Norepinephrine Dose-response Curves Research Articles

Effects of magnesium on the action of vasodilatory agents.

Studies have shown that alterations of the magnesium (Mg2+) concentration can alter the response of certain vasoactive compounds. Responses of rabbit thoracic aorta to verapamil, diltiazem, nitroglycerin and isoproterenol were examined in zero Mg2+ (0.0 M), N Mg2+ (1.2 mM), 2 N Mg2+ (2.4 mM) and 4 N Mg2+ (4.8 mM). Preconstriction was induced with norepinephrine and cumulative dose-response curves were obtained for the vasodilators. The dose-response curve for isoproterenol was shifted to the right in zero Mg2+ while there was no effect on the other vasodilators. Elevation of the Mg2+ concentration to 4.8 mM produced a shift to the left in the dose-response curves for diltiazem, nitroglycerin and isoproterenol with no effect on verapamil. Therefore, Mg2+ deficiency does not appear to affect the vasodilatory actions of the agents tested except for the beta-receptor agonist, isoproterenol. Elevated Mg2+, however, potentiated the actions of isoproterenol, nitroglycerin and diltiazem, but not verapamil.

Sympathetic vasoconstriction sensitive to alpha 2-adrenergic receptor blockade. No evidence for preferential innervation of alpha 1-adrenergic receptors in the canine femoral bed.

In the canine femoral bed, we studied the involvement of vascular alpha 2-adrenergic receptors in vasoconstriction by stimulating the sympathetic nerve during different degrees of activation of metabolic counterregulation (constant pressure and constant flow perfusion). In chloralose-anesthetized, despinalized dogs under beta-blockade (2 mg/kg nadolol) and under a constant femoral perfusion pressure, cumulative doses of rauwolscine (0.03, 0.3, and 3.0 mg/kg i.v., n = 8) or of prazosin (0.012, 0.12, and 1.2 mg/kg i.v., n = 8) caused dose-dependent shifts to the right of the dose-response curve of intraarterial norepinephrine (NE) infusions. These cumulative doses also caused attenuations of the vasoconstriction initiated by lumbar sympathetic stimulation (0.1, 0.3, 1.0, and 3.0 Hz). Sham treatment (n = 8) had no such results. In experiments with constant flow perfusion (n = 6 for each antagonist), rauwolscine shifted the NE dose-response curve significantly more compared to the experiments with constant pressure perfusion, while prazosin was similarly effective under both conditions. Under constant flow perfusion, both antagonists dose-dependently attenuated the vasoconstrictions caused by sympathetic stimulation. While prazosin and sham treatment did not modify the overflow of NE from the femoral bed during stimulation, this overflow was augmented by rauwolscine during stimulation at 3 Hz, which indicated presynaptic modulation of NE release. Under both experimental conditions, no significant difference could be observed in the attenuation of low-frequency sympathetic vasoconstriction by the two antagonists, when dosages were compared on the basis of their action against infused NE. It is concluded that both a rauwolscine-sensitive component and a prazosin-sensitive component are involved in the competition between sympathetic vasoconstriction and metabolic dilation. The vascular alpha-adrenergic receptors activated by these two components have a similar postsynaptic localization relative to the nerve endings.

Effects of captopril on vascular noradrenergic transmission in SHR.

The effects of captopril, 3 and 10 mg/kg, on vascular noradrenergic transmission were examined in vivo in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). These experiments were performed on mesenteric vascular beds perfused in situ. In WKY, 3 mg/kg captopril failed to significantly lower mean arterial blood pressure (MAP) and also failed to have a significant effect on the frequency-response curve to sympathetic nerve stimulation or dose-response curve to norepinephrine (NE) in the mesentery of WKY. In SHR mesentery, 3 mg/kg captopril failed to alter the frequency response curve or NE dose-response curve, while it significantly lowered MAP. The higher dose of captopril, 10 mg/kg, also failed to lower MAP in WKY mesentery, although it caused some reduction in pressor responses to sympathetic nerve stimulation and NE. In SHR mesentery, 10 mg/kg captopril significantly lowered MAP and reduced pressor responses to both nerve stimulation and NE. It should be noted, however, that captopril lowered responses to nerve stimulation and NE to a similar degree in both SHR and WKY, and there was no indication of a prejunctional action on vascular noradrenergic transmission. In conclusion, although captopril was more effective in lowering MAP in SHR than in WKY, no evidence was found for significantly greater facilitation of vascular sympathetic neurotransmission by endogenous angiotensin II in SHR than in WKY, and most of the actions of captopril on vascular neurotransmission appeared to be postjunctional in nature and unrelated to either the renin-angiotensin system or the kallikrein-kinin system.

Vascular hypersensitivity to noradrenaline: a possible mechanism of hypertension in rats with chronic uraemia.

Studies were performed to evaluate the mechanism involved in the hypertension of moderate renal failure in partially (five-sixth) nephrectomized rats. Cardiac index (CI) was studied by means of the microsphere technique, and systemic vascular resistance (SVR) calculated from the mean arterial resistance MAP/CI, in four groups of experimental animals: (A) partially nephrectomized rats; (B) group A rats chronically treated with the calcium channel blocker verapamil; (C) sham-operated rats; (D) sham-operated rats treated with verapamil. The results demonstrate a significant increase in MAP in group A rats, which was due to a 72% increase in SVR as compared with groups C and D. In group B rats, MAP decreased significantly owing to a marked decrease in SVR (40%) as compared with group A. However, MAP remained higher in group B than in group C. The vascular responsiveness to noradrenaline was studied in group A, group C and group A rats after parathyroidectomy (group A1). An increased pressor responsiveness to noradrenaline was indicated by a shift of the noradrenaline dose-response curve to the left in group A rats as compared with group C rats. This change was corrected after partial nephrectomy. We conclude that hypertension in nephrectomized rats is due to an increase in SVR, and that an increased pressor responsiveness to catecholamines may play a role in this phenomenon. Furthermore, verapamil reduced the hypertension, and parathyroidectomy improved the abnormal sensitivity to noradrenaline in group A rats. These results raise the possibility that an abnormality in calcium metabolism, possibly due to secondary hyperparathyroidism, may be implicated in the hypertension of mildly uraemic rats.

Atrial natriuretic factor inhibits angiotensin-, norepinephrine-, and potassium-induced vascular contractility.

We have previously shown that the natriuretic effect of rat atrial extract (AE) may be due, perhaps entirely, to its powerful renal hemodynamic actions. The present study was undertaken to test the hypothesis that mammalian atria contain a substance that behaves as a functional antagonist of endogenous vasoconstrictors, by examining the direct effects of AE and extensively purified atrial "natriuretic" factor on the contractile response of rabbit aortic rings to angiotensin II (AII), norepinephrine (NE), and K+-induced depolarization. Dose-response curves to AII and NE (i.e., change in tension vs log hormone concentration) were determined in the absence or presence of boiled AE or ventricular extracts (VE). Increasing concentrations of boiled AE caused a progressive right-ward shift of the AII and NE dose-response curves, whereas VE was without effect. A similar inhibitory effect was produced after extensive purification of atrial natriuretic factor by gel filtration and reversed-phase high performance liquid chromatography (HPLC). It appeared that this factor antagonized AII-induced contractility to a greater degree than that of NE. Moreover, the partially purified factor also inhibited the contraction induced by depolarization with 15 mM KCl in a concentration-dependent manner. These studies show that a substance present in the atria, but not ventricles, blocks both hormone- (receptor) and depolarization- (nonreceptor) induced vasoconstriction in aortic rings. Moreover, this antagonism is retained following extensive purification of an atrial factor that induces natriuresis in the intact rat and isolated rat kidney, suggesting that both the vasoactive and natriuretic properties of AE may reside in a single substance.(ABSTRACT TRUNCATED AT 250 WORDS)

Is there a role for dopamine in the regulation of motility of sow oviducts?

Dose-response curves for norepinephrine (NE), dopamine (DA) and 2-bromo-alpha-ergocryptine (BEC) in the isthmic and ampullary regions isolated from proestrous sow oviducts, were drawn. NE, DA and BEC depressed the contractile activity of ampullary segments in dose-dependent fashion. In the isthmic region, NE induced a dose-related stimulation whereas DA and BEC evoked relaxation. Propranolol (10(-6)M) did not modify significantly the effect of DA on the ampulla, whereas spiperone, chlorpromazine and haloperidol, shifted to the right DA dose-response curves. Haloperidol and spiperone were able to partially antagonize responses to DA of the isthmus. The catecholamine contents of the ampullary (a) and isthmic (i) regions of sow oviducts during proestrus (P), estrus (E) and metestrus (M) proved to be quite different and differently affected by the variations of the sex cycle: NE, DA and epinephrine (EPI) in (i) higher than in (a); NE in (i) and (a) during M higher than during E; NE in (i) lower during E than during P. The probable presence of specific dopamine receptors in sow oviducts as well as their eventual role in modulating tubal motility are discussed in this paper.

Study of two alkylating derivatives: The p-isothiocyanato- and the p-methylisothiocyanato-clonidine

Pharmacological experiments with isolated rat aorta and radioligand binding studies in rat cerebral membranes were performed with the p-isothiocyanato (p-NCS) and p-methylisothiocyanato (p-CH 2-NCS) derivatives of clonidine in order to assess their selectivity for α 1- and α 2-adrenoceptors, and to characterie their ability to alkylate α-adrenoceptors. Preincubation of rat aortic strips with both derivatives produced non-parallel rightward shifts in the dose-response curves of noradrenaline and significantly depressed the maximum response in a manner characteristic of irreversible receptor antagonists. The p-CH 2-NCS derivative was slightly more potent than the p-NCS derivative. Further analysis of the data indicated that treatment of rat aorta with a 30 μM concentration of the p-CH 2-NCS derivative alkylated all but 2.4 percent of the α-adrenoceptors, whereas a 100 μM concentration of the p-NCS derivative was required to produce a similar degree of α-adrenoceptor alkylation. Radioligand binding studies indicate an apparent 2 fold α 2-adrenoceptor selectivity for the p-NCS derivative. In contrast, the p-CH 2-NCS derivative displayed 7 fold selectivity for α 1-adrenoceptors. Interestingly, both alkylating derivatives of clonidine produced dose-dependent contractile responses in rat aorta with pD 2 values of 6.30 and 5.56 for the p-NCS and p-CH 2-NCS derivatives, respectively, relative to a pD 2 of 7.67 for clonidine. The order of potency of the two alkylating derivatives of clonidine for producing contraction of rat aorta is the opposite of that for antagonizing the contractile effects of noradrenaline. The results suggest that the p-NCS and p-CH 2-NCS derivatives of clonidine non-competitively antagonize noradrenaline by irreversibly alkylating α-adrenoceptors.

Effects of acute blood volume expansion on vascular resistance and reactivity in anaesthetized dogs.

1. The effects of acute volume expansion on vascular resistance and reactivity to noradrenaline and angiotensin II are reported in this study. The estimated circulating blood volume of pentobartibal-anaesthetized dogs was expanded by about 35% with equilibrated donor blood. The animals were bilaterally nephrectomized to sustain expanded volume. 2. Functional changes in vascular smooth muscle were determined in the flow controlled, vascularly isolated, denervated, perfused hind limb preparation in the same animal. 3. Systemic volume expansion per se had no immediate influence on vascular resistance. However, resistance in the hind limb, as determined by the shift of the pressure-flow curves, progressively increased 60 and 120 min after volume expansion. The changes noted after 120 min were significantly greater than those observed after 60 min. 4. The changes in vascular resistance were accompanied by potentiation of the vascular responses to noradrenaline but not to angiotensin II. Significant shifts which occurred in the noradrenaline dose-response curves were similar to those of the resistance curves. 5. in closely simulated control experiments in dogs whose kidneys were intact or had been removed, and whose blood had or had not been equilibrated with donor blood, the above-mentioned vascular changes were not observed in the absence of volume expansion. 6. It is suggested that the functional changes observed in the hind limb vasculature after volume expansion are related to the presence of a circulating substance. From the data obtained from the experimental model used in this study, it can be concluded that such a substance is not released from the kidney.

In vitro contractile responses of the uterus from ‘restricted diet’ rats to adrenoceptor agonists. Influence of cyclo-oxygenase inhibitors

The experiments concerned the effects of 15 days of restricted diet (50% of the normal food intake) on the magnitude of phasic contractions (Isometric Developed Tension, IDT) of uterine horns isolated from estrous rats. During 60 min following isolation, the IDT of normally fed controls diminished significantly whereas preparations from animals on the restricted diet had a better contractile constancy. This improved motility was prevented by blockers of prostaglandin (PG) synthesis as well as by return to a normal diet. Cumulative dose-response curves for isoproterenol, norepinephrine and methoxamine were made for the different groups. Isoproterenol and norepinephrine evoked a dose-dependent inhibition of IDT. This response was significantly shifted to the right with uteri from restricted diet animals. Following incubation with propranolol, norepinephrine stimulated the magnitude of contractions significantly more in uterine horns from restricted diet rats than in those from controls. The dose-response curve showing the enhancement of motility induced by methoxamine was displaced tothe left in preparations from animals on a restricted diet. This shift was abolished by restoring the normal diet as well as by the presence in vitro of indomethacin or acetylsalicylic acid. The results suggest that tissue PGS, the prevalence of α-adrenoceptor mechanisms and the reduction of β-ones, are involved in the contractile behavior of the uterus isolated from restricted diet rats.

Alteration of islet neurotransmitter sensitivity following ventromedial hypothalamic lesion.

Recent studies suggest that alterations in autonomic neural activity may mediate the obese state observed following ventromedial hypothalamic (VMH) lesion. To assess the role of these alterations in the increased glucose responsiveness of the beta-cell observed in this state, we have determined the sensitivity of insulin secretion to norepinephrine or/and acetylcholine in statically incubated pancreatic islets from rats 30-40 days after VMH lesion. In islets from VMH-lesioned rats compared with islets from sham-operated and intact rats, the acetylcholine dose-response curve was shifted down and to the right, indicating a decreased sensitivity, whereas the norepinephrine dose-response curve was translated to the left, indicating an increased sensitivity. The interaction profile, which summarizes combined neurotransmitter exposure on insulin secretion, was shifted in the direction of net inhibition. Thus it was concluded that, following VMH lesion, autonomic neurotransmitter sensitivity of the pancreatic beta-cell was altered. It is suggested that these alterations play a role in the adaptation of the beta-cell to the experimentally induced obese state.

Contractions of amphibian Wolffian duct in response to acetylcholine, norepinephrine, and arginine vasotocin.

The regulation of sperm transport through the Wolffian duct of male amphibians is poorly understood. These experiments were conducted using rough-skinned newts (Taricha granulosa) to determine if Wolffian ducts are capable of contracting in vitro and, if so, to characterize the contractile responses to acetylcholine (ACh), norepinephrine (NE), and neurohypophysial hormones. Dose-response curves for NE and ACh, which were prepared by measuring isometric contractions, are similar to those reported for mammalian vas deferens. For NE, the minimum effective dose and ED50 were found to be 1 X 10(-5)M and 4.17 X 10(-5)M, respectively. For ACh, the minimum effective dose was 3.2 X 10(-8)M and the ED50 was 1.37 X 10(-5)M. Alpha-adrenoreceptors appear to mediate the contractile responses to NE because phentolamine (10(-5)M) blocked or attenuated the response to NE (10(-6)M, 10(-5)M or 10(-4) M). Beta-adrenoreceptors appear to mediate relaxation because dichloroisoproterenol (10(-5)M) enhanced the response to 10(-5)M NE. The contractile response to three neurohypophysial hormones were also investigated. Arginine vasotocin was more effective in eliciting contractions than oxytocin. The effect of lysine vasopressin was intermediate between arginine vasotocin and oxytocin. These experiments demonstrate that amphibian (Taricha) Wolffian ducts contract in vitro in response to neurotransmitters and neurohypophysial hormones. The contractile response to neurotransmitters occurs in a dose-dependent manner; the response to neurohypophysial hormones is hormone specific.

Effect of superior cervical ganglion ectomy on the response to some drugs of rat iris dilator muscle

We examined the effect of superior cervical ganglionectomy on the contractile response of dilator muscle of rat iris to norepinephrine (NE), methoxamine (Met), 5-HT and K+. The validity of the ganglionectomy was confirmed by the disappearance of catecholamine fluorescence and of transmural nerve stimulation induced-contraction of the dilator. The dose-response curve for NE was significantly shifted to the left (ca. × 10) 7 days after denervation, while those for Met, 5-HT and K+ were not. Cocaine did not further sensitize the denervated muscle to NE, although it sensitized the normal muscle to a similar extent as was caused by denervation. Sensitivity to Met was not affected in both control and denervated muscles by cocaine. The maximum response to these drugs was little affected or rather tended to be decreased. These results indicate that in the dilator muscle, the denervation causes specific supersensitivity to the transmitter in contrast to the specific plus nonspecific supersensitivity to cholinergic drugs observed in sphincter muscle and suggest that this supersensitivity results from an impairment of the neuronal uptake process after degeneration of the adrenergic nerve endings.

Evidence for a vascular sensitizing factor in plasma of saline-loaded dogs.

This study investigates whether plasma extracts previously demonstrated to have natriuretic and antinatriferic activity have effects on vascular reactivity of rat cremaster arterioles. Plasma from hydropenic and saline-loaded dogs was subjected to Diafiltration, and eluted on a strong cation exchange column (SCX). The effects of intraarterial injections of various column fractions on constrictor responses to repeated injections of 33.3 ng of norepinephrine (NE) were used to indicate changes in vascular responsiveness in third order cremaster arterioles. SCX fraction I (void volume) from saline-loaded dogs (FI-S) caused an increase in constrictor response to NE of 101%. Increased vascular responsiveness peaked at 40 minutes and remained significantly elevated (p less than 0.05) for 130 minutes. Fraction I from plasma of hydropenic dogs (FI-H) and fraction III from plasma of saline-loaded dogs (FIII-S) did not increase vascular responsiveness to NE. FI-S shifted the dose response curves for NE, arginine vasopressin, and angiotensin II parallel and to the left relative to control by a factor of 3.05-, 2.95-, and 5.63-fold, respectively, at the 50% constrictor dose. Systemic injections of FI-S, but not FI-H, caused a 10 mm Hg rise in blood pressure at 50 minutes, and blood pressure was significantly elevated for 30 to 90 minutes after injection (p less than 0.01). These data demonstrate a vascular-sensitizing factor in FI-S. The factor appears in the same chromatographic fraction previously demonstrated to contain natriuretic, antinatriferic, and digoxin-like activity. The correlation of these activities with salt loading suggests they are due to the same substance, which may be the putative natriuretic hormone.

Prostaglandin F 2α modifies the action of norepinephrine on α- and β-adrenoceptors of isolated rat uterus

Cumulative dose-response curves were constructed for the effect of norepinephrine (NE) and isoproterenol (ISO) on the contractions of uterine strips from proestrous, estrous and metestrous rats. Both adrenergic agonists inhibited uterine spontaneous contractions in all three stages of the cycle. However strips isolated from estrous rats were more sensitive to the inhibitory action of NE or ISO than preparations obtained from proestrous or metestrous animals. It was also observed that PGF-like material released by uterine horns was significantly higher during estrus than during proestrus or metestrus, whereas PGE-like material was significantly higher in metestrus than in estrus or proestrus. The EC 50 of NE and ISO and the amount of PGF-like material generated by uterine horns correlated significantly during the three stages of the sex cycle. No correlation was found between the β-adrenergic inhibitory action of catecholamines and the PGE-like material released in the medium. A sub-threshold dose of PGF 2α (10 −10 M) shifted to the left the dose-response curves to NE of strips isolated from metestrous rats. When the tissue was pretreated with indomethacin and propranolol the dose-response curve to NE showed a clear shift to the left. On the other hand, the combination of indomethacin and propranolol shifted the NE dose-response curve to the right in the presence of sub-threshold doses of PGF 2α. Dose-response curves to methoxamine were constructed in the presence or absence of several PGs using uterine strips isolated from estrous rats. With indomethacin, a threshold dose of PGE 1 (10 −8 M) and PGE 2 (10 −8 M) shifted to the left the control curve of methoxamine, whereas PGF 2α (10 −8 M) shifted the curve to the right. The interaction between sex hormones, PGs and catecholamines acting on α- and β-adrenoceptors in the isolated rat uterus is discussed.

Pre- and postsynaptic alpha-adrenoceptor blocking activity of raubasine in the rat vas deferens.

1 The actions of raubasine, yohimbine and corynanthine at pre- and postsynaptic alpha-adrenoceptors were studied in the rat vas deferens. 2 Low frequency electrical stimulation of the isolated vas deferens of the rat produced regular contractions that were inhibited by low concentrations of clonidine. This inhibition was presynaptic in origin and involved alpha-adrenoceptors. 3 Presynaptic alpha-adrenoceptor antagonist activity was assessed by studying the effect of increasing antagonist concentrations on cumulative clonidine dose-response curves on the stimulated vas deferens. 4 Postsynaptic alpha-adrenoceptor antagonist activity in the isolated vas deferens was assessed by comparing control cumulative noradrenaline dose-response curves in the absence and in the presence of increasing concentrations of antagonists. 5 The results indicate that raubasine and corynanthine preferentially block postsynaptic alpha-adrenoceptors. Yohimbine is more potent in blocking pre- than postsynaptic alpha-adrenoceptors. The ration of the pre/postsynaptic potency declines in the order yohimbine less than raubasine less than corynanthine.

Norepinephrine effect on in situ venous membrane potential in spontaneously hypertensive rats

Comparative in situ (innervation and circulation intact) and in vitro measurements of transmembrane potential (Em) were made in vascular smooth muscle cells (VSM) of small (300-500 micrometers) veins of an externalized intestinal mesenteric loop in 13- to 15-wk-old anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive controls (WKY). During suffusion with physiological salt solution (PSS), the mean in situ Em in SHR was significantly lower (-34 +/- 0.8 mV) than in WKY (-49 +/- 1.3 mV). In situ neural blockade with 1 microgram/ml tetrodotoxin (TTX) in PSS hyperpolarized venous Em in SHR (-45 +/- 1.7 mV) but not in WKY. In vitro Em in SHR (-51 +/- 1.0 mV) and WKY (-54 +/- 1.1 mV), though significantly elevated above respective in situ values, did not differ significantly from each other and were not altered by TTX. Increasing norepinephrine (NE) concentrations in the PSS gradedly depolarized the venous VSM of WKY in situ to a plateau Em of -32 +/- 0.9 mV at 6 microM (1 micrograms/ml) NE but had no significant depolarizing effect on the less-polarized venous VSM of SHR. However, after addition of 1 micrograms/ml TTX to the PSS, the in situ Em in SHR followed a depolarizing NE dose-response curve similar to that observed in WKY (with or without TTX). These results support the hypothesis that the neurogenic vasoconstrictor component of VSM tone is significantly elevated in mesenteric veins of the SHR model of essential hypertension.

A new technique for recording compliance of human hand veins.

1 A new technique for determining venous compliance at a standardized congestion pressure has been developed based on the optical method described by Nachev, Collier & Robinson (1971). It uses a linear variable differential transformer for a direct and continuous recording of venous compliance. 2 This method has been used to establish dose-response curves for the constrictor effects of noradrenaline, adrenaline, 5-hydroxytryptamine and dihydroergotamine after direct local infusion. 3 A parallel shift to the right of the noradrenaline dose-response curves was observed after local infusion of phentolamine, showing that the method can be used also to study interactions between agonists and antagonists on human veins in vivo. The usefulness of this technique for investigating the effects of orally administered drugs has also been established. The venoconstrictor action of dihydroergotamine reached its maximum after 1.5 h and remained almost constant for the period of observation (8 h).

Neonatal rat pinealocytes: typical and atypical characteristics of [125I]iodohydroxybenzylpindolol binding and adenosine 3',5'-monophosphate accumulation.

Techniques are described which make it possible to study beta-adrenergic receptors on intact neuroendocrine cells. Receptors were characterized on neonatal pinealocytes using the radioligand [125I]iodohydroxybenzylpindolol ([125I]IHYP). Specific binding of [125I]IHYP, which is 4-fold greater than nonspecific binding, is concentration and temperature dependent, reversible, and saturable. [125I]IHYP binds noncooperatively (Kd = 35 pM), and Scatchard analysis indicates that only a single class of receptor sites for [125I]IHYP is present. Under the conditions used, it appears that there are about 12,000 +/- 1,100 sites/cell. Inhibition of specific [125I]IHYP binding by beta-adrenergic agonists and antagonists is stereospecific, and the relative potency of agonists is characteristic of binding to beta-adrenergic receptors. Analysis of adrenergic stimulation of intracellular cAMP accumulation indicates that similar half-maximal concentrations of antagonists inhibit [125I]IHYP binding and adrenergically stimulated cAMP accumulation. In contrast, beta-adrenergic agonists are considerably more potent in stimulating cAMP than in inhibiting [125I]IHYP binding. Unexpected differences, not previously reportd, were found in the shapes of the cAMP accumulation dose-response curves of norepinephrine and isoproterenol. The relative potencies of these two agonists appear to be partially concentration dependent. This raises the possibility that there may be distinct differences in the intrinsic effects of these compounds on the regulation of intracellular cAMP accumulation in pinealocytes. (Endocrinology 108: 559, 1981)

Inotropic responsiveness of the heart in catecholamine cardiomyopathy

Inotropic responsiveness to norepinephrine (NE) or Ca 2+ was studied in 15 rabbits with catecholamine cardiomyopathy (CM) and the results were compared with 11 controls. The former group was prepared by infusing NE (2 μg/min/kg) for 90 minutes, 2 to 3 days prior to study, and injury was confirmed and quantified histologically. Comparison of NE dose-response curves relating percent increase of left ventricular (LV) dP dt max to NE dose in six controls and 10 CM hearts revealed significant depression of CM contractility. Responses to graded infusions of Ca 2+ were also determined in five controls and in five CM animals. With the increases in serum Ca 2+ identical in the two groups, the percent increases in dP dt max were less in CM hearts. Further, NE dose-response curves obtained during continuous CaCl 2 infusion were sharply attenuated in CM hearts and initial LV end-diastolic pressure (LVEDP) in the CM hearts was considerably higher than in the controls. It is concluded that inotropic sensitivity to NE is reduced in CM hearts. This cannot be ascribed to altered β-receptors alone, because responsiveness to Ca 2+ was also reduced. Myocardial damage was indicated by histology and elevated LVEDP. Moreover, the normalized percent data suggest that the remaining viable fibers in the CM hearts were functioning subnormally and thus reduced performance was not due solely to the decreased number of contracting units.

Artificial buffers do not inhibit contractile responses in the smooth muscle of rat portal vein and guinea pig taenia coli.

Effects of substitution for NaHCO3 (and 5% CO2) in the physiological solution with equimolar N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) or morpholinopropane sulfonic acid (MOPS) (and 100% O2) at various pH levels on the contractility of smooth muscle were examined. At pH 7.4, spontaneous contraction in rat portal vein was not inhibited by the artificial buffer solutions, as compared to findings in the case of bicarbonate buffer solution. Norepinephrine-dose response curve in the case of rat portal vein and the histamine-dose response curve in cases of guinea pig taenia coli remained unchanged in the artificial buffer solutions. At pH 7.2 and 7.0, the spontaneous contraction in portal vein was reversibly inhibited either in artificial or in bicarbonate buffer solutions. The norepinephrine- and histamine-dose response curve shifted downwards and/or to the right in these low pH solutions. Thus, HEPES and MOPS had no inhibitory effect on the smooth muscle contractility. Since low pH strongly inhibited the contractility, attention should be directed to the temperature-dependent decreases in pKa of the artificial buffers (i.e., if pH of the solution is adjusted at room temperature and then warmed, pH decreases).