K-ATP-blocking diuretic PNU-37883A reduces plasma renin activity in dogs

We determined the effects of the K-adenosine triphosphate (ATP)-blocking diuretic PNU-37883A on plasma renin activity (PRA) in conscious and anesthetized dogs. In conscious dogs, oral PNU-37883A (6-60 mg/kg) was less potent than hydrochlorothiazide (0.15-1.5 mg/kg) and furosemide (FURO; 0.3-3.0 mg/kg) but exhibited high natriuretic efficacy with little kaliuresis. Unlike the standard diuretics, PNU-37883A reduced PRA by 46-76%, and its high dose minimally affected 24-h urinary aldosterone excretion. PNU-37883A, 1 mg/kg i.v., also blunted the hyperreninemia induced by 1 mg/kg i.v. FURO. In cannulated dogs, 10 mg/kg i.v. PNU-37883A maximally increased fractional Na+ clearance 140% and reduced PRA 76%, but these effects were accompanied by a mean 13 mm Hg pressor effect. In anesthetized dogs, renal artery-infused PNU-37883A (3 mg/kg/h i.r.a.) increased Na+ excretion and reduced renal venous PRA independent of hemodynamics, whereas half this dosage selectively reduced renal venous PRA and renin release, independent of hemodynamics and natriuresis. These data demonstrate that the K-ATP blocker diuretic PNU-37883A reduces PRA in dogs after oral, i.v., and i.r.a. administration and could be a useful pharmacologic agent for exploring the role of K-ATP channels in regulating renin release.     

Anesthesia with sodium pentobarbital enhances lipopolysaccharide-induced cardiovascular dysfunction in rats

Lipopolysaccharide (LPS)-induced hypotension and impaired aortic contraction to norepinephrine (NE) are thought to be consequent to induction of nitric oxide synthase (iNOS). Anesthesia is often employed in studies of the mechanisms mediating LPS-induced cardiovascular dysfunction in rats. Since sympathetic nervous system activity and compensatory mechanisms can be altered by anesthesia, this study was designed to determine a) if the cardiovascular dysfunction associated with LPS (5 mg/kg, i.v.)-induced endotoxin shock is enhanced in anesthetized compared with conscious male Wistar rats, and b) the potential role of iNOS in these responses to LPS. Arterial pressure and heart rate were continuously measured via a femoral arterial cannula. Six hours after LPS, conscious rats had a stable mean arterial pressure (MAP) and were tachycardic, while anesthetized rats showed a significant decrease in MAP without tachycardia. Small mesenteric arterioles (200-300 microns) were isolated, and the endothelium was removed six h after LPS. Intraluminal diameter was continuously recorded while vessels were maintained at a constant intraluminal pressure of 40 mmHg. Norepinephrine-induced contraction and oscillations/min were impaired to a greater extent in arterioles from LPS-treated anesthetized rats than in those from conscious rats. Calcium-dependent and -independent nitric oxide formation, reflected as cGMP accumulation, were also determined in aortic rings treated with a chelator of Ca2+, EGTA, or the inhibitor of nitric oxide synthase activity, L-NAME. In rings from saline-treated conscious and anesthetized rats, cGMP accumulation was significantly reduced by EGTA and L-NAME, indicating calcium-dependent constitutive (cNOS) activity. However, in aortic rings from LPS-treated conscious and anesthetized rats, cGMP accumulation was not affected by EGTA and was significantly greater in rings from anesthetized vs. conscious rats. These results suggest that cardiovascular dysfunction is more prominent in LPS-treated anesthetized vs. conscious rats. This effect may be related to increased induction of iNOS in the presence of anesthesia.     

Antagonism between the anti-inflammatory activity of the cannabinoid WIN 55212-2 and SR 141716A

The CB1/CB2 receptor agonist WIN 55212-2 (0.75 mg/kg, i.v.) caused a significant reduction in neurogenic plasma extravasation induced by electrical stimulation of the saphenous nerve in anesthetized rats; WIN 55212-2 at 2.5-10 mg/kg, s.c., also produced a significant reduction in the carrageenan-induced paw edema in conscious rats. The selective CB1 antagonist SR 141716A (0.075-0.75 mg/kg i.v.) antagonized the WIN 55212-2 effects in the plasma extravasation model and antagonized the WIN 55212-2 (2.5 mg/kg, s.c.)-induced decreases in rectal temperature and increases in tail-flick latencies. However, SR 141716A (10 mg/kg, p.o.) failed to antagonize the effects of Win 55212-2 (2.5 mg/kg, s.c.) in the carrageenan model, suggesting that cannabinoid receptors found in the periphery may be able to modulate inflammatory processes in rats.     

Comparison of a conscious versus anesthetized canine model in response to milrinone, hydralazine and nitroprusside

The purpose of this study was to demonstrate, based on previous and new data, that the differences between a conscious and anesthetized canine model in the cardiovascular responses to cardiovasoactive agents were beyond their difference in the sensitivity of the compensatory mechanisms. In both conscious and anesthetized canine models, mean arterial pressure (MAP) was decreased by hydralazine (at 1-3 mg/kg and 0.3-3 mg/kg; by -26.5 +/- 4.5 and -18.8 +/- 11.7% [max. changes expressed as mean +/- SEM], respectively). MAP was also decreased by nitroprusside (both at 0.01-0.1 mg/kg, by 54.6 +/- 2.8 and -60.5 +/- 3.0%, respectively) in the conscious and anesthetized models. However, the differential MAP responses to hydralazine and nitroprusside between the two models are inconsistent with a difference in the sensitivity of the two models. Hydralazine at 1 mg/kg decreased MAP greater in the conscious than anesthetized model, whereas nitroprusside decreased MAP similarly in the two models. In conclusion, not all differential responses to hydralazine and nitroprusside between conscious and anesthetized canine models can be explained by a difference in the sensitivity of their compensatory mechanisms.     

Selective ETA receptor blockade prevents left ventricular remodeling and deterioration of cardiac function in experimental heart failure

BACKGROUND: Left ventricular (LV) dilation, which is a predictor of survival in humans with chronic heart failure (CHF), is limited by a mixed endothelin ETA-ETB antagonist. Whether selective ETA receptor blockade influences LV dilation is unknown. We determined, in a rat model of CHF, the effects of the ETA receptor blocker LU 135,252 on LV remodeling. METHODS AND RESULTS: Rats were subjected to coronary artery ligation and treated for ten weeks with placebo or LU 135,252 (LU), at a dose of 10 or 30 mg kg-1 day-1. Systolic blood pressure and heart rate (plethysmography) were determined in conscious animals before and after four and ten weeks of treatment. At these time points, cardiac output and LV dimensions were measured in anesthetized rats by transthoracic echocardiography. LV hemodynamics were determined in anesthetized rats after ten weeks. Pressor responses to ET-1 (1 nmol/kg, i.v.) and sarafotoxin S6c (0.3 ng/kg, i.v.) were measured, to assess the efficacy of ET receptor antagonism and the lack of blockade of ETB receptor blockade, respectively. The pressor response to ET-1 was significantly reduced by LU (% change in systolic blood pressure: sham: 9 +/- 1; CHF: 5 +/- 1; CHF LU: 0 +/- 3 and -4 +/- 2% for the low and high dose, respectively). LU did not affect the response to sarafotoxin (CHF: -37 +/- 3; CHF LU: -29 +/- 3 and -28 +/- 2% for the low and high dose, respectively). Both doses of LU decreased systolic blood pressure, but only the high dose of LU reduced heart rate. Furthermore, LU restored cardiac output dose-dependently throughout the study. Both doses of LU limited LV dilatation and deterioration of LV fractional shortening to the same extent. After ten weeks, LU normalized LV end-diastolic- and central venous pressures, but did not affect LV dP/dtmax or dP/dtmin. LU did not prevent the development of cardiac hypertrophy, but reduced LV collagen density. CONCLUSIONS: In this rat model, the selective ETA receptor blocker LU, at the dose of 30 mg kg-1 day-1, reduced blood pressure and heart rate, limited progressive left ventricular remodeling and improved cardiac hemodynamics and function. These effects of LU might have important clinical relevance in the treatment of heart failure.     

Assessment of the role of the renin-angiotensin system in cardiac contractility utilizing the renin inhibitor remikiren

1. The role of the renin-angiotensin system in the regulation of myocardial contractility is still debated. In order to investigate whether renin inhibition affects myocardial contractility and whether this action depends on intracardiac rather than circulating angiotensin II, the regional myocardial effects of systemic (i.v.) and intracoronary (i.c.) infusions of the renin inhibitor remikiren, were compared and related to the effects on systemic haemodynamics and circulating angiotensin II in open-chest anaesthetized pigs (25-30 kg). The specificity of the remikiren-induced effects was tested (1) by studying its i.c. effects after administration of the AT1-receptor antagonist L-158,809 and (2) by measuring its effects on contractile force of porcine isolated cardiac trabeculae. 2. Consecutive 10 min i.v. infusions of remikiren were given at 2, 5, 10 and 20 mg min-1. Mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), systemic vascular resistance (SVR), myocardial oxygen consumption (MVO2) and left ventricular (LV) dP/dtmax were not affected by remikiren at 2 and 5 mg min-1, and were lowered at higher doses. At the highest dose, MAP decreased by 48%, CO by 13%, HR by 14%, SVR by 40%, MVO2 by 28% and LV dp/dtmax by 52% (mean values; P < 0.05 for difference from baseline, n = 5). The decrease in MVO2 was accompanied by a decrease in myocardial work (MAP x CO), but the larger decline in work (55% vs. 28%; P < 0.05) implies a reduced myocardial efficiency ((MAP x CO)/MVO2). 3. Consecutive 10 min i.c. infusions of remikiren were given at 0.2, 0.5, 1, 2, 5 and 10 mg min-1. MAP, CO, MVO2 and LV dP/dtmax were not affected by remikiren at 0.2, 0.5 and 1 mg min-1, and were reduced at higher doses. At the highest dose, MAP decreased by 31%, CO by 26%, MVO2 by 46% and LV dP/dtmax by 43% (mean values; P < 0.05 for difference from baseline, n = 6). HR and SVR did not change at any dose. 4. Thirty minutes after a 10 min i.v. infusion of the AT1 receptor antagonist, L-158,809 at 1 mg min-1, consecutive 10 min i.c. infusions (n = 5) of remikiren at 2, 5 and 10 mg min-1 no longer affected CO and MVO2, and decreased LV dP/dtmax by maximally 27% (P < 0.05) and MAP by 14% (P < 0.05), which was less than without AT1-receptor blockade (P < 0.05). HR and SVR remained unaffected. 5. Plasma renin activity and angiotensin I and II were reduced to levels at or below the detection limit at doses of remikiren that were not high enough to affect systemic haemodynamics or regional myocardial function, both after i.v. and i.c. infusion. 6. Remikiren (10(-10) to 10(-4) M) did not affect contractile force of porcine isolated cardiac trabeculae precontracted with noradrenaline. In trabeculae that were not precontracted no decrease in baseline contractility was observed with remikiren in concentrations up to 10(-5) M, whereas at 10(-4) M baseline contractility decreased by 19% (P < 0.05). 7. Results show that with remikiren i.v., at the doses we used, blood pressure was lowered primarily by vasodilation and with remikiren i.c. by cardiac depression. The blood levels of remikiren required for its vasodilator action are lower than the levels affecting cardiac contractile function. A decrease in circulating angiotensin II does not appear to be the sole explanation for these haemodynamic responses. Data support the contention that myocardial contractility is increased by renin-dependent angiotensin II formation in the heart.     

Effect of KATP channel blocker U37883A on renal function in experimental diabetes mellitus in rats

An increase in glomerular filtration rate (GFR) in early diabetes mellitus is considered a risk factor for the development of diabetic nephropathy. Insulin deficiency may increase the activity of ATP-sensitive potassium channels (KATP), which could promote afferent arteriolar vasodilation und thus contribute to glomerular hyperfiltration in early diabetes mellitus. To further elucidate this hypothesis we performed renal clearance experiments in anesthetized rats at 2 and 6 weeks after onset of streptozotocin-induced insulin-treated diabetes mellitus and studied the acute effect of the putative KATP channel blocker 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (U37883A) on renal function. In control rats, application of U37883A (1.5 mg/kg i.v. bolus plus 1.5 mg/kg/hr) induced a significant reduction in heart rate, but did not affect or even slightly increased mean arterial blood pressure. Furthermore, U37883A did not significantly affect renal vascular resistance, renal blood flow or GFR, but caused an eukaliuretic diuresis and natriuresis and lowered plasma renin activity. Diabetic rats at both 2 or 6 weeks after streptozotocin exhibited essentially an identical response to U37883A; in particular, RVR and glomerular hyperfiltration remained unchanged. These results show that in both control and diabetic rats, the renal excretory function, renin secretion and pace setting in the heart were sensitiv to U37883A, implying a functional contribution of KATP channel activity. However, in both control and diabetic rats, renal vascular resistance, renal blood flow, or GFR were not altered by U37883A. These results argue against a substantial role for KATP channels in the basal control of renal hemodynamics in both nondiabetic and diabetic rats.     

Inhibition of nitric oxide synthesis extends cerebrovascular autoregulation during hypertension

In anesthetized intact rats, cerebral blood flow is autoregulated until mean arterial blood pressure (MAP) exceeds 150 mmHg. At higher pressures cerebral blood flow breaks through autoregulation and rapidly increases. However, interruption of the arterial baroreceptor reflex eliminates breakthrough of autoregulation. Thus, breakthrough may reflect active rather than passive vasodilatation. We, therefore, sought to determine if breakthrough depends upon synthesis of the vasodilator nitric oxide. Thirty-eight anesthetized adult male Sprague-Dawley rats were studied. In all, MAP was raised by slow i.v. infusion of phenylephrine. In rats pretreated with the nitric oxide synthase inhibitor L-nitroarginine (L-NA; 22 mg/kg i.v.) or with a combination of L-NA plus D-arginine (D-Arg; 240 mg/kg i.v.), breakthrough did not occur even when MAP exceeded 185 mmHg (L-NA) and 165 mmHg (D-Arg). In contrast, breakthrough occurred in rats treated with L-NA plus L-arginine (L-Arg; 240 mg/kg i.v.) and in rats whose basal vascular tone had been increased by pretreatment with arginine vasopressin prior to infusion of phenylephrine. Removal of sympathetic innervation to cerebral vessels attenuated, but did not eliminate, effects of L-NA on breakthrough. Thus, vasodilatation seen with breakthrough of autoregulation depends upon release of nitric oxide or a nitric oxide donor.     

Differential effects of specific delta and kappa opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of renin inhibition compared to angiotensin converting enzyme inhibition in conscious dogs with pacing-induced heart failure

OBJECTIVE: To compare the effects of angiotensin converting enzyme inhibition (ACEI) (captopril 1 mg/kg i.v.) to direct renin inhibition (CP80794 3 mg/kg i.v.) on left ventricular and systemic hemodynamics and peripheral blood flows in advanced congestive heart failure (CHF). METHODS: Conscious chronically instrumented dogs (n = 14) were treated with captopril, 1 mg/kg, i.v., or CP80794, 3 mg/kg, i.v., before and after development of advanced CHF induced by 4-7 weeks of rapid ventricular pacing. After advanced CHF, comparisons between the inhibitors were made at equihypotensive doses. RESULTS: In advanced CHF, both agents caused comparable reductions in mean arterial pressure (MAP) (-22% from 79 +/- 4 mmHg) and comparable increases (P < 0.01) in cardiac output (CP80794, 1.4 +/- 0.3 to 1.8 +/- 0.1 l/min; captopril, 1.4 +/- 0.1 to 1.9 +/- 0.1 l/min). Neither agent had a significant effect on LV contractility. In contrast, CP80794 caused a greater (P < 0.05) increase in renal blood flow (66 +/- 6% from 64 +/- 5 ml/min) compared to captopril (33 +/- 4% from 66 +/- 7 ml/min). CONCLUSIONS: Renin inhibition with CP80794 and ACEI with captopril caused comparable hemodynamic effects in advanced CHF. However, CP80794 caused significantly greater increases in renal blood flow and suppressed renin activity to a greater degree than captopril.     

Hemodynamic effects of amlodipine and benazeprilat in spontaneously hypertensive rats

We wished to assess the hemodynamic effects of administration of the combination of the calcium channel blocking agent amlodipine and the angiotensin-converting enzyme (ACE) inhibitor benazeprilat in conscious spontaneously hypertensive rats (SHR). In SHR previously instrumented for measurement of mean arterial blood pressure (MAP) and heart rate (HR), intravenous (i.v.) injection of amlodipine (0.25-4 mg/kg) produced dose-dependent decreases in blood pressure (BP). Administration of benazeprilat (0.1-10 mg/kg i.v.) decreased arterial MAP, and benazeprilat (10 mg/kg) effectively blocked the effects of exogenously administered angiotensin I (AI). In animals surgically prepared for measurement of BP, HR, and hindquarter, renal, and mesenteric blood flows, administration (i.v.) of the combination of amlodipine (0.5 mg/kg) with benazeprilat (10 mg/kg) evoked a decrease in BP that was greater than that elicited by monotherapy. The tachycardic response observed after administration of the combination was no different from that observed after monotherapy with amlodipine. Simultaneous administration of amlodipine and benazeprilat produced reductions in vascular resistance in the hindquarter, renal and mesenteric beds that were greater than the responses evoked by injection of either agent. The major finding of these studies was that dual therapy with amlodipine and benazeprilat produced an additive hypotensive effect in conscious SHR. Regional vasodilation accompanied the large degree of hypotension evoked by the combination.     

Effects of moguisteine on the cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve in guinea pigs

The study aimed to further demonstrate the peripheral antitussive properties of moguisteine. Firstly, the antitussive effect of moguisteine on the cough reflex induced by inhalation of citric acid aerosol was evaluated in conscious guinea pigs. Secondly, the effects of both moguisteine and codeine on the centrally mediated cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve were investigated in anesthetized guinea pigs. Moguisteine (2.5-10 mg/kg, intravenously, i.v.) reduced the cough reflex induced by 7.5% citric acid aerosol in a dose-dependent manner, with an ED50 value of 0.55 mg/kg. Both i.v. (0.5-4 mg/kg) and intracerebroventricular (i.c.v., 5-20 microg) injection of codeine dose dependently inhibited the cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve; the ED50 values were 0.91 mg/kg and 7.90 microg, respectively. The inhibitory effect of codeine (4 mg/kg i.v.) was abolished by pretreatment with naloxone (2 mg/kg intraperitoneally). In contrast to codeine, neither i.v. (4 and 20 mg/kg) nor i.c.v. (20 microg) injection of moguisteine affected the cough reflex. These results suggest that the antitussive effect of codeine is mediated by central opioid mechanisms, whereas the antitussive effect of moguisteine is mediated by peripheral mechanisms.     

The in vivo pharmacological profile of the novel glycoprotein IIb/IIIa antagonist, SK&F 106760

The in vivo pharmacological profile of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 micrograms/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T1/2 of 66 +/- 12 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +/- 26 ml/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)     

Left ventricular atrioventricular plane displacement: an echocardiographic technique for rapid assessment of prognosis in heart failure

We evaluated the cardiovascular effects of YM430, a novel 1,4-dihydropyridine derivative with beta-adrenoceptor blocking activity, in dogs and rats. In anesthetized dogs, YM430 (0.01-0.3 mg/kg, i.v.) dose-dependently decreased mean blood pressure, total peripheral resistance and double product without increasing the heart rate. YM430 (0.01-0.3 mg/kg, i.v.) increased coronary artery as well as vertebral artery blood flow, whereas its effects on carotid, mesenteric, femoral and renal blood flow were small. At the same dose range as that which induced vasodilation effects, YM430 had little effect on the max. dp/dt or PQ-interval. In conscious dogs, YM430 (0.1-1 mg/kg, i.v.) produced dose-dependent hypotension with tachycardia. In conscious rats, oral dosing of YM430 (100 mg/kg p.o.) produced a long-lasting hypotensive effect with slight tachycardia. YM430 also inhibited isoproterenol (0.1 micrograms/kg i.v.)-induced tachycardia. These two effects of YM430 may be attributable to its calcium entry blocking and beta(1)-adrenoceptor blocking activity, respectively. The time course of the hypotensive (calcium entry blocking) effect of YM430 after oral dosing was very similar to that of its inhibition of isoproterenol-induced tachycardia (beta(1)-adrenoceptor blocking effect). These results indicate that the ratio of the two activities (calcium entry blocking and beta(1)-adrenoceptor blocking) of YM430 is constant after oral administration. In conclusion, YM430 could be both an antianginal and antihypertensive agent, because of its dual activities.     

Effects of guan-fu base a on experimental cardiac arrhythmias and myocardial contractility

Guan-fu base A (GFA) is a terpenoid alkaloid isolated from the tuber of Aconitum coreanum in our institute. GFA (20-30 mg.L-1) reduced the ventricular tachycardia (VT) and ventricular fibrillation (VF) rate induced by K(+)-free and high Ca2+ solution in Langendorf heart of rats. Pretreatment of conscious rats with GFA 2.5-10 mg.kg-1 iv, increased the amount of beiwutine necessary to produce arrhythmias. Ouabain-induced VT in conscious dogs was reverted to sinus rhythm in 1-2 min by iv GFA 9-10 mg.kg-1. GFA 10-20 mg.kg-1 iv was also found to be effective in protecting anesthetized dogs from atrial fibrillation induced by topical application of ACh. GFA 10 mg.kg-1 iv obviously decreased heart rate and prolonged the P-R interval, but slightly affected the myocardial contractility in anesthetized dogs. GFA showed no obvious effect on stroke volume and cardiac output in conscious dogs. In conclusion, GFA showed therapeutic and prophylactic effect on different models of experimental arrhythmias without causing marked effect on myocardial contractility.     

Large unidentified open reading frame in plastid DNA (ORF2280) is expressed in chloroplasts

Although many studies investigating the effect of cromakalim on bladder contractility exist, thus far, there are no published studies investigating its effect on micturition function in conscious rats. We measured the effect of cromakalim i.v. on urine output, frequency, volume of each micturition, and blood pressure in saline-diuresed and non-diuresed rats. In saline-diuresed rats cromakalim produced significant decreases in urine output (0.1 mg/kg, 32%; 0.3 mg/kg, 46%; 1.0 mg/kg, 68%) and average frequency (0.1 mg/kg, 36%; 0.3 mg/kg, 51%; 1.0 mg/kg, 70%) in the first 3 hours. At 3-6 hours after administration of cromakalim there were rebound increases in both urine output (0.1 mg/kg, 290%; 0.3 mg/kg, 373%; 1.0 mg/kg, 538%), and frequency (0.1 mg/kg, 147%; 0.3 mg/kg, 181%; 1.0 mg/kg, 314%) and by 6-12 hours the effects of cromakalim on micturition function were gone. Mean arterial pressure dropped to 50% of control immediately after cromakalim administration in saline-diuresed rats and began to return to control levels after 3 hours. Cromakalim produced similar results in non-diuresed rats. The decrease in urine output 0-3 hours after cromakalim administration may have been a consequence of cromakalim's profound decrease in blood pressure that occurred during that time.     

Mechanisms of platelet-induced angiospastic reactions: potentiation of calcium sensitivity

BACKGROUND: Zatebradine is a new specific bradycardiac agent that selectively slows the depolarization in the pacemaker cells of the sinoatrial node. The purpose of our investigation was to determine whether the tachycardia induced by dobutamine can be attenuated by the administration of zatebradine. The results were compared with those produced by propranolol, which is used in the treatment of sinus tachycardia. METHODS: Twelve pigs were anesthetized with sodium pentobarbital, intubated, and ventilated. After baseline hemodynamic measurements were obtained, dobutamine was administered until the heart rate reached 25% above baseline. Animals were randomized to one of two groups. Group I received zatebradine, 0.5 mg/kg i.v., and Group II received propranolol, 0.5 mg/kg i.v. RESULTS: Dobutamine 10 micrograms.kg-1.min-1 increased the heart rate (FIR) by 25%, and increased mean arterial blood pressure (MAP) left ventricular (LV) dp/dt, and cardiac output (CO) (P < 0.05). Zatebradine decreased the HR to baseline (P < 0.05) without affecting left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LV dP/dt, or CO. Stroke volume (SV) increased significantly (P < 0.05). Propranolol also reduced HR to baseline, but decreased LV dP/dt, LVSP, CO, and SV (P < 0.05). CONCLUSION: Zatebradine effectively attenuates the tachycardia caused by dobutamine in anesthetized pigs, without reducing cardiac performance.     

Effects of natriuretic peptide receptor inhibition on remnant kidney function in rats

To identify the contribution of natriuretic peptide (NP) activity to the adaptative increases in glomerular filtration rate (GFR), effective renal plasma flow rate (ERPF) and fractional sodium excretion (FENa) observed in the remnant kidney, we investigated the acute effects of administering HS-142-1 (HS), a potent NP receptor antagonist, in 5/6th nephrectomized (NPX) rats. In addition to normal sodium intake, high or low sodium intakes were used to stimulate or suppress, respectively, endogenous NP activity in NPX rats. In rats three days after NPX on high sodium, HS (20 mg/kg bolus i.v.) reduced GFR from 0.55 +/- 0.05 to 0.35 +/- 0.04 ml/min; ERPF from 1.83 +/- 0.19 to 1.53 +/- 0.16 ml/min; and FENa from 7.1 +/- 1.1 to 1.6 +/- 0.4%, without affecting MAP. Similar changes of lesser magnitude were observed in NPX rats on normal sodium intake. By contrast, GFR, ERPF, FENa and MAP were unchanged following HS in NPX rats on low sodium intake, suggesting that the magnitude of responses to HS is dependent upon the expected levels of activity of NP. We conclude that in anesthetized rats, natriuretic peptides contribute to the compensatory increases in GFR, ERPF and FENa observed in the remnant kidney under normal and salt-replete conditions.     

The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure

OBJECTIVES: We sought to identify the effects of endothelin (ET) subtype-A (ET(A))) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. BACKGROUND: Congested heart failure causes increased plasma levels of ET and ET(A) receptor activation. METHODS: Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n=7; 2) CHF/ET(A)-High Dose: paced for 2 weeks then ET(A) receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n=6; 3) CHF/ET(A)-Low Dose: pacing for 2 weeks then ET(A) receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n=6; and 4) Control: n=8. RESULTS: Left ventricle fractional shortening decreased with CHF compared with control (12+/-1 vs. 39+/-1%, p < 0.05) and increased in the CHF/ET(A) High and Low Dose groups (23+/-3 and 25+/-1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET(A) receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET(A) High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET(A) blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32+/-3 vs. 54+/-3 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/s, p < 0.05), and was similar to CHF values in the Low Dose group. CONCLUSIONS: ET(A) receptor activation may contribute to the progression of LV dysfunction with CHF.     

Cardiovascular pharmacology of SKP-450, a new potassium channel activator, and its major metabolites SKP-818 and SKP-310

The cardiovascular effects of SKP-450, a newly synthesized potassium channel activator, and its two major metabolites SKP-818 and SKP-310 were evaluated on isolated rat aorta and in freely moving rats and anesthetized beagle dogs. The rank order of potency in relaxing rat aorta precontracted with norepinephrine was SKP-450 > SKP-818 > Lemakalim > SKP-310 (EC50: 0.12, 0.55, 0.71 and 5.89 mumol/l, respectively). In rats, SKP-450, SKP-818 and lemakalim (3-100 micrograms/kg, i.v.) induced a dose-dependent decrease in mean arterial pressure (MAP; ED20: 9.8, 11.7 and 22.4 micrograms/kg, respectively) followed by reflex tachycardia. In dogs, SKP-818 and SKP-310 (0.3-1,000 micrograms/kg, i.v.) had quite similar hemodynamic profiles to SKP-450 but with a smaller potency. SKP-450, SKP-818 and SKP-310 dose-relatedly decreased MAP (ED20: 2.6, 4.2 and 588.8 micrograms/kg, respectively). They slightly increased left ventricular positive dP/dtmax with a transient decrease at the highest dose, while inducing a dose-related decrease in rate-pressure product, tension time index and systolic time. SKP-450, SKP-818 and SKP-310 induced a marked dose-dependent increase in coronary blood flow (Emax: 172.8, 257.9 and 178.7%, respectively) with less effects on blood flow through other arteries. Glybenclamide antagonized all the hemodynamic effects of SKP-450 in rats and dogs, whereas propranolol antagonized its reflex tachycardia in rats. These results indicate that SKP-450 is a potent coronary and peripheral vasodilator in rats and dogs activating ATP-sensitive potassium channels and that SKP-818 and SKP-310 exert a similar hemodynamic profile to the parent compound with equi- and weaker potency, respectively.