Impaired renal vascular response to a D1-like receptor agonist but not to an ACE inhibitor in conscious spontaneously hypertensive rats.

The natriuretic response to a dopamine 1-like receptor agonist is blunted in spontaneously hypertensive rats (SHRs). Whether the renal vasodilator response to D1-like receptor stimulation in SHRs is defective also is unclear. To determine whether the renal hemodynamic response to a D1-like receptor is impaired in SHR, we examined the effect of a continuous infusion of the D1-like receptor agonist fenoldopam (2 microg/kg/min) on systemic and renal hemodynamics in conscious SHRs and Wistar-Kyoto (WKY) rats. As an active control, we used an equivalent antihypertensive dosage of captopril (10 mg/kg). Fenoldopam significantly increased effective renal plasma flow (ERPF) in WKY rats (+22 +/- 5%; p < 0.01), whereas this response was absent in SHRs (+7 +/- 3%; NS). Mean arterial pressure (MAP) was significantly reduced in SHRs (-11 +/- 2%; p < 0.001), demonstrating a systemic vasodilator response to fenoldopam in SHRs. The reduction in renal vascular resistance (RVR) was more pronounced in WKY rats (-24 +/- 2%) than in SHRs (-13 +/- 4%; p < 0.05). Captopril significantly increased ERPF in SHRs (+16 +/- 3%; p < 0.001), demonstrating a preserved renal vasodilatory capacity in SHRs. The blunting of the renal vasodilatory response to fenoldopam in SHRs is present during a high as well as a low sodium intake. In conscious SHRs, the renal vasodilatory response to a D1-like receptor agonist is impaired, whereas the blood pressure response is more pronounced. The preserved renal vasodilatory response to captopril indicates that the defective vasodilatory response in SHRs is functional rather than due to altered structural properties of the renal vascular bed.     

D2 -like receptor stimulation decreases effective renal plasma flow and glomerular filtration rate in spontaneously hypertensive rats

In spontaneously hypertensive rats (SHRs) the dopaminergic D1-like renal vasodilator response is impaired. The renal vascular response to D2-like receptor stimulation in vivo is incompletely known. Therefore, renal hemodynamics were studied in conscious SHRs during continuous infusion of D2-like agonist N,N-Di-n-propyldopamine (DPDA) (10 microg/kg/min) with Wistar-Kyoto (WKY) rats as controls. As sodium status may affect dopaminergic responses, rats were studied during both low- and high-sodium diets. D2-like stimulation reduced mean arterial pressure and effective renal plasma flow and glomerular filtration rate (GFR) similarly in SHR and WKY rats. Renal vascular resistance increased significantly in both strains. The response to DPDA is modified by sodium status, with a more pronounced fall in blood pressure (in WKYs and SHRs) and GFR (in WKYs) during high-sodium conditions. The responses were blocked by co-infusion with D2 antagonist domperidone. Thus, D2-like renal vascular responses are normal in SHRs irrespective of sodium intake. The combination of a preserved D2-like renal vasoconstrictive and an impaired D1-like renal vasodilatory response may contribute to maintenance of hypertension in SHRs.     

Dopamine D3 receptor-mediated inhibition of Na+/H+ exchanger activity in normotensive and spontaneously hypertensive rat proximal tubular epithelial cells

This study evaluated the response of the Na(+)/H(+) exchanger (NHE) to dopamine D(1)- and D(2)-like receptor stimulation in immortalized renal proximal tubular epithelial cells and freshly isolated renal proximal tubules from the spontaneously hypertensive rat (SHR) and their normotensive controls (Wistar Kyoto rats; WKY). Stimulation of D(1)-like receptors with SKF 38393 attenuated NHE activity in WKY cells (IC(50)=151 nM), but not in SHR cells. Stimulation of D(2)-like receptors with quinerolane (IC(50)=120 nM) attenuated NHE activity in SHR cells, but not in WKY cells. Forskolin was equipotent in SHR and WKY cells in inhibiting NHE activity. The effect of SKF 38393 was abolished by overnight treatment of WKY cells with cholera toxin (CTX, 500 ng ml(-1)), but not with pertussis toxin (PTX, 100 ng ml(-1)). The effect of quinerolane (1 microm) was abolished by overnight treatment of SHR cells with PTX, but not with CTX. The D(3) receptor agonist 7-OH-DPAT (IC(50)=0.8 microM) attenuated NHE activity in SHR cells only. This effect was abolished by S-sulpiride and by overnight treatment with PTX. The D(4) receptor agonist RBI 257 did not affect NHE activity. The 7-OH-DPAT inhibited NHE activity in freshly isolated renal proximal tubules from 4- and 12-week-old SHR and 12-week-old WKY, but not in freshly isolated renal proximal tubules from 4-week-old WKY. It is concluded that D(3) receptors coupled to a G(i/o) protein play a role in the handling of tubular Na(+), namely through inhibition of the NHE activity, this being of particular relevance in the SHR, which fail to respond to D(1)-like dopamine receptor stimulation.     

Pharmacological profile of the vascular responses to dopamine in the canine external carotid circulation

The present study investigated the effects of dopamine on the canine external carotid circulation. One min. intracarotid artery (i.c.) infusions of dopamine (10-310 microg min.-1) produced dose-dependent decreases in the canine external carotid conductance without affecting blood pressure or heart rate. This effect was mimicked by the D1/2-like receptor agonist apomorphine (1-310 microg min-1), but not by the D2-like receptor agonist, bromocriptine (31-310 microg min.-1). In contrast, fenoldopam (1-310 microg min.-1, intracarotid), a D1-like receptor agonist, produced dose-dependent increases in external carotid conductance. The vasoconstrictor response to dopamine was abolished after intravenous administration of the antagonists, phentolamine (alpha1/2; 2000 microg kg-1) or rauwolscine (alpha2; 100 microg kg-1), but remained unaffected after prazosin (alpha1; 100 microg kg-1) or haloperidol (D2-like; 1000 microg kg-1). Interestingly, after phentolamine not only were the vasoconstrictor responses to dopamine abolished, but even a dose-dependent vasodilator component was unmasked. These vasodilator responses to dopamine remained unchanged after intravenous haloperidol or propranolol (1000 microg kg-1 each). On the other hand, the vasodilator responses to fenoldopam, which remained unchanged after intravenous saline (0.1 ml kg-1), propranolol (1000 microg kg-1) or vagosympathectomy, were abolished by the D1-like receptor antagonist, SCH-23390 (10 microg kg-1). Lastly, the responses to dopamine and fenoldopam were not significantly altered after intraperitoneal pretreatment with reserpine (5 mg kg-1; -24 hr). The above results suggest that the canine external carotid vasoconstrictor responses to dopamine: (i) are mainly mediated by alpha2-adrenoceptors; and (ii) overshadow a vasodilator component, which involves vascular D1-like receptors.     

Decreased postsynaptic dopaminergic and cholinergic functions in the ventrolateral striatum of spontaneously hypertensive rat

Dopamine and acetylcholine receptor functions in spontaneously hypertensive rats (SHR) and in control progenitor Wistar-Kyoto (WKY) rats were assessed, using dopamine D1-like/D2-like receptor-mediated and acetylcholine receptor-mediated jaw movements as readout parameters. Spontaneous behaviours such as locomotor activity, vacuous chewing, grooming, sniffing and rearing occurred significantly more in SHR than in WKY rats. In the anaesthetised rats, a mixture of SKF 38393 (5 micrograms), a dopamine D1-like receptor agonist, and quinpirole (10 micrograms), a dopamine D2-like receptor agonist, readily produced repetitive jaw movements in WKY rats, but not SHR, when bilaterally injected into the ventrolateral striatum; such injections into the nucleus accumbens shell were ineffective in each strain. Bilateral injections of carbachol (2.5 micrograms each side), an acetylcholine receptor agonist, into the ventrolateral striatum elicited repetitive jaw movements in both SHR and WKY rats, but to a far less degree in SHR. The present study demonstrates that spontaneous behaviours are enhanced in SHR, and that postsynaptic dopamine D1-like/D2-like receptors and acetylcholine receptors in the ventrolateral striatum of SHR are hyposensitive when compared to those of WKY rats.     

Effects of antihypertensive drugs on capillary rarefaction in spontaneously hypertensive rats: intravital microscopy and histologic analysis

We investigated the effects of chronic oral antihypertensive treatment on functional and structural capillary rarefaction in spontaneously hypertensive rats (SHR). Wistar Kyoto rats (WKY) were used as a normotensive control group. In untreated rats, intravital videomicroscopy showed that functional capillary density was lower in SHR skeletal muscle (WKY 395 +/- 17 and SHR 258 +/- 13 capillaries/mm, P < 0.01) and ear skin (WKY 391 +/- 18 and SHR 210 +/- 15 capillaries/mm, P < 0.01). A linear relationship was seen between skeletal muscle and skin capillary densities (r = 0.654, P < 0.0001). Histologic analysis showed that SHR had a lower capillary-to-fiber ratio in the skeletal muscle (WKY 1.74 +/- 0.08 and SHR 1.40 +/- 0.06, P < 0.01). Capillary volume density-to-fiber volume density ratio in the left ventricle of SHR was also reduced (WKY 0.55 +/- 0.09 and SHR 0.42 +/- 0.09, P < 0.01). The animals were treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril, the angiotensin II type I receptor (AT1) receptor antagonist losartan, the beta-blocker atenolol, or the calcium channel blocker nifedipine, resulting in similar reductions in systolic blood pressure (19.8%, 19.1%, 17.4%, and 18.2%, respectively, P > 0.05). Atenolol did not induce any change in functional capillary density of SHR. Losartan and nifedipine completely reversed functional capillary rarefaction in both muscle and cutaneous tissues, whereas enalapril significantly increased functional capillary density only in the skin. The skeletal muscle capillary-to-fiber ratio was normalized by enalapril, losartan, and nifedipine. Treatments with enalapril or losartan normalized the cardiac structural capillary rarefaction of SHRs, whereas atenolol and nifedipine had no effect. Our results suggest that different pharmacologic classes of antihypertensive drugs with similar effect on blood pressure differ in terms of their effect on the microcirculation.     

Role of cardiac hypertrophy in reducing the sensitivity of cardiopulmonary reflex control of renal sympathetic nerve activity in spontaneously hypertensive rats

The gain of the volume-sensitive cardiopulmonary reflex (VSCR) is impaired in spontaneously hypertensive rats (SHR). Sensitivity of VSCR control of efferent renal sympathetic nerve activity (RSNA) in SHR is restored when cardiac hypertrophy and hypertension are reduced by enalapril treatment. The present study investigated which of these two parameters, cardiac hypertrophy or hypertension, has more influence on the impairment of VSCR control of RSNA in SHR. Rats (SHR or Wistar-Kyoto (WKY) rats) were treated with enalapril (10 mg/kg per day; SHRE and WKYE groups, respectively) or hydralazine (5 mg/kg per day; SHRH and WKYH groups, respectively) mixed in their food for 1 month. Control SHR and WKY rats were fed a normal diet. After the treatment regimen, the VSCR was evaluated by determining the decrease in RSNA elicited by acute isotonic saline volume expansion. Mean arterial pressure (MAP) was assessed via an intrafemural catheter and cardiac hypertrophy was determined by the left ventricular (LV) weight/bodyweight (BW) ratio. Afferent baroceptor nerve activity (BNA) was also evaluated during volume expansion to verify participation of the baroreflex. Volume expansion produced an attenuated renal sympathoinhibitory response in SHR compared with WKY rats. Enalapril treatment restored the volume expansion-induced decrease in RSNA in SHRE (-41 +/- 8%) compared with WKY rats (-44 +/- 3%). Although both enalapril and hydralazine treatment reduced MAP in SHR (P < 0.01; 126 +/- 5, 133 +/- 6 and 160 +/- 6 mmHg in SHRE, SHRH and SHR, respectively), hydralazine did not restore the sensitivity of VSCR control of RSNA in SHRH. Spontaneously hypertensive rats with established hypertension had a higher LV/BW ratio compared with WKY rats (3.22 +/- 0.14 vs 1.98 +/- 0.06 mg/g, respectively; P < 0.01). Enalapril reduced the LV/BW ratio in SHRE (2.30 +/- 0.07 mg/g; P < 0.01). Although hydralazine reduced LV hypertrophy, there was a weaker reduction in SHRH (2.68 +/- 0.04 mg/g; P < 0.05) compared with SHRE. There was no statistically significant difference among the WKY rat, WKYE and WKYH groups (P > 0.05). There was no change in afferent BNA during volume expansion in normal or hypertensive animals. Taken together, these results indicate that the impairment of VSCR control of RSNA in the SHR model of hypertension correlates better with the magnitude of cardiac hypertrophy than the level of arterial pressure.     

Inhibition of Ang II and renal sympathetic nerve influence dopamine-and isoprenaline-induced renal haemodynamic changes in normal Wistar-Kyoto and spontaneously hypertensive rats

1. This study was undertaken to elucidate the effects of inhibiting the renin-angiotensin system (RAS) with losartan, and acute unilateral renal denervation on renal haemodynamic responses to intrarenal administration of vasoconstrictor doses of dopamine and vasodilator doses of isoprenaline in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Acute unilateral renal denervation of the left kidney in rats was confirmed by a drop in the renal vasoconstrictor response to renal nerve stimulation (P < 0.05) along with diuresis and natriuresis. Rats were pretreated with losartan for 7 days and thereafter animals fasted overnight were anaesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and acute renal haemodynamic responses studied. 3. Dose-response curves were constructed for dopamine and isoprenaline that induced falls or increases in renal blood flow, respectively. It was observed that renal vascular responses were greater in the denervated as compared with rats with intact renal nerves (all P < 0.05). Dopamine-induced renal vasoconstrictor responses were markedly lower in losartan-treated denervated WKY and SHR compared with their untreated counterparts (all P < 0.05). It was also observed that in losartan-treated and denervated WKY rats the vasodilatory responses to isoprenaline were markedly lower compared with untreated rats (all P < 0.05). However, in SHR, under the same conditions, there was no difference in the renal response to isoprenaline whether or not rats were treated with losartan (P > 0.05). 4. The data obtained showed that the renal vasoconstrictor effect of dopamine depends on intact renal nerves and RAS in WKY and SHR. Isoprenaline responses were likewise sensitive to renal denervation and RAS inhibition in WKY rats but not SHRs. Our observations reveal a possible relationship between renal AT(1) receptors and alpha(1)-adrenoceptors in WKY and SHR. There is also evidence to suggest an interaction between renal beta-adrenoceptors and AT(1) receptors in WKY rats.     

Upregulation of tachykinin NK-1 and NK-3 receptor binding sites in the spinal cord of spontaneously hypertensive rat: impact on the autonomic control of blood pressure

1 Effects of intrathecally (i.t.) injected tachykinin NK-1 and -3 receptor agonists and antagonists were measured on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR,15-week-old) and age-matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiography was also performed on the lower thoracic spinal cord of both strains and Wistar rats using specific radioligands for NK-1 receptor ([(125)I]HPP[Arg(3),Sar(9),Met(O(2))(11)]SP (3-11)) and NK-3 receptor ([(125)I]HPP-Asp-Asp-Phe-N-MePhe-Gly-Leu-Met-NH(2)). 2 The NK-1 agonist [Sar(9),Met(O(2))(11)]SP (650 and 6500 pmol) decreased MAP and increased HR in WKY. The fall in MAP was blunted in SHR and substituted by increases in MAP (65-6500 pmol) and more sustained tachycardia. The NK-3 agonist senktide (6.5-65 pmol) evoked marked increases in MAP and HR (SHR>WKY), yet this response was rapidly desensitized. Cardiovascular effects of [Sar(9),Met(O(2))(11)]SP (650 pmol) and senktide (6.5 pmol) were selectively blocked by the prior i.t. injection of LY303870 (NK-1 antagonist, 65 nmol) and SB235375 (NK-3 antagonist, 6.5 nmol), respectively. Antagonists had no direct effect on MAP and HR in both strains. 3 Densities of NK-1 and -3 receptor binding sites were significantly increased in all laminae of the spinal cord in SHR when compared to control WKY and Wistar rats. The dissociation constant was however not affected in SHR for both NK-1 (K(d)=2.5 nM) and NK-3 (K(d)=5 nM) receptors. 4 Data highlight an upregulation of NK-1 and -3 receptor binding sites in the thoracic spinal cord of SHR that may contribute to the hypersensitivity of the pressor response to agonists and to the greater sympathetic activity seen in this model of arterial hypertension.     

The effect of medetomidine, an alpha 2-adrenoceptor agonist, on plasma atrial natriuretic peptide levels, haemodynamics and renal excretory function in spontaneously hypertensive and Wistar-Kyoto rats.

1. The effects of the selective alpha 2-adrenoceptor agonist, medetomidine, were assessed on plasma levels of immunoreactive atrial natriuretic peptide (IR-ANP), haemodynamics and on urine water and solute excretion in conscious, chronically cannulated, 7 month-old spontaneously hypertensive (SHR) and age-matched Wistar-Kyoto (WKY) rats, in order to examine the role of alpha 2-adrenoceptors in the control of ANP secretion. 2. A 60 min i.v. infusion of medetomidine (0.2 or 0.6 microgram kg-1 min-1) decreased heart rate dose-dependently in both strains. Medetomidine infusion (0.6 microgram kg-1 min-1) resulted in an increase in mean arterial pressure in WKY, whereas both doses decreased blood pressure in SHR. There was a slight increase in the right atrial pressure in both strains (WKY: +1.18 +/- 0.26 mmHg; SHR: +1.64 +/- 0.64 mmHg, NS) in response to infusion of 0.6 microgram kg-1 min-1 of medetomidine. 3. No differences were found in resting plasma IR-ANP levels between WKY (114 +/- 8 pg ml-1, n = 19) and SHR (117 +/- 10 pg ml-1, n = 21). Infusion of equibradycardic doses of medetomidine increased dose-dependently plasma IR-ANP levels in WKY, but did not affect the plasma IR-ANP concentration in SHR rats. 4. Despite the different effect of medetomidine on ANP release in WKY and SHR rats, i.v. administration of medetomidine affected renal excretory functions similarly in both strains; urine flow and sodium excretion increased and urine osmolality decreased significantly, while there was no consistent change in urinary potassium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Release of atrial natriuretic peptide from rat myocardium in vitro: effect of minoxidil-induced hypertrophy.

1. Ventricular hypertrophy is characterized by stimulation of ventricular synthesis of atrial natriuretic peptide (ANP). To examine the role of ventricular ANP levels in the secretion of ANP into the circulation, atrial and ventricular levels of immunoreactive-ANP (IR-ANP) as well as ANP messenger RNA (mRNA), and the release of IR-ANP from isolated perfused hearts, both before and after atrialectomy, were measured simultaneously in control and minoxidil-treated Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. 2. IR-ANP levels in the ventricles of untreated, 12 month-old SHR with severe ventricular hypertrophy were increased when compared to age-matched WKY rats. Minoxidil treatment for 8 weeks in both strains resulted in a decrease in mean arterial pressure and increases in ventricular weight to body weight ratios, plasma IR-ANP concentrations (in WKY from 133 +/- 20 to 281 +/- 34 pg ml-1, P less than 0.01; in SHR from 184 +/- 38 to 339 +/- 61 pg ml-1, P less than 0.05), and in ventricular IR-ANP contents (in WKY: 53%; in SHR: 41%). A highly significant correlation was found between ventricular IR-ANP content and ventricular weight to body weight ratio (r = 0.59, P less than 0.001, n = 26). 3. When studied in vitro, in isolated perfused heart preparations, the hypertrophied ventricular tissue after atrialectomy secreted more ANP into the perfusate than ventricles of the control hearts; ventricles contributed 28%, 22%, 18% and 15% of the total ANP release to perfusate in the minoxidil-treated SHR, control SHR, minoxidil-treated WKY and control WKY, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats

1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. 2. Quercetin induced a significant reduction in systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha) excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. 6. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug.     

Tissue angiotensin II and endothelin-1 modulate differently the response to flow in mesenteric resistance arteries of normotensive and spontaneously hypertensive rats

In resistance arteries pressure-induced (myogenic) tone (MT) and flow (shear stress)-induced dilation (FD) are potent determinant of vascular resistance. We investigated the role of angiotensin II and endothelin-1 in FD and MT in resistance arteries and their potential change in hypertension. Flow - diameter - pressure relationship was established in situ, under anaesthesia, in two daughter branches of a mesenteric resistance artery (180 microM, n=7 per group) from spontaneously hypertensive (SHR) or normotensive (WKY) rats. One artery was ligated distally, so that it was submitted to pressure only, while the other was submitted to pressure and flow. Drugs were added to the preparation and external diameter, pressure and flow measured continuously. External diameter (with flow) ranged from 150+/-3 to 191+/-7 microM in WKY (n=28) rats and from 168+/-6 to 186+/-6 microM in SHR (n=28). Flow induced a dilation of the non-ligated arteries which was lower in SHR (13+/-5 - 31+/-4 microM vs WKY: 5+/-5 - 44+/-4 microM). In the ligated artery, the diameter did not significantly change, due to MT. In the vessels submitted to flow angiotensin converting enzyme inhibition (perindopril, 10 micromol L(-1)) increased the diameter in SHR (+11+/-2 microM) significantly more than in WKY (+2+/-1 microM). Angiotensin type 1 receptor (AT(1)R) blockade (losartan, 10 micromol L(-1)) increased the diameter in the vessels with flow in SHR only (+6+/-1 microM). Angiotensin type 2 receptor (AT(2)R) blockade (PD 123319, 1 micromol L(-1)) decreased arterial diameter in WKY only (9+/-2). Endothelin-1 type A receptor (ET(A)R) blockade (LU135252, 0.1 micromol L(-1)) increased the diameter only in SHR in the artery submitted to flow (by 6+/-1 microM). Thus FD was counteracted by a flow-dependent AT(1) and ET(A) receptors-activation in SHR whereas in WKY FD AT(2)-dependent dilation is involved.     

Decreased responsiveness of the aortae of hypertensive rats to acetylcholine, histamine and noradrenaline.

The responses to noradrenaline (NA) of the aortae of various hypertensive rats, namely the spontaneously hypertensive rat (SHR), the low blood pressure SHR (LBP-SHR), and the left renal artery stenosed LBP-SHR (LRAS-LBR-SHR), were compared to those of the normotensive Wistar-Kyoto rats (WKY). The aortae of the hypertensive rats were significantly more responsive (P less than 0.05) to 10(-8) M NA. However, the reverse was true for higher doses of NA. The ED50 values for the aortae of WKY, LBP-SHR, SHR and LRAS-LBP-SHR were 20, 8.5, 7.8 and 8 nM respectively. The NA-contracted aortae of the LRAS-LBP-SHR were significantly less responsive (P less than 0.05) to the relaxant action of histamine and acetylcholine (ACh) compared to those of the WKY. This observation was not made in the aortae of the LBP-SHR. The maximal relaxation (% of the maximal contraction induced by 10(-8) M NA) observed in the aortae of WKY, LBP-SHR and LRAS-LBP-SHR were, respectively, 72 +/- 2, 66 +/- 6, 39 +/- 7 for ACh and 50 +/- 3, 36 +/- 4, 27 +/- 3 for histamine. In aortae where the endothelium had been removed by collagenase treatment, histamine induced a dose-related contraction. The rank order of this dose-related contraction was WKY greater than LBP-SHR greater than SHR greater than LRAS-LBP-SHR with the corresponding maximal tension (g) 0.89 +/- 0.04, 0.59 +/- 0.04, 0.36 +/- 0.04, 0.19 +/- 0.05.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in the in vitro pharmacodynamic properties of metoprolol in atria isolated from spontaneously hypertensive rats

1. The present study addressed possible changes in the dissociation constant of metoprolol and its inverse agonist activity in spontaneously hypertensive rats (SHR). In addition, a possible correlation between cardiac hypertrophy and the inverse agonist activity of metoprolol was explored. 2. In order to determine the dissociation constant (expressed as the pKb) of metoprolol, a cumulative concentration-response curve to noradrenaline was constructed in the absence or presence of metoprolol (0.1, 1 or 10 micromol/L). In a second experiment, a cumulative concentration-response curve to metoprolol was constructed to determine its inverse agonist activity. 3. The ventricular weight of SHR was significantly greater compared with Wistar-Kyoto (WKY) rats. A rightward shift of the concentration-response curve to noradrenaline was observed in SHR compared with WKY rats. The pKb of metoprolol was smaller in SHR compared with WKY rats (6.35 +/- 0.14 vs 6.99 +/- 0.12, respectively; P < 0.05). No difference was observed in the maximal response (Emax) of the concentration-time effect of metoprolol in WKY rats and SHR (-29.1 +/- 7.1 vs-28.2 +/- 8.5%, respectively; n = 6 for both). However, the concentration of metoprolol eliciting a half-maximal effect (expressed as the pEC50) was significantly smaller in SHR compared with WKY rats (4.82 +/- 0.07 vs 5.29 +/- 0.13, respectively; n = 6; P < 0.05). Although a significant correlation (r = -0.876) between the ventricular weight/bodyweight (VW/BW) ratio and the pEC50 of the chronotropic effect of metoprolol was found, no relationship (r = -0.257) was found between the VW/BW ratio and Emax. 4. In summary, the present study provides the first evidence of a change in the in vitro pharmacodynamic properties of metoprolol in SHR. The sympathetic overactivity present in SHR not only reduces the positive chronotropic effect of noradrenaline, but also diminishes the constant dissociation of metoprolol from atrial beta1-adrenoceptors and its inverse agonist activity. A significant correlation between the VW/BW ratio and the inverse agonist potency of metoprolol was found, suggesting a possible link between cardiac hypertrophy and the reduction of the inverse agonist activity of metoprolol.     

Alterations of renal vasopressin V1A and V2 receptors in spontaneously hypertensive rats

To elucidate the role of arginine vasopressin (AVP) in a hypertensive state, the characteristics of renal cortex V(1A) and medulla V(2) receptors in young spontaneously hypertensive rats (SHR) during the developmental phase of hypertension were compared with those of age-matched Wistar-Kyoto (WKY) rats using the radioligand receptor assay technique. The systolic blood pressure of 8-week-old SHR was statistically significantly higher than that of WKY rats (142 +/- 1 vs. 125 +/- 2 mm Hg). The plasma AVP levels were also significantly higher in SHR than in WKY rats (3.20 +/- 0.41 vs. 1.96 +/- 0.34 pg/ml). In SHR, the maximum capacity of (3)H-d(CH(2))(5)Tyr(Me)AVP binding to cortical V(1A) receptors (B(max)) was statistically significantly higher than that of WKY rats (39.7 +/- 2.7 vs. 22.4 +/- 0.9 fmol/mg protein). Furthermore, the B(max) values of (3)H-AVP binding to medullary V(2) receptors in SHR were also significantly higher than in WKY rats (40.2 +/- 1.9 vs. 28.3 +/- 1.3 fmol/mg protein). However, the apparent dissociation constant (K(d)) values of renal cortex V(1A) and medulla V(2) receptors in SHR and WKY rats were not significantly different. These results indicate that increased amounts of renal cortex V(1A) and medulla V(2) receptors in SHR play an important role in the pathophysiology of hypertension.     

Pharmacological characterization of the effects of dopamine D(1) agonists on eye blinking in rats

Dopamine D(1)-like partial agonists antagonize some abuse-related effects of cocaine and have been proposed as candidate medications for psychostimulant abuse. Earlier studies have showed that D(1)-like agonists increase eye blinking in monkeys and that the magnitude of this effect may be related to agonist efficacy. These studies characterized the effects of D(1)-like agonists on eye blinking in female Sprague-Dawley rats placed in customized restraint tubes. After vehicle injections, eye blink rates averaged 2.1+/-0.25 blinks/min, or 31+/-4 blinks/15 min. The D(1)-like agonists SKF 82958 and R(+)-6Br-APB dose-dependently increased eye blinking to 136 and 124/15 min, respectively. The selective D(1)-like antagonist SCH 23390 decreased eye blinking and the peripherally selective D(1)-like agonist fenoldopam, the D(2)-like agonist (+)PHNO, and the indirect dopamine agonist methamphetamine all failed to alter eye blink rates relative to vehicle levels. Additional studies with unique congeners and isomers of the D(1)-like partial agonist SKF 83959, MCL 202, MCL 204, MCL 206, MCL 207 and MCL 209, resulted in only moderate increases in eye blink rates (27-84 blinks/15 min). These effects were dose-related for one compound, MCL 209 (max 84+/-19 blinks/15 min) and plateaued at the highest doses, suggestive of partial agonist effects. Additionally, the agonist MCL 206, like the D(1)antagonist SCH 23390, antagonized the effects of SKF 82958 on eye blinking. The findings suggest that D(1)-like agonists increase eye blinking in rats and that these effects may provide a simple measure that can be used to distinguish partial D(1)-like ligands. Further studies with novel D(1)-like partial agonists may be useful in the development of pharmacotherapies for cocaine abuse.     

Renal vasodilatation by dopexamine and fenoldopam due to alpha 1-adrenoceptor blockade.

1. The renal vascular responses of the rat isolated perfused kidney to the dopamine D1-receptor agonists, dopexamine and fenoldopam, were examined. 2. Both kidneys were perfused in situ at constant flow rate (11 ml min-1) with Krebs-bicarbonate solution at 37 degrees C. The perfusion pressure was monitored and to enable vasodilator responses to be measured, the resting perfusion pressure was raised by infusing noradrenaline (6 x 10(-9) M). 3. Dose-related vasodilator responses to bolus doses of dopexamine and fenoldopam were obtained. However, these were not antagonized by the D1-receptor antagonist, SCH 23390, indicating that D1-receptors were not involved. 4. Bolus doses of the alpha 1-adrenoceptor antagonist, prazosin, caused similar dose-related vasodilator responses indicating the possibility that alpha 1-adrenoceptor blocking properties of dopexamine and fenoldopam were responsible for the vasodilatation. 5. alpha-Adrenoceptor blockade by dopexamine and fenoldopam was confirmed by the parallel displacement of dose-response curves for the vasopressor responses to noradrenaline. pA2 values were determined by Schild analysis for dopexamine, fenoldopam and prazosin antagonism of noradrenaline in the presence of neuronal (cocaine, 10(-5) M) and extraneuronal uptake blockade (metanephrine, 10(-5) M). The values were 6.23, 6.02 and 8.91, respectively. Schild plot slopes of unity were obtained for dopexamine and fenoldopam indicating competitive antagonism. A slope of greater than unity for prazosin may be explained by the lack of equilibrium conditions associated with bolus doses of noradrenaline, the responses of which are affected more by the high affinity antagonist, prazosin, than the two lower affinity antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

The contribution of adrenoceptor subtype(s) in the renal vasculature of diabetic spontaneously hypertensive rats

1. Diabetes and hypertension are both associated with an increased risk of renal disease and are associated with neuropathies, which can cause defective autonomic control of major organs including the kidney. This study aimed to examine the alpha(1)-adrenoceptor subtype(s) involved in mediating adrenergically induced renal vasoconstriction in a rat model of diabetes and hypertension. 2. Male spontaneously hypertensive rats (SHR), 220-280 g, were anaesthetized with sodium pentobarbitone 7-day poststreptozotocin (55 mg x kg(-1) i.p.) treatment. The reductions in renal blood flow (RBF) induced by increasing frequencies of electrical renal nerve stimulation (RNS), close intrarenal bolus doses of noradrenaline (NA), phenylephrine (PE) or methoxamine were determined before and after administration of nitrendipine (Nit), 5-methylurapidil (5-MeU), chloroethylclonidine (CEC) and BMY 7378. 3. In the nondiabetic SHR group, mean arterial pressure (MAP) was 146+/-6 mmHg, RBF was 28.0+/-1.4 ml x min(-1) x kg(-1) and blood glucose was 112.3+/-4.7 mg x dl(-1), and in the diabetic SHR Group, MAP was 144+/-3 mmHg, RBF 26.9+/-1.3 ml(-1) min x kg(-1) and blood glucose 316.2+/-10.5 mg x dl(-1). Nit, 5-MeU and BMY 7378 blunted all the adrenergically induced renal vasoconstrictor responses in SHR and diabetic SHR by 25-35% (all P<0.05), but in diabetic rats the responses induced by RNS and NA treated with 5-MeU were not changed. By contrast, during the administration of CEC, vasoconstrictor responses to all agonists were enhanced by 20-25% (all P<0.05) in both the SHR and diabetic SHR. 4. These findings suggest that alpha(1A) and alpha(1D)-adrenoceptor subtypes contribute in mediating the adrenergically induced constriction of the renal vasculature in both the SHR and diabetic SHR. There was also an indication of a greater contribution of presynaptic adrenoceptors, that is, alpha(1B)-, and/or alpha(2)-subtypes.     

Effects of endothelin-1 on systemic and renal hemodynamics in hypertensive-diabetic rats (CRDH), diabetic rats (CDR), and hypertensive rats (SHR)

The Cohen-Rosenthal diabetic hypertensive rat is a unique animal model in which genetic hypertension and diabetes developed after crossbreeding of a sensitive substrain of Cohen diabetic rats and spontaneously hypertensive rats (SHR) and feeding them a copper-poor sucrose diet. This study examined the acute effects of endothelin-1 on the systemic and renal hemodynamics in Cohen-Rosenthal diabetic hypertensive rats, Cohen diabetic rats and spontaneously hypertensive rats. Intravenous injection of endothelin- 1 (1.0 nmol/kg) into anesthetized SHR resulted in a significant immediate depressor response in mean arterial pressure [from 165 +/- 3 mmHg to 124 +/- 12 mmHg (P < 0.0001)] followed by a minor hypertensive phase (mean arterial pressure increased to 170 +/- 2 mmHg). Simultaneously, the administration of endothelin-1 caused a significant decrease in renal blood flow from 5.8 +/- 0.9 mL/minute to 3.2 +/- 0.5 mL/minute (P = 0.026). These responses were blunted in Cohen-Rosenthal diabetic hypertensive rats and Cohen diabetic rats. Analysis of intrarenal blood flow by laser-Doppler in Cohen-Rosenthal diabetic hypertensive rats revealed that endothelin-1 injection caused a decrease in cortical blood flow (Delta = -12 +/- 2.9%). However, in contrast to its well known renal medullary vasodilatory effect, endothelin-1 produced a significant decline in the medulla blood flow (Delta = -17.5 +/- 3.4%) (P = 0.0125). These findings suggest that Cohen diabetic rats and Cohen-Rosenthal diabetic hypertensive rats have reduced sensitivity to the vascular and renal action of endothelin-1. Furthermore, in the Cohen-Rosenthal diabetic hypertensive rats the expected endothelin- 1-induced medullary vasodilation was abolished and even reversed into prolonged vasoconstrictor response.