Neuropeptide Y prevents agonist-stimulated increases in contractility.

Neuropeptide Y has been shown to inhibit contractility in the rat heart. Although the reasons for this effect are not known, it is possible that postsynaptic adrenergic mechanisms involving neuropeptide Y may be responsible. To ascertain whether this neuromodulatory effect is possible for decreasing contractility, we investigated the effect of neuropeptide Y on agonist-stimulated contractility of the isolated rat myocardium. Receptor binding studies of purified cardiac membranes showed that incubating membrane in the presence of neuropeptide Y (10(-7) mol/L) decreased the number of alpha-/beta-adrenoceptor binding sites without affecting the affinity of these receptors. Isolated hearts perfused with phenylephrine (10(-5) to 10(-10) mol/L) or isoproterenol (10(-5) to 10(-10) mol/L) in a nonrecirculating Langendorff setup demonstrated a significant increase in contractility over control values, whereas no change in contractility was observed when the hearts were perfused with neuropeptide Y (10(-7) mol/L). However, in the presence of both agonist and neuropeptide Y the increase in contractility previously seen with agonist alone was not evident. Comparisons made with hearts taken from aortic banded rats yielded similar results. Although neuropeptide Y itself was ineffective in decreasing contractility, it prevented the agonists from stimulating contractility when perfused together. We conclude that neuropeptide Y does not directly decrease contractility but prevents agonist-stimulated increases in contractility through alpha-/beta-adrenoceptor pathways. This neuromodulatory effect of neuropeptide Y is unchanged in situations of increased sympathetic activity, such as hypertension.

Adrenoreceptor-mediated effect of neuropeptide Y decreases cardiac inotropic responses.

The effect of neuropeptide Y on the number and affinity of catecholamine receptors in the ventricular myocardium was investigated. Receptor binding studies showed that incubation of cardiac membrane in the presence of neuropeptide Y (NPY, 10(-7) M) decreased the number of alpha/beta-adrenoceptor binding sites (Bmax) without affecting the affinity (KD) of these receptors. Although not able to modulate the contractility by itself, NPY was able to decrease the positive inotropic effects of phenylephrine and isoproterenol in the isolated, perfused myocardium. Ca2+/Mg(2+)-ATPase activity, measured from the sarcolemma, sarcoplasmic reticulum and myofibrils, was unaltered whereas the activity of sarcolemmal Na+/K(+)-ATPase was decreased when NPY was included in the media. On the other hand, NPY was shown to increase the phosphoinositide-phospholipase C associated with the sarcolemma. These findings support the hypothesis that NPY modulates postsynaptic adrenergic receptors in the myocardium and can affect the adrenergic-induced, inotropic response.

Altered neuropeptide Y effects on noradrenaline levels in the paraventricular nucleus of rats following aortic constriction.

OBJECTIVE: To clarify whether central catecholamine systems are modulated by neuropeptide Y (NPY) soon after imposing an increased pressure overload on the heart. Recent evidence supports the view that the sympathetic nervous system actively participates in the development of cardiac hypertrophy. Since noradrenaline-containing neurons involved with cardiovascular regulation within the brain are known to coexist with NPY, it is possible that a functional interaction between NPY and noradrenaline exists centrally. DESIGN: The paraventricular nucleus (PVN) of aortic-banded Sprague-Dawley rats were sampled for noradrenaline levels using in vivo microdialysis and compared with samples taken from sham-operated controls. Autoradiographical localization of NPY receptors in the PVN was also carried out between animal groups. ANIMALS: Forty-eight Sprague-Dawley rats (weighing between 175 and 200 g). INTERVENTIONS: The 48 rats were randomly divided into two groups. One group underwent abdominal suprarenal aortic constriction. The control group underwent the same procedure without being banded. At 14 days postsurgery, the animals had microdialysis probes stereotaxically implanted into the PVN under anesthesia. A solution of NPY (10(-8) M) was perfused through the probe for 20 mins, and catecholamine levels were measured in the resulting perfusate. MAIN RESULTS: Extracellular noradrenaline concentrations in the PVN were found to be increased following aortic constriction compared with sham controls (P < 0.05). Infusion of NPY resulted in a reduction of noradrenaline concentration in sham animals (P < 0.05), whereas no change in noradrenaline concentration was evident in the aortic-constricted group. Autoradiography of NPY receptors in the PVN showed a significant decrease in the receptor density in aortic-constricted rats versus sham controls (P < 0.05). CONCLUSIONS: The results strongly support the view that NPY plays an important neuromodulatory role in the PVN regarding control of sympathetic output. It is suggested that cardiac hypertrophy may be precipitated secondary to changes in brain NPY levels and increased sympathetic activity.

Norepinephrine levels in paraventricular nucleus of spontaneously hypertensive rats: role of neuropeptide Y.

Recent evidence supports the view that the sympathetic system actively participates in the development of hypertension. Because norepinephrine, contained within central neurons involved in cardiovascular sympathetic regulation, is known to coexist with neuropeptide Y, it is possible that a functional interaction between neuropeptide Y and norepinephrine exists within the brain. In an effort to clarify whether or not central catecholamine systems are modulated by neuropeptide Y in hypertensive situations, the paraventricular nucleus of spontaneously hypertensive rats was exposed to neuropeptide Y (10(-9) M), and levels of norepinephrine were sampled by microdialysis. Norepinephrine levels in spontaneously hypertensive rats were significantly increased and did not change after exposure to neuropeptide Y, in sharp contrast to the decreases seen in Wistar-Kyoto controls. To ascertain whether these alterations in norepinephrine control were specific to the model used, a similar series of experiments was carried out in the paraventricular nucleus of aortic-banded rats. These studies supported the previous findings. Norepinephrine levels in aortic-banded rats were markedly elevated when compared with sham-operated controls and demonstrated no change after exposure to neuropeptide Y, whereas decreases of > 50% were seen in sham-operated controls. These results support the view that mechanisms normally involving neuropeptide Y as a neuromodulator in the paraventricular nucleus are altered in hypertensive situations. It is suggested that hypertension may precipitate changes in mechanisms involving brain neuropeptide Y and increased sympathetic activity.

Modulation of sympathetic activity by brain neuropeptide Y in cardiac hypertrophy.

Several observations now support the view that the sympathetic system actively participates in the development of cardiac hypertrophy. Since norepinephrine (NE)-containing neurons involved in cardiovascular regulation in the brain are known to coexist with neuropeptide Y (NPY), it is possible that a functional interaction between NPY and NE exists centrally. In an effort to clarify whether or not central catecholamine systems are modulated by NPY soon after imposing an increased pressure overload on the heart, male Sprague-Dawley rats underwent aortic constriction and were examined 14 days later. Rats were anesthetized and subjected to microdialysis sampling by stereotaxically implanting a probe into the caudal ventrolateral medulla (A1). Perfusate was collected after a 1-hour stabilization period, purified, and analyzed for interstitial concentrations of NE and other catecholamines using high-performance liquid chromatography with an electrochemical detector. Extracellular NE concentrations in the A1 area were found to be decreased. These results were associated with increased rate of change in the specific activity of NE (NE turnover) in heart, indicating increased sympathetic activity and an increased left ventricular weight. Also, infusion of NPY (10(-9) mol/L) by microdialysis in the A1 area resulted in the reduction of NE concentration; epinephrine and dopamine levels were also decreased. In contrast, methionine-enkephalin, another neuropeptide, had no effect on the extracellular catecholamine concentrations in the A1 area. Since neurons of the A1 group project almost exclusively to forebrain structures inhibiting sympathetic activity, it is concluded that decreases of NE and other catecholamines in afferent pathways regulating the caudal ventrolateral medulla may lead to an enhanced sympathetic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Rat embryogenesis following exposure to alcohol and nicotine.

Pregnant Sprague-Dawley rats were treated from day 9 through 12 of gestation with either ethanol (12.5% v/v in physiological saline, 0.015 ml/g, i.p.) and nicotine (16.7 mg/kg, s.c.), alone or in combination. Corresponding groups of animals received physiological saline in a similar manner and these served as controls. Embryos were recovered on gestational day 12 and were quantitatively assessed on the basis of 16 recognizable developmental endpoints (morphological scores). The head and the crown-rump lengths of the embryos were also measured. Embryos exposed to nicotine and to ethanol-nicotine were significantly affected in their development whereas those exposed to ethanol alone were spared.