not attenuated. BIBP3226 unmasked a negative contraction effect of NPY, elicited over the concentration range (10(-12) to 3 x 10(-9) M) in which NPY and PYY(3-36) attenuated the positive contraction effects of isoproterenol, the potencies of which were increased in cardiomyocytes from SHRs at 20 weeks (175- and 145-fold versus controls); maximal responses were not altered. Expression of NPY-Y(1) and NPY-Y(2) receptor mRNAs was decreased (55 and 69%) in left ventricular cardiomyocytes from 20-week-old SHRs versus age-matched WKY rats; parallel decreases (32 and 80%) were observed at protein level. Enhancement of NPY potency, producing (opposing) contractile effects on cardiomyocytes together with unchanged maximal response despite reduced receptor number, enables NPY to contribute to regulating cardiac performance during compensatory LVH.     

Evidence for enhanced inhibitory modulation by cyclooxygenase products of noradrenergic neurotransmission in the mesenteric vasculature of young spontaneously hypertensive rats.

The effects of cyclooxygenase inhibition by indomethacin and meclofenamate on pre- and postjunctional aspects of noradrenergic neurotransmission were determined in mesenteric vascular preparations from 4- to 6-week-old spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats (WKYs). Perfusion pressure responses to periarterial nerve stimulation and to exogenous norepinephrine (NE) were significantly greater in SHR than in WKY preparations, whereas fractional NE overflow was equivalent between the two strains. Indomethacin and meclofenamate enhanced perfusion pressure responses to periarterial nerve stimulation in both strains. Fractional NE overflow was significantly enhanced by indomethacin but only at 14 Hz in SHR preparations, whereas it was unaffected in WKY preparations. The combination of indomethacin and cocaine resulted in a significant enhancement of perfusion pressure responses to periarterial nerve stimulation in both strains that was significantly greater than that produced by either drug alone. This effect was significantly greater in SHR than in WKY preparations. This combination also resulted in a significant enhancement of responses to exogenous NE in both strains. Fractional NE overflow was significantly increased in SHR preparations in the presence of the combination of cocaine and indomethacin, whereas it remained unaltered in WKY preparations. These findings suggest that a cyclooxygenase product exerts both pre- and postjunctional inhibitory effects on vascular noradrenergic neurotransmission that differ in these two strains of rats. The prejunctional inhibitory effect of this cyclooxygenase product was observed only in SHR preparations and was especially evident in the presence of cocaine.