Arterial stiffness and the autonomic nervous system during the development of Zucker diabetic fatty rats.

AIM: This study aimed to investigate the role played by sympathovagal balance in arterial stiffness, a common feature of insulin resistance and type 2 diabetes. METHODS: We investigated the relationship between autonomic nervous system activity and arterial stiffness in Zucker diabetic fatty rats (ZDF: Gmi-fa/fa) and their age-matched controls (lean: ?/fa). Using simultaneous catheterization of the proximal and distal aorta, we measured intra-arterial blood pressure (BP), heart rate (HR), their variability (spectral analysis) and aortic pulse wave velocity (PWV) in a series of at least six conscious rats aged 6, 12, 18 and 24 weeks. RESULTS: BP and PWV increased with age (P<0.001) in both strains with no differences between strains, despite the insulin resistance already present at 6 weeks in ZDF rats. HR was significantly lower (P<0.001) in ZDF than in lean rats. In ZDF compared with lean rats, the low-frequency (LF) component of the systolic BP variations and the LF/high-frequency (HF) component of the pulse interval (PI) variation ratio were reduced (P<0.01 and P<0.05, respectively), while the HF component of the PI (HF-PI) variation was raised (P<0.05). PWV was negatively correlated with HF-PI (r=-0.37, P<0.01), but not with biochemical parameters. HF-PI was an independent variable explaining the variation in PWV. CONCLUSION: During the development of disease of ZDF rats, sympathovagal balance might account for the lack of increase in PWV.

Motor and sensory nerve conduction velocities in Yucatan minipigs.

Motor and/or sensory conduction velocities are used to assess peripheral nervous system disorders. Although the miniature pig represents a model of choice for long-term pharmacological experimentation, no study has so far been reported on this model in relation to the measurement of nerve conduction velocities. We developed the present technique and applied it to 34 3-18-month-old Yucatan minipigs. Motor and sensory conduction velocities were measured using the anterior tibial nerve and the internal plantar nerve, a branch of the posterior tibial nerve, respectively. The nerve conduction velocity data of motor (MNCV) and sensory (SNCV) nerves, together with the amplitude of the sensory nerve signal, were logarithmically dependent on the age of the tested animals (r(2)=0.92, 0.81 and 0.76, respectively). The mean values of MNCV and SNCV were 70.9 +/- 1.1 and 67.9 +/- 0.2 m/s, respectively, at the age of 16 months for these miniature pigs. In order to validate this model, we compared it with other known models when the velocities reached a plateau at the end of the study. These values were found to be higher than those in humans or rats, but are comparable to those of the baboon, one of the best large animal models for human pathologies. Because the physiology and metabolism of the minipig resemble those of humans, and due to its long lifetime, this animal represents a good model for studying the development of neuropathology.

[Hemodynamic consequences of endogenous hyperinsulinism in obese rats with lesions of the ventromedial hypothalamus]. / Conséquences hémodynamiques de l'hyperinsulinisme endogène chez les rats obèses ayant des lésions de l'hypothalamus ventro-médian.

The rat with ventromedian hypothalamus lesions (VMH) is characterized by massive obesity, hyperinsulinemia, increase in parasympathetic tonus and sympathetic depression. The aim of this study was to examine in this model the hemodynamic changes and the baroreflex response and to compare the data with the evaluation of beta adrenergic sensitivity. In VMH rats and Sham operated rats hemodynamic parameters were followed until 8 weeks after operation. Heart rate (HR) and blood pressure (BP) were monitored each week during 24 hours by a telemetric system, a catheter being implanted in aorta. In VMH, HR was significantly lower by the first week (p = 0.02) and until the last measurement. Systolic BP increased progressively in the two groups but was higher in VMH only at 8 weeks (p = 0.03). Compared with Sham rats, 5 days after operation, the percentage of HR acceleration in response to atropine and isoprenaline was significantly higher in VMH, whereas HR response to sodium nitroprussiate was similar in the two groups. Plasma epinephrine and norepinephrine levels were significantly higher in VMH rats. The density of cardiac beta receptors decreased from 15 days to 3 months after operation, similarly in VMH and Sham rats. The affinity of cardiac beta receptors remained stable during the same period and very similar in VMH and Sham rats. This study suggests that in VMH rats 1. bradycardia results mainly from an increase in parasympathetic tone; 2. the increase in reflex tachycardia described in normal rats after insulin infusion needs a normal activity of the sympathetic nervous system; 3. catecholamine levels may be increased despite sympathetic depression, probably as a result of an increase in adrenomedullary secretion possibly due to endogenous hyperinsulinemia; 4. the lack of hypertension in this model including a massive obesity is likely to result from the proper vasodilatory effect of insulin.

Early detection of cardiovascular autonomic neuropathy in diabetic pigs using blood pressure and heart rate variability.

Cardiac autonomic neuropathy is a common complication in insulin dependent diabetes mellitus. Nevertheless, little is known about when this impairment occurs during the time course of the disease. Analysis of blood pressure (BP) and heart rate (HR) variability could be used to detect early signs of autonomic alteration. To test this proposal, twelve sexually mature male Yucatan miniature pigs were equipped with an arterial catheter for telemetric BP analysis, and with a venous access. BP and HR were recorded together with respiratory movements while the animals were resting in a sling. After the first recording session performed when the pigs were 5 months old, streptozotocin (STZ) was used to induce diabetes in seven pigs, while the five others were controls. BP and HR were measured 3 and 6 months after the onset of diabetes and at a similar age in the controls. BP and HR oscillated at the respiratory range (0.19 Hz). Spectral analysis showed this respiratory component was the main determinant of the short-term variability of BP and HR. Atropine increased HR and BP and markedly diminished the respiratory sinus arrhythmia. Propranolol diminished HR and the respiratory peak of HR. A reduced respiratory oscillation of BP paralleled the diminution of the respiratory peak of HR. Baroreceptor-HR reflex was estimated using injections of phenylephrine and nitroprusside, and by cross-spectral analysis between BP and HR. Atropine shifted the curve to higher HR values, while propranolol reduced the level of the upper plateau. Atropine decreased both the coherence and gain of the cross-spectral analysis. STZ injection resulted in a type 1 diabetes. At 3 months, diabetic pigs exhibited low levels of BP and a reduced overall variability of HR and BP. Spectral analysis indicated the respiratory sinus arrhythmia was markedly reduced. In addition, the sensitivity of the baroreceptor-HR reflex was reduced. At a latter stage of diabetes these alterations were marked and the level of the resting HR was increased. These data demonstrate the dual (vagal and sympathetic) control of HR in pigs and the dominant role of respiration in the genesis of HR and BP fluctuations. The spectral and cross-spectral analysis of BP and HR were altered after 3 months of diabetes and could be proposed as early detectors of cardiac autonomic neuropathy.

[Erythrocyte rheology and heart hypertrophy in diabetes mellitus]. / Rhéologie erythrocytaire et hypertrophie cardiaque au cours du diabète sucré.

Reduced red cell filtration and increased aggregation have been reported in diabetic patients. Heart enlargement is a classical complication of high blood pressure but is also frequently encountered in diabetics. The aim of this work was to explore the relationship between rheological disorders and heart enlargement in diabetics and in an animal model of genetically diabetic rats. 1. Among a series of 92 patients with insulin-dependent or non-insulin-dependent diabetes mellitus, silent myocardial ischemia was evidenced in 28. Coronarography in 24 of these patients was strictly normal in 15. In the patients with angiographically normal coronary arteries, the coronary reserve was perturbed by intracoronary injection of papaverine. The left ventricular mass was normal in 79 patients. In patients with silent myocardial ischemia and angiographically normal coronary arteries, there was a positive correlation between left ventricular mass and red cell filtration index using the Hanss hemorheometer (n = 8, r = 0.954, p = 0.001). 2. Red cell stiffness was studied sequentially from 3 to 18 months in diabetic rats Goto Kakisaki (GK). In these rats, cardiac index (heart weight/body weight) was significantly higher than that in Wistors control rats (0.27 +/- 0.02% vs. 0.17 +/- 0.01%, p < 0.001) and was significantly correlated with erythrocyte magnesium (r = 0.920, p 0.026). Overall, the cardiac index in the rats was significantly correlated with red cell filtration (r = 0.370, p = 0.044). In GK rats, heart rate was significantly slower and systolic blood pressure was slightly higher than in control rats (telemetric measures). These findings show that in diabetes mellitus, heart enlargement may be determined by factors other than hypertension or sensitivity to sympathetic stimulation and might be favored by rheological changes and/or excessive intracellular magnesium. In patients with diabetes, the reduced coronary reserve could result in left ventricular hypertrophy but also rheological changes.

CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-ethane]: a new diuretic and antihypertensive drug acting by in vivo sulfation.

CRE 10904 [2-(p-fluorophenoxy), 1-(o-hydroxyphenyl)-ethane, the leading compound of a new family of loop diuretic and antihypertensive agents: 1-aryl, 2-aryloxy-ethanes] induced high-ceiling natriuretic action in dogs and rats, but was completely inactive in pigs. High-performance liquid chromatography determinations revealed that all CRE 10904 (p.o. or i.v. administered) was rapidly sulfo-conjugated in dogs and rats, and glucurono-conjugated in pigs. The (O-sulfonyl)-CRE10904 metabolite (or simply CRE 11296) rapidly appeared in plasma, reached a concentration peak at about 40 min and disappeared with a half-life time of about 3 hr. The urinary excretion of CRE 11296 was correlated with the natriuretic activity of CRE 10904. Moreover, CRE 11296 was a powerful natriuretic compound in rats and dogs and, even in pigs, i.v. CRE 11296 induced transient natriuresis (just before its rapid hydrolysis and glucurono-conjugation). Studies in human red blood cells revealed that: 1) CRE 11296 was a potent inhibitor of the [Na+,K+,Cl-]-cotransport system (IC50 of 1.5 +/- 0.3 x 10(-5) M; mean +/- S.E.M. of 5 experiments), slightly more powerful than furosemide (IC50 of 2 x 10(-5) M), 2) it was the only diuretic drug potently inhibiting the [K+,Cl-]-cotransport system (IC50 of 2.1 +/- 0.6 x 10(-5) M; N = 3) and the [Cl/HCO3-] exchanger (IC50 of 4.5 +/- 1.0 x 10(-5) M; N = 3) and 3) CRE 10904 and its glucuronide were much less potent Cl- transport inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiarrhythmic activity of cetiedil and its analogues.

Cetiedil), originally a molecule used for treatment of some vascular diseases, exhibits several pharmacological effects. The authors studied cetiedil's stabilizing effect on the membrane and the antagonism against calcium of Cetiedil and its analogues (amino 3-thienylacetic esters). After completion of numerous pharmacological tests giving evidence of antidysrhythmic effects of the molecule and more especially in the digitalic arrhythmias and ventricular fibrillation induced by calcium (where it is more active than other products tested), the authors conclude that Cetiedil might enter in group I of Vaughan and William's classification of antiarrhythmic drugs. It is like Verapamil an inhibitor of the calcium penetration. This especially interesting antidysrhythmic profile suggests clinica research to determine the special position of Cetiedil in the treatment of heart rhythm troubles.