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The effects of substance P (SP) and the naturally occurring met-enkephalin and the synthetic mu-specific opioid agonist, DAGO (Tyr-D-Ala-Gly-N-Methy-Phe-Gly-ol) and the delta-specific opioid agonist DADL (Tyr-D-Ala-Gly-Phe-D-Leu) on basal ventilation were investigated in halothane-anaesthetized rats. Local injections of SP (0.75-1.5 nmol) in the ventrolateral medulla oblongata (VLM), e.g. nucleus paragigantocellularis, and nucleus reticularis lateralis increased ventilation because of an elevation of tidal volume. Met-enkephalin induced a short-lasting ventilatory depression mainly because of a depression of tidal volume. Activation of delta- and mu-opioid receptors in the VLM by local application of DADL and DAGO, respectively, induced ventilatory depression, which was later in onset and more long-lasting. Local administration of met-enkephalin into the VLM also produced a long-lasting inhibition of the SP-induced ventilatory excitation. A similar blockade of the SP-induced excitatory ventilatory response could be elicited by DADL but not by DAGO. This antagonistic effect was attenuated by local application of the delta-opioid receptor antagonist ICI 154. 129. We conclude that the naturally occurring met-enkephalin as well as synthetic mu- and delta-specific enkephalin analogues (DAGO and DADL, respectively) in VLM depress basal ventilation by an effect on inspiratory drive. There is a functional antagonism between activation of delta-opioid receptors and SP receptors into the VLM in respect to respiratory regulation.

Atrial natriuretic peptide (ANP) was measured in plasma during acute volume load in conscious, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. During basal conditions immunoreactive ANP were similar in the SHR (630 +/- 56 pmoles l-1) and the WKY (657 +/- 114 pmoles l-1) groups. An acute 10% and 20% whole blood volume expansion resulted in a linear increase in immunoreactive plasma ANP in the WKY. In the SHR the increase in plasma ANP was attenuated during the 20% volume load. During the 10% and 20% volume load central venous pressure (CVP), central blood volume (CBV) and cardiac output increased relatively more in the SHR compared with the WKY group. In contrast, the increase in peripheral blood volume (PBV) and decrease in heart rate (HR) was attenuated in the SH rats. In the SHR group there was a shift of the ANP vs. CVP and ANP vs. CBV curves to the right compared with the WKY. We conclude that acute volume loading is a potent stimulus for ANP release in WKY as well as SHR. However, in the SHR, ANP release was blunted in spite of the increased centralization of the volume load in this rat strain. Thus, the decreased responsiveness of the ANP hormonal system may contribute to the development and maintenance of hypertension in this genetic form of hypertension.

Thyrotropin-releasing hormone (TRH) has previously been found to have a potent respiratory stimulant effect following intracerebroventricular administration. One part of the respiratory response, the shortening of inspiratory time, seems to be elicited from the raphe obscurus in the medulla. The prominent tachypnoea however is not elicited after local injections in the medullary region. In the present paper a micro-injection technique was employed to study respiratory actions of TRH in lightly anaesthetized rats kept in a whole body plethysmograph. Thyrotropin-releasing hormone in a dose of 100 ng per 0.5 microliter was found to induce an immediate tachypnoea after injections into the region of the interpeduncular nucleus of the midbrain. No effects on systemic circulation were seen. More rostral or dorsal sites of injection were without effect. The localization of the sites responsible for respiratory stimulation corresponds to the reticular activating system where electrical stimulation induces hyperventilation in cats. The tachypnoea might be closely related to the well known arousal effects of TRH.

The diuretic and natriuretic effects of r-alpha-ANP (99-126) were investigated in rats with chronic ischaemic heart failure (IHF) produced by left coronary artery ligation. The plasma concentration of immunoreactive ANP (IrANP) was significantly higher, 91.8 +/- 16.0 pm in the IHF rats compared to 31.0 +/- 4.9 pm in sham-operated controls. In the control rats, ANP infusion (0.25-1.0 micrograms kg 1 mm 1) increased urine flow rate (V) and urinary sodium (UNa V) excretion. At the highest dose level, both V and UNa V were increased approximately fivefold. The diuresis and natriuresis seen in the control group after the infusion of ANP were blunted in the IHF rats. A bilateral surgical renal denervation in the IHF rats did not alter the renal dopamine levels, but induced a significant decrease in renal noradrenaline content, and almost completely restored the renal responsiveness to the ANP infusions. We conclude that renal denervation reversed the blunted renal excretory response to ANP in IHF rats. Thus, in experimental IHF, there seems to be a functional antagonism between efferent renal sympathetic nerve activity and ANP.

Central haemodynamic parameters and cardiac performance were measured in conscious spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) control rats after a 10-min infusion of rat ANP (103-125), 1 micrograms kg-1 min-1. Mean Arterial blood pressure (MAP) decreased by approximately 10% in both groups of rats. Heart rate (HR) increased slightly in both strains during the infusion. In the normotensive group the fall in MAP was due to a reduction in cardiac output (CO) while in the SHR there was a decrease in CO as well as in total peripheral resistance (TPR). The ANP infusion also reduced central blood volume (CBV) and stroke volume (SV) in both groups of rats. The reduction in CBV and CO was significantly more pronounced in the WKY strain. Left ventricular end diastolic pressure (LVEDP) and cardiac contractility (dP/dt) did not change while central venous pressure (CVP) was slightly decreased in the WKY group as a result of the ANP infusion. We conclude that ANP reduces MAP in normotensive animals by a reduction in CO. In the SHR a reduction in TPR also contributes to the fall in MAP. Atrial natriuretic peptide did not exert any negative inotropic effects, but the reduction of CO was due to an increased venous compliance.

The effects of various adrenergic agonists and antagonists on the diuretic/natriuretic effects of rANP (103-125) were investigated in conscious and anaesthetized normotensive rats. Pharmacological sympathetic inhibition by reserpine completely inhibited the diuretic/natriuretic effects of ANP. However, surgical renal nerve denervation did not influence the renal response to ANP. Further studies using various pharmacological agents which interfere with adrenergic activity revealed that the diuretic mechanism of action differed between conscious and anaesthetized animals. In the anaesthetized group only, dopamine (D1) blockade reduced ANP-induced diuresis. In the conscious as well as anaesthetized rats, however, pre-synaptic dopamine (D2) stimulation and alpha 2-adrenergic receptor blockade effectively inhibited the renal response to ANP. The results of this study are compatible with the notion that ANP acts indirectly within the kidney via interaction with dopamine-containing neuronal or non-neuronal structures in the kidney.

Respiratory activity was studied in rats during light halothane anesthesia. Thyrotropin releasing hormone (TRH) and two TRH analogues: the desamidated form (TRH-OH) and gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate (DN 1417) were administered intracerebroventricularly. TRH 0.5-5 micrograms induced a marked tachypnoea with a rapid onset and a duration of at least 20 min. DN 1417, a potent analogue of TRH with a very low TSH (thyroid stimulating hormone) releasing activity was more effective in stimulating respiratory frequency, while TRH-OH, regarded to have neither TSH releasing nor extra hypothalamic effects, at equimolar doses was unable to induce any changes in the respiratory pattern. When TRH was given into the fourth ventricle the dose response curve was slightly shifted to the left. In experiments employing the occluded breath technique, P0.1 was increased in the same magnitude as the mean inspiratory flow (VT/T1). The results also indicated an increase in the gain of the inflation reflex loop whereas the central bulbopontine setting for T1 and TTOT were not significantly changed. Local injection of TRH into the nucleus tractus solitarii induced a stimulation of respiratory frequency which was slower in onset compared to the response seen after injection into the lateral or fourth ventricles. Concomitantly to the respiratory changes, i.c.v. TRH injection induced a hypocarbia and an alkalosis. No changes in blood pressure or heart rate were seen. The respiratory stimulant effect of TRH could be potentiated by pretreatment with naloxone, methylatropine or a low dose of GABA. Haloperidol or propranolol did not significantly change the respiratory effects of TRH, while reserpine pretreatment seemed to blunt some of the ventilatory effects of TRH. It seems likely that TRH has few direct effects on brain stem neurones involved in the central regulation of respiration, but the main effects seem to be elicited in areas rostral to the brain stem. The respiratory stimulating effect of TRH is unrelated to TSH. Furthermore, other neurotransmitter systems might also be involved in modulation of the respiratory stimulation evoked by TRH.

Plasma concentrations of immunoreactive atrial natriuretic peptide (ANP) was measured in spontaneously hypertensive rats (SHR) during chronic salt loading (1.5% NaCl in drinking water). During the 3-week experimental period mean arterial blood pressure, heart rate, urinary sodium excretion and body weight was assessed in salt-loaded as well as in control rats. The sodium excretion was more than 10-fold increased in the rats on the high salt diet. The plasma ANP concentration was significantly increased only 24 h after the start of the high salt intake. Thereafter plasma ANP concentrations were not significantly different from values obtained in control rats. The blood pressure was significantly increased after 3 weeks on the high salt diet. At the end of the 3-week experimental period the rats were subjected to a 10 and 20% acute volume expansion with homologous whole blood. During this intervention the increase in plasma ANP concentrations was blunted in the high salt rats compared to the control group. It is concluded that during chronic salt loading in SHR there is an initial rise in plasma ANP levels and that other hormonal and neuronal systems are more important in the long term maintenance of fluid and electrolyte balance.

Rat portal veins were incubated with 3 different concentrations of 3H-l-noradrenaline (3H-l-NA) and the radioactive material retained in the tissue as well as that present in the postincubation medium was analyzed after a postincubation period in substrate-free medium. Inhibition of the neuronal amine uptake mechanism (by preincubation with LU 3-010) reduced the retention of radioactivity in the tissue more at low than at high substrate concentrations. At increasing substrate concentrations the relative role of the extraneuronal amine uptake was increased. Corticosterone and hydrocortisone reduced extraneuronal accumulation whereas betamethasone and methylprednisolone in the concentrations used were ineffective, indicating that the inhibition of extraneuronal uptake by the corticosteroids is unrelated to their glucocorticoid potency. When the composition of the retained radioactivity was analyzed, NA was found to be the major component of the retained radioactivity after inhibition of extraneuronal uptake, whereas tritiated catabolites were found to be the predominating constituent of the retained radioactivity after neuronal uptake inhibition. The possible role of inactivation of the adrenergic transmitter by the extraneuronal uptake mechanism in different situations is discussed.