Biomedical subjects

D D Smyth

Publications and source records attributed to D D Smyth.

82 records · Page 5Linked to original sources

PubMed1985

The role of renal catecholamines in hypertension.

We have found increased renal alpha 2-adrenoceptor density and a defect in prostaglandin and parathyroid stimulated adenylate cyclase in two genetic forms of rat hypertension. Changes in serum calcium and parathyroid hormone (PTH) levels suggest biologic significance to this defective adenylate cyclase response. Our hypothesis is that one or more of these defects contribute to excess renal retention of sodium and increase vascular resistance of genetically hypertensive rats and humans with essential hypertension who have similar abnormalities of calcium and PTH.

Adenylyl Cyclase Inhibitors↗

PubMed1985

Defective renal adenylate cyclase response to prostaglandin E2 in spontaneously hypertensive rats.

We activated three known components of the adenylate cyclase system in renal membranes from spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. The basal adenylate cyclase activity and responses to plasma membrane receptor activation by parathyroid hormone, isoproterenol and vasopressin were not different between the two strains. The response to prostaglandin E2 (PGE2), however, was less in the SHR than in the WKY at five, (P less than 0.05), 12 (P less than 0.01) and 16 (P less than 0.01) weeks of age. Activation of either the guanosine-5'-triphosphate (GTP) binding regulatory protein (N) with sodium fluoride (NaF) and guanyl-5'-yl-imidodiphosphate [Gpp(NH)p], or the catalytic unit with manganese chloride (MnCl2) or forskolin were not different between the two groups. When the medullary and cortical plasma membrane adenylate cyclase responses were studied separately, the observed decreased response to PGE2 (of SHR) was found to be entirely in the cortex. Also, the NaF response was reduced in the cortical region of the 12-week-old rats, a finding suggesting a possibility of a post receptor defect. These results show that there is a defective renal adenylate cyclase response specific to prostaglandin E2 in SHR. This defect could be related to the development of hypertension, by changing the natriuretic and/or renal vasodilating effects of these prostaglandins.

Adenylyl Cyclases↗

PubMed1985

Dietary and pharmacological alterations in endogenous angiotensin II: effect on noradrenaline pressor responsiveness in the rat.

Rats were placed on either a low sodium intake (low sodium diet 0.025% dry weight, tap water for drinking) or a high sodium intake (normal sodium diet 0.45% dry weight, 0.9% saline for drinking) for 10 days. The pressor-response curve to angiotensin II in rats previously on a high sodium intake was shifted to the left of that found in rats previously on a low sodium intake. Suppression of endogenous angiotensin II formation with captopril (0.3 mg kg-1) or acute volume repletion (3% body wt per 30 min) resulted in a significant parallel shift of the pressor-response curve for angiotensin II to the left in the low salt group. In the high salt group captopril produced a similar but smaller parallel shift of the dose-response curve to the left. Similar manipulation of endogenous angiotensin II concentrations with high and low salt intake plus captopril treatment or acute volume repletion, produced no alterations in the pressor response for noradrenaline. The attenuated in vivo response to angiotensin II in the low salt intake group may be explained in part by the suppressed vascular sensitivity to angiotensin II in this group, as measured in the isolated perfused kidney of the rat. In kidneys from rats previously on a low sodium intake, an enhanced maximal vasoconstrictor response to noradrenaline was observed as compared to kidneys from high sodium intake rats. These results indicate that, whereas alterations in endogenous angiotensin II concentrations within physiological limits affects the response to exogenous angiotensin, there is little if any effect on the pressor response to noradrenaline.

Angiotensin II↗

PubMed1985

Alpha 2-adrenoceptor antagonism of vasopressin-induced changes in sodium excretion.

Alpha 2-adrenoceptor agonists attenuate vasopressin-mediated changes in water excretion. The effects on sodium excretion, however, are unclear. We therefore utilized the nonrecirculating isolated perfused rat kidney to study the direct effects of vasopressin and alpha 2-adrenoceptor stimulation on sodium and water excretion in the absence of systemic regulatory systems. The perfusate was a Krebs-Henseleit solution (3.5 g/100 ml Ficoll; 1.0% albumin; 36 degrees C) containing prazosin (30 nM) and propranolol (100 nM) to prevent effects of alpha 1- and beta-adrenoceptor stimulation. Vasopressin (10 microU/ml) produced a significant (P less than 0.05) decrease in both water and sodium excretion. Potassium excretion was not significantly altered. Alpha 2-Adrenoceptor stimulation with l-epinephrine (28 nM) reversed (P less than 0.05) the effects of vasopressin on water and sodium excretion. To confirm that this attenuation was mediated by alpha 2-adrenoceptors, an alpha 2-adrenoceptor antagonist, yohimbine, was administered. Yohimbine (300 nM) blocked the effects of epinephrine on sodium and water excretion (P less than 0.05). The adenosine P-site agonist, SQ 22,536 (100 microM), which mediates its effects through inhibition of adenylate cyclase, produced the same reversal as that of epinephrine on vasopressin-mediated changes. Thus alpha 2-adrenoceptor stimulation antagonized the effects of vasopressin on both water and sodium excretion at the renal level. A corollary to this conclusion is that the function-specific activation of renal adenylate cyclase determines the effect of alpha 2-adrenoceptor stimulation.

Adenine↗

PubMed1985

Alpha2-adrenoceptors and cellular cAMP levels in single nephron segments from the rat.

A functional role for the numerically predominant renal alpha2-adrenoceptors, which in other tissues inhibit adenylate cyclase, remains undefined. We therefore examined the effect of alpha2-adrenoceptor stimulation with (-)-epinephrine (E) on cell cAMP content in the isolated proximal convoluted tubule (PCT), medullary and cortical thick ascending limb of Henle, and collecting tubule (MTAL, CTAL, MCT, and CCT, respectively). Parathyroid hormone (1-34 PTH), in PCT or CTAL, or arginine vasopressin (AVP), in MTAL, CTAL, MCT, or CCT, was used to activate adenylate cyclase in intact cells from these microdissected nephron segments in the presence of 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor) and propranolol. Alpha2-Adrenoceptors were activated using varying concentrations of E (37 degrees C, 2 min). Alpha2-Adrenoceptor activation with E (5 X 10(-7) to 5 X 10(-6) M) suppressed cellular cAMP stimulation by PTH by 35% in PCT and stimulation by AVP in CCT by 50%. This suppression by E in PCT and CCT was inhibited by 5 X 10(-6) M yohimbine or 5 X 10(-7) M phentolamine but not by 5 X 10(-6) M prazosin. E also suppressed cAMP stimulated by AVP in MCT, but it did not suppress the PTH-or AVP-stimulated increase in cellular cAMP in CTAL and MTAL. These studies show that there are alpha2-adrenoceptors in the rat nephron. Activation of these alpha 2-adrenoceptors can inhibit cAMP formation stimulated by PTH in PCT and by AVP in the CCT and MCT but not in the CTAL and MTAL. A pathophysiological role of altered regulation of these receptors is yet to be described.

Adenylyl Cyclases↗

PubMed1985

Renal nerve stimulation causes alpha 1-adrenoceptor-mediated sodium retention but not alpha 2-adrenoceptor antagonism of vasopressin.

Renal alpha 2-adrenoceptor stimulation by epinephrine infusion reverses cyclic adenosine monophosphate-mediated effects of vasopressin on sodium and water excretion. We used this response to determine whether renal nerve stimulation can activate renal alpha 2-adrenoceptors in the non-recirculating isolated perfused rat kidney (Krebs-Henseleit solution; 3.5 g/100 ml Ficoll; 1 g/100 ml albumin; 36 degrees C; propranolol 100 nM). In the presence of alpha 1-adrenoceptor blockade with prazosin (30 nM) alpha 2-adrenoceptor stimulation with epinephrine reversed the cyclic adenosine monophosphate-mediated effects of vasopressin on sodium (P less than 0.05) and water (P less than 0.05) excretion. Subthreshold (for vasoconstriction) renal nerve stimulation (10 V; 1 msec; 0.65 +/- 0.10 Hz) failed to alter the effect of vasopressin. Similarly, higher levels of renal nerve stimulation [plus prazosin (100 nM) or phenoxybenzamine (1.0 mg/kg per hr) to block alpha 1-adrenoceptors] did not activate renal alpha 2-adrenoceptors which are associated with the antagonism of the effects of vasopressin. The same level of subthreshold renal nerve stimulation (0.85 +/- 0.14 Hz) in the absence of vasopressin, and without alpha 1- or alpha 2-adrenoceptor blockade, decreased (P less than 0.05) sodium and water excretion. The reversal of this effect by alpha 1-adrenoceptor blockade (prazosin 30 nM) but not alpha 2-adrenoceptor blockade (yohimbine 300 nM) indicates that this effect of renal nerve stimulation is mediated through alpha 1-adrenoceptors. Thus, subthreshold renal nerve stimulation in the rat kidney induces sodium and water retention through activation of alpha 1-adrenoceptors, as shown by others in the rabbit and dog.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Renal alpha 2-adrenoceptors, their locations and effects on sodium excretion.

Research on alpha 2-adrenoceptors has been explosive since the first functional or pharmacologic classification of these agents in 1977. While several properties of renal alpha 2-adrenoceptors have been characterized, their possible role in the pathophysiology of hypertension remains elusive. Under normal circumstances, alpha 1-adrenoceptors appear to be located postjunctionally and alpha 2-adrenoceptors are extrajunctional. However, following chronic alpha 1-adrenoceptor blockade with prazosin, the renal alpha 2-adrenoceptor density increases and they may assume the otherwise exclusive alpha 1-adrenoceptor postjunctional domain. This assumed role of alpha 2-adrenoceptors may explain the absence of natriuresis with the clinical use of prazosin and, if a similar change occurs in vascular tissue, the temporary nature of the first-dose phenomenon (orthostatic hypotension) that occurs with the use of this drug. Finally, our description of the "postsynaptic" location of the ubiquitous plasma membrane alpha 2-adrenoceptors in the original functional or pharmacologic basis of classification of alpha-adrenoceptors should now be updated. Under normal conditions, the predominant alpha 2-adrenoceptors on effector organ plasma membranes appear to be extrajunctional and do not ordinarily mediate the effects of sympathetic neuronally released norepinephrine. Postjunctional alpha 1-adrenoceptors remain postjunctional and ordinarily mediate effects of nerve-stimulated norepinephrine release.

Animals↗

PubMed1984

Indomethacin and angiotensin II pressor responsiveness: importance of dietary sodium.

Dietary sodium intake alters pressor responsiveness to angiotensin II (AII) as well as altering prostaglandin production. As a result, the effect of prostaglandin synthesis inhibition on the pressor responsiveness to AII was evaluated. Prostaglandin synthesis inhibition with meclofenamate (5 mg/kg) or indomethacin (5 mg/kg) significantly enhanced the pressor response for AII at infusion rates of 0.10, 0.30 and 1.0 microgram/kg per min (P less than 0.05) in rats previously on a low sodium intake but had no effect in rats previously on a high sodium intake. In low sodium intake rats, pretreatment with captopril (1 mg/kg) prevented the enhancing effect of indomethacin on angiotensin II pressor responsiveness. The pressor response for norepinephrine was unaltered by sodium intake or prostaglandin inhibition. These results suggest that prostaglandin synthetase inhibition may enhance the pressor response for angiotensin II in situations where endogenous angiotensin II levels are elevated (i.e. low sodium intake). In situations where angiotensin II levels are suppressed (i.e. captopril pretreatment or high salt intake), prostaglandin synthetase inhibitors have no effect on the pressor response to exogenous angiotensin II.

Angiotensin II↗

PubMed1984

Alpha 2-adrenoceptors and sodium reabsorption in the isolated perfused rat kidney.

Alpha 2-Adrenoceptors are known to inhibit adenylate cyclase in a number of tissues, but their function in the kidney is unknown. Adenylate cyclase and sodium excretion were stimulated with furosemide (30 microM) in the rat kidney perfused with Krebs-Henseleit solution (albumin 6.5 g/100 ml, 36 degrees C). beta-Adrenoceptors and alpha 1-adrenoceptors were blocked by propranolol (100 nM) and prazosin (30 nM) in the perfusate. Urinary cAMP and sodium excretion increased with furosemide. Activation of alpha 2-adrenoceptors with epinephrine (28 nM) caused no change in perfusion pressure or flow but decreased urinary cAMP and sodium excretion. These effects of epinephrine were reversed by the alpha 2-selective adrenoceptor blocking agent yohimbine (300 nM). Thus, in the setting of furosemide-stimulated sodium excretion and an associated elevation of adenylate cyclase, alpha 2-adrenoceptor stimulation resulted in sodium retention and inhibition of adenylate cyclase. By this receptor mechanism the sympathoadrenal system may contribute to retention of sodium.

Adenylyl Cyclases↗

PubMed1984

Alpha-1 adrenoceptor selectivity of phenoxybenzamine in the rat kidney.

The dose-dependent selectivity of an irreversible binding antagonist, phenoxybenzamine (POB), for renal alpha-1 adrenoceptors, was biochemically and physiologically characterized. Receptors were quantified with the radioligands [3H]prazosin and [3H]rauwolscine for alpha-1 and alpha-2 adrenoceptors, respectively. Alpha-1 adrenoceptor function was quantified by the shift of the norepinephrine and phenylephrine pressor response in vivo and the vasoconstrictor response in the isolated perfused kidney preparation. A renal alpha-2 adrenoceptor response was demonstrated by showing that epinephrine could reverse the effect of vasopressin on water and sodium in the presence of beta blockade and alpha-1 destruction by POB. Doses of POB from 0.1 to 10.0 mg/kg progressively reduced [3H]prazosin binding to renal alpha-1 adrenoceptors until there was no specific binding at the 10.0-mg/kg dose. At this dose more than 60% of [3H]rauwolscine binding to renal alpha-2 adrenoceptors was still present. POB 1.0 mg/kg/hr decreased specific binding to renal alpha-1 adrenoceptors by approximately 40% (P less than .05) but reduced the alpha-1 adrenoceptor-induced vasoconstriction in the nonrecirculating isolated perfused kidney to 10 to 20% of the control. This was the maximal dose of POB studied which did not affect the alpha-2 adrenoceptor-induced antagonism of vasopressin. Higher doses of POB (3.0 mg/kg/hr) demonstrated some alpha-2 adrenoceptor binding as indicated by an attenuation of the antagonism by alpha-2 adrenoceptors. Thus, POB displays selectivity for renal alpha-1 over alpha-2 adrenoceptors. Our data indicate that a dose of 1.0 mg/kg/hr of POB will leave alpha-2 adrenoceptors intact while functionally incapacitating alpha-1 adrenoceptors to 10 to 20% of the control value.

Animals↗