Biomedical subjects

N L Howell

Publications and source records attributed to N L Howell.

9 recordsLinked to original sources

PubMed2001

Angiotensin type 2 receptor-mediated hypotension in angiotensin type-1 receptor-blocked rats.

The type-2 (AT(2)) angiotensin (Ang) II receptor has been characterized as potentially counterregulatory to the actions of Ang II at its type-1 (AT(1)) receptor. We investigated the effects of Ang II and CGP-42112A (CGP), a selective peptide AT(2) receptor agonist, on blood pressure (BP) in rats with or without pharmacological blockade of the AT(1) receptor with losartan (LOS) or valsartan (VAL). In anesthetized rats (n=5 per group) receiving normal sodium intake, Ang II (200 pmol/kg per minute IV) alone increased BP from a control of 112+/-3 to 168+/-7 mm Hg (P<0.001) and LOS (30 mg/kg) alone decreased BP to 89+/-7 mm Hg (P<0.0001 from control). Ang II administered together with LOS decreased BP further to 71+/-4 mm Hg (P<0.00001 from control and LOS alone). AT(2) receptor antagonist PD 123,319 (PD) completely blocked the hypotensive response to LOS combined with Ang II (P=NS from control). In conscious rats (n=5 per group) receiving normal sodium intake, VAL (10 mg/kg) alone decreased BP from a control of 98+/-5 to 86+/-3 mm Hg (P<0.00001). Ang II combined with VAL induced a consistent, highly significant decline in BP for 6 days to a nadir of 69+/-3 mm Hg (P<0.01 versus daily VAL alone). PD completely blocked the chronic hypotensive response to the combination of Ang II and VAL to control levels before VAL administration. In another study in conscious rats (n=5 per group), CGP (70 microg/kg per minute) also decreased BP in VAL-treated conscious rats. BP was 119+/-3 mm Hg during the control period, decreased to 86+/-6 mm Hg during 3 days of VAL alone, (P<0.00001) and decreased further to 65+/-7 mm Hg (P<0.001 from daily VAL alone) with 7 days of CGP in the presence of VAL. In the absence of VAL, CGP decreased BP for 4 consecutive days, and this response was blocked by PD. Also, the CGP-induced decrease in BP over a 7-day period was blocked by N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase. The results strongly suggest that the AT(2) receptor induces a systemic vasodilator response mediated by NO that counterbalances the vasoconstrictor action of Ang II at the AT(1) receptor.

Angiotensin Receptor Antagonists↗

PubMed2001

Selective inhibition of the renal angiotensin type 2 receptor increases blood pressure in conscious rats.

The angiotensin II type 2 (AT(2)) receptor is present in rat kidney; however, its function is not well understood. The purpose of this study was to evaluate the role of the AT(2) receptor in blood pressure (BP) regulation. The effects of selective inhibition of the renal AT(2) receptor with phosphorothioated antisense oligodeoxynucleotide (AS-ODN) were examined in conscious uninephrectomized rats. Oligodeoxynucleotides (AS-ODN or scrambled [S-ODN]) were infused directly into the renal interstitial space by using an osmotic pump at 1 microL/h for 7 days. Texas red-labeled AS-ODN was distributed in renal tubules in the infused but not the contralateral kidney of normal rats. Continuous renal interstitial infusion of the AS-ODN, but not S-ODN, caused a significant (P<0.01) increase in BP 1 to 5 days after the initiation of the infusion. AS-ODN-treated rats experienced an increase in systolic BP from 109+/-4 to 130+/-4 mm Hg (n=8, P<0.01), whereas S-ODN-treated (n=8) and vehicle-treated (n=8) rats did not show any significant change in BP. On day 5 of the oligodeoxynucleotide infusion, AS-ODN-treated rats exhibited a greater pressor response to systemic angiotensin II infusion (30 ng/kg per hour) than did S-ODN-treated rats (P<0.01). Renal interstitial fluid cGMP decreased from 11.9+/-0.8 to 3.6+/-0.5 pmol/mL (P<0.001), and bradykinin decreased from 0.05+/-0.05 to 0.18+/-0.03 ng/mL (P<0.001) in response to AS-ODN, but they were not significantly changed in response to S-ODN. To evaluate the effects of AS-ODN and S-ODN on AT(2) receptor expression, Western Blot analysis was performed on treated kidneys. Kidneys treated with AS-ODN had approximately 40% less expression of AT(2) receptor than did kidneys treated with S-ODN or vehicle (P<0.05). These results suggest that AS-ODN directed selectively against the renal AT(2) receptor decreased receptor expression and caused an increase in BP. We conclude that the renal AT(2) receptor plays an important role in the regulation of BP via a bradykinin/cGMP vasodilator signaling cascade.

Actins↗

PubMed1995

Renal interstitial fluid angiotensin. Modulation by anesthesia, epinephrine, sodium depletion, and renin inhibition.

Using a microdialysis technique, we monitored changes in right and left renal interstitial fluid angiotensins in anesthetized and conscious dogs (both n = 5) in response to right renal interstitial epinephrine (0.2 mg/kg per minute) administration. Renal interstitial and plasma angiotensin levels also were monitored in conscious dogs (n = 4) in response to dietary sodium deprivation (10 mmol/d) for 5 consecutive days. Changes in renal interstitial and plasma angiotensins in response to interstitial administration of a specific renin inhibitor, ACRIP (0.5 micrograms/kg per minute for 20 minutes), were monitored on day 5 of sodium depletion. At basal levels, there were no significant differences between the right and left renal interstitial immunoreactive angiotensin levels in anesthetized dogs. Renal interstitial epinephrine administration caused a significant increase in renal interstitial immunoreactive angiotensin concentrations in both anesthetized and conscious dogs (P < .01). However, anesthetized dogs had significantly higher renal interstitial immunoreactive angiotensin levels basally and in response to epinephrine than conscious dogs (P < .05). Renal interstitial immunoreactive angiotensin concentrations increased significantly and progressively during exposure to a low sodium diet from 3.9 +/- 1 nmol on day 1 to 740 +/- 332 nmol on day 5 (P < .01). Renal interstitial immunoreactive angiotensin decreased significantly to 124 +/- 37 nmol (P < .01) in response to intrarenal renin inhibition at the end of day 5 of sodium depletion. Plasma immunoreactive angiotensin increased significantly (P < .01) in response to sodium depletion, and no change occurred during intrarenal renin inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1990

Dopamine-1 and dopamine-2 mechanisms in the control of renal function.

Dopamine (DA), a catecholamine produced in the kidney, is a renal vasodilator and natriuretic substance, but its action at dopamine-1 (DA-1), dopamine-2 (DA-2) and alpha- and beta-adrenergic receptors limits its effectiveness as a heuristic tool and pharmacologic agent. We have studied the effects of highly selective DA-1 and DA-2 receptor agonists and antagonists in normal human subjects and experimental animals to determine the precise physiological role of renal dopamine at DA-1 and DA-2 receptors within the kidney. We studied fenoldopam, a selective DA-1 agonist, in normal human subjects in metabolic balances at high (300 mEq/day) and low (10 mEq/day) sodium (Na) intake. Selective DA-1 receptor stimulation during high Na intake resulted in renal vasodilation, natriuresis and diuresis in a sustained manner for 3 hours. The natriuresis was mediated by a reduction in Na reabsorption at both proximal and distal tubular sites. In contrast, during low Na intake, DA-1 receptor stimulation did not engender a natriuretic or diuretic response. Thus, sodium depletion may inhibit the function of renal tubular cells in response to DA-1 stimulation. DA-1 receptors are present in the medial layer of the renal vasculature, proximal tubule and cortical collecting duct; DA-2 receptors are localized to the glomerulus, the renal nerves surrounding renal blood vessels and possibly the renal vascular endothelium. We have performed studies in conscious dogs with indwelling renal arterial catheters to identify the physiological role of renal DA to DA-1 and DA-2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1990

Combined intrarenal blockade of the renin-angiotensin system in the conscious dog.

We produced maximal or near-maximal acute intrarenal blockade of the renin-angiotensin system (RAS) by combining inhibitors. Intrarenal infusion of the renin inhibitor, ACRIP, the converting enzyme inhibitor, teprotide, and saralasin were administered individually or combined in random order. The inhibitors were infused for 20 min in doses that did not produce systemic effects in uninephrectomized conscious dogs in sodium balance at 10 meq/day. Significant increases in urine flow rate (UV; F = 97, P less than 0.0001), urinary sodium excretion (UNaV; F = 220, P less than 0.0001), glomerular filtration rate (GFR; F = 64, P less than 0.0001), and renal plasma flow (RPF; F = 108, P less than 0.0001) were observed with each blocker, whether alone or in combination except that ACRIP alone did not alter GFR or RPF. The increase in renal function was related to the number of blockers (3 greater than 2 greater than 1). With the three blockers combined UV increased approximately sixfold (from 0.5 +/- 0.06 to 2.9 +/- 0.03 ml/min), UNaV approximately 10-fold (from 3 +/- 0.4 to 34 +/- 2.8 mueq/min), GFR from 31 +/- 2 to 49 +/- 2 ml/min, RPF from 59 +/- 1 to 120 +/- 4 ml/min, and fractional excretion of sodium from 0.06 +/- 0.01 to 0.5 +/- 0.4% (all P less than 0.001). These changes did not occur where the inhibitors were infused systemically and the changes during intrarenal blocker administration were blocked completely with co-administration of angiotensin II intrarenally. The intrarenal RAS is a potent physiological regulator of renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1990

Evidence that dopamine-2 mechanisms control renal function.

Dopamine is synthesized by the kidney, and dopamine-2 (DA2) receptors are present in the renal glomerulus. However, no role for DA2 receptors in the kidney has been defined. We investigated the possible role of DA2 receptors in control of renal function by intrarenal infusion of a highly specific DA2 antagonist YM-09151 (YM), in conscious uninephrectomized dogs (n = 5) in metabolic balance at Na intake 40 meq/day. YM infused at 0.01 pmol.kg-1.min-1 did not cause any changes in urinary flow rate or Na excretion. Administration of YM (infusions from 0.1 to 10.0 pmol.kg-1.min-1) caused a significant dose-dependent diuresis (F = 20.3; P less than 0.001) and natriuresis (F = 35.2; P less than 0.0001) and an increase in glomerular filtration rate (F = 45.4; P less than 0.0001), renal plasma flow (F = 209.3; P less than 0.0001), and filtration fraction (F = 11.2; P less than 0.0001). No significant changes in plasma renin activity, plasma aldosterone concentration, or mean arterial blood pressure occurred with any of the doses of YM infused into the renal artery. Coinfusion of LY-171555, a specific DA2 agonist, at a dose that itself did not affect renal function, completely abrogated the renal hemodynamic and excretory changes induced by YM. The data suggest that dopamine produced intrarenally may act at renal vascular and/or glomerular DA2 receptors to control renal function.

Animals↗

PubMed1989

Combined intrarenal renin-angiotensin blockade alters renal function and this is reversed by angiotensin II.

All the components of the renin-angiotensin system are present within the kidney and intrarenal effects have been demonstrated. We have previously shown that intrarenally confined doses of angiotensin II (Ang II) decreased renal excretory and haemodynamic function. In the present study we investigated an increase in renal excretory and haemodynamic function in response to intrarenally confined doses of the renin inhibitor ACRIP to inhibit renin, teprotide to inhibit the angiotensin converting enzyme (ACE) and saralasin to block Ang II receptors. We studied the effects of combined intrarenal blockade of the renin-angiotensin system in five female uninephrectomized conscious dogs on a sodium metabolic balance of 5 mmol/day. We infused ACRIP, teprotide and saralasin combined over 30 min in doses confined to the kidney, and again with an intrarenally confined dose of Ang II. There were no changes in renal function during the control study. During the combined infusion (ACRIP + teprotide + saralasin), the urine flow rate increased from 0.4 +/- 0.1 to 0.9 +/- 0.1 ml/min (P less than 0.001), urinary sodium excretion increased from 6.4 +/- 0.4 to 30.2 +/- 2.5 mumol/min (P less than 0.0001), the glomerular filtration rate increased from 29.3 +/- 0.7 to 42.0 +/- 1.2 ml/min (P less than 0.0001), renal plasma flow increased from 60.3 +/- 0.8 to 139.6 +/- 1.8 ml/min (P less than 0.001) and the fractional sodium excretion increased from 0.1 +/- 0.01 to 0.5 +/- 0.04% (P less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1989

Evidence that intrarenal dopamine acts as a paracrine substance at the renal tubule.

Dopamine is synthesized within the kidney and dopamine 1 (DA1) receptors are associated with the proximal tubule. In pharmacological doses, dopamine increases renal blood flow and sodium excretion. It is possible that dopamine formed intrarenally acts locally via renal dopamine receptors to control renal function. We investigated the possible paracrine action of renal dopamine by intrarenal administration of a specific DA1 antagonist, Sch 23390, in doses confined to the kidney in conscious uninephrectomized dogs (n = 5) in metabolic balance at a sodium intake of 40 meq/day. Changes (mean +/- SE) in renal excretory and hemodynamic function in response to cumulative infusions of several doses of Sch 23390 (0.01, 0.1, 1.0, 5.0, and 10.0 pmol.kg-1.min-1) were studied. Sch 23390 at 0.01 pmol.kg-1.min-1 did not cause any changes in urinary flow rate or sodium excretion. Sch 23390 in doses from 0.1 to 10.0 mol.kg-1.min-1 caused a significant dose-dependent antidiuresis (F = 44.9, P less than 0.0001) and antinatriuresis (F = 42.1, P less than 0.0001) and a decrease in fractional sodium excretion (F = 44.2, P less than 0.0001). No changes in estimated renal plasma flow, glomerular filtration rate, plasma aldosterone concentration, plasma renin activity, or systemic arterial pressure occurred with any dose of intrarenal Sch 23390 infused into the renal artery. Rebound diuresis and natriuresis occurred after cessation of the DA1 blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Intrarenal dopamine-1 receptors control renal function.

Dopamine receptors are classified to DA-1 and DA-2 and are characterized in renal tissue by radioligand binding and by the response of renal adenylate cyclase to dopaminergic agonists and antagonists. DA-1 receptors are localized in the renal tubules, the medial layer of renal microvessels, and the juxtaglomerular apparatus. DA-1 receptor stimulation causes dilation of renal, mesenteric, coronary, and cerebral vessels. In the present study, we tested the hypothesis that dopamine is a paracrine substance in the control of renal function. We employed a potent specific DA-1 receptor antagonist, SCH, to evaluate the role of intrarenal DA-1 receptor in the maintenance of renal function. Intrarenal DA-1 receptor blockade with SCH caused a highly significant dose-dependent antidiuresis and antinatriuresis, and decreased FENa. A rebound diuresis and natriuresis above control values were observed after cessation of DA-1 receptor blockade. There were no changes in renal hemodynamic function during DA-1 receptor blockade. These results strongly suggest that the antinatriuresis and antidiuresis induced by DA-1 receptor blockade are mediated by an action at the renal tubule. The infusion rate of SCH administered intrarenally was sufficiently low to produce no measurable systemic effects including PRA, PAC, and MAP. Thus, these results can be interpreted as due to intrarenal DA-1 blockade. In summary, we have demonstrated that renal excretory function is highly sensitive to DA-1 receptor blockade within the kidney and appears to be mediated by renal tubular events. This study provides strong evidence that DA-1 receptors play a physiological role in the control of renal function.

Animals↗