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Biomedical subjects

R Loutzenhiser

Publications and source records attributed to R Loutzenhiser.

At least 55 records · Page 3Linked to original sources
PubMed1986

Reversal of renal and smooth muscle actions of the thromboxane mimetic U-44069 by diltiazem.

U-44069 is a stable prostaglandin (PG) H2 analogue and a potent vasoconstrictor. Its in vivo and in vitro actions mimic those of thromboxane A2. We have studied the effects of the calcium antagonist diltiazem upon the vasoconstriction induced by U-44069 using isolated rat aortic smooth muscle and isolated perfused rat kidney (IPRK). The administration of 10(-6)M U-44069 elicited maximally effective contractions in isolated aortic rings and increased 45Ca uptake from a control value of 285 +/- 6 mumol/kg to 344 +/- 8 mumol/kg. Diltiazem reduced U-44069-induced tension development and 45Ca uptake of isolated aortic smooth muscle 73 +/- 2 and 91 +/- 3%, respectively. The dose dependency of each of these effects of diltiazem was similar (EC50 = 369 nM and 334 nM for tension and 45Ca flux, respectively). When administered to the IPRK, 10(-6) M U-44069 caused a 82 +/- 3% decrease in glomerular filtration rate (GFR) and a 80 +/- 4% decrease in filtration fraction but reduced renal perfusate flow (RPF) only 13 +/- 8% (P less than 0.005). Diltiazem completely reversed the actions of U-44069 on the IPRK (EC50 = 288 nM and 323 nM for GFR and RPF, respectively). Diltiazem thus inhibited U-44069-induced tension development and 45Ca uptake by vascular smooth muscle and increased GFR within identical dose ranges. The contractile response of isolated rat glomeruli was also assessed. U-44069 reduced the volume of isolated glomeruli, but this action was neither prevented nor reversed by diltiazem. These results are consistent with the hypothesis that diltiazem increased GFR by inhibiting U-44069-induced Ca influx at preglomerular vessels.

Animals↗
PubMed1986

Spectrum of deranged sodium homeostasis in essential hypertension.

Essential hypertension is thought to produce a uniform exaggerated natriuresis and diuresis. Because validation of this formulation in humans is incomplete, the natriuretic and diuretic responses to acute volume expansion were characterized by using water immersion to the neck. This method provides a volume stimulus identical to that induced by 2 L of saline without plasma compositional change. Twenty-seven subjects with essential hypertension were studied on three occasions in the seated posture while in balance on a 10 mEq Na, 100 mEq K diet: during the seated control study, during 4 hours of head-out immersion, and during saline infusion (2 L/2 hours). Four subjects had exaggerated urinary Na excretion in response to neck immersion (Group 3), and 16 had a normal response (Group 2) indistinguishable from that of 15 previously studied normal subjects. The remaining seven subjects (Group 1) had blunted or absent natriuretic responses compared with that in normal subjects (p less than 0.005). Similar results were obtained with saline administration; cumulative Na excretion in Group 1 was markedly less than that in Group 2 and the normal subjects. The heterogeneity in Na excretion indicates that an exaggerated natriuresis is not a uniform concomitant of essential hypertension. The significant inverse correlation between basal plasma aldosterone level and peak urinary as well as cumulative Na excretion suggests that plasma aldosterone constitutes a determinant of the differing natriuretic responses. In contrast to findings with urinary Na excretion, the diuretic responses of Groups 1 and 2 were identical. The striking dissociation between renal Na and water handling underscores the specificity of the derangement in renal Na handling.

Adult↗
PubMed1985

Effects of calcium antagonists on renal hemodynamics.

The renal hemodynamic effects of Ca2+ antagonists are considered in the context of their actions on Ca2+ movements during activation of vascular smooth muscle. Observations in intact animals reveal that the renal hemodynamic response to Ca2+ antagonists is highly variable, depending on the neural and hormonal determinants of renal vascular tone. Studies in the isolated perfused kidney and in isolated renal vessels indicate that diverse agonists use different activating mechanisms with differing sensitivities to Ca2+ antagonists. In comparison with other direct-acting vasodilators, Ca2+ antagonists are unique in their ability to maintain or increase glomerular filtration rate. This effect is due, in part, to their selective reduction of afferent arteriolar resistance. This implies that activating mechanisms of the afferent and efferent arterioles differ. The ability of Ca2+ antagonists to augment glomerular filtration rate by concomitant actions on nonvascular sites remains to be elucidated.

Animals↗
PubMed1985

Effects of diltiazem and manganese renal hemodynamics: studies in the isolated perfused rat kidney.

The effects of the organic calcium antagonist diltiazem (DIL) upon the alterations in renal hemodynamics produced by norepinephrine (NE) were assessed in the isolated perfused rat kidney. In the presence of propranolol, the administration of NE (3 X 10(-7)M) caused sustained reductions in renal perfusate flow (RPF) and glomerular filtration rate (GFR). The administration of 10(-5) M DIL to NE-treated kidneys did not reverse the NE-induced decrease in RPF. In contrast, DIL produced a striking reversal of the NE-induced decrease in GFR. In the absence of NE-treatment, DIL did not alter GFR or RPF. We conclude that NE-induced constriction of major postglomerular resistance vessels of the rat kidney is not inhibited by DIL. In contrast, the DIL-induced increase in GFR of the NE-treated kidneys indicates that the NE-constriction of preglomerular resistance vessels is inhibited by this organic Ca entry blocker. Under identical conditions, manganese, an inorganic calcium entry blocker, reversed the NE-induced reductions in both RPF and GFR, indicating that although both responses depend upon Ca entry, only the latter is sensitive to DIL. These data are, therefore, consistent with the postulate that different regions of the renal vasculature are heterogeneous with regard to the mechanisms mediating NE-induced vasoconstriction.

Animals↗
PubMed1985

Nitrendipine-induced stimulation of renin release by the isolated perfused rat kidney.

The direct effects of the organic calcium antagonist nitrendipine upon renin release were assessed using the isolated rat kidney perfused at constant pressure. This model circumvents the indirect actions of vasodilating agents by artificially maintaining perfusion pressure constant, thereby avoiding the hypotensive effects associated with the systemic administration of such agents. Renin release as assessed by radioimmunoassay was stimulated 2.6-fold upon the administration of 10(-6) M nitrendipine. Since this stimulation of renin release occurred in the absence of any alteration in perfusion pressure, we conclude that it represents a direct action of nitrendipine. This finding is in support of the current hypothesis concerning the inverse relationship between cytosolic Ca2+ and renin secretory rate, and suggests that Ca entry into the juxtaglomerular cells of the juxtaglomerular apparatus is sensitive to blockade by organic calcium antagonists such as nitrendipine.

Angiotensin I↗
PubMed1985

Reversal by the calcium antagonist nisoldipine of norepinephrine-induced reduction of GFR: evidence for preferential antagonism of preglomerular vasoconstriction.

We have demonstrated previously that the organic Ca++ antagonist diltiazem augments the glomerular filtration rate (GFR) of the isolated perfused rat kidney during norepinephrine (NE) - induced vasoconstriction. These earlier studies, however, did not elucidate the precise mechanism or site of action responsible for this effect. Nisoldipine (NIS) interacts with the same Ca+2 channels as diltiazem but differs in its physicochemical properties, binding characteristics and tissue specificity. We examined, therefore, the effects of NIS using an identical model. Renal perfusate flow and GRF were assessed in the isolated perfused rat kidney under conditions of constant renal perfusion pressure (100 mm Hg). NIS (10(-7) M) completely reversed the NE-induced reduction in GFR but was significantly less effective in augmenting renal perfusate flow. In additional series of experiments, filtration pressure was estimated during these manipulations by monitoring ureteral pressure during ureteral occlusion (stop-flow pressure). The NE-induced decrease in GFR was accompanied by a reduction in stop-flow pressure, which was abolished by the subsequent administration of NIS. Thus, nisoldipine preferentially attenuated NE-induced constriction of preglomerular resistance vessels but was less effective in reversing the effects of NE on postglomerular arterioles. These findings indicate that separate postreceptor mechanisms mediate the activation of pre- and postglomerular vessels by NE.

Animals↗
PubMed1984

Activation mechanisms of human renal artery: effects of KCl, norepinephrine and nitrendipine upon tension development and 45Ca influx.

The activation of human vascular smooth muscle by KCl-induced depolarization or norepinephrine and the inhibition produced by nitrendipine were studied in the isolated human renal artery. The contractile response of arterial rings to 80 mM KCl was abolished when extracellular Ca2+ was removed, and was inhibited by nitrendipine (IC50 = 10(-8) M). In contrast, a residual, transient contractile response to norepinephrine remained when extracellular Ca2+ was removed and the norepinephrine-induced contractions obtained in the presence of extracellular Ca2+ were not blocked by nitrendipine. KCl caused a stimulation of 45Ca influx which was completely prevented by 10(-6) M nitrendipine. Norepinephrine also caused a stimulation of 45Ca influx; however, the norepinephrine-induced 45Ca influx was not prevented by 10(-6) M nitrendipine. These findings are consistent with the concept that depolarization-induced activation of the human renal artery is primarily dependent upon a stimulation of Ca2+ influx; whereas activation by norepinephrine involves the release of intracellular Ca2+ in addition to the activation of a separate, receptor-operated Ca2+ influx pathway.

Biological Transport↗
PubMed1984

Studies on the mechanism of action of the vasoconstrictive dihydropyridine, CGP 28392.

The effects of the vasoconstrictive dihydropyridine, CGP 29392, upon tension development and 45Ca2+ uptake by vascular smooth muscle were studied using isolated rabbit aorta. CGP 28392 did not elicit contractile responses when administered alone but lowered the threshold for the contractile response to elevated extracellular K+. CGP 28392 also increased the magnitude of the contractions elicited by submaximal concentrations of K+. This effect was competitively antagonized by PY 108-068, a Ca antagonist of the dihydropyridine class. Similarly, the relaxing effects of PY 108-068 upon KCl-constricted rabbit aorta were competitively antagonized by CGP 28392. The calcium content of unstimulated tissues was only minimally increased by CGP 28392 but the 45Ca2+ uptake stimulated by depolarizing levels of K+ was markedly augmented by this agent. Further analysis of the data indicated that CGP 28392 did not alter the relationship between tension development and 45Ca2+ uptake. In contrast, CGP 28392 was much less effective in augmenting the contractile response and 45Ca2+ uptake elicited by noradrenaline. These results thus support the hypothesis that CGP 28392 predominantly facilitates Ca2+ entry through potential-operated Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1983

Involvement of extracellularly bound calcium in the activation of arterial smooth muscle.

The role of extracellularly bound Ca in the activation of rabbit aorta by the PGH2 analogue U-44069 was assessed using 45Ca flux determinations. The 45Ca influx process, which is activated by U-44069, was found to exhibit two phases: an initial rapid phase which was transient and a slower phase which was sustained. The 45Ca-40Ca exchange labeling rate of the Ca pool which enters the cell during the initial phase of Ca influx was found to be much slower than that of the free extracellular Ca2+, but quite similar to that of an extracellularly bound Ca pool. These findings suggest that an extracellularly bound Ca pool, possibly located on the outer surface of the plasmalemma, is involved in the U-44069-stimulated Ca influx process.

Animals↗
PubMed1983

The influence of receptor occupation on Ca++ influx-mediated vascular smooth muscle contraction.

A possible role of the agonist-induced intracellular calcium release process in mediating the utilization of the Ca++ ions which enter the smooth muscle cells during activation is proposed. The rate of refilling of the agonist-sensitive intracellularly bound calcium pool was found to be decreased when Ca++ influx was reduced by D-600 and increased when Ca++ influx was stimulated by KCl. Similarly, the rate of tension development in response to a stimulation of Ca++ influx by KCl was found to be slowed when the agonist-sensitive internal calcium pool had been depleted prior to addition of KCl and to be accelerated in the presence of an agonist capable of releasing this pool. These findings indicate that the agonist-sensitive internal Ca++ pool is capable of sequestering Ca++ which enters during the stimulation of Ca++ influx and that receptor occupation reduces the sequestration capacity of this pool. It is suggested that the agonist-induced internal calcium release process may play two roles in arterial smooth muscle activation: (1) the released Ca++ is directly involved in activation and (2) receptor occupation may reduce the ability of intracellular sites to sequester Ca++, thereby allowing more of the stimulated Ca++ influx to be utilized for activation.

Animals↗
PubMed1982

Calcium fluxes in isolated rabbit aorta and guinea pig tenia coli.

Studies utilizing 45Ca have been helpful in analyzing the Ca control system in smooth muscle. Activation of rabbit aortic alpha receptors stimulates Ca influx and a release of Ca from superficial binding sites. Membrane depolarization by high K causes an influx, but no release. However, the influx pathways activated by alpha agonists and membrane depolarization are different and independent, because the maximal Ca influxes induced by each type of stimulation are additive. The cellular Ca pools that release Ca during pharmacological activation are shared by several agonists; release of cellular Ca by one agent after abolition of Ca influx inhibits Ca release by a second, different agonist. U44069, a stable prostaglandin H2 analog, induces both Ca influx and release. The extracellular Ca source for initial influx exchanges more slowly than free interstitial Ca, and may be located within the glycocalyx or on the outer membrane surface. An Na-Ca exchange process has been suggested as the important determinant of the transmembrane electrochemical Ca gradient. However, manipulation of the Na gradient by Na pump inhibition and Na substitution has provided data showing that Na-Ca exchange is a nonspecific process not directly involved in regulating [Ca]i. It is more likely that Ca extrusion is dependent on an ATPase in smooth muscle.

Animals↗
PubMed1981

Mechanism of activation of isolated rabbit aorta by PGH2 analogue U-44069.

The effects of a stable analogue of PGH2 on 45Ca fluxes and tension were studied in the isolated rabbit aorta. U-44069 produced maximal tension responses at a concentration of 10(-7) M. The analogue increased smooth muscle Ca2+ content and increased the unidirectional 45Ca influx. U-44069 also induced contractions of reduced magnitude in the absence of external Ca2+ and caused a transient stimulation of 45Ca efflux, suggesting that the analogue releases intracellularly bound Ca2+. Both the contractile response in CA2+-free media and the stimulation of 45Ca efflux were greatly attenuated by prior exposure to norepinephrine. The analogue-induced contractions in Ca2+-free media were also prevented by prior exposure to histamine but not angiotensin II. D-600 completely blocked the U-44069-induced gain in calcium content (IC50 = 10(-6) M) but inhibited the contractile response by only 40%. It was concluded that the PGH2 analogue activates rabbit aorta by activating a CA2+ influx pathway and releasing a fraction of the intracellular Ca2+ pool that is sensitive to norepinephrine and other agonists.

Angiotensin II↗
PubMed1980

Uptake and release of amino acids by normal and remnant kidneys: studies in the isolated perfused rat kidney.

In order to evaluate the capacity of normal and remnant kidneys to take up and release amino acids when plasma concentrations are increased above normal levels, we have determined the simultaneous net uptake or release of eight representative amino acids using the isolated perfused rat kidney model. Eight normal and five partially infarcted kidneys from Sprague-Dawley rats were perfused with Krebs-Ringer's bicarbonate buffer containing glucose 8 g/100 ml albumin and amino acids at concentrations approximately 10 times above normal plasma levels. Urine was collected every 15 min for 75 min, and perfusate samples were obtained at the midpoint of each urine collection. Amino acids were measured by gas-liquid chromatography. During perfusion, there was substantial net utilization of asparate, proline, alanine, and glycine by normal kidneys. In remnant kidneys the net uptake of amino acids tended to be lower than that of the normal kidneys. The fractional excretion of most amino acids by remnant kidneys was significantly higher than that of controls. These studies demonstrate the substantial capacity of the kidney to take up or release amino acids when presented with an increased load. The findings suggest that the fractional reabsorption of amino acids by residual nephrons of remnant kidneys is decreased.

Amino Acids↗
PubMed1980

Ca2+ movements in smooth muscle.

We describe the Ca2+ movements in smooth muscle cells at rest and during activation and relaxation as deduced from transplasmalemmal Ca2+ fluxes and contractile respnses. The general picture which emerges is: the resting cell has a [Ca2+]cyt below 10(-7) M and large gradients are poised across both the cell membrane and intracellular membranes. Excitation opens up Ca2+ channels which are linked to receptors and, if depolarization occurs, to other channels not linked to specific receptors but capable of sensing the membrane potential. Receptor activation also leads to release of Ca2+ from a limited intracellular Ca2+ pool which is superficially located because it has to be refilled from the outside. Relaxation is effected by Ca2+ accumulation by another intracellular Ca2+ pool, very likely sarcoplasmic reticulum, which does not release Ca2+ during activation. The sarcoplasmic reticulum Ca2+ pump can also decrease initial activation of the myofilaments. Elevation of cAMP levels may inhibit contraction by stimulating the sarcoplasmic reticulum Ca-ATPase. An enormous amount of research is still required to prove the above scheme and to localize and quantitate the various intracellular Ca2+ pools.

Animals↗