Systemic factors and renal hemodynamic effects of high-protein meal versus low-protein meal in conscious dogs.

The effects of a high-protein (HP) and low-protein (LP) meal on glomerular filtration rate (GFR), effective renal plasma flow (ERPF), and renal vascular resistance (RVR) were examined in conscious dogs. Ingestion of the HP and LP meal produced a temporary increase in systemic hemodynamic parameters due in part to a 'cephalic phase' of sympathetic excitement. However only the HP significantly altered renal hemodynamics, i.e. GFR, ERPF and RVR. Plasma renin activity (PRA), serum aldosterone and plasma atrial natriuretic peptide (ANP) concentrations were not significantly altered by either a HP or LP meal. Of all the serum electrolytes measured, serum Ca2+ concentrations were significantly lower after a HP meal. It would appear that protein-meal-induced changes in renal hemodynamics are independent of changes in systemic hemodynamics. The exact mechanism of action of a HP meal on renal hemodynamics is not clear, but it appears that one mechanism by which a HP meal may alter renal hemodynamics is by altered calcium homeostasis.

High-calcium diet in spontaneously hypertensive rats: intervention with calcium antagonist verapamil.

A number of studies have shown an antihypertensive effect for high-calcium diets, but others have found no effect or, even a prohypertensive effect. Because of these disparate results, studies were conducted in spontaneously hypertensive rats (SHR) fed either a normal calcium diet (1.0% calcium) or a high-calcium diet (4.0% calcium) with or without verapamil HCl (50 mg/kg body weight) from ages 5 to 12 weeks. Systolic blood pressure (SBP) and heart rate (HR) were measured by indirect tail cuff method. During the analysis of the electrolytes and vasoactive hormones monitored in this study, it was found that rats fed high-calcium diet had significantly elevated serum ionized and total calcium and calcium excretion. Systolic blood pressure for the verapamil-normal calcium diet (week 5, 148 +/- 4 mm Hg; week 7, 162 +/- 4 mm Hg) did not differ significantly from that of normal calcium diet (week 5, 152 +/- 2 mm Hg; week 7, 160 +/- 1 mm Hg). The high-calcium diet potentiated the development of hypertension, i.e., SBP was (157 +/- 2 mm Hg) on the 5th week and (174 +/- 4 mm Hg) on the 7th week. Conversely, verapamil high-calcium diet prevented the development of hypertension (week 5, SBP was 139 +/- 4 mm Hg; week 7, SBP was 146 +/- 3 mm Hg).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of calcium infusion on plasma atrial natriuretic peptide in conscious dogs: intervention with calcium antagonist, verapamil.

In studies in conscious dogs, 1 liter 0.3% calcium chloride infusion resulted in a 163% increase in serum ionized calcium (iCa2+), 166% increase in plasma immunoreactive atrial natriuretic peptide (irANP) and 33% increase in mean blood pressure with significant positive correlation between serum iCa2+ and plasma irANP levels. Pretreatment with verapamil reversed the effects of calcium infusion. These studies have demonstrated that calcium ions play an important role in ANP secretion with reversal by calcium antagonist, verapamil. Hyponatremia seen with calcium infusion could reflect calcium-enhanced sodium excretion. Hypercalcemia was accompanied by non-significant changes in plasma renin activity and significantly elevated serum aldosterone not reversed by verapamil.

Release of norepinephrine by electrical field stimulation of collateral arteries from the hindlimb of the dog.

Studies were conducted comparing the electrical field-stimulated contractile response and endogenous norepinephrine overflow of developing collateral arteries to that of branch arteries from normal extremities. Norepinephrine overflow was measured by radioenzymatic assay. Experiments on collateral arteries were undertaken 6 weeks after occlusion of the femoral artery. Collateral arteries had a lesser contractile response at lower voltages of stimulation with a greater direct smooth muscle component. This occurred despite previously reported greater sensitivity to alpha-adrenergic agonists. Stimulated norepinephrine overflow was significantly greater despite a lower norepinephrine content. These findings may reflect alterations in local control of adrenergic neuronal transmission. The results also suggest an inefficient innervation of vascular smooth muscle by adrenergic nerve endings. Lack of difference between anterior tibial artery from unoccluded (normotensive) and occluded (hypotensive) extremities excluded the possibility that differences between collateral and normotensive branch arteries were due to hypotension alone.

Evidence for prejunctional alpha- and beta-adrenoceptors in the canine saphenous vein: influence of frequency of stimulation and external calcium concentration.

Most studies of adrenergic neurotransmission have utilized 3H-labeled transmitter-preloaded isolated tissues. The present study has employed a radioenzymatic assay to measure field-stimulated endogenous norepinephrine overflow from the canine saphenous vein preparation. The presence of prejunctional alpha- and beta-adrenoceptors was documented in experiments conducted at two frequencies of stimulation (1 and 5 Hz) and three external calcium concentrations (1.25, 2.5, and 5 mM). There was a direct relationship between frequency of stimulation or external calcium concentration and per pulse norepinephrine overflow. Diminution of stimulated norepinephrine overflow in the presence of clonidine (10(-6) M) was taken as evidence for prejunctional alpha-adrenoceptors. Enhanced overflow in the presence of isoproterenol (10(-6) M) was evidence for prejunctional beta-adrenoceptors. The effects of these alpha- and beta-adrenergic agonists were partially reversed by antagonists, phentolamine (10(-6) M) and propranolol (10(-6) M), respectively. The influence of clonidine or isoproterenol on stimulated norepinephrine overflow was inversely related to frequency of stimulation and external calcium concentration. Enhanced stimulated norepinephrine overflow in the presence of phentolamine is evidence for negative feedback prejunctional alpha-adrenoceptor tone in the canine saphenous vein.

Radioenzymatic assay measurement of yohimbine's influence on adrenergic neurotransmission of rat vas deferens: unique consequence of using normetanephrine as an uptake2-blocking agent.

The effect of the alpha 2-receptor antagonist, yohimbine on norepinephrine overflow was studied in the transmural-stimulated isolated rat vas deferens. A radioenzymatic assay was used to measure the endogenous norepinephrine overflow. In initial studies conducted in the presence of uptake1 blocker desipramine (10(-6) M) and uptake 2 blocker, normetanephrine (10(-5) M) there was an apparent uncoupling of the influence of yohimbine on nerve-stimulated contractile response from norepinephrine overflow. These results were found to be due to the electrolytic O-demethylation of normetanephrine with the resultant generation of large quantities of norepinephrine obscuring the influence of yohimbine on nerve-stimulated norepinephrine overflow from the vas deferens. These findings serve as a warming to the use of normetanephrine as an uptake1 blocker when radioenzymatic assay is used to measure norepinephrine overflow from transmural-stimulated isolated tissue preparations. Yohimbine (10(-6) M), in the absence of uptake blockade, causes a 3-fold enhancement of nerve-stimulated norepinephrine overflow at 1 Hz and a 2-fold enhancement at 10 Hz. This report demonstrates utilization of a radioenzymatic assay to study endogenous norepinephrine overflow from rat vas deferens. Results for yohimbine are complementary to others using measurement of 3H-label overflow from [3H]norepinephrine prelabeled isolated tissue.

The effects of perhexiline on the sympathetic nervous system.

The effects of perhexiline on sympathetic nervous system function were studied in vitro and in vivo. Perhexiline decreased the field stimulation-induced contractile response of the isolated vas deferens and significantly decreased the quantity of norepinephrine released during stimulation of this preparation. In vivo studies in dogs showed that perhexiline reduced the heart rate response to cardiac accelerator nerve stimulation, an effect not associated with an increase in cholinergic tone or beta adrenergic blockade. Measurements of norepinephrine released from the heart during cardiac nerve stimulation showed that perhexiline (3 mg/kg) decreased norepinephrine release by approximately 35%. These results suggest that a presynatpic effect of perhexiline, which results in a decrease in norepinephrine release, contributes significantly to the attenuated heart rate response which occurs after administration of this drug. A decrease in transmitter release during sympathetic stimulation could play an important role in the mechanism for the protective effects of perhexiline in myocardial ischemic damage.

Studies on the contribution of active metabolites to the anticonvulsant effects of propranolol.

The anticonvulsant activity of propranolol and two selected metabolites, propranolol glycol and N-desisopropylpropranolol were compared in mice against 4 types of experimentally induced seizures: pentylenetetrazol, strychnine, low frequency and maximal electroshock. Both metabolites possessed significant anticonvulsant activity with propranolol glycol being 1/2 to 1/3 as potent and N-desisopropylpropranolol being 1/6 as potent as propranolol. The possible contribution of these two active metabolites to the acute anticonvulsant efficacy of propranolol was assessed in time course studies. Maximal anticonvulsant activity occurred between 2.5--10 min after propranolol (5-20 mg/kg, i.v.) and was significantly diminished after 30 min. Following propranolol, brain levels of both metabolites were extremely low ( less than 10 ng/g) at the onset of anticonvulsant action and reached peak levels between 15-30 min at which time anticonvulsant activity was already declining. In contrast, brain levels of propranolol were similar in time course to that observed for its anticonvulsant effect and there was significant positive correlation between these two parameters in 3 of the 4 seizure models. These data indicate that although these two metabolites are pharmacologically active, they do not contribute significantly to the acute anticonvulsant actions observed after propranolol administration.