Terguride attenuates prolactin levels and ameliorates insulin sensitivity and insulin binding in obese spontaneously hypertensive rats

Glucose tolerance, serum insulin, insulin receptors in epididymal fat tissue, circulating total cholesterol and triglyceride concentrations as well as serum prolactin were studied in obese and lean spontaneously hypertensive rats (SHR) of both sexes. Obese animals displayed insulin resistance and elevated insulin and triglyceride concentrations. Moreover, in obese rats the increased mass of epididymal fat tissue was accompanied with decreased capacity of high affinity binding sites of insulin receptors in the tissue plasma membranes. Terguride treatment lowered prolactin serum levels which was accompanied by ameliorated insulin sensitivity in obese animals of both sexes. In addition, terguride treatment decreased serum insulin and triglyceride concentrations in obese females and at the same time enhanced the affinity of high affinity insulin binding sites. Our results show that obesity in SHR is associated with a decreased capacity of insulin receptors and that prolactin may play a role in obesity-induced insulin resistance, particularly in female rats.     

Circadian rhythm of circulating glucose,insulin and growth hormone in spontaneously hypertensive rats

Circulating levels of growth hormone (GH), insulin, and glucose were measured at hourly intervals during a 24 h period to establish the diurnal rhythm of these hormones in spontaneously hypertensive rats (SHR). There was no statistically significant correlation between circulating GH levels and pituitary GH content. Serum GH appeared to be higher at night in female SHR and higher during day-light hrs in male SHR. GH levels fluctuated considerably, whereas insulin levels showed much less diurnal variation. Although there was no statistically significant correlation between blood glucose and insulin levels, glucose levels rose and fell considerably during the 24 hr period with a definite decline in blood glucose during the nocturnal hyperactivity observed in SHR. These findings are of interest in that SHR have giant-sized islets of Langerhans, develop hyperglycemia spontaneously, and are growth-retarded compared to most normotensive strains of rat.     

Kidney adaptation in nitric oxide-deficient Wistar and spontaneously hypertensive rats

We investigated the renal structural and functional consequences of nitric oxide (NO) deficiency co-treated with angiotensin-converting enzyme inhibitor (ACEi) in 20 adult male Wistar rats and 20 spontaneously hypertensive rats (SHR). The animals were separated into eight groups (n = 5) and treated for 30 days: Control, L-NAME (NO deficient group), Enalapril, L-NAME + Enalapril. The elevated blood pressure in NO deficient rats was partially reduced by enalapril. Serum creatinine was elevated in L-NAME-SHRs and effectively treated with enalapril. The proteinuria was significantly higher only in L-NAME-SHRs, and this was reduced by treatment with ACEi. The glomerular volume density (Vv(gl)) in L-NAME rats, both Wistar and SHR, was greater than in matched control rats, and enalapril treatment effectively prevented this Vv(gl) increase. No significant differences were observed in tubular volume density, Vv(tub), or tubular surface density, Sv(tub), in all Wistar groups. The Vv(tub) was smaller in L-NAME-SHRs than in control SHRs, and this tubular alteration was not prevented by enalapril. The Sv(tub) was not different among the SHR groups. In Wistar rats no changes were seen in vascular surface density, but a greatly increased cortical vascular volume density was seen in the enalapril treated rats. The vascular length density was greatly diminished in NO deficient rats that was effectively prevented with enalapril treatment. The vascular cortical renal stereological indices are normally reduced in SHRs. Administration of enalapril, but not L-NAME, changed this tendency. However, enalapril was not totally effective in preventing vascular damage in SHR NO deficient animals.     

Effects of high-sucrose feeding on insulin resistance and hemodynamic responses to insulin in spontaneously hypertensive rats

This study was designed to investigate the effects of a sucrose diet on vascular and metabolic actions of insulin in spontaneously hypertensive rats (SHR). Male SHR were randomized to receive a sucrose or regular chow diet for 4 wk. Age-matched, chow-fed Wistar-Kyoto (WKY) rats were used as normotensive control. In a first series of experiments, the three groups of rats had pulsed Doppler flow probes and intravascular catheters implanted to determine blood pressure, heart rate, and blood flows. Insulin sensitivity was assessed during a euglycemic hyperinsulinemic clamp performed in conscious rats. In a second series of experiments, new groups of rats were used to examine glucose transport activity in isolated muscles and to determine endothelial nitric oxide synthase (eNOS) protein expression in muscles and endothelin content in vascular tissues. Sucrose feeding was shown to markedly enhance the pressor response to insulin and its hindquarter vasoconstrictor effect when compared with chow-fed SHR. A reduction in eNOS protein content in muscle, but no change in vascular endothelin-1 protein, was noted in sucrose-fed SHR when compared with WKY rats, but these changes were not different from those noted in chow-fed SHR. Similar reductions in insulin-stimulated glucose transport were observed in soleus muscles from both groups of SHR when compared with WKY rats. In extensor digitorum longus muscles, a significant reduction in insulin-stimulated glucose transport was only seen in sucrose-fed rats when compared with the other two groups. Environmental factors, that is, high intake of simple sugars, could possibly potentiate the genetic predisposition in SHR to endothelial dysfunction and insulin resistance.     

Hypertension in spontaneously hypertensive rats occurs despite low plasma levels of homocysteine

Hyperhomocysteinemia has been suggested to induce hypertension due to its role in endothelial dysfunction. However, it remains controversial whether homocysteine and hypertension are truly causally related or merely loosely associated. To test the hypothesis that hyperhomocysteinemia occurs in spontaneously hypertensive rats (SHR) we measured plasma levels of homocysteine in 10 male adult SHR and in 10 normotensive controls using ion exchange chromatography. In addition, plasma concentrations of the 22 most common amino acids were measured to explore the relation of homocysteine with amino acid metabolism. Plasma levels of homocysteine were significantly lower in SHR (4.1+/-0.1 micromol/l) than in controls (7.2+/-0.3 micromol/l) (p<0.00001). The amounts of aminobutyric acid, alanine, citrulline and valine were also decreased, whereas we found increased levels of aspartate, glutamate, glutamine, histidine and ornithine. Thus, contrary to our hypothesis, hypertension in SHR occurs despite low plasma levels of homocysteine. We provide a new hypothesis whereby reduced conversion of arginine to citrulline is related to increased ornithine levels, but decreased bioavailability of nitric oxide, resulting in impaired blood vessel relaxation and hypertension. In conclusion, our findings do not necessarily exclude that homocysteine and hypertension might be pathophysiologically connected, but corroborate the notion that hypertension can arise due to mechanisms independent of high homocysteine levels.     

Magnesium, calcium and zinc levels in plasma and erythrocytes of spontaneously hypertensive rats

Magnesium, calcium and zinc determinations were performed by flame absorption spectrophotometry and induced coupled plasma on the red blood cells (RBC) and plasma (P) of spontaneously hypertensive (SHR) and control (WKR) male rats, aged of 45 to 158 days. The blood sampling was done by cardiac puncture after ether anaesthesia. SHR rats have lower RBC and P Mg values and higher RBC Zinc values than WKR. These differences are very significant (P less than 0.002 to P less than 0.0001) among the animals aged of 96 days or more. When compared to the data of the literature, these results confirm the existence of associations between hypertension, low blood Mg and high RBC Zn values but reveal only minor changes in RBC Ca concentrations.     

Production of lysophosphatidic acid by lysophospholipase D in incubated plasma of spontaneously hypertensive rats and Wistar Kyoto rats.

Lysophosphatidic acid has been identified as a vasopressor principle in incubated mammalian plasma and sera, and shown to be generated extracellulary by lysophospholipase D-like activity. In this study, we monitored the time course of changes in the major phospholipid fractions during incubation of plasma, and found that polyunsaturated lysophosphatidic acids accumulate more rapidly than saturated lysophosphatidic acids at expense of the corresponding lysophosphatidylcholines. We compared the phospholipase activities for producing bioactive LPA in age-matched spontaneously hypertensive rats and Wistar Kyoto rats. The lysophospholipase D activity in rat plasma was found to be independent of strain and age. We suggest that lysophospholipase D functions in rat for persistent production of bioactive LPA in the circulation throughout life. However, our finding that production of LPA in spontaneously hypertensive rats was not greater than that in Wistar Kyoto rats does not seem to support the idea that increased production of LPA is involved in the pathogenesis of hypertension.     

Adrenocorticotropin and corticosterone levels in pre-weanling spontaneously hypertensive rats

Circulating plasma ACTH and corticosterone levels were measured in spontaneously hypertensive rats (SHR) and the corresponding, normotensive Wistar-Kyoto (WKY) strain at 10 and 20 days of age. In addition, stored levels of ACTH were measured in the pituitary glands of these animals. Circulating corticosterone levels were significantly lower, in both strains, at 10 days than at 20 days. Although the glucocorticoid was undetectable in WKY animals at 10 days, significant levels were observed in age-matched SHR. No difference in corticosterone concentrations was observed between the two strains at 20 days. Circulating ACTH levels did not reflect the values for circulating glucocorticoids. There were no significant differences in the levels of ACTH between strains or between age groups. Moreover, pituitary stores of ACTH between animals of different strains and ages were not found to be significantly different among any of the groups tested. These results demonstrate that there is a difference in circulating corticosterone levels between spontaneously hypertensive and Wistar-Kyoto rats at 10 days postnatally which is not evident just prior to weaning (20 days). This difference is not due to variations in stored or circulating ACTH. Indeed, ACTH levels are high at a time (10 days) when corticosterone is low - thus suggesting that the difference may reside within the responsiveness of the adrenal cortex.     

Differential sensitivity to cocaine in spontaneously hypertensive and Wistar-Kyoto rats

Physiological, pharmacological and toxicological responses to two regimens of cocaine administration were compared between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. An initial experiment examined renal excretory and hemodynamic function in response to an acute volume load in anesthetized SHR and WKY following subacute cocaine treatment (20 mg/kg, s.c., twice a day for 9 days). Anticipated renal responses to volume loading were obtained but the responses of cocaine-treated SHR and WKY did not differ from vehicle-treated rats. A second group of experiments compared responses to continuous i.v. infusions of cocaine (1.25 mg/kg.min). In freely moving animals, no differences were noted between SHR and WKY in the increases in mean blood pressure (MBP) and heart rate (HR) produced during cocaine infusion. The elapsed time-to-onset of convulsions (Tc) elicited by cocaine was similar in both strains. However, when rats were subjected to restraint during the infusion period, pressor and tachycardic responses were observed to be significantly less in WKY than in SHR or in freely moving rats of either strain. Restraint also differentially affected rectal temperature (RT) responses to cocaine. Hypothermic responses to cocaine were observed in all WKY. Both hypothermic and hyperthermic responses were observed in SHR. A significant correlation was demonstrated between the Tc and the maximal change in RT produced during cocaine infusion. Division of SHR into two arbitrary groups was made, based on the direction of cocaine-induced change in RT. A significant (p less than 0.01) shortening of the Tc was obvious in SHR (8 of 15) in whom cocaine produced a hyperthermia. These animals were designated SHRH. The mean value for Tc in those SHR which demonstrated a lowering in RT (SHRL; 7 of 15) in response to cocaine was similar to that for WKY. Moreover, the SHRH evidenced significantly greater increases in HR, but not MBP, to cocaine infusion than did SHRL. The results indicate that restraint stress causes expression of a significant heterogeneity in the RT response of SHR to cocaine. The magnitude and direction of the RT responses are negatively correlated with sensitivity to the convulsive effects of cocaine in SHR. Stress may modify toxic responses to cocaine by interactions with body temperature homeostasis.     

The dissociation between the plasma levels of aminopeptidases A and B in spontaneously hypertensive rats

We performed a longitudinal study for 20 weeks on spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKR) to determine the relationship between peptide metabolism and the age-dependent increase in blood pressure. In both SHR and WKR, the plasma level of aminopeptidase A (AP-A) clearly showed an age-dependent decrease. The plasma level of aminopeptidase B paralleled that of AP-A in WKR, but such an age-dependency was not observed in SHR, thus showing a dissociation between the two aminopeptidases. With age in both strains, the level of angiotensin-converting enzyme tended to decrease, while that of kallikrein activity tended to increase. In addition to these findings, a multivariate study testing the relationship of blood pressure to these enzyme activities, as well as to plasma levels of angiotensin I and renin activity, suggested abnormalities in the networks of proteolytic enzymes and in the peptide metabolism surrounding the renin-angiotensin system in SHR. These abnormalities may play some important roles in pathophysiological mechanisms of hypertension in SHR.     

Effects of pro-opiomelanocortin-derived peptides on plasma levels of glucagon, insulin and glucose

Pro-opiomelanocortin (POMC) is a prohormone for several peptides including corticotropin, melanocyte stimulating hormones and beta-endorphin. POMC-derived peptides have been demonstrated in many tissues, including the hypothalamus and the endocrine pancreas, which play important roles in the control of plasma levels of glucagon, insulin and glucose. This article reviews the present knowledge concerning in vitro and in vivo effects of POMC-derived peptides on glucagon, insulin and glucose levels involving several possible mechanisms: direct effects on the endocrine pancreas (including endocrine, paracrine and peptidergic regulation) and glucose production, and indirect effects involving the hypothalamus, the autonomic nervous system and the adrenal gland.     

Effects of captopril on acute phase in two-kidney Goldblatt hypertensive rats and spontaneously hypertensive rats]

Effects of continuous oral administration of captopril were investigated on acute phase in two-kidney Goldblatt hypertensive (2 KGH) rats and spontaneously hypertensive rats (SHR). Systolic blood pressure gradually rose throughout the experimental period of 7, 14, 21 and 28 days in both 2 KGH rats and SHR. These gradual increases of systolic blood pressure were reduced by administration of captopril in both rats. Plasma renin activity were markedly increased throughout the experimental period in both rats treated with captopril, and were modestly increased in 2 KGH rats. In contrast, those changes in plasma renin activity were not obvious in SHR. In 2 KGH rats, juxtaglomerular index (JGI) and juxtaglomerular cell count (JGCC) of the clipped kidneys increased whereas JGI of the opposite kidneys decreased. In contrast, those changes in JGI and JGCC were not obvius in SHR. On the other hand, JGI and JGCC of the clipped kidneys increased in 2 KGH rats treated with captopril and those of the both kidneys increased in SHR treated with captopril. These results suggested that juxtaglomerular cells were related to the development of hypertension in 2 KGH rats, but were not clear in SHR. And these results were found that captopril showed antihypertensive effects, in spite of rises in JGI and JGCC of both 2 KGH rats and SHR.     

Effects of aging on the responsiveness and sensitivity of glucose metabolism to insulin in the incubated soleus muscle isolated from Sprague-Dawley and Wistar rats.

1. The effects of aging on the sensitivity and responsiveness of glucose transport, lactate formation and glycogen synthesis to insulin were studied in the incubated stripped soleus muscle isolated from aging Sprague-Dawley and Wistar rats. 2. As Sprague-Dawley rats aged from 5 to 13 weeks, there were marked increases in the concentrations of insulin that were required for half-maximal stimulation (i.e. EC50 value, which is a measure of sensitivity) of glucose transport, lactate formation and glycogen synthesis. 3. In marked contrast, there were no alterations in sensitivities of any of these processes to insulin in soleus muscle prepared from Wistar rats aged between 6 and 12 weeks. 4. However, in soleus muscles from 85-week-old Wistar rats the rates of glycogen synthesis in response to basal, sub-maximal and maximal concentrations of insulin were markedly decreased. The insulin EC50 value of glycogen synthesis was increased 4-fold, but was unchanged for lactate formation. 5. The insulin-stimulated rates of glucose transport in soleus muscles from 5- or 85-week-old Wistar rats were not significantly different.     

Stress ulcer and open-field behavior of spontaneously hypertensive, normotensive, and Wistar rats

Spontaneously hypertensive rats (SHRs) and the normotensive Wistar/Kyoto (WKY) rat were observed, along with Wistar rats (which represent the parent strain), on various open-field behaviors. All three strains were subsequently exposed to the activity-stress (A-S) ulcerogenic procedure. SHR and Wistar rats were very active in most open-field measures as compared with WKY rats, but only SHRs were active during the A-S treatment. WKY rats were very ulcer prone and had significantly more ulcers than SHRs, which in turn had more ulcers than Wistar rats. It was anticipated that Wistar rats would resemble the WKY rats, but in most measures the Wistars resembled the SHRs. The study suggests that although WKY rats function as an appropriate control for hypertension studies, these rats may be inappropriate as controls for other physiological and behavioral studies.     

Fatty acid composition of brain hemispheres of spontaneously hypertensive rats suckled by female Wistar rats

Total lipid fatty acid composition was investigated in brain hemispheres of male Spontaneously Hypertensive Rats (SHR), compared with normotensive Wistar Kyoto rats (WKY) used as controls. Both strains were suckled by adoptive Wistar mothers, and then fed a standard diet after weaning. No difference was observed between the two hemispheres of WKY killed either at 10 or 30 days. In SHR killed at 10 days, the two hemispheres showed differences, SHR left hemispheres exhibiting greater fatty acid composition changes than those of WKY, phenomenon that toned down at 30 days. Hence, SHR pups showed a different total lipid fatty acid composition of their brain hemispheres when compared with their WKY controls, though the two strains received the same diet. Genetically programmed hypertension might be, directly or not, involved in these changes.     

Effects of dietary D-psicose on diurnal variation in plasma glucose and insulin concentrations of rats

The effects of supplemental D-psicose in the diet on diurnal variation in plasma glucose and insulin concentrations were investigated in rats. Forty-eight male Wistar rats were divided into four groups. Each group except for the control group was fed a diet of 5% D-fructose, D-psicose, or psico-rare sugar (3:1 mixture of D-fructose and D-psicose) for 8 weeks. Plasma glucose levels were lower and plasma insulin levels were higher at all times of day in the psicose and psico-rare sugar groups than in the control and fructose groups. Weight gain was significantly lower in the psicose group than in the control and fructose groups. Liver glycogen content, both before and after meals was higher in the psicose group than in the control and fructose groups. These results suggest that supplemental D-psicose can lower plasma glucose levels and reduce body fat accumulation. Hence, D-psicose might be useful in preventing postprandial hyperglycemia in diabetic patients.     

Differential size distribution of atrial dense granules in spontaneously hypertensive, Wistar-Kyoto and Wistar rats

The differential size distribution of atrial dense granules (ADGs) in spontaneously hypertensive rats (SHR) and two normotensive controls, Wistar and Wistar-Kyoto (WKY) rats, was investigated. The ADGs in SHR were smaller than those in Wistar rats. The ADGs of WKY rats were of intermediate size. It is possible that ADGs are more rapidly secreted in SHR compared with WKY and Wistar rats or that the smaller-diameter granules may contain more atriopeptinogen than the larger granules. The intermediate size of the ADGs in WKY suggests that the WKY variant is morphologically intermediate between the SHR and Wistar strains.