Effects of the novel coronary selective calcium channel blocker, McN-6186, on cardiocirculatory dynamics, coronary vascular resistance, and cardiac output distribution in normal, conscious rats.

The purpose of this study was to characterize the cardiocirculatory effects of the novel calcium channel blocker, McN-6186 (McN), normal, conscious rats. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive microsphere technique was used to measure regional blood flow (RBF) and cardiac output (CO) before (control) and during intravenous (i.v.) infusion of either McN at three doses (0.03, 0.1, 0.3 mg/kg) or vehicle at an equal infusion rate (0.0408 ml/min). Nifedipine (NIF) was also studied at three similar blood pressure (BP)-lowering doses (0.025, 0.150, and 0.375 mg/kg). The predominant effect of McN in conscious rats was to cause coronary vasodilation. The coronary vasodilator potency of McN was similar to NIF (ED25, McN = 0.03 mg/kg, NIF = 0.025 mg/kg). Neither McN nor NIF significantly changed systemic vascular resistance (SVR) over their respective coronary vasodilator dose ranges, suggesting that both compounds are selective coronary vasodilators. The doses of McN and NIF that reduced mean arterial pressure (MAP) by 25% (ED25) were similar (McN = 0.3 mg/kg, NIF = 0.375 mg/kg). At equal BP-lowering doses, McN increased coronary flow by 145% versus 110% for NIF. McN did not have major effects on other regions of the peripheral circulation. There was, however, some vasodilator activity in the renal and cerebral vascular beds. Because McN reduced coronary vascular resistance at a dose lower than that required to reduce resistance in other vascular beds, this compound appears to be a selective coronary vasodilator and may have therapeutic efficacy as an antianginal agent.     

Effects of intravenous diltiazem on cardiocirculatory dynamics and cardiac output distribution in conscious spontaneously hypertensive rats

The effects of the calcium channel blocker, diltiazem hydrochloride (DZ), on conscious, resting spontaneously hypertensive rats (SHR) were evaluated and compared with results from parallel studies on Wistar-Kyoto (WKY) controls. DZ was administered as a continuous, cumulative infusion at rates equal to 0.40, 2.00, and 10.00 mg/kg/h (each dose was administered for 15 min). Parallel volume infusion (saline) controls were simultaneously conducted using volume infusion rates identical to those used in DZ studies (0.015, 0.100, and 0.500 ml/min). Three hours prior to study, animals were instrumented under halothane anesthesia for measurement of left ventricular, arterial, and central venous pressures; heart rate and arterial blood gases; and for injection of radioactive microspheres and subsequent determination of cardiac output, regional blood flows, and cardiac output distribution. All data were collected at control (C) before initiation of infusion, and at the end of each 15-min infusion period in each animal. At C and compared with WKY, SHR had increased heart rate (392 vs. 280 beats/min), mean arterial pressure (155 vs. 100 mm Hg), left ventricular peak systolic pressure (200 vs. 132 mm Hg), and systemic vascular resistance (0.3 vs. 0.2 mm Hg/ml/min/kg), and reduced stroke volume (1.8 vs. 2.2 ml/beat/kg); but no difference in cardiac output, left ventricular end diastolic pressure, or central venous pressure was found. At C, SHR tended to have increased blood flow and reduced vascular resistance in the coronary circulation and increased vascular resistance in the cutaneous, renal, bronchial arterial, hepatic arterial, testicular, and cerebral circulations. Infusion of DZ increased cardiac output and stroke volume and decreased heart rate, left ventricular and arterial pressures, and systemic vascular resistance in SHR. Similar changes of substantially smaller magnitude were observed in WKY. DZ increased flow and reduced resistance in the coronary and skeletal muscle circulations of SHR to a greater extent than in WKY. DZ also normalized vascular resistance in previously elevated regions. These results suggest that acute intravenous infusion of DZ at doses ranging between 2 and 5 mg/kg is capable of normalizing cardiovascular hemodynamics and regional blood flow distribution in SHR.     

Effects of bepridil hydrochloride on cardiocirculatory dynamics, coronary vascular resistance, and cardiac output distribution in normal, conscious rats

The purpose of this study was to characterize the cardiocirculatory effects of bepridil hydrochloride (BP) in the normal, conscious rat. Animals were instrumented under halothane anesthesia for right atrial, left ventricular, arterial, and venous pressure recordings. The radioactive-microsphere technique was used to measure regional blood flow and cardiac output before (control) and during intravenous (i.v.) infusion of either BP at three dosage levels (3.0, 6.0, 12.0 mg/kg) or vehicle (VH) at infusion rates matching those of the BP protocol (0.0408 ml/min). The predominant effects of BP (cumulative dose = 9.0 mg/kg i.v.) in the conscious rat were reduced coronary vascular resistance and heart rate. BP showed selectivity for the coronary circulation since systemic vascular resistance was not significantly reduced until a cumulative i.v. dosage of 21.0 mg/kg was administered. BP had few effects on other regions of the peripheral circulation. BP (21 mg/kg) reduced blood flow and increased vascular resistance in the arterial circulations of four of six skeletal muscles studied although opposite effects occurred in two of six muscles studied. BP had no significant effect on blood flow or vascular resistance in the other major arterial circulations. The results of this study show that BP is a selective coronary vasodilator that also reduces the primary indices of myocardial oxygen demand. These results suggest that the clinical therapeutic antianginal efficacy of BP occurs through a combined effect to increase myocardial oxygen supply and to reduce myocardial oxygen demand.     

Effects of the antihypertensive prostaglandin analog CL 115,347 on cardiac output distribution in the spontaneously hypertensive rat

The effects of CL 115,347, a novel prostaglandin E2 (PGE2) congener, on a variety of hemodynamic variables were examined in conscious spontaneously hypertensive rats. Within minutes of topical administration (0.03, 0.3, or 3.0 mg/kg), a dose-dependent decrease in mean arterial blood pressure (MABP) was observed. One hour following drug application, a stable, dose-related hypotensive effect was still apparent, with MABP from 18 to 33 mm Hg lower than control, predose values. Quantitation of blood flow using radioactive microspheres indicated that a significant increase in stroke volume and cardiac output (3.0 mg/kg only), as well as a reduction in total peripheral resistance, was associated with the administration of CL 115,347. Further analysis of regional blood flow implied that vasodilation in specific vascular beds may contribute importantly to the antihypertensive activity of this compound.     

Effects of the calcium channel blocker AE0047 on renal function in conscious spontaneously hypertensive rats: Focus on renal proximal tubules

The hypotension induced by peripheral vasodilators is occasionally accompanied by diminished urine formation induced via various anti-diuretic mechanisms. The question of whether an antihypertensive agent has diuretic action is therefore relevant to its usefulness. In the present study, conducted in conscious, spontaneously hypertensive rats (SHR), the lithium clearance technique was used to investigate the effect of intravenously administered AE0047 on renal function; the effect of orally administered AE0047 on uric acid excretion was also investigated. Intravenous injection of AE0047 (10 and 30 μg/kg) produced potent hypotension, accompanied by diuresis and natriuresis. The diuretic action was accompanied by an elevation of FE_Na and FE_Li levels, with minimal change in GFR. Oral administration of AE0047 (1 and 3 mg/kg) led to a dose-related increase in urine volume and in urinary excretion of sodium and uric acid (U_UAV). Simultaneous administration of pyrazinamide, an inhibitor of uric acid secretion in proximal tubules, mitigated the increase in U_UAV. These findings indicate that systemically administered AE0047 produces diuresis and natriuresis, in part via an inhibition of sodium and water reabsorption in the proximal tubules. The action of AE0047 at renal proximal tubular sites thus offers benefit in hypertension therapy. Drug Dev. Res. 41:91–98, 1997. © 1997 Wiley-Liss, Inc.     

Protection against endothelial abnormalities by a novel calcium channel blocker, AE0047, in stroke-prone spontaneously hypertensive rats

We investigated the protective effect of chronic treatment with AE0047, a dihydropyridine-type calcium channel blocker, on vascular endothelial abnormalities in stroke-prone spontaneously hypertensive rats (SHRSP). Ten-week repeated antihypertensive treatment with AE0047 inhibited blood pressure elevation and improved endothelium-dependent relaxation in response to acetylcholine in aorta isolated from SHRSP. Furthermore, the abnormal production of prostaglandin I2 and thromboxane A2 in the aorta was normalized to a level equivalent to that in Wistar-Kyoto rats. These results suggest that chronic treatment with AE0047 exerts protective effects against endothelial abnormalities associated with the development of hypertension.     

Natriuretic action of manidipine hydrochloride, a new calcium channel blocker, in spontaneously hypertensive rats

Effects of manidipine, a new dihydropyridine derivative, on sodium and water excretion were examined in conscious spontaneously hypertensive rats. Manidipine (3 mg/kg) significantly increased the sodium and water excretion in the urine collected for 3 hr after the calcium antagonist was orally administered, and its natriuretic action was more prominent than those of nifedipine and nicardipine (3 mg/kg). These results suggest that manidipine may be useful for treating hypertension.     

Antihypertensive effect of CS-905, a novel dihydropyridine calcium blocker, in conscious hypertensive dogs

CS-905, (+-)-3-(1-diphenylmethylazetidin-3-yl)5-isopropyl 2-amino-1,4-dihydro-6-methyl-4-(m-nitrophenyl)-3,5-pyridine-dicarboxy lat e, is a novel dihydropyridine calcium blocker. Both CS-905 and nicardipine, when administered orally, produced a dose-dependent fall of blood pressure in conscious perinephritic hypertensive dogs. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in the heart rate and plasma renin activity (PRA). The lack of both tachycardia and increase of PRA is probably mostly due to the slow onset of antihypertensive action following CS-905.     

Effects of benidipine hydrochloride (Coniel®), a new calcium antagonist,on the cardiac output,regional blood flow and vascular resistance in conscious,spontaneously hypertensive rats

Benidipine hydrochloride is a calcium antagonist with a 1,4-dihydropyridine derivative structure, and exhibits long-lasting antihypertensive effects by inhibiting the voltagedependent Ca²⁺ channels. This study was undertaken to examine the effect of benidipine on central haemodynamics and regional blood flow (RBF) after intravenous administration of benidipine in conscious, spontaneously hypertensive rats. The microsphere method was used to measure cardiac output and RBF before and after the drug administration, using microspheres labelled with ⁵⁷Co and ⁵¹Cr. Thirty minutes after the intravenous administration of benidipine (3 μg kg^?1), the mean arterial pressure fell by 15% without significantly increasing the heart rate. The cardiac output increased by 41% and the systemic resistance decreased by 39%. Benidipine significantly increased RBF by 37,35, and 22% in kidney, heart, and small intestine, respectively, and decreased vascular resistance by 38, 38, and 32%, respectively. We concluded that benidipine reduced blood pressure by increasing RBF in the kidney and heart, while keeping RBF in other organs at a normal level. These results will provide a fundamental basis in support of the clinical benefits of benidipine for hypertensive patients, particularly those with renal failure.     

Effects of the L- and N-type calcium channel blocker cilnidipine on growth of vascular smooth muscle cells from spontaneously hypertensive rats

Cultured vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) show exaggerated growth compared with cells from Wistar-Kyoto (WKY) rats. Calcium antagonists have recently been reported to have an in vivo antiproliferative effect on hypertensive cardiovascular organs. We investigated the effects of the calcium antagonist cilnidipine that blocks both L- and N-type calcium channels on the growth of VSMC from SHR. Cilnidipine (1 and 10 microM) significantly inhibited basal DNA synthesis in VSMC from both rat strains; the inhibition was significantly larger in VSMC from SHR than in cells from WKY rats, and was significantly greater than effects of nifedipine. Cilnidipine (1 microM) significantly inhibited serum-stimulated DNA synthesis in VSMC from both rat strains. The inhibition was more marked in VSMC from SHR than in cells from WKY rats. Angiotensin II, platelet-derived growth factor (PDGF)-AA, and phorbol-12-myristate-13-acetate dose-dependently increased DNA synthesis in VSMC from SHR but not in cells from WKY rats. Cilnidipine (1 microM) significantly suppressed this increase in DNA synthesis in VSMC from SHR. Expression of basic fibroblast growth factor (bFGF), transforming growth factor-beta1, and PDGF A-chain mRNAs was markedly greater in VSMC from SHR than in cells from WKY rats. Cilnidipine (1 microM) significantly inhibited the expression of TGF-beta1 mRNA in VSMC from SHR but not in cells from WKY rats. These findings suggest that cilnidipine exerts its antiproliferative effects through the inhibition of DNA synthesis induced by growth-promoting factors and by inhibiting the expression of TGF-beta1 mRNA in VSMC from SHR.     

Effects of the novel calcium channel blocker,anipamil, on the isolated rabbit heart

Summary The calcium channel blocking activity of the novel phenylalkylamine derivative, anipamil, was tested on the isolated rabbit heart, in comparison with verapamil and gallopamil. Anipamil and the other calcium channel blockers lower left ventricular pressure in the same concentration range (10^–8 –10^–4 mol/1). The negative inotropic effect of anipamil is only partially reversed (nearly 65%) by rising calcium concentration in the perfusion fluid, whilst a complete recovery is observed for verapamil and gallopamil. The negative inotropic effect of anipamil is of rapid onset but long lasting, being still present 12 h after washout. On the contrary, that of gallopamil or verapamil completely disappears within 3 h of washout.Verapamil and gallopamil (10^–8 –10^–4 mol/1) depress spontaneous heart rate up to asystolia and abolish the vasopressin- and Bay K 8644-induced coronary spasm. Anipamil, on the contrary, does not modify coronary spasm elicited by both stimulants and spontaneous heart rate up to 10^–4 mol/l.These observations suggest that anipamil, in the isolated rabbit heart, possesses a peculiar pharmacological profile, since its calcium channel blocking activity is confined to the myocardial muscle.     

Effects of CV-4093, a new dihydropyridine calcium channel blocker, on renal hemodynamics and function in stroke-prone spontaneously hypertensive rats (SHRSP)

Renal effects of CV-4093, a newly developed dihydropyridine calcium channel blocker, were examined using anesthetized stroke-prone spontaneously hypertensive rats, and the findings were compared with those of nicardipine. An intravenous injection of CV-4093 (2 micrograms/kg) produced long-lasting hypotension with a slow-onset accompanied by moderate renal vasodilation. There were no appreciable alterations in glomerular filtration rate (GFR) and urine formation, except that urine flow (UF) increased significantly during the first 10 min after injection. When CV-4093 was administered at 10 micrograms/kg, the hypotensive action was markedly augmented. Eighty minutes after the injection, a decrease in mean arterial pressure of about 45 mmHg was observed. Simultaneously, renal blood flow increased significantly from the control value of 5.76 +/- 0.46 ml/g.min to 6.94 +/- 0.28 ml/g.min. Renal vascular resistance decreased immediately after the injection, and the response lasted for over 3 hr, thereby indicating the marked and sustained renal vasodilating effect of CV-4093. GFR was constant throughout the experiment, but UF and urinary excretion of sodium were increased significantly. Fractional excretion of sodium was also elevated, thereby suggesting an inhibitory action of CV-4093 on renal tubular reabsorption of sodium. Nicardipine at a dose of 10 micrograms/kg, a dose producing an effective hypotensive action, caused no significant increases in RBF and urine formation. The renal vasodilating and diuretic actions of CV-4093 may provide a beneficial effect in the treatment of hypertension.     

Effects of cromakalim, a potassium channel opener, on regional blood flow in conscious spontaneously hypertensive rats

We studied the effects of cromakalim, a potassium channel opener, on regional blood flow in conscious spontaneously hypertensive rats using microspheres. Cromakalim produced significant hypotension and increased blood flow in the stomach, skeletal muscle and skin. Calculated vascular resistances decreased in many organ vascular beds. Although nifedipine also showed a similar hemodynamic profile, differences were observed in the brain, gastrointestinal tract and skin.     

Haemodynamic effects of bromocriptine in the conscious spontaneously hypertensive rat

The systemic haemodynamic effects of 0.3 mg kg-1 bromocriptine s.c. in conscious, chronically instrumented spontaneously hypertensive rats (SHR) has been investigated. Bromocriptine caused a gradual, long-lasting significant fall in mean arterial pressure with a maximum of 26 +/- 3 mmHg (-17%). The fall was related to a significant decrease in stroke volume index (-9 +/- 2 microliters 100 g-1; -10%) and cardiac index (-3.9 +/- 0.8 ml min-1 100 g-1; -12%). No significant changes in heart rate or total peripheral resistance index were observed. These data do not support previous suggestions that the antihypertensive effect of bromocriptine is caused by inhibition of the release of vasopressor substances. It is suggested that bromocriptine causes a reduction of venous return of the blood to the heart, possibly related to intrarenal effects.     

Long-term renal vasodilator effect of the beta-adrenoceptor blocker tertatolol in conscious spontaneously hypertensive rats

In conscious spontaneously hypertensive rats (SHR), 5-day intravenous infusions with the beta-adrenoceptor blockers propranolol (5 mg/kg/day) or tertatolol (0.5 mg/kg/day) caused a chronic reduction of blood pressure (-12% +/- 1% and -28% +/- 1%, respectively, on day 5) and heart rate (-13% +/- 3% and -8% +/- 2%, respectively, on day 5). Propranolol infusion led to a 23%-31% reduction of blood flow through the renal, mesenteric, and hindquarter vascular bed. Tertatolol caused similar flow reductions, with the exception of the renal vascular bed, which was dilated. Tertatolol induced reduction of renal vascular resistance of 29% +/- 2% on day 5. These studies show a long-term renal vasodilatory activity of tertatolol during chronic administration to SHR.     

Changes of cardiac calcium homeostasis in spontaneously hypertensive rats

1 The aim of the present study was to assess the alterations in cardiac Ca²⁺ homeostasis induced by hypertension using electrically paced right ventricular strips from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2 Basal contractile force was higher in SHR than in WKY. Similarly, the β-adrenoceptor agonist isoprenaline (10 n m –10 μm ) induced a concentration-dependent positive inotropic effect that was higher in SHR than in WKY, which was in turn inhibited by the β-adrenoceptor antagonist propranolol (1 μm ) in both strains. 3 Preincubation of strips with the L-type Ca²⁺ channel blockers, nifedipine (1 μm ) or verapamil (10 μm ), markedly inhibited the isoprenaline response, the inhibition being higher in SHR than in WKY. However, this inhibition was minor by the T-type Ca²⁺ channel blocker mibefradil (10 μm ). 4 Bay K 8644 (10 n m –10 μm ), a L-type Ca²⁺ channel activator induced a concentration-dependent positive inotropic effect, that was greater in SHR than WKY. 5 Nifedipine and verapamil (both 0.1 n m –10 μm ) inhibited in a concentration-dependent way the inotropic effect induced by 0.3 μm isoprenaline or 1 μm Bay K 8644. The inhibition was higher in SHR than in WKY. Mibefradil (0.1 n m –10 μm ) only clearly inhibited the isoprenaline and Bay K 8644 inotropic effects at 10 μm in both strains. 6 The inhibitor of the sarcoplasmic reticulum Ca²⁺ release, ryanodine (10 n m –10 μm ), was a more effective depressor of isoprenaline-induced response in SHR than in WKY. 7 These results suggest that cardiac Ca²⁺ homeostasis in SHR ventricular strips is altered compared with those of WKY, showing an increased Ca²⁺ entry through L-type Ca²⁺ channels and release from sarcoplasmic reticulum; the participation of T-type Ca²⁺ channels are irrelevant in this tissue.     

Effects of benidipine, a long-lasting dihydropyridine-Ca2+ channel blocker, on cerebral blood flow autoregulation in spontaneously hypertensive rats

Chronic hypertension shifts cerebral blood flow (CBF) autoregulation towards higher blood pressure. We examined whether or not benidipine, a long-lasting dihydropyridine calcium channel blocker (CCB), improves the CBF autoregulation in spontaneously hypertensive rats (SHRs). CBF was analyzed by laser-Doppler flowmetry during stepwise hypotension by controlled bleeding. The lower limit of CBF autoregulation was calculated as the mean arterial blood pressure at which CBF decreased by 10% of the baseline. Mean arterial blood pressure and cerebral vascular resistance in SHRs were higher than those in normotensive Wistar rats. Oral administration of benidipine (3 mg/kg) for 8 d lowered the mean arterial blood pressure and cerebral vascular resistance, which were equivalent to the effects of amlodipine (3 mg/kg), another CCB, or candesartan (1 mg/kg), an Angiotensin II type-1 receptor blocker. The lower limit of CBF autoregulation in SHRs (142+/-4 mmHg) was significantly shifted to a higher-pressure level compared with Wistar rats (59+/-2 mmHg). The lower limit of CBF autoregulation was significantly lower in the benidipine-treated group (91+/-4 mmHg) than that in the control SHRs, and similar to that of the amlodipine group (97+/-6 mmHg). Benidipine reduced the lower limit of CBF autoregulation more effectively than candesartan (109+/-4 mmHg). In conclusion, benidipine shifted the limit of CBF autoregulation towards lower blood pressure in SHRs under hypotensive conditions by hemorrhage. These results suggest that benidipine may be useful for the treatment of hypertensive patients with the elderly or cerebrovascular disorders, in whom autoregulation of CBF is impaired.     

Action of the calcium channel blocker lacidipine on cardiac hypertrophy and endothelin-1 gene expression in stroke-prone hypertensive rats.

1. The tissue-protective effects of calcium channel blockers in hypertension are not well dissociated from their effect on systolic blood pressure (SBP). We have previously shown that lacidipine, a dihydropyridine-type calcium antagonist, reduced the cardiac hypertrophy and the cardiac endothelin-1 (ET-1) gene overexpression occurring in salt-loaded stroke-prone spontaneously hypertensive rats (SL-SHRSP), an effect occurring without systolic blood pressure (SBP) change. In the present study, we have examined whether this action was dose-related and if it could be associated with ET receptor changes. The action of lacidipine was also examined in control SHRSP and in Wistar Kyoto rats (WKY). 2. The daily dose of 0.3 mg kg-1 lacidipine which did not lower SBP but significantly prevented ventricle hypertrophy and cardiac preproET-1-mRNA expression in SL-SHRSP was inactive in control SHRSP. With the higher dose of lacidipine (1 mg kg-1 day-1), we observed a further reduction of cardiac hypertrophy and of ET-1 gene expression in SL-SHRSP and a significant effect on those parameters in control SHRSP but only a small reduction of SBP in both groups. 3. In WKY, salt loading did not induce change in SBP or increase of cardiac ET-1 gene expression and ventricle mass. In these normotensive rats, lacidipine (1 mg kg-1 day-1) did not modulate the basal preproET-1-mRNA expression and did not affect SBP or heart weight. 4. The maximum binding capacity (Bmax) and the dissociation constant (KD) of [125I]-ET-1 binding and the relative proportion of low- and high-affinity binding sites for ET-3 were not significantly affected by salt loading or lacidipine treatment in SHRSP. 5. These results show that lacidipine exerted a dose-related inhibition of ventricle hypertrophy and preproET-1-mRNA expression in SHRSP and indicate that this effect was unrelated to SBP changes. The dose-dependency of this inhibition suggests that salt-induced cardiac hypertrophy could be related to ET-1 gene overexpression. The results further show that ET receptor changes are not involved in the pathophysiological process studied here.     

OPC-13340, a new dihydropyridine calcium channel blocker attenuates rapid vascular smooth muscle cell growth in spontaneously hypertensive rats.

We investigated the mechanism of the antimitotic effects of calcium channel blockers in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR). VSMC from SHR exhibited rapid proliferation through a quick transition from the G0/G1 to the DNA synthetic (S) phase and from the S to the G2/mitotic (M) phase, whereas the DNA synthetic rate itself was equal to that of Wistar-Kyoto rats (WKY). OPC-13340, a new dihydropyridine calcium channel blocker, dose-dependently decreased incorporation of [3H]thymidine into the DNA fragments in randomly cycling VSMC in SHR. Cell cycle analysis showed that the rapid transition from the S to the G2/M period was restored by OPC-13340 to the control level in WKY, whereas the quick transition from G0/G1 to S was unaffected. This antimitotic effect of OPC-13340 was reflected by attenuation of enhanced cellular protein synthesis during the G2/M period. Protein synthesis in the G0/G1 period was not influenced by OPC-13340. Thus, these data indicate that the calcium channel blocker OPC-13340 mitigates the enhanced proliferation observed in randomly cycling VSMC from SHR and that this effect is primarily due to normalization of the premature mitosis during the G2/M period.     

Effects of ketanserin on hemodynamics and baroreflex effects in conscious spontaneously hypertensive rats

Ketanserin is an antihypertensive compound that binds to 5-HT2 receptors as well as to alpha 1-adrenoceptors. The relative importance of the two pharmacological interactions is still unclear. In the present study we compared the central hemodynamic effects of ketanserin with those of the alpha 1-adrenoceptor antagonist prazosin in conscious, unrestrained spontaneously hypertensive rats (SHR). Both drugs rapidly reduced mean arterial pressure (0.1 mg/kg prazosin, -22 +/- 3%; 3 mg/kg ketanserin, -27 +/- 4%) and total peripheral resistance (30 +/- 4 and 26 +/- 4%, respectively). The compounds differed with respect to their effects on heart rate and cardiac output, which increased following prazosin treatment and did not change following ketanserin administration. To investigate involvement of the baroreflex in the latter phenomenon, SHR were challenged with angiotensin II and sodium nitroprusside to increase and decrease blood pressure. Ketanserin did not influence bradycardia following elevation of blood pressure. However, reduction of blood pressure with nitroprusside following ketanserin treatment resulted in extreme vagal bradycardia. This phenomenon was not observed following administration of other antihypertensive agents or serotonin antagonists in SHR. We conclude that this latter interaction with the baroreflex is specific for ketanserin and that it may substantially contribute to its antihypertensive effect. The exact pharmacological mechanism underlying this effect is still under investigation.