nitroarginine and candesartan

The angiotensin II-induced vasodilatation was evaluated in rat middle cerebral artery, especially regarding endothelium-derived hyperpolarising factor (EDHF), by use of a pressurised arteriograph. The angiotensin II dilatation was partly antagonised by inhibitors of nitric oxide synthase and cyclo-oxygenase. The remaining dilatation was inhibited by the potassium channel blockers, charybdotoxin and apamin, providing direct evidence that angiotensin II induces EDHF-mediated dilatation in cerebral arteries. The angiotensin II dilatation was blocked by the angiotensin AT1 and AT2 receptor blockers candesartan and PD 123319. Both angiotensin AT1 and AT2 receptors were detected on the endothelium by immunohistochemistry.

Topics: Adenosine Triphosphate; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apamin; Benzimidazoles; Biological Factors; Biphenyl Compounds; Cerebral Arteries; Charybdotoxin; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; Imidazoles; In Vitro Techniques; Indomethacin; Male; Neurotoxins; Nitric Oxide Synthase; Nitroarginine; Pyridines; Rats; Rats, Sprague-Dawley; Serotonin; Tetrazoles; Vasoconstriction; Vasoconstrictor Agents

The role of local endogenous angiotensin II (Ang II) in endothelial function in resistance arteries was investigated using rabbit mesenteric resistance arteries. First, the presence of immunoreactive Ang II together with Ang II type-1 receptor (AT1R) and angiotensin converting enzyme (ACE) was confirmed in these arteries. In endothelium-intact strips, the AT1R-blocker olmesartan (1 microM) and the ACE-inhibitor temocaprilat (1 microM) each enhanced the ACh (0.03 microM)-induced relaxation during the contraction induced by noradrenaline (NA, 10 microM). Similar effects were obtained using CV-11974 (another AT1R blocker) and enalaprilat (another ACE inhibitor). The nitric-oxide-synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished the above effect of olmesartan. In endothelium-denuded strips, olmesartan enhanced the relaxation induced by the NO donor NOC-7 (10 nM). Olmesartan had no effect on cGMP production (1) in endothelium-intact strips (in the absence or presence of ACh) or (2) in endothelium-denuded strips (in the absence or presence of NOC-7). In beta-escin-skinned strips, 8-bromoguanosine 3',5' cyclic monophosphate (8-Br-cGMP, 0.01-1 microM) concentration dependently inhibited the contractions induced (a) by 0.3 microM Ca2+ in the presence of NA+GTP and (b) by 0.2 microM Ca2++GTPgammaS. Olmesartan significantly enhanced, while Ang II (0.1 nM) significantly inhibited, the 8-Br-cGMP-induced relaxation. We propose the novel hypothesis that in these arteries, Ang II localized within smooth muscle cells activates AT1Rs and inhibits ACh-induced, endothelium-dependent relaxation at least partly by inhibiting the action of cGMP on these cells.

Topics: Acetylcholine; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Cell Membrane Permeability; Cyclic GMP; Enalaprilat; Endothelium, Vascular; In Vitro Techniques; Kinetics; Male; Mesenteric Arteries; Muscle, Smooth, Vascular; Nitroarginine; Rabbits; Receptor, Angiotensin, Type 1; Tetrazoles; Thiazepines; Vasodilation

The objective of the present study is to investigate whether plasma insulin levels play a role in the antinatriuretic and vasoconstrictor actions of angiotensin-II (Ang-II). We evaluated antinatriuretic function of endogenous Ang-II using an AT1 receptor antagonist, candesartan in anesthetized Sprague-Dawley rats. In control rats, candesartan produced significant increases in natriuresis and diuresis and these effects were abolished in streptozocin (STZ, 55 mg/kg i.p.) treated rats. Replacement of insulin restored these renal effects of candesartan. In a separate group of rats pretreated with an autonomic ganglionic blocker, pressor responses to Ang-II and norepinephrine (NE) before or after L-NNA, a nitric oxide synthase inhibitor were not affected by STZ treatment. However, insulin replacement greatly augmented these responses. These data provide evidence in vivo showing that insulin can enhance both antinatriuretic and vasoconstrictor actions of Ang-II. Hence exaggerated renal and vascular effects of Ang-II in the obese Zucker rats observed in our previous studies may be related to hyperinsulimemia and this phenomena could contribute to salt-sensitivity and development of sustained hypertension.

Topics: Angiotensin II; Animals; Anti-Bacterial Agents; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Experimental; Diuresis; Drug Interactions; Enzyme Inhibitors; Ganglionic Blockers; Heart Rate; Hypoglycemic Agents; Insulin; Kidney; Natriuresis; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Sprague-Dawley; Streptozocin; Tetrazoles; Vasoconstrictor Agents

The aim of this study was to evaluate the effectiveness of an angiotensin-converting enzyne inhibitor (ACEI, quinapril) or angiotensin II receptor blocker (ARB, candesartan) on atrial natriuretic peptide (ANP) activity in rats with hypertension induced by nitric oxide (NO) inhibition. ACEI and ARB have a number of pharmacologic effects, including blood pressure reduction, myocardial preservation, and an unknown effect in the circulation. The changes in ANP in NO inhibitor-induced hypertensive rats were evaluated in order to elucidate the interaction between ANP and NO in the regulation of blood pressure. Thirty-six rats were divided into 4 groups and administered the experimental agents for 8 weeks: group CONTROL was given regular food (n=9), group N(G)-nitro-L-arginine (L-NNA) was administered L-NNA (25 mg. kg(-1). day(-1), n=9), group ACEI was administered L-NNA and quinapril (10 mg. kg(-1). day(-1), n=9), and group ARB was administered L-NNA and candesartan (10 mg. kg(-1). day(-1), n=9). Blood pressure, plasma ANP, atrial ANP, ANP mRNA, and ANP granules were measured. A significant elevation in blood pressure was observed in group L-NNA. However, there were no increases in plasma ANP (L-NNA: 138.8+/-64.4, CONTROL: 86.7+/-36.4), ANP mRNA (L-NNA: 2.2+/-1.0, CONTROL: 1.7+/-0.5) or ANP granules (L-NNA: 61.1+/-10.2, CONTROL: 64.5+/-8.5). No increase in blood pressure was seen in groups ACEI and ARB. However, plasma ANP (ACEI: 1,392.3+/-1,034.4, ARB: 1,142.8+/-667.3), ANP mRNA (ACEI: 52.8+/-29.1, ARB: 42.9+/-21.2), and ANP granules (ACEI: 122.5+/-23.4, ARB: 136.3+/-33.2) increased significantly. NO inhibitor-induced hypertension caused no changes in ANP concentrations. However, the ACEI and ARB had a direct effect on the induction of ANP secretion. The findings suggest that ANP secretion is directly effected by ACEI and ARB, which seems to play a key role in lowering blood pressure, relieving heart failure symptoms, and preserving the myocardium.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Body Weight; Heart; Male; Nitroarginine; Organ Size; Quinapril; Rats; Rats, Wistar; RNA, Messenger; Systole; Tetrahydroisoquinolines; Tetrazoles; Transcription, Genetic

Bradykinin evokes endothelium-dependent relaxation in some vascular beds; on the other hand, the possibility has been demonstrated that in certain organs, such as the adrenal medulla or atria, bradykinin may enhance transmitter release from the sympathetic nerves. We hypothesized that bradykinin may also enhance postganglionic sympathetic neurotransmission in blood vessels. To test this hypothesis, we recorded excitatory junction potentials (EJPs), a measure of sympathetic purinergic neurotransmission, in rat mesenteric resistance arteries with a conventional microelectrode technique. EJPs were elicited by repetitive perivascular nerve stimulation (1 Hz, 20 to 50 V, 30 to 60 micros, 11 pulses). In this preparation, bradykinin (10(-7) or 10(-6) mol/L) significantly enhanced the amplitude of EJPs without altering the resting membrane potential. This effect of bradykinin was blocked by Hoe 140, a bradykinin B2 receptor antagonist, but not by des-Arg(9),[Leu(8)]-bradykinin, a bradykinin B1 receptor antagonist. The cyclooxygenase inhibitor indomethacin or NO synthase inhibitor N(G)-nitro-L-arginine did not alter the effect of bradykinin. Captopril, an ACE inhibitor, but not candesartan, an angiotensin II type 1 receptor antagonist, enhanced the action of a low concentration (10(-8) mol/L) of bradykinin on EJPs. These findings suggest that in rat mesenteric resistance arteries, bradykinin enhances sympathetic purinergic neurotransmission, presumably through presynaptic bradykinin B2 receptors. The clinical relevance of the present findings remains unclear; however, the fact that the ACE inhibitor, but not the angiotensin II type 1 receptor antagonist, enhanced the action of bradykinin on sympathetic neurotransmission may warrant further investigation.

Topics: Adenosine Triphosphate; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Bradykinin; Captopril; Cyclooxygenase Inhibitors; Drug Interactions; Excitatory Postsynaptic Potentials; In Vitro Techniques; Indomethacin; Male; Membrane Potentials; Mesenteric Arteries; Microelectrodes; Neuromuscular Junction; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Stimulation, Chemical; Sympathetic Nervous System; Synaptic Transmission; Tetrazoles

Acute systemic blockade of nitric oxide (NO) production by nonselective inhibitors of NO synthase (NOS) isoforms, including N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-nitro-L-arginine (L-NNA), has been shown to produce a long-lasting pressor response in conscious and anaesthetised animals. The present study was undertaken to clarify whether the renin-angiotensin system contributes to the development of this pressor response to L-NNA. Systemic blood pressure and heart rate were continuously monitored in dogs anaesthetised with pentobarbital. Plasma renin activity in the blood obtained from a femoral artery and a renal vein was measured by use of radioimmunoassay. The acute pressor response produced by the intravenous administration of L-NNA was accompanied by reduced renin activity in both systemic and renal vascular beds. Captopril, an angiotensin converting enzyme inhibitor, counteracted the pressor response to L-NNA, whereas candesartan, an angiotensin AT1-receptor antagonist, had no apparent effect on it. The counteraction by captopril of the L-NNA-induced pressor response was likely to be attributable to enhancement by captopril of depressor responses to bradykinin, as HOE-140, a bradykinin B2 receptor antagonist, neutralised the effect of captopril. These results suggest that the pressor response acutely produced by the intravenous injection of a NOS inhibitor is not mediated by the renin-angiotensin system in anaesthetised dogs.

Topics: Animals; Antihypertensive Agents; Arginine; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradycardia; Bradykinin; Captopril; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Heart Rate; Injections, Intravenous; Male; Nitroarginine; Renin; Renin-Angiotensin System; Stereoisomerism; Tetrazoles