Marie L. Steenberg

Effects of several tricyclic antidepressants on the hemodynamics and myocardial contractility of the anesthetized dogs

Cardiovascular effects of several imipramine analogs were investigated in the anesthetized mongrel dogs. Significant reduction in the cardiac output produced by lower doses (2.5 mg/kg, i.v.) of imipramine and 2-OH-DMI was not due to a depression of myocardial contractility. In contrast, 2-OH-imipramine (1.25 mg/kg) and DMI (2.5 mg/kg) significantly reduced contractility within 10 min after i.v. administration; however, significant decrease in the cardiac output did not occur until after 60 min. Higher doses (5 mg/kg) of imipramine, DMI and 2-OH-DMI significantly attenuated cardiac rate, contractility and output within 5 min after i.v. administration. 2-OH-imipramine, 2.5 mg/kg, i.v., depressed contractility and cardiac output to a degree equivalent to that produced by 5 mg/kg of imipramine, DMI and 2-OH-DMI. 3-Chloro-imipramine (5 mg/kg, i.v.) induced decrease in the cardiac output was essentially due to a significant reduction in the heart rate since the effects of this compound on the contractility were transient in nature. 3-Cl-8-OH-metabolite of this compound had no significant effects on the cardiovascular system. The results of this investigation demonstrated that the complex cardiovascular effects of tricyclic antidepressants observed in these studies were perhaps due to a direct and/or autonomically mediated effects on the heart and vasculature. Further, the data support the conclusions that the activity of the parent compounds together with that of the metabolites contributes to overall changes observed. While all the agents are capable of reducing cardiac output, 2-OH-metabolite of imipramine appears to be most toxic on the myocardium and 3-Cl-imipramine possessed only transient effects on the contractile properties.

Effect of epinephrine on norepinephrine release from rat kidney during sympathetic nerve stimulation

Experiments were performed to study presynaptic beta-adrenoceptor facilitation of sympathetic neurotransmitter release in the isolated perfused rat kidney and evaluate the effect of epinephrine on norepinephrine release during sympathetic nerve stimulation. The right kidney was isolated and perfused with Krebs-Ringer solution. Norepinephrine storage sites were labelled with [3H]norepinephrine. Increasing concentrations of isoproterenol and salbutamol when perfused through the kidney, caused an enhancement of the stimulus-induced release of [3H]norepinephrine at 0.5 and 2 Hz, with the maximum facilitatory effect being observed at 0.5 Hz. The effect of salbutamol on [3H]norepinephrine release was concentration-dependent and more pronounced than that of isoproterenol. While propranolol (10(-9)-10(-5)M) by itself did not cause any significant changes in the stimulus-induced release of [3H]norepinephrine, it antagonized the facilitatory action of salbutamol on [3H]norepinephrine release during periarterial nerve stimulation. When epinephrine (10(-10)-10(-7)M), was perfused through the kidney in the presence of cocaine, it caused a concentration-dependent inhibition of the stimulus-induced release of [3H]norepinephrine release elicited during periarterial nerve stimulation. However, when epinephrine was perfused in the presence of cocaine, phentolamine and corticosterone it caused a slight but significant increase in the stimulus-induced release of [3H]norepinephrine; the highest concentration (10(-7)M) still caused a decrease in the [3H]norepinephrine release. These results, while providing evidence for the existence of presynaptic facilitatory beta-adrenoceptors on renal sympathetic nerves, fail to support the hypothesis that these receptors have a physiological role in the regulation of sympathetic neurotransmitter release.

Presynaptic inhibition of sympathetic neurotransmision by adenosine in the rat kidney

The effect of adenosine on responses to sympathetic nerve stimulation was studied in the isolated perfused rat kidney. Adenosine at 1, 3 and 10 micrograms/ml caused significant impairment of renal sympathetic neurotransmission as evidenced in a dose-dependent reduction in the vasoconstrictor responses elicited by periarterial nerve stimulation at 2, 4 and 8 Hz. Vasoconstriction to exogenous norepinephrine was unaffected by adenosine except at 10 micrograms/ml where there was a slight reduction in response to norepinephrine. Theophylline, an adenosine receptor antagonist, inhibited the above action of adenosine at the frequencies of 2 and 4 Hz. At 2 Hz, 10 microM theophylline completely blocked the effect of 1 and 3 micrograms/ml adenosine and reduced by 50% the inhibitory action of 10 micrograms/ml. Higher concentration of theophylline (50 microM) was required to antagonize the action of adenosine at 4 Hz. These results indicate that adenosine can inhibit sympathetic neurotransmission in the rat kidney through a presynaptic purinergic mechanism. The physiological and pharmacological significance of this presynaptic action of adenosine is discussed.

Increased norepinephrine release during sympathetic nerve stimulation and its inhibition by adenosine in the isolated perfused kidney of spontaneously hypertensive rats

The present study was performed to measure norepinephrine release during sympathetic nerve stimulation and determine the inhibitory action of adenosine on stimulus-induced release of norepinephrine in the isolated perfused kidney of WKY and SHR. Norepinephrine release during periarterial nerve stimulation was measured as total 3H-overflow since greater than 75% of total 3H-overflow was 3H-norepinephrine in both the WKY and SHR. A significantly greater increase in 3H-norepinephrine overflow was observed during periarterial nerve stimulation in SHR in comparison with WKY. Adenosine (0.3, 1.0, 3.0 and 10.0 micrograms/ml) produced dose-dependent inhibition of 3H-norepinephrine overflow elicited by periarterial nerve stimulation. However, the effect of adenosine on transmitter release was more pronounced in the SHR in that the threshold dose required to cause inhibition of stimulus-induced release of 3H-norepinephrine was smaller in the SHR. These results demonstrate that while norepinephrine release during sympathetic nerve stimulation is greater in the SHR, this finding can not be explained on the basis of a decrease in the presynaptic inhibitory action of adenosine. Therefore, the mechanism responsible for the increased release of norepinephrine in the SHR remains to be determined.

Influence of Felodipine and Verapamil on the Sympathetic Transmitter Release and on the Pre- and Post-Junctional Effects of Exogenous Noradrenaline in the Perfused Rat Kidney

SummaryThe effects of various concentrations (0.01 to 10 µmol/L) of felodipine and verapamil on the peripheral sympathetic function were studied in perfused rat kidney preparations in vitro. Neither of these agents inhibited stimulus-induced 3H- noradrenaline (norepinephrine) release (at 0.5 and 2.0Hz). Higher concentrations of felodipine (10 µmol/L) and verapamil (1 and 10 µmol/L) significantly potentiated the transmitter release at both frequencies of stimulation. Unlike phenotolamine, felodipine 10 µmol/L enhanced the ability of exogenous noradrenaline to inhibit 3H- noradrenaline-release, indicating that this vasodilator did not antagonise prejunctional α2- receptors. The effects of verapamil 1 µmol/ L were similar to that of felodipine in this respect; however, verapamil in higher concentrations (JO µmol/L) produced slight but significant attenuation of exogenous nor adrenaline-induced inhibition of the transmitter release. Both felodipine and verapamil produced concentration-dependent inhibition of the vasoconstrictor responses to exogenous noradrenaline. It is concluded from these studies that the effects of these agents on the transmitter release may not have any clinical significance, but their ability to attenuate vascular effects of noradrenaline could contribute to their antihypertensive properties.

Cardiovascular Effects of Chronic Intraventricular Administration of Angiotensin II in Dogs

Intracerebroventricular administration of angiotensin II (AII), 1 microgram twice a day to mongrel dogs plus saline as the drinking fluid for 4 weeks produced a significant sustained elevation in systolic and diastolic blood pressures. The hypertensive state appeared to be due to an increase in total peripheral resistance. Fluid intake and urine output were elevated and there was a significant increase in body weight at the end of week 2, 3 and 4. Serum Na+ levels were significantly decreased and serum Ca++ levels significantly increased in the hypertensive animals. These studies indicate that increasing AII levels in the cerebrospinal fluid for a prolonged period of time produces a sustained hypertensive state only if the daily intake of sodium is increased and that the alterations in vascular resistance may be due to changes in the Na+ - Ca++ fluxes.

Abnormalities in the sodium transport as the causative factor for enhanced norepinephrine overflow in the spontaneously hypertensive rat.

These studies were designed to investigate whether alterations in the sodium transport could account for the enhanced transmitter release observed during sympathetic nerve stimulation in SHR. In the isolated in vitro perfused rat kidneys, norepinephrine (NE) storage sites were labelled with [3H]-NE and the transmitter overflow was evaluated at various frequencies during the periarterial nerve stimulation. Stimulus-induced transmitter overflow was consistently greater and the maximal overflow was 2-fold higher in the kidneys of SHR when compared to that of normotensive WKY. Addition of ouabain, a selective inhibitor of the sodium pump, (10(-3)M in the medium) significantly enhanced stimulus induced overflow in both the groups. However, the magnitude of these changes was significantly greater in WKY than in SHR kidneys suggesting that the membrane Na+-pump was functionally less efficient in the SHR. Ouabain virtually eliminated the differences between the two groups in that the transmitter overflow was essentially identical in SHR and WKY in the presence of the Na+-pump inhibitor. These observations suggest that a genetic abnormality in the neuronal sodium pump could account for the enhanced sympathetic transmitter overflow and contribute to hypertension in the spontaneously hypertensive rats.